mercaptopurine and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Sinusoidal obstruction syndrome (SOS) of the liver is a complication of chemotherapy most often encountered with hematopoietic stem cell transplant due to high-dose conditioning regimens, but it can also occur with regimens outside of the transplant setting. Mild-to-moderate SOS is a well-described 6-thioguanine toxicity; however, it has rarely been reported as secondary to 6-mercaptopurine, a related thiopurine. This report details a case of a 10-year-old male with T-cell acute lymphoblastic leukemia who developed severe SOS during maintenance therapy with 6-mercaptopurine, and a review of the related literature.

Topics: Child; Hepatic Veno-Occlusive Disease; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Thioguanine

Topics: Humans; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thioguanine

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response.

Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines

As an important drug during maintenance treatment of acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) has several side effects, including hepatotoxicity and bone marrow suppression. Since its tolerability varies from person to person, 6-MP treatment should be individualized. The deficiency of thiopurine methyltransferase (TPMT) enzyme activity is associated with 6-MP intolerance. There is a lower frequency of mutation in TPMT alleles among Asian patients. Recent studies have shown that in ALL patients with NUDT15 gene mutation, the maximum tolerated dose of 6-MP is lower than the conventional dose. The article reviews the significance of NUDT15 gene in individualized treatment with 6-MP in children with ALL.

Topics: Antimetabolites, Antineoplastic; Child; Humans; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Mutations in the cytosolic 5' nucleotidase II (

Topics: 5'-Nucleotidase; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Mercaptopurine; Mutation; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.

Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Despite more than 80% long term survival in ALL, morbidity due to drug related myelotoxicity remains high. Germline variants of thiopurine metabolizing enzymes (TPMT and ITPA) have been described which are associated with increased drug toxicity during maintenance phase, but their prevalence in different ethnic groups is variable to account for relatively high myelotoxicity incidence. NUDT15 variant (rs116855232) has been recently identified as a novel polymorphism related with thiopurine-induced leucopenia in inflammatory bowel disease and ALL. Current review highlights the scientific data on NUDT15 enzyme variant and its relation to 6-MP toxicity in various ethnic populations.

Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Pharmacogenomics is a fast-growing field of personalized medicine using a patient's genomic profile to determine drug disposition or response to drug therapy, in order to develop safer and more effective pharmacotherapy. Childhood acute lymphoblastic leukemia (ALL), being the most common malignancy in childhood, which is treated with uniform and standardized clinical trials, is remarkably poised for pharmacogenomic studies. In the last decade, unbiased genome-wide association studies have identified multiple germline risk factors that strongly modify host response to drug therapy. Some of these genomic associations (e.g. TPMT, NUDT15 and mercaptopurine dosing) have accumulated a significant level of evidence on their clinical utility such that they are warranted as routine clinical tests to guide modification of treatment. Most of these germline associations however, have not yet reached such actionability. Insights have also been gathered on germline factors that affect host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, methotrexate). Further large-scale studies are required, along with the assimilation of both germline and somatic variants, to precisely predict host drug response and drug toxicities, with the eventual aim of executing genomic-based precision-pharmacotherapy in the treatment of ALL.

Topics: Antimetabolites, Antineoplastic; Asparaginase; Child; Clinical Trials as Topic; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Mercaptopurine; Methotrexate; Methyltransferases; Molecular Targeted Therapy; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Signal Transduction; Vincristine

Outcomes for children with cancer have improved dramatically. Although the contribution of disease biology and therapy resistance to treatment failure continues to be a focus of intense research efforts, the role of medication nonadherence on the part of caregivers or patients has been relatively neglected. Efforts to further improve childhood cancer cure rates must include a focus on improving medication adherence.. Recent studies in children with acute lymphoblastic leukemia have conclusively demonstrated that nonadherence to oral antimetabolite therapy is associated with a significant increase in relapse risk. The impact of nonadherence to other oral medications in acute lymphoblastic leukemia and in other childhood cancers remains unknown. Tools by which clinicians can accurately identify nonadherent families are currently being developed but remain suboptimal. Similarly, while current efforts to develop interventions aimed at increasing adherence rates are underway, their feasibility and effectiveness is still unknown.. Future studies must focus on the development and widespread implementation of methods by which to identify and minimize nonadherence. Doing so will allow for further improve childhood cancer cure outcomes.

Topics: Administration, Oral; Antineoplastic Agents; Child; Humans; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.

Topics: Antimetabolites, Antineoplastic; Genetic Association Studies; Hematopoiesis; Humans; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. Despite good remission rate has achieved nowadays, the patients still face a substantial risk of relapse. It has long been recognized that thiopurines are critical components in the treatment for prevention of recurrence in childhood ALL, the 6-mercaptopurine (6-MP) has usually been used in daily long-term maintenance therapy, and 6-thioguanine (6-TG) limited to the reinforcement of therapy. However, there is no optimal regimen for 6-TG or 6-MP. The related research advances on the clinical effectiveness of the two thiopurines are reviewed.

Topics: Child; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

In the last two decades, tremendous advances have been made in the treatment of acute lymphocytic leukaemia (ALL) in children with 5 year 'cure' rates in excess of 90%. The maintenance of remission is due, in part, to individualisation of therapy which must consider age, body size, genetic constitution and the impact of disease on drug disposition and action. This review, focused on treatment of ALL and one of the therapeutic mainstays, 6-mercaptopurine, illustrates the importance of obesity as a modulating factor in dose individualisation.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Humans; Mercaptopurine; Pediatric Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.

Topics: Antimetabolites, Antineoplastic; Child; Drug Therapy, Combination; Humans; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Child, Preschool; Clinical Trials as Topic; Cytarabine; Dexamethasone; Drug Discovery; Humans; Imatinib Mesylate; Induction Chemotherapy; Mercaptopurine; Methotrexate; Molecular Targeted Therapy; Neoplasm, Residual; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Pyrimidines

Several lympholytic and cytotoxic agents are used in acute lymphoblastic leukemia (ALL) polychemotherapy. Genetic variants for cellular components involved in the pharmacokinetics and pharmacodynamics of these drugs can influence the pharmacological response, and molecular characterization of these genetic variants could be helpful for the comprehension of the mechanisms of resistance or increased sensitivity. The purpose of this review is to carry out an update of recent publications on genes that might influence ALL treatment in terms of outcome and/or toxicity and to underlie the role of genetic variants, particularly single nucleotide polymorphisms (SNP), in predicting clinical response, with particular reference to the current protocol for ALL therapy used in Italy, AIEOP-BFM ALL 2009.

Topics: Alkaloids; Antineoplastic Agents; Benzamides; Child; Glucocorticoids; Hepatic Veno-Occlusive Disease; Humans; Imatinib Mesylate; Mercaptopurine; Methotrexate; Nucleotides; Pharmacogenetics; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Thioguanine; Vincristine

The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.. This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.

Topics: Age Factors; Antimetabolites, Antineoplastic; Biotransformation; Child; Genotype; Humans; Mercaptopurine; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Methotrexate (MTX) is a key agent for the treatment of acute lymphoblastic leukemia in children and the benefit of high-dose MTX is well established as it significantly increases cure rates and improves patients' prognosis. However, the determinants of MTX therapeutic effect are not clearly identified, although intracellular polyglutamation is essential. MTX, the monoglutamate form (MTXG₁) inhibits the dihydrofolate reductase (DHFR) implicated in the folate cycle. MTXG₁ is metabolized to active methotrexate polyglutamates (MTXPG) with sequential gamma-linkage of 2 to 6 glutamyl residues by the folylpolyglutamate synthetase (FPGS). Long chain MTXPG have higher affinity than MTX for the enzymes involved in de novo purine synthesis such as 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidilate synthase (TS), which results in a reinforcement of MTX inhibition. Thus, intracellular formation of MTXPG enhances the cytotoxic and antileukemic effect of MTX. Different pharmacogenetic polymorphisms contribute to interindividual variability in MTX response to treatment. In addition, pharmacokinetic interactions with 6-mercaptopurine (6-MP), frequently co-administered, have been reported. And factors affecting intracellular MTX disposition and 6-MP/MTX interactions, including pharmacogenetic polymorphisms affecting MTX disposition are reviewed.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Child; Humans; Mercaptopurine; Methotrexate; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine has been used in continuing treatment of childhood acute lymphoblastic leukaemia since the mid 1950s. Recent advances in the understanding of thiopurine pharmacology indicated that thioguanine (TG) might be more effective than mercaptopurine (MP). The US and UK cooperative groups began randomised thiopurine trials and agreed prospectively to a meta-analysis. All randomised trials of TG versus MP were sought, and data on individual patients were analysed by standard methods. Combining three trials (from US, UK and Germany), the overall event-free survival (EFS) was not significantly improved with TG (odds ratio (OR)=0.89; 95% confidence interval 0.78-1.03). Apparent differences in results between trials may be partly explained by the different types of patients studied. The larger treatment effect reported in males in the US trial was confirmed in the other trials. There was heterogeneity between sex/age subgroups (P=0.001), with significant EFS benefit of TG only observed for males aged <10 years old (OR=0.70; 0.58-0.84), although this did not result in a significant difference in overall survival (OR=0.83; 0.62-1.10). Additional toxicity occurs with TG. Mercaptopurine remains the standard thiopurine of choice, but further study of TG may be warranted to determine whether it could benefit particular subgroups.

Topics: Age Factors; Antimetabolites, Antineoplastic; Child; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Sex Factors; Survival Analysis; Thioguanine; Treatment Outcome

Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which mercaptopurine doses are individualized based on TPMT genotype.. In this review, we summarize the knowledge available about the effect and clinical relevance of TPMT and ITPA on mercaptopurine pharmacogenomics, with a particular focus on the use of this medication in pediatric patients with ALL.. Reader will gain insights into: i) the effects of pharmacogenomic traits on mercaptopurine toxicity and efficacy for the treatment of ALL and ii) individualization strategies that can be used to mitigate toxicity without compromising efficacy in pediatric patients with ALL.. Mercaptopurine dose can be adjusted on the basis of TPMT genotype to mitigate toxicity in pediatric patients with ALL. As treatment is individualized in this way for the most relevant genetic determinant of drug response (i.e., for mercaptopurine, TPMT), the importance of other genetic polymorphisms emerges (e.g., ITPA).

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Inosine Triphosphatase; Mercaptopurine; Methyltransferases; Models, Biological; Neutropenia; Nucleotide Transport Proteins; Polymorphism, Genetic; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

The metabolism of a given drug depends, not solely on a particular enzyme, but rather on a complex metabolic network. Thiopurine S-methyltransferase (TPMT) catalyzes the methylation, and thus deactivation, of 6-mercaptopurine, a thiopurine used in the treatment of acute lymphoblastic leukemia. Low TPMT activity has been associated with severe toxicity of 6-mercaptopurine. Determination of mutations in the TPMT gene before starting 6-mercaptopurine therapy constitutes a quick, simple and cost-effective strategy to individualize thiopurine dosing. However, TPMT phenotype-to-genotype correlation is not complete, indicating a need for identification of novel biomarkers. Based on our recent findings and reviewing seemingly unrelated literature reports we present a synthesis of the current understanding of factors that influence TPMT activity and consequently modulate responsiveness to thiopurine treatment. Identification and understanding of these factors is crucial for improving the efficacy and safety of acute lymphoblastic leukemia treatment.

Topics: Animals; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Genotype; Humans; Inactivation, Metabolic; Mercaptopurine; Methyltransferases; Pharmacogenetics; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Survival of children with acute lymphoblastic leukemia (ALL) is often described as the success story for oncology. The improvements in the treatment of ALL represent the work of cooperative groups at their best. Fifty years ago a pediatric oncologist would have never considered using the term "cure" in a discussion with a family whose child was diagnosed with ALL. Today the term is not only used in the initial discussion but referred to frequently thereafter. However, as we all know, cure is not assured and is not obtained without sequelae. This review will focus on the improvements in treatment for newly diagnosed ALL in children and adolescents according to risk group and some of the challenges that remain despite the improved outcome.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Diploidy; Disease-Free Survival; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Retrospective Studies; Risk Assessment; Survival Rate; Treatment Outcome; Young Adult

Present day paediatric co-operative group acute lymphoblastic leukaemia (ALL) protocols cure approximately 80% of patients, a result achieved largely through the use of risk-stratified therapies that employ multiple chemotherapy agents. These risk-based therapies utilize host and leukaemia traits to select the most appropriate therapy. However, these risk-stratified approaches predict therapy response imperfectly and an important fraction of patients experience relapse or therapy-related toxicity. Pharmacogenetics, the study of genetic variations in drug-processing genes and individual responses to drugs, may enable the improved identification of patients at higher risk for either disease relapse or chemotherapy-associated side effects. While the impact of genetic variation in the thiopurine-S-methyltransferase gene on ALL treatment outcome and toxicity has been extensively studied, the role of other polymorphisms remains less well known. This review summarizes current research on the impact of genetic variation in drug-processing genes in paediatric ALL and reviews important methodological and statistical issues presently challenging the field of pharmacogenetics.

Topics: Alkylating Agents; Child; Child, Preschool; Drug Resistance, Multiple; Genetic Variation; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Treatment Outcome

Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Although current treatment results in long term survival in over 70% of cases there is evidence that as many as 50% could have been cured using a less complex regimen with a lower incidence of long term side effects. In previous studies it has been found that thiopurines given as part of continuing therapy are key agents in preventing relapse. However, optimal administration during continuing therapy is often not achieved. Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent of thiopurine metabolism. TPMT activity shows a trimodal distribution pattern. A lack of activity is found in approximately one in 300 Caucasians; approximately 11% have intermediate activity and the remaining 89% high activity. Congenital loss of activity is associated with grossly elevated levels of active drug and profound myelosuppression on exposure to thiopurines. This loss of activity has been attributed to single nucleotide polymorphisms (SNPs) within the TPMT gene. The frequency of SNPs is related to ethnicity, with the most common in Caucasians being TPMT*3A which is characterized by a G to A transition at position 460 with a substitution of alanine for tyrosine at amino acid 154 (A154Y) and a transition of A to G at nucleotide 719 resulting in a change of tyrosine to cysteine at position 240 (Y240C). Polymorphisms have also been identified within the 5' flanking promoter region of the TPMT gene due to a variable number of tandem repeats (VNTR*3-*8). An overview of the polymorphisms identified to date, their implication on the metabolism of the thiopurine drugs and therapeutic importance will be discussed.

Topics: Alanine; Antimetabolites, Antineoplastic; Azathioprine; DNA; DNA Methylation; Drug Resistance, Neoplasm; Genotype; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Models, Biological; Mutation; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Time Factors; Tyrosine

In the last 30 years, a multitude of treatment regimens for adult acute lymphocytic leukemia (ALL) has been developed. Essentially, all of these regimens use an induction therapy vincristine, prednisone, and an anthracycline intensified with L-asparaginase or cyclophosphamide. Though such regimens induce most patients to enter a remission, relapse is frequent, and most adult patients ultimately die of their disease. The author postulated that further refinements in this approach to induction therapy were unlikely to markedly improve treatment results in this disease. Therefore, the author is studying a new intensive strategy using cytarabine with a single very high dose of mitoxantrone (without vincristine or prednisone) as induction therapy for adult patients with ALL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Dactinomycin; Doxorubicin; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Remission Induction; Survival Analysis; Treatment Outcome; Vincristine

Intrathecal chemotherapy with antineoplastic agents is mainly utilised in children with leukaemia and lymphoma, and in selected brain tumours. In these diseases, intrathecal use is restricted to methotrexate (MTX), cytosine arabinoside (Ara-C) and corticosteroids. A number of other agents are, at the present time, under evaluation. Intrathecal MTX administered sequentially with systemic high dose MTX infusion prolongs therapeutic cerebral spinal fluid (CSF) levels of the drug. Prolonged therapeutic CSF levels can also be achieved by giving repeated small intrathecal doses of MTX over an extended period in selected patients, with an implanted Ommaya reservoir. In the CSF, the metabolic inactivation of Ara-C is significantly lower than in plasma with a CSF clearance similar to the rate of CSF bulk flow. A slow-release formulation of Ara-C may be given intrathecally, resulting in a prolonged cytotoxic concentration in the CSF. CNS relapse and neurotoxicity in patients with acute lymphoblastic leukaemia, especially younger children, may be reduced by using age-related dosing of intrathecal MTX and Ara-C. Hydrocortisone is used in combination with MTX and Ara-C for so-called 'triple intrathecal chemotherapy' in the treatment of meningeal leukaemia. Intrathecal thiotepa does not appear to be advantageous over systemic administration in patients with brain and meningeal leukaemia. Monoclonal antibodies, reactive with tumour-associated antigens, can be used as delivery systems for chemotherapeutic agents and radionuclides. However, the development of this new approach is currently under evaluation in larger clinical studies. Neurological adverse effects may be expected with intrathecal chemotherapy and are increased by high dose systemic therapy, concomitant cranial radiotherapy or meningeal infiltration by neoplastic cells. Inadvertant intrathecal administration of antineoplastic agents that are indicated for systemic administration only, is dangerous and may result in a fatal outcome.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Blood-Brain Barrier; Cerebellar Neoplasms; Cerebrospinal Fluid; Child; Cytarabine; Humans; Injections, Spinal; Lymphoma; Medulloblastoma; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thiotepa

Across the world, therapy with 6-mercaptopurine (6-MP) and methotrexate (MTX) forms the basis of the continuing therapy of childhood acute lymphoblastic leukaemia (ALL). In this review, the pharmacological determinants of the sensitivity of human leukaemia cell lines and lymphoblasts derived from children with ALL will be discussed. In addition, clinical pharmacological studies of 6-MP and MTX in relation to the continuing therapy with childhood ALL will be reviewed. For 6-MP in vitro, prolonged exposure times to relatively high extracellular drug concentrations are necessary for cytotoxicity, and these concentrations are much higher than those achieved during continuing therapy for childhood ALL. For MTX, plasma concentrations are achieved during continuing therapy that would be cytotoxic to human leukaemia cells during prolonged exposures in vitro. For both MTX and 6-MP, wide inter- and intrapatient variation in plasma pharmacokinetic parameters has been described. For 6-MP and MTX, cellular pharmacological studies have been largely restricted to erythrocytes as a surrogate of the possible effects in leukaemic blasts. Although measures of the pharmacology of 6-MP and MTX in erythrocytes has been related to prognosis in many studies, 6-MP systemic exposure and the dose intensity of 6-MP and MTX actually received by children during this phase of therapy seems to be the most important determinant of efficacy. Further studies will be needed to determine the importance of pharmacokinetic variability during continuing therapy as a determinant of outcome for children with ALL. In this respect, minimal residual disease status during this phase of treatment may prove to be a useful pharmacodynamic endpoint.

Topics: Antineoplastic Agents; Child; Humans; Mercaptopurine; Methotrexate; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMTdeficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.

Topics: Antimetabolites, Antineoplastic; Asia; Black People; Child; Child, Preschool; Codon; Disease-Free Survival; Drug Resistance, Neoplasm; England; Ethnicity; France; Gene Frequency; Genotype; Humans; Inactivation, Metabolic; India; Infant; Mercaptopurine; Methyltransferases; Neoplasm Proteins; Neoplasms, Second Primary; Point Mutation; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Fusion Proteins; Risk; Safety; Treatment Outcome; White People

Topics: Antimetabolites, Antineoplastic; Child; Cytarabine; Drug Administration Schedule; Etoposide; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide; Thioguanine

The regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) has demonstrated significant activity in adult lymphocytic leukemia (ALL) and in other hematologic malignancies, including Burkitt's disease, lymphoblastic lymphoma, mantle cell lymphoma, and multiple myeloma. This article presents the rationale for the development of this regimen, describes the program, summarizes the results of the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, and discusses strategies to improve the results.

Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Antibiotic Prophylaxis; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Immunization, Passive; Immunophenotyping; Infusions, Intravenous; Injections, Spinal; Karyotyping; Mercaptopurine; Methotrexate; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk; Rituximab; Survival Analysis; Texas; Treatment Outcome; Vincristine

Topics: Antimetabolites, Antineoplastic; Bone Marrow; Child; Humans; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines

The antimetabolites 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of children's acute lymphoblastic leukemia (ALL). The biochemical mechanisms underlying the increased therapeutic efficacy of the combination of these drugs have not yet been elucidated. However, both drugs interact with important pathways. such as purine de novo synthesis (PDNS), purine salvage, and methylation reactions. A review of the mechanistic aspects of the interactions between 6-MP and MTX is given.

Topics: Antimetabolites, Antineoplastic; Child; Drug Interactions; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Since 1981, the Children's Cancer and Leukemia Study Group (CCLSG) has developed a series of protocols for treatment of acute childhood leukemia in children. Life-table analysis of serial CCLSG protocols for acute lymphoblastic leukemia (ALL) revealed that the outcome of overall All has gradually improved with a increase of the event free survival (EFS) rates; 41.4 +/- 3.6% at 14 years for the 811 protocol, 51.3 +/- 3.5% at 11 years for the 841 protocol, 56.7 +/- 3.1% at 8 year for the 874 protocol, and 78.2 +/- 3.1% at 5 year for the 911 protocol. Treatment outcome and prognostic factors were evaluated in 152 children with acute myeloblastic leukemia (AML) treated on three consecutive protocols (ANLL-861, 8912 and 9205) of CCLSG. Forty-two of these 46 patients (91.3%) in the ANLL-9205 protocol achieved complete remission and 58.8% of these patients projected a 3-year disease free survival. These results were apparently superior to those obtained with the ANLL-861 and 8912 protocols, which used conventional doses of multiple drugs followed by a moderate post remission chemotherapy of long duration. This favorable response with the ANLL-9205 protocol was mainly to high induction rate of patients with the M4 and M5 subtypes, as compared to those in the previous two protocols. An older age (> or = 8 years) and high WBC count (> or = 10 x 10(9)/l) predicted an increased risk of relapse in multivariate analyses; patients with an age > 8 years and WBC counts > or = 10 x 10(9)/l had a 4.5 times higher risk of relapse than patients without these adverse features.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Disease-Free Survival; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Remission Induction; Survival Rate; Treatment Outcome; Vincristine

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blast Crisis; Bone Marrow; Chromosome Deletion; Chromosomes, Human, Pair 5; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Flow Cytometry; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Primary Myelofibrosis; Remission Induction; Vincristine

Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of 6-mercaptopurine (6MP), which is used in the treatment of acute lymphoblastic leukemia (ALL). TPMT catalyzes the formation of methylthioinosine monophosphate (MetIMP), which is cytotoxic for cultured cell lines, and it plays a role in detoxification of 6MP. Population studies show a genetic polymorphism for TPMT with both high and low activity alleles. About 1 of 300 subjects is homozygous for the low activity. The function TPMT plays in detoxification or therapeutic efficacy of 6MP in vivo is not clear. In this article the genetic polymorphism of TPMT is reviewed and the contribution of TPMT to the cytotoxic action, or detoxification, of 6MP in children with ALL is discussed. Induction of TPMT activity has been described during the treatment for ALL. We performed a pilot study on the influence of high-dose 6MP infusions (1300 mg/m2 in 24 h) on TPMT activity of peripheral blood mononuclear cells (pMNC) of eleven patients with ALL. The TPMT activities were in, or, above the normal range. There was no statistically significant difference between the TPMT activities before and after the 6MP infusions. MetIMP levels in pMNC increased during successive courses. This might be explained by TPMT induction, but other explanations are plausible as well. Twenty five percent of the TPMT assays failed, because less than the necessary 5.10(6) pMNC could be isolated from the blood of leukopenic patients. Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions. Therefore, the influence of high-dose 6MP infusions on TPMT activity can only be investigated further when a TPMT assay which requires less pMNC has been developed.

Topics: Antimetabolites, Antineoplastic; Humans; Inactivation, Metabolic; Mercaptopurine; Methyltransferases; Pilot Projects; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Attitude to Health; Biological Availability; Child; Humans; Mercaptopurine; Methotrexate; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone

Due to the advance of chemotherapy and bone marrow transplantation (BMT), adult acute leukemia has become a curable disease. Since in BMT a good prognosis is obtained in chemotherapy-induced remission cases, chemotherapy plays a major role for the cure of this disease. In acute myeloid leukemia, the JALSG AML 89 study resulted in a 77% complete remission (CR) rate in 326 adults, 38% of whom had a 4.5-year diseases-free survival (DFS) rate in CR cases. However, the results of acute lymphoblastic leukemia in the JALSG ALL 87 study were not satisfactory; 84% CR in 116 adults and only 24% 6-year DFS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Disease-Free Survival; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Remission Induction; Survival Rate

Topics: Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

The articles selected in this review highlight some advances in the use of the "old standards" methotrexate and 6-mercaptopurine for the treatment of children with acute lymphoblastic leukemia, especially the laboratory studies, which may allow a "pharmacologic phenotyping" to identify children most likely to relapse. In addition, we review the use of "newer" drugs (epipodophyllotoxins), which may be effective but are also associated with high morbidity (ie, secondary acute myeloid leukemia). As a second issue, "dose intensity" and the use of high-dose chemotherapy followed by bone marrow transplantation will be challenged, especially in light of peripheral stem cell harvest and the use of growth factors.

Topics: Bone Marrow Transplantation; Child; Combined Modality Therapy; Growth Substances; Humans; Leukemia, Myeloid, Acute; Medical Oncology; Mercaptopurine; Methotrexate; Pediatrics; Phenotype; Podophyllotoxin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality of Life; Recurrence; Survival Rate

The cellular pharmacology of 6-Mercaptopurine (6MP) in acute lymphoblastic leukemia (ALL) is reviewed.. Relevant studies on the clinical pharmacology of 6MP were reviewed.. 6MP is one of the major drugs used in maintenance therapy of acute lymphoblastic leukemia (ALL). It is also used to treat steroid unresponsive inflammatory bowel disease. 6MP is an inactive prodrug that requires absorption, cellular uptake, and intracellular anabolism to nucleotides for cytotoxic activity. These nucleotides are ultimately incorporated into DNA and RNA, resulting in cell death. Two analogs of 6MP, azathioprine and 6-thioguanine, are also anabolized to the same intracellular metabolites, suggesting they should be therapeutically equivalent to 6MP. 6MP may be anabolized to nonmethylated nucleotides or may undergo methylation by the enzyme thiopurine methyltransferase to S-methylated nucleotides, which are also cytotoxic.. Recent studies of 6MP pharmacokinetics in children with ALL have suggested that a higher systemic exposure, as measured by a greater area under the plasma concentration time curve or a higher concentration of 6MP metabolites in red blood cells, is associated with a decreased risk of relapse.

Topics: Biological Availability; Biotransformation; Child; Circadian Rhythm; Erythrocytes; Half-Life; Humans; Leukocytes; Mercaptopurine; Methylation; Methyltransferases; Nucleic Acids; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Treatment Outcome

Current understanding of molecular genetics enables the establishment of new categories based on pathogenesis. Philadelphia (Ph) chromosome-positive leukemia has been reclassified into two molecularly distinct subsets, and the leukemogenesis at the cell level might be linked to the molecular changes. Therefore, treatment for leukemia patients with Ph chromosome could be based on the molecular characteristics. In this review, we discuss the strategy of treating patients with Ph-positive acute lymphoblastic leukemia and the benefit of the combined modality of interferon and chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Gene Rearrangement; Genes, abl; Humans; Immunologic Factors; Interferon-alpha; Male; Mercaptopurine; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

Maturation of physiologic process which govern the disposition of pharmacologic agents can yield significant changes in absorption, distribution, metabolism, and elimination of drugs in neonates, infants and children. However, there are very little data concerning the disposition of anticancer drugs in young children. Pharmacokinetic data for six anticancer agents were compared in infants less than 1 year of age and children greater than 1 year of age treated at St Jude Children's Research Hospital. No pharmacokinetic data were available for infants less than 2 months of age. Median methotrexate clearance tended to be lower in four infants (0.26-0.99 years) vs 108 children (1-19 years): 80 vs 103 ml min-1 m-2, respectively (P = 0.01). There was no difference in the median 42 h methotrexate concentration. Teniposide systemic clearance and terminal half-life and cytarabine systemic clearance were not different between the two groups. There was no significant difference in etoposide systemic clearance when normalised to body surface area (ml min-1 m-2), however a significantly lower systemic clearance relative to body weight (ml min-1 kg-1) was observed in two infants, 0.5 to 1 year of age, vs 23 children, 3-18 years of age. Doxorubicin systemic clearance was not significantly different between the two groups when systemic clearance was expressed in ml min-1 kg-1. However, there was a trend toward a lower rate of systemic clearance in ml min-1 m-2 in infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Antineoplastic Agents; Blood Proteins; Child; Child, Preschool; Doxorubicin; Etoposide; Humans; Infant; Infant, Newborn; Liver; Mercaptopurine; Methotrexate; Neoplasms; Nervous System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs

We report here a patient with acute lymphoblastic leukemia (ALL) in whom hypofibrinogenemia developed during chemotherapy. The patient was a 65-year-old female who was diagnosed as having common ALL, and she was treated with BHAC-DMPV (enocitabine: 160 mg, daunorubicin : 40 mg, 6-MP: 35 mg, prednisolone (PSL): 60 mg, and vincristine: 2 mg). Hypofibrinogenemia appeared promptly each chemotherapy, including PSL was given. To ascertain a correlation between hypofibrinogenemia and the drugs given in this patient, a trial administration of PSL was attempted during a complete remission state. The level of fibrinogen, in terms of the amount of antigen or coagulability, decreased during PSL treatment, although the levels of AT III, plasminogen, alpha 2PI.Plm complex, and FDP did not change. Thus, it is difficult to speculate that PSL induced destruction of leukemia cells and release of protease from the cells resulting in fibrinolysis and hypofibrinogenemia in this case. These findings also suggest that the administration of only PSL could induce hypofibrinogenemia.

Topics: Afibrinogenemia; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Vincristine

Thiopurines [e.g. 6-mercaptopurine (6MP)] are essential for the cure of acute lymphoblastic leukemia (ALL) but can cause dose-limiting hematopoietic toxicity. Germline variants in drug-metabolizing enzyme genes TPMT and NUDT15 have been linked to the risk of thiopurine toxicity. However, the full spectrum of genetic polymorphism in these genes and their impact on the pharmacological effects of thiopurines remain unclear. Herein, we comprehensively sequenced the TPMT and NUDT15 genes in 685 children with ALL from the Children's Oncology Group AALL03N1 trial and evaluated their association with 6MP dose intensity. We identified 6 and 5 coding variants in TPMT and NUDT15 respectively, confirming the association at known pharmacogenetic variants. Importantly, we discovered a novel gain-of-function noncoding variants in TPMT associated with increased 6MP tolerance (rs12199316), with independent validation in 380 patients from the St. Jude Total Therapy XV protocol. Located adjacent to a regulatory DNA element, this intergenic variant was strongly associated TPMT transcription, with the variant allele linked to higher expression (P = 2.6 × 10-9). For NUDT15, one noncoding common variant, rs73189762, was identified as potentially related to 6MP intolerance. Collectively, we described pharmacogenetic variants in TPMT and NUDT15 associated with thiopurine sensitivity, providing further insights for implementing pharmacogenetics-based thiopurine individualization.

Topics: Child; Humans; Mercaptopurine; Methyltransferases; Pharmacogenomic Variants; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Skewed drug metabolism of 6-mercaptopurine (6-MP) can jeopardize antileukemic effects and result in toxicities during the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Allopurinol can alter 6-MP metabolism to maximize therapeutic effects while reducing toxicities. Over 75% of our patients with acute lymphoblastic leukemia or lymphoblastic lymphoma experienced a 6-MP-related toxicity. Review of metabolite date a showed 6-methylmercaptopurine nucleotide levels were >10,000 in 55% of the cohort, suggesting 6-MP shunting. Allopurinol was initiated in 12 of 23 shunters with resolution of toxicities. We propose an algorithm to incorporate allopurinol into chemotherapy regimens for patients with inappropriate 6-MP metabolism.

Topics: Adolescent; Adult; Algorithms; Allopurinol; Antimetabolites; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies; Young Adult

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) represent a unique patient population with specific characteristics and needs. Growing evidences suggest that pediatric-inspired approaches improve the outcome in AYA. These results prompted the design of a pediatric AIEOP-BFM ALL 2000-based regimen - the GIMEMA LAL-1308 protocol - for newly diagnosed AYA (range 18-35 years) with Philadelphia negative (Ph-) ALL. The protocol included minimal residual disease (MRD) analysis at two different time-points (TP), that is, at the end of induction IA and consolidation IB, and a modulation in post-consolidation intensity according to MRD. Seventy-six patients were eligible between September 2010 and October 2014. The regimen was well tolerated, with 2.7% induction deaths and no deaths in the post-consolidation phase. The complete response (CR) rate was 92%; the 48-month overall survival (OS) and disease-free survival (DFS) were 60.3% and 60.4%. Both OS and DFS were significantly better in T-ALL than B-ALL. A molecular MRD <10

Topics: Adolescent; Adult; Allografts; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Italy; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome; Vincristine; Young Adult

Large inter-individual variations in drug metabolism pose a challenge in determining 6-mercaptopurine (6MP) doses. As the last product of 6MP metabolism, DNA-thioguanine nucleotide (DNA-TGN) could reflect the efficacy of 6MP, especially in patients harboring variants in the 6MP metabolism pathway. The aim of this study was to investigate the clinical significance of DNA-TGN monitoring in Korean pediatric acute lymphoblastic leukemia (ALL) patients, focusing on the NUDT15 genotype.. The subjects of this study were patients who underwent ALL treatment with 6MP. Tests for the NUDT15 and TPMT genotypes were performed, and prospective DNA-TGN and erythrocyte TGN samples were collected after two weeks or more of 6MP treatment. DNA-TGN was quantified using the liquid chromatography-tandem mass spectrometry method.. A total of 471 DNA-TGN measurements in 71 patients were analyzed, which ranged from 1.0 to 903.1 fmol thioguanine/μg DNA. The 6MP intensity demonstrated a significant relationship with DNA-TGN concentration (P<0.001). Patients harboring NUDT15 variants were treated with a lower dose of 6MP (P<0.001); however, there was no significant difference in DNA-TGN concentration when compared to patients carrying wild-type NUDT15 (P = 0.261). These patients also presented higher variation in DNA-TGN levels (P = 0.002) and DNA-TGN/6MP intensity (P = 0.019) compared to patients carrying wild-type NUDT15. DNA-TGN concentration did not show a significant correlation with WBC count (P = 0.093).. Patients harboring NUDT15 variants demonstrated similar DNA-TGN concentrations even at low doses of 6MP and showed high variability in DNA-TGN. Particularly in patients with NUDT15 variants who need a reduced 6MP dose, DNA-TGN could be applied as a useful marker to monitor the therapeutic effect of 6MP.

Topics: Adolescent; Adult; Biomarkers, Tumor; Child; Child, Preschool; DNA, Neoplasm; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Thioguanine

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs.. We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study.. After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex.. Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; DNA Adducts; Erythrocytes; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Middle Aged; Osteonecrosis; Polyglutamic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Thioguanine; Young Adult

The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0.049). A similar trend was present also for severe hematological toxicity during maintenance. In IBD, no significant effect of rs2413739 could be found on TPMT activity, however azathioprine effectiveness was reduced in patients carrying the T allele (linear mixed effect, p = 0.0058). In PBMC from healthy donors, a positive correlation between PACSIN2 and TPMT protein concentration could be detected (linear mixed effect, p = 0.045). These results support the role of PACSIN2 polymorphism on TPMT activity and mercaptopurine adverse effects in patients with ALL. Further evidence on PBMC and pediatric patients with IBD supports an association between PACSIN2 variants, TPMT activity, and thiopurines effects, even if more studies are needed since some of these effects may be tissue specific.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Azathioprine; Child; Child, Preschool; Cohort Studies; Female; Humans; Inflammatory Bowel Diseases; Italy; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Time; Treatment Outcome; Vincristine

Suboptimal adherence to oral mercaptopurine treatment in children with acute lymphoblastic leukemia (ALL) increases the risk of relapse. A frequently expressed barrier to adherence is forgetfulness, which is often overcome by parental vigilance.. To determine whether a multicomponent intervention, compared with education alone, will result in a higher proportion of patients with ALL who have mercaptopurine adherence rates 95% or higher, for all study participants and among patients younger than 12 years and vs those aged 12 years and older.. The adherence intervention trial was an investigator-initiated, multi-institutional, parallel-group, unblinded, randomized clinical trial conducted between July 16, 2012, and August 8, 2018, at 59 Children's Oncology Group institutions in the US, enrolling patients with ALL diagnosed through age 21 years and receiving mercaptopurine for maintenance. The date of final follow-up was January 2, 2019. Data analysis was performed from February to October 2019.. Patients were randomized 1:1 to education alone or the intervention package, which consisted of education and personalized text message reminders daily to prompt directly supervised therapy. Four weeks of baseline adherence monitoring were followed with a 16-week intervention.. The primary end point was the proportion of patients with adherence rates 95% or higher over the duration of the intervention for all study participants, and for those younger than 12 years vs those aged 12 years and older.. There were 444 evaluable patients (median age, 8.1 years; interquartile range, 5.3-14.3 years), including 230 in the intervention group and 214 in the education group. Three hundred two patients (68.0%) were boys, 180 (40.5%) were non-Hispanic White, 170 (38.3%) were Hispanic, 43 (9.7%) were African American, and 51 (11.5%) were Asian or of mixed race/ethnicity. The proportion of patients with adherence rates 95% or higher did not differ between the intervention vs education groups (65% vs 59%; odds ratio, 1.33; 95% CI, 1.0-2.0; P = .08). Exploratory analyses showed that among patients aged 12 years and older, those in the intervention group had higher mean (SE) adherence rates than those in the education group (93.1% [1.1%] vs 90.0% [1.3%]; difference, 3.1%; 95% CI, 0.1%-6.0%; P = .04). In particular, among patients aged 12 years and older with baseline adherence less than 90%, those in the intervention group had higher mean (SE) adherence rates than those in the education group (83.4% [2.5%] vs 74.6% [3.4%]; difference, 8.8%; 95% CI, 2.2%-15.4%; P = .008). No safety concerns were identified.. Although this multicomponent intervention did not result in an increase in the proportion of patients with ALL who had mercaptopurine adherence rates 95% or higher, it did identify a high-risk subpopulation to target for future adherence intervention strategies: adolescents with low baseline adherence.. ClinicalTrials.gov Identifier: NCT01503632.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Directly Observed Therapy; Female; Humans; Male; Medication Adherence; Mercaptopurine; Patient Education as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Text Messaging

The Children's Cancer Group 1991 study was a clinical trial for children with National Cancer Institute standard-risk acute lymphoblastic leukemia (ALL). This trial demonstrated that 5 doses of vincristine and escalating IV methotrexate (MTX) without leucovorin rescue in the interim maintenance (IM) phases resulted in superior event-free survival (EFS) when compared with 2 doses of vincristine, oral (PO) MTX, PO mercaptopurine, and dexamethasone. This report describes a favorable outcome of this regimen in patients with Down syndrome (DS). Forty-four patients with DS were randomized to the arms containing PO MTX during IM, and 31 to those containing IV MTX. Ten-year EFS rates for patients with DS randomized to IV MTX vs PO MTX were 94.4% ± 5.4% vs 81.5% ± 6.6%, respectively. IV methotrexate with strict escalation parameters, as given in this study, was well tolerated, although the mean total tolerated dose received was lower in patients with DS than in those without DS. There was no increase in hepatic toxicity, systemic infections, or treatment-related deaths in patients with DS during IM on either the IV or PO MTX arms, as compared with those without DS. The incidence of mucositis was increased in patients with DS as compared with patients without DS, particularly among patients who received IV MTX. This trial was registered at www.clinicaltrials.gov as #NCT00005945.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dexamethasone; Disease-Free Survival; Down Syndrome; Female; Humans; Male; Mercaptopurine; Mucositis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Vincristine

To explore parents' and adolescents' motives for accepting/declining participation in the ALL2008 trials and adolescents' involvement in the decision-making process.. Children and adolescents with acute lymphoblastic leukaemia treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol were eligible for two randomizations testing 6-mercaptopurine treatment intensifications to improve efficacy and Asparaginase de-escalation to reduce toxicity. We recently reported that while adolescents favoured treatment reduction, parents of young children favoured treatment intensification.. A qualitative, exploratory study.. A maximum variation sampling strategy was used. Five adolescents aged 12-17 years, six parents of adolescents and five parents of children aged 1-12 years were interviewed in the period March-May 2015. Data were analysed using content analysis.. Adolescents and parents emphasized the importance of adolescents' active participation in decisions regarding enrolment into clinical trials. A majority of adolescents were either final or collaborative decision-makers. Parents stated that in case of disagreement, they would overrule the adolescents' decision. There were no differences between motivations of preferences held by parents of children or adolescents, respectively. Decisions were based on subjective values attributed to cure contra toxicity and individual preferences for either standard or experimental treatment. The possibility of a negative outcome induced fear of decisional regret and distress by the parents, yet they invested considerable trust in the physician's expertise.. Our findings highlight the importance of adolescents' active involvement in consent conferences. Research on management of disagreements between adolescents and parents in trial decisions is needed.

Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Decision Making; Female; Humans; Infant; Interviews as Topic; Male; Mercaptopurine; Parents; Patient Participation; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Qualitative Research; Survival Rate; Uncertainty

Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.. In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.. PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Drug Interactions; Female; Hepatic Veno-Occlusive Disease; Humans; Infant; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models

This study described the prospective relationship between pharmacological and behavioral measures of 6-mercaptopurine (6MP) medication adherence in a multisite cohort of pediatric patients diagnosed with cancer ( N  = 139).. Pharmacological measures (i.e., metabolite concentrations) assessed 6MP intake. Behavioral measures (e.g., electronic monitoring) described adherence patterns over time.. Three metabolite profiles were identified across 15 months: one group demonstrated low levels of both metabolites (40.8%) consistent with nonadherence and/or suboptimal therapy; two other groups demonstrated metabolite clusters indicative of adequate adherence (59.2%). Those patients whose metabolite profile demonstrated low levels of both metabolites had consistently lower behavioral adherence rates.. To our knowledge, this was the first study to prospectively validate a pharmacological measure of medication adherence with a behavioral adherence measure in a relatively large sample of pediatric patients with cancer. Using multiple methods of adherence measurement could inform clinical care and target patients in need of intervention.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Cohort Studies; Female; Humans; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Reproducibility of Results; Young Adult

Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion.. To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome.. The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis.. In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Chromosomes, Human, Pair 17; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Male; Mercaptopurine; Methotrexate; Mosaicism; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Survival Rate; Time Factors; Trisomy; Vincristine

Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures.. Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity.. Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations.. Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cognition Disorders; Cytarabine; Dexamethasone; Female; Humans; Hydrocortisone; Incidence; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Neuropsychological Tests; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Seizures; Vincristine

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity,

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Monitoring, Physiologic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Self Report

A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation.. Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m. Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

Topics: Adolescent; Antimetabolites, Antineoplastic; Area Under Curve; Child; Child, Preschool; Chromatography, Liquid; Cross-Over Studies; Dosage Forms; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tandem Mass Spectrometry

6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.. The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.. The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.. Pharmacokinetic, palatability and safety data support the use of Loulla in children.

Topics: Adolescent; Adult; Animals; Antimetabolites, Antineoplastic; Biological Availability; Chemistry, Pharmaceutical; Child; Cricetinae; Cross-Over Studies; Dosage Forms; Female; Humans; Male; Maximum Tolerated Dose; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Taste Perception; Young Adult

Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi-centre, prospective, randomized phase III trial, investigating treatment intensification or de-escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16-24 years. These patients were significantly more likely to have high risk MRD compared to 10-15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5-year event-free survival for the TYA cohort (aged 16-24 years) was 72·3% [95% confidence interval (CI): 66·2-78·4] overall and 92·6% (95% CI: 85·5-99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age-specific patterns of treatment-related toxicity were observed. TYA patients obtain excellent outcomes with a risk- and response-adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Daunorubicin; Dexamethasone; Female; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Assessment; Survival Analysis; Treatment Outcome; Vincristine; Young Adult

When offered participation in clinical trials, families of children with cancer face a delicate balance between cure and toxicity. Since parents and children may perceive this balance differently, this paper explores whether adolescent patients have different enrollment patterns compared to younger children in trials with different toxicity profiles.. Age-dependent participation rates in three consecutive, randomized childhood leukemia trials conducted by the Nordic Society of Paediatric Haematology and Oncology were evaluated. The ALL2000 dexamethasone/vincristine (Dx/VCR) trial tested treatment intensifications to improve cure, and the back-to-back ALL2008 6-mercaptopurine (6MP) and ALL2008 PEG-asparaginase (ASP) trials tested treatment intensifications (6MP) and toxicity reduction without compromising survival (ASP). Patient randomization and toxicity data were prospectively registered by the treating physicians.. Parents of young children favored treatment intensifications (Dx/VCR: 12% refusal; 6MP: 14%; ASP: 21%), whereas parents of adolescents favored treatment reductions (Dx/VCR: 52% refusal; 6MP: 30%; ASP: 8%). Adolescents were more likely to refuse intensification trials than young children (adjusted ORs 6.3; P < 0.01 [Dx/VCR] and 2.1; P = 0.04 [6MP]). Adolescents were less likely to refuse the ASP trial, with varying effect size depending on the length of the preceding consolidation treatment (adjusted OR for median consolidation length 0.15; P = 0.01). Younger children participated more frequently in only 6MP than in only ASP (14% vs. 5%), and adolescents vice versa (2% vs. 17%; P = 0.001).. Parents' and adolescents' divergent inclinations toward intensified or reduced therapy emphasize the necessity of actively involving adolescents in the informed consent process, which should also address motives for trial participation.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Disease-Free Survival; Female; Humans; Male; Mercaptopurine; Middle Aged; Parents; Patient Preference; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Treatment Refusal; Vincristine

This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment.. This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated.. The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea.. Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Anxiety; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dexamethasone; Female; Humans; Induction Chemotherapy; Longitudinal Studies; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Nausea; Pain; Parents; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Surveys and Questionnaires; Vincristine

Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.. The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.. MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.. We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Topics: Age Factors; Antimetabolites, Antineoplastic; Asian People; Drug Dosage Calculations; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Heredity; Heterozygote; Hispanic or Latino; Homozygote; Humans; Linear Models; Mercaptopurine; Pharmacogenetics; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Pyrophosphatases; Risk Factors; Treatment Outcome; White People

Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49-20·80; P = 2·7 × 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

Topics: Adolescent; Alleles; Antimetabolites, Antineoplastic; Asian People; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Infant; Japan; Leukopenia; Male; Mercaptopurine; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning.. In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening.. Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0-99.9% of the time, and 101 in the evening <50% of the time, six did not have any registrations. The circadian schedule did not differ significantly by age, sex, MTX/6MP doses, and average absolute neutrophil counts. The circadian schedule groups did differ on risk groups (P = 0.003) with fewer HR patients in the 50-99.9% group, and there was a negative correlation between percentage of time on evening schedule and average WBC (Spearman's rho -0.15; P = 0.0004). Average WBC was not associated with relapse on ALL92. In a Cox multivariate model the circadian schedule of MTX/6MP was not of prognostic significance for the risk of relapse, and the 10-year cumulative relapse risk was below 20% in all groups.. An evening schedule may still be recommended based on the previous publications, but in this study morning administration of MTX and 6MP does not seem to impact EFS.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Circadian Rhythm; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Survival Rate

We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia.. We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the 'thiopurine pathway' (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines.. SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes.. The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway.

Topics: Adolescent; Antimetabolites, Antineoplastic; Cell Line; Cell Line, Tumor; Child; Child, Preschool; Female; Genome-Wide Association Study; Genotype; HeLa Cells; Humans; Infant; Male; Mercaptopurine; Pharmacogenetics; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Small Interfering; Thioguanine

Pediatric patients with acute lymphoblastic leukemia (ALL) are treated with oral 6-mercaptopurine (6MP) for nearly 2 years, but no pediatric formulation has been available. In this study, an oral 6MP liquid suitable for pediatric use was developed and tested in the target population.. A randomized cross-over study was performed in 20 pediatric ALL patients (age 1.9 - 14.6 years), comparing pharmacokinetics and pharmacodynamics of a newly developed 6MP liquid formulation to 6MP capsules, both taken orally for 4 weeks.. Based upon trough levels of the principal active metabolite,6-thioguanine nucleotides (6-TGN),a relative bioavailability of the liquid vs. capsules of 1.01 was found (90% CI 0.86 - 1.20), demonstrating bioequivalence. This was supported by the similarly observed 6MP dosages needed for leucocyte depletion, for both formulations (35 mg/day (range 10 - 115 mg)). 75% of the parents/patients (p = 0.005) preferred the oral liquid over the capsules because of the ease of administration.. We conclude that the novel 6MP liquid is a promising treatment for ALL.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Biological Availability; Child; Child, Preschool; Cross-Over Studies; Female; Guanine Nucleotides; Humans; Infant; Leukocytes; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Therapeutic Equivalency; Thionucleotides; Young Adult

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<$50 000: 84.5%, vs ≥$50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Cohort Studies; Demography; Female; Humans; Infant; Male; Medication Adherence; Mercaptopurine; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Racial Groups; Recurrence; Regression Analysis; Young Adult

No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy.. Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119.. 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]).. Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen.. Medical Research Council and Leukaemia and Lymphoma Research.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Mucositis; Neoplasm, Residual; Pancreatitis; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Assessment; Stomatitis; Survival Rate; Vincristine

Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N=236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP--TGN and meTIN--showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Erythrocytes; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Remission Induction; Risk Factors; Transplantation, Homologous; Treatment Outcome; Vincristine

Children with acute leukemia are at high risk of hepatitis C infection, either by immunosuppression secondary to chemotherapy or by multiple transfusions of blood products during the course of the disease. Hepatitis C virus (HCV) infection constitutes a major problem during management of acute leukemia due to resultant portal hypertension or bleeding esophageal varices. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma in leukemic survivors. The effect of amlodipine treatment on children with acute lymphoblastic leukemia (ALL) having portal hypertension secondary to HCV infection during maintenance chemotherapy has been studied. Sixty male children (mean age 11.83 ± 1.1 years) with ALL in remission and have HCV infection were included. Diagnosis of HCV infection was confirmed by real-time PCR. Thirty patients received 5 mg amlodipine orally per day for 4 weeks and compared to another 30 patients received placebo therapy and 30 age- and sex-matched children as a control group. Amlodipine significantly reduced the elevated portal blood pressure to normal level in doses which did not interfere with mechanism of action of chemotherapy (p ≤ 0.001). Treatment with amlodipine can be used to control portal hypertension in leukemic children having HCV-induced portal hypertension. HCV in leukemics could be virtually eliminated by proper testing of the blood transfusion pool.

Topics: Administration, Oral; Amlodipine; Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Calcium Channel Blockers; Child; Cohort Studies; Heart Rate; Hepatitis C; Humans; Hypertension, Portal; Male; Mercaptopurine; Methotrexate; Portal Pressure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; DNA; Female; Genotype; Guanine Nucleotides; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides

Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.. Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.. Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (-9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).. Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Child; Child, Preschool; Enzyme Inhibitors; Female; Humans; Infant; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins

The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Genetic Markers; Humans; Mercaptopurine; Methotrexate; Neoplasm, Residual; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Vincristine

In the ALL-BFM studies for treatment of acute lymphoblastic leukemia, reduction of leukemic blasts in peripheral blood after a one-week prednisone pre-phase - the so-called prednisone response - has been used for risk stratification since the 1980s and has been one of the most relevant factors for identification of high-risk patients. In the trial ALL-BFM 95, early cytomorphological marrow response on day 15 of induction therapy was prospectively evaluated and its prognostic value was analyzed in comparison to the prednisone response and other established prognostic factors.. Compared to prednisone response, day 15 marrow response was superior in outcome prediction - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response.. Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Bone Marrow; Cell Lineage; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Patient Outcome Assessment; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Remission Induction; Risk Assessment; Vincristine

In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation.. We measured TPMT (activity, as units ml(-1) packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 10(8) RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97.. Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P < 0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P < 0.0001), whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients.. In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genotype; Guanine Nucleotides; Heterozygote; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thionucleotides; United Kingdom

Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during maintenance therapy. Of 447 study patients treated by the NOPHO ALL92 protocol, 120 patients received TMP/SMX continuously for 2-7 d/wk (TMP/SMX(2-7) ) and 287 patients never received TMP/SMX (TMP/SMX(never) ). Ten patients (all TMP/SMX(never) ) developed PCP, eight of which occurred within 7 months from the start of maintenance therapy. The TMP/SMX(2-7) group received lower oral 6MP doses than TMP/SMX(never) patients (50.6 vs. 63.9 mg/m(2) /d; P<0.001) but had lower absolute neutrophil counts (ANC) (median 1.7 vs. 2.0 × 10(9) /L; P<0.001). In Cox multivariate analysis, higher ANC levels (P=0.04) and male gender (P=0.06) were related to reduced EFS. ANC had no effect on EFS among TMP/SMX(2-7) patients (P=0.40) but did for TMP/SMX(never) patients (P=0.02). The difference in the effect on EFS between TMP/SMX(2-7) and TMP/SMX(never) patients was not significant (P=0.46). EFS did not differ between TMP/SMX(2-7) and TMP/SMX(never) patients (0.83 vs. 0.83; P=0.82). These results suggest that TMP/SMX is effective in preventing PCP and may have an antileukemic effect. TMP/SMX should be given the entire duration of maintenance therapy.

Topics: Administration, Oral; Anti-Infective Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Male; Mercaptopurine; Methotrexate; Pneumocystis carinii; Pneumonia, Pneumocystis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Trimethoprim, Sulfamethoxazole Drug Combination

To explore the role of genetic variants of thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) in 6-mercaptopurine (6-MP)-induced toxicity in Indian children with acute lymphoblastic leukemia (ALL).. Children with ALL receiving 6-MP in maintenance phase of treatment (n = 90) were enrolled in the study. Bidirectional sequencing of TPMT (whole gene) and ITPA (exon 2, exon 3, and intron 2) was undertaken, and correlation between genotype and 6-MP toxicity was assessed.. Five variations were observed in TPMT, including two exonic variations, TPMT*12 (374 C > T) and TPMT*3C (719A > G), and three intronic, intron 3 (12356 C > T), intron 4 (16638 C > T), and TPMT rs2842949. Two exonic, ITPA exon -2 (94 C → A) and exon 3 of ITPA (138 G > A), and one intronic, ITPA intron 2 (A→C), variations were observed in ITPA. Multifactor dimensionality reduction analysis of all the genetic variants showed independent association of ITPA 94 C→A as well as synergic epistatic interactions, i.e., TPMT*12 × ITPA ex3, ITPA ex2 × TPMT*12 × ITPA ex3, and TPMT*3C × ITPA ex2 × TPMT*12 × ITPA ex3, in determining hematological toxicity. This is further substantiated by a multiple linear regression model, which showed moderate predictability of toxicity with these variants (area under the curve = 0.70, p = 0.004).. Our results suggest that apart from the individual effect of ITPA 94 C→A, epistatic interactions between the variations of TPMT (*3C, *12) and ITPA (ex2, ex3) are associated with the 6-MP toxicity. Testing these variants facilitates tailoring of the 6-MP therapy in children with ALL.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genetic Variation; Humans; India; Leukocyte Count; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Biological Availability; Cross-Over Studies; Humans; Mercaptopurine; Methyltransferases; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Suspensions; Tablets; Young Adult

Although L-asparaginase (ASP) is associated with several toxicities, its myelosuppressive effect has not been well characterized. On DFCI ALL Consortium Protocol 05-01 for children with newly diagnosed acute lymphoblastic leukemia, the Consolidation phase and the initial portion of the Continuation phase were identical for standard risk patients, except ASP was given only during Consolidation. Comparing the two treatment phases revealed that low blood counts during Consolidation with ASP resulted in more dosage reductions of 6-mercaptopurine and methotrexate. The myelosuppressive effect of ASP should be considered when designing treatment regimens to avoid excessive toxicity and dose reductions of other critical chemotherapy agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Female; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The main outcomes of the Programa Español para Tratamiento de Hemopatías (PETHEMA)-acute lymphoblastic leukaemia (ALL)-Ph-08 trial were described and compared with those of the historical PETHEMA-CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL-Ph-08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant-related mortality observed in the ALL-Ph-08 trial resulted in an improved 2-year event-free survival (63% vs. 37%, P = 0·009).

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Female; Humans; Imatinib Mesylate; Male; Mercaptopurine; Methotrexate; Middle Aged; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pyrimidines; Stem Cell Transplantation; Transplantation, Homologous; Treatment Outcome; Vincristine; Young Adult

Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality.. Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ(2) analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided.. Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance.. Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Attention; Child; Child, Preschool; Cognition; Cranial Irradiation; Cytarabine; Dexamethasone; Drug Administration Schedule; Female; Humans; Hydrocortisone; Infant; Injections, Spinal; Intelligence; Intelligence Tests; Logistic Models; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Patient Selection; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk Factors; Sex Factors; Time Factors; Treatment Outcome; Vincristine

The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.. Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.. The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥ 100,000/microliter. Day 29 marrow MRD positive (≥ 0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors.. Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Thioguanine; Treatment Outcome; Vincristine

This article gives the status of clinical cancer research in the 1950's-1960's and tells the story of the development and conduct of the 6-mercaptopurine (6-MP) versus placebo clinical trial in acute leukemia through the initiation, design, conduct and analysis stages, with emphasis on the ethical aspects of randomizing patients to 6-MP or placebo when in remission.. The specific objective was to compare the lengths of remission for patients receiving 6-MP or placebo after achieving complete or partial remission from steroid treatment.. A randomized, double-blind, placebo controlled sequential study was conducted in which patients were paired by remission status at each of the eleven institutions participating in the study, and randomized to 6-MP or placebo within each pair of patients. A preference for 6-MP or placebo was recorded depending on which patient in the pair had the longer remission. The preferences were plotted according to a restricted sequential procedure devised by Peter Armitage and, depending on which boundary of the design was crossed, a statistically significant difference could be declared favoring 6-MP, placebo or no preference.. The trial established the efficacy of 6-MP for maintaining longer remissions in acute leukemia and led to the concept of 'adjuvant chemotherapy', namely that patients with minimal disease have a substantially better response to chemotherapy than patients with advanced disease, a concept that has been followed in many other forms of cancer. Statistically, the fact that many patients were still in remission when the study was stopped (i.e. the length of remission data for these patients was 'right censored') led to the development of a generalized Wilcoxon test and was an important influence on Cox's development of the proportional hazards model. The trial had an innovative design in the early 1960's and has been an important influence on subsequent clinical research in cancer and statistical research in survival analysis.

Topics: Antimetabolites, Antineoplastic; Double-Blind Method; Humans; Mercaptopurine; Outcome Assessment, Health Care; Placebos; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Remission Induction

This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2) per day if they did not develop myelotoxicity within 2 weeks after HDM. 6MP could be increased in 31 patients (81%). Toxicity was acceptable and did not differ significantly between groups. Patients receiving 75 mg/m(2) per day had significantly shorter duration of treatment interruptions of 6MP than the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Female; Fever; Humans; Infant; Male; Mercaptopurine; Methotrexate; Mucositis; Pancreatitis; Pilot Projects; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brazil; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors; Survival Rate; Treatment Outcome

A total of 201 pediatric cases of acute lymphoblastic leukemia were treated with the ALL-96 protocol by the Kyushu-Yamaguchi Children's Cancer Study Group.. Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). All of the patients were classified into standard-risk (SR) or high-risk (HR) groups and were randomly assigned to receive maintenance therapy with either LSA2L2-type or 6-mercaptopurine (6-MP)/methotrexate (MTX) with vincristine (VCR) and dexamethasone (DEX) pulse in both risk groups.. The 7-year event-free survival (EFS) and overall survival (OS) rates in the entire study population were 72.1% (95% CI: 68.0-76.2%) and 84.8% (95% CI: 79.7-89.9%), respectively, and the EFS of the SR patients (85.3% [95% CI: 78.2-92.4%]) was significantly better than HR patients (62.4% [95% CI: 52.2-72.6%]) (P = 0.0007).. There were no differences in the EFS between the different maintenance therapies in each risk group; however, grade IV liver toxicity occurred more often in the patients receiving 6-MP/MTX with VCR and DEX therapy than in patients receiving LSA2L2.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Dexamethasone; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Assessment; Survival Analysis; Treatment Outcome; Vincristine

6-Mercaptopurine (6-MP) has been the backbone of maintenance chemotherapy for acute lymphoblastic leukemia (ALL), the response to 6-MP is highly variable, adverse events leading to discontinuation or dose-reduction (children intolerant) of 6-MP occur in many children with ALL. The aim of this study was to investigate the tolerability of 6-MP and to optimize thiopurine use.. The authors evaluated in a prospective manner the tolerance of 6-MP in ALL children from Oct. 1, 2004 to Sept. 30, 2007 who were newly diagnosed in Beijing Children's Hospital, using BCH-ALL-2003 protocols, during the maintenance therapy and followed up to Sept. 30, 2008. All children had a treatment period of at least 3 months for maintenance therapy.. Totally 133 children including 81 boys and 52 girls at median age of 67 months (18 - 188 months), 100% of the patients went into complete remission (CR) on day 33 of induction chemotherapy, and the median time to CR was 26 months (6 - 47 months). All the children had maintenance therapy from 3 to 25 months (mean 13.5 +/- 7.4) and 72(54%) received 6-MP standard doses continuously for total courses, the median daily dose of 6-MP was 46 mg/(m(2).d) 6-MP, their WBC was (3 - 4) x 10(9)/L, ANC (1.5 - 2) x 10(9)/L, they had no severe liver toxicity. In 4 children the dose of 6-MP was increased to 125% because WBC was higher than 6 x 10(9)/L, ANC higher than 3 x 10(9)/L. Sixty one children (46%) had poor tolerability to 6-MP, they experienced adverse events that led to discontinuation (n = 19) or dose reduction (n = 42) of 6-MP, the actual mean dose for the 42 cases was 25 - 30 mg/(m(2).d) and the time to occurrence of toxic effects was 2.5 weeks. Reasons for discontinuation or dose reduction were severe myelotoxicity occurred in 48 children, hepatotoxicity in 12, and skin rash in one.. In this cohort of ALL children, the difference of tolerance to oral 6-MP was obvious, 54% of the children well tolerated 6-MP during the whole course at oral standard dose, and severe granulocytopenia did not occur. However, 46% developed severe granulopenia or hepatotoxicity, the dosage had to be reduced in order to decrease the probability of severe toxicity. It is suggested that standard dose of 6-MP is not always the maximum tolerant dose in some children and inadequate dose may be the cause of therapy failure.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.. This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1-18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10(-4) cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10(-4) cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.. Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9-45·9) in the idarubicin group versus 64·6% (54·2-73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5-55·3) versus 69·0% (58·5-77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34-0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24-1·11, p=0·11).. As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.. Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.

Topics: Adolescent; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Etoposide; Female; Humans; Idarubicin; Infant; Kaplan-Meier Estimate; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk Assessment; Treatment Outcome; United Kingdom; Vidarabine; Vincristine

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it.. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection.. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Daunorubicin; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Secondary Prevention; Survival Analysis; Treatment Outcome; Vincristine

The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count > or =50 x 10/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who received LSA2L2 maintenance therapy, which was the case for both B-lineage (27%+/-5% vs. 45%+/-9%; P=0.02) and T-lineage ALL (8%+/-5% vs. 21%+/-5%; P=0.12). In multivariate Cox regression analysis stratified for immune phenotype, a higher white blood count (P=0.01) and administration of LSA2L2 maintenance therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus <25% lymphoblasts were of statistical significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Survival Analysis; Treatment Outcome; Vincristine

The aim of the study was to analyze the impact of minimal residual disease (MRD) after reinduction therapy on the outcome of children with relapsed 'high-risk' acute lymphoblastic leukemia (ALL). Sixty patients with isolated or combined marrow relapse were studied. All patients belonged to the S3 or S4 groups, as defined by the Berlin-Frankfurt-Münster stratification for relapsed ALL. MRD was studied by real-time quantitative PCR after the first, second and third chemotherapy course (time points 1 (TP1), 2 (TP2) and 3 (TP3), respectively). MRD results, not used for treatment refinement, were categorized as negative (NEG MRD), positive not-quantifiable (POS-NQ MRD) when MRD level was below quantitative range (a level <10(-4)) or positive within quantitative range (POS MRD) when MRD level was >or=10(-4). With a median observation time of 15 months, overall 3-year event-free survival (EFS) was 27%. The 3-year EFS was 73, 45 and 19% for patients with NEG-MRD, POS NQ-MRD and POS-MRD at TP1, respectively (P<0.05). The prognostic predictive value of MRD was statistically confirmed in multivariate analysis. MRD quantitation early and efficiently differentiates patients who benefit from conventional treatment, including allogeneic hematopoietic stem cell transplantation, from those needing innovative, experimental therapies.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prednisone; Prognosis; Prospective Studies; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Survival Analysis; Treatment Outcome; Vincristine

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) -oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting.. A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index >/= 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non-T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase.. The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission.. Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chi-Square Distribution; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; DNA, Neoplasm; Female; Humans; Infant; Italy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Treatment Outcome; Vincristine

Only 20-30% of elderly patients with acute lymphoblastic leukemia (ALL) are enrolled in clinical trials because of co-morbid disorders or poor performance status. We present the results of treatment of Philadelphia chromosome-negative (Ph-) ALL patients over 55 yr treated in the PETHEMA ALL-96 trial.. From 1996 to 2006, 33 patients > or = 55 yr with Ph- ALL were included. Induction therapy was vincristine, daunorubicin, prednisone, asparaginase, and cyclophosphamide over 5 weeks. Central nervous system (CNS) prophylaxis involved triple intrathecal (IT) therapy, 14 doses over the first year. Consolidation-1 included mercaptopurine, methotrexate, teniposide and cytarabine, followed by one consolidation-2 cycle similar to the induction cycle. Maintenance consisted of mercaptopurine and methotrexate up to 2 yr in complete remission (CR) with monthly reinduction cycles (vincristine, prednisone and asparaginase) during the first year.. Median (range) age was 65 yr (56-77). Phenotype (30 patients): early-pre-B 7, common/pre-B 18, T 5. Cytogenetics (28 patients): normal 12, complex 10, t(4;11) 2 and other 4. CR was achieved in 19/33 (57.6%) patients, early death occurred in 12 (36.4%) and 2 (6%) were resistant. Overall survival and disease-free survival probabilities (2 yr, 95% CI) were 39% (21%-57%) and 46% (22%-70%), respectively (median follow up of 24 months). Removal of asparaginase and cyclophosphamide from the induction decreased induction death (OR 0.119, CI 95% 0.022-0.637, P = 0.013) and increased survival (20% vs. 52%, P = 0.05).. The prognosis of elderly Ph- ALL patients is poor. In this study, less intensive induction decreased toxic death, allowing delivery of planned consolidation therapy and increased survival probability.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Comorbidity; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Middle Aged; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Severity of Illness Index; Survival Analysis; Teniposide; Treatment Outcome; Vincristine

Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy.. 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541.. 174 patients (5.6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89.2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4.8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79.8% (SE 1.2) and 77.5% (1.5) in the treatment group and 79.2% (1.2) and 78.4% (1.3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0.97; 95% CI 0.81-1.15; p=0.70).. Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone.

Topics: Adolescent; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dexamethasone; Disease-Free Survival; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Pediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk B-lineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 x 10(9)/L (50,000/microL), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m(2)) with daily mercaptopurine. Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P = .068) was noted for superior outcomes in patients with trisomies of chromosomes 4 and 10 versus those lacking double trisomies. Sex, ethnicity, CNS status, and WBC were not predictive. This indicates the great majority of children with lesser-risk B-lineage ALL are curable without agents with substantial late effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Cell Lineage; Central Nervous System Neoplasms; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Infusions, Intravenous; Injections, Intramuscular; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Treatment Outcome; Vincristine

This study was designed to evaluate the efficacy and toxicity of modified BFM-90 regimen originated from Germany authors in the treatment of Chinese childhood and adolescent lymphoblastic lymphoma.. Thirty-six untreated lymphoblastic lymphoma patients aged from 3 to 18 years were included, with 1 patient in stage II , 9 in stage III and 26 in stage IV. Of these 36 patients, 28 (77.7%) were diagnosed as T cell phenotype, 26 (72. 2%) were found to have mediastinal mass, 21 (58. 3%) had bone marrow involvement. All patients received chemotherapy of modified BFM-90 regimen consisting of induction remission, central nerve system prophylaxis, re-induction remission and maintenance therapy. Total treatment duration was two years. The difference from standard BFM-90 is that we omitted cranial radiotherapy but gave regular high dose methotrexate (MTX) iv infusion and intrathecal MTX therapy during maintenance therapy period. Kaplan-Meier method was used to evaluate survival rate.. Of 36 patients, 32 (88%) achieved complete remission (CR) , 1 (2. 7%) partial remission (PR) with an overall response rate of 90.7%. One patient had disease progression ( DP). Two patients received autologous stem cell transplantation at CR1, and two patients received radiotherapy to mediastinum. Totally, 5 patients relapsed, while 2 of them were still alive after salvage chemotherapy. The other 3 died of tumor progression. Two patients died during induction remission, 1 of fungal septicemia, the other of cerebral hemorrhage; one PR and one DP patient died of disease, therefore, totally 7 patients died at last. Median follow-up time was 28 months. Overall three-year survival rate was 78. 3%. The major toxicity was myelosuppression.. Modified BFM-90 protocol can improve the efficacy and survival of Chinese childhood and adolescent lymphoblastic lymphoma with tolerable toxicity. However, this modified protocol should only be used in experienced cancer center or hematological unit.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asian People; Asparaginase; Child; Child, Preschool; China; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Treatment Outcome; Vincristine

This study examined renal function in 42 children with acute lymphoblastic leukemia (ALL) treated according to BFM-95 protocol. Fifteen (group 1) were investigated longitudinally at 3 time points: before (T1), 4 weeks after (T2), and 2-6 months after (T3) consolidation therapy with high-dose methotrexate (HDMTX). The frequency of abnormalities in glomerular and tubular tests were nil at T1 and ranged from 13 to 40% at T2 and 7 to 33% at T3 in group 1. Twenty percent of the patients (n = 10) in group 2, who were examined at a single time point 7-36 months after consolidation, had glomerular and tubular abnormalities. There was only mild tubular abnormality in 5.8% of patients (n = 17) in group 3, who were examined at a single time point a mean of 56.1 +/- 12.5 months after completion chemotherapy. These data show that consolidation therapy with HDMTX is frequently associated with acute renal toxicity in children with ALL but does not leave clinically significant late sequelae.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Kidney Diseases; Kidney Function Tests; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Turkey; Vincristine

Granulocyte colony-stimulating factor (G-CSF)-supported, post-remission chemotherapy (Cx) for adult acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) was evaluated. One hundred and forty-three eligible patients (median age, 41 years) including 126 ALL and 17 LBL receiving induction Cx (vincristine, cyclophosphamide, prednisolone [PSL], doxorubicin, L-asparaginase, intrathecal-methotrexate [IT-MTX]) were analyzed. For patients achieving complete response (CR), two courses of post-remission Cx (course A of daunorubicin, cytosine arabinoside, vindesine, PSL plus IT-MTX; course B of mitoxantrone, etoposide, vincristine, PSL plus IT-MTX) with the use of G-CSF were repeated alternately; thereafter, maintenance Cx including MTX and 6-mercaptopurine was given for 2 years. One hundred and nineteen (83%) patients achieved CR, while 14 (10%) died during induction. Among the 119 patients achieving CR, five died in remission, 76 relapsed, and the remaining 38 were alive without disease. The median survival time of the 143 eligible patients was 26 months (95% confidence interval, 19-34). At a median follow-up time of 9 years, the 5-year survival rate was 32% and the 5-year progression-free survival (PFS) rate was 26%. The 5-year survival rate of 36 patients who underwent autologous (n = 20) or allogeneic stem cell transplantation (SCT; n = 16) in the first CR group was 58%. Compared with the authors' previous trials, survival and PFS were markedly improved. In conclusion, G-CSF-supported, intensive post-remission Cx and subsequent SCT are worthy of further investigation for the treatment of adult ALL and LBL.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Combined Modality Therapy; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Transplantation, Autologous

A comparative analysis of efficacy and toxicity of two chemotherapy regimens: standard German protocol ALL-BFM 90m and less intensive original test protocol ALL-MB 91 in a multicenter trial of acute lymphoblastic leukemia (ALL) in children.. In 1995-2002 a total of 834 patients with newly diagnosed ALL aged 0-18 years were admitted to 10 clinics of Russia. Of them, 713 were randomized in two groups: treatment program ALL-BFM 90m (n = 355) and ALL-MB 91 program (n = 358).. In 7-year follow-up median, 10-year event-free survival (EFS) and overall survival (OS) did not differ significantly between the groups and was 67 +/- 3 and 68 +/- 3% (ALL-MB 91) and 74 +/- 2, 71 +/- 3% (ALL-BFM 90m), respectively. Though the rate of isolated recurrences in CNS in patients on the protocol ALL-MB 91 was 2.8%, they developed only in 0.8% patients of the standard risk group. Anemia, thrombocytopenia and agranulocytosis developed less frequently, hospital stay was significantly shorter on the test protocol vs the control one (p < 0.01).. EFS and OS on the test (ALL-MB 91) and control (ALL-BFM 90m) protocols were equivalent in lower toxicity and cost of therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome; Vincristine

The event-free survival (EFS) of children with standard-risk acute lymphoblastic leukemia (SR-ALL) is now more than 80%. However, prognosis after relapse continues to be poor. We examined postrelapse outcomes of children initially treated on the Children's Cancer Group CCG-1952 study.. We evaluated outcomes after bone marrow (BM) relapse and isolated extramedullary (EM) relapse for 347 patients with SR-ALL (WBC < 50,000/microL; age, 1 to 9 years). The prognostic significance of several factors for EFS after relapse (EFS2) was assessed by Cox regression analysis. Stem-cell transplant (SCT) was compared with chemotherapy as salvage treatment.. The mean +/- SE times to isolated central nervous system relapse, BM relapse, and isolated testicular relapse were 23 +/- 1 months (range, 1 to 88 months), 36 +/- 1 months (range, 2 to 79 months), and 40 +/- 2 months (range, 16 to 64 months), respectively. The estimated percent +/- SE 3-year EFS2 and overall survival rates after BM relapse were 37% +/- 4% and 46% +/- 4%, respectively, and rates after isolated EM relapse were 57% +/- 5% and 71% +/- 5%, respectively. By multivariate analysis, we found the duration of first remission to be the most significant predictor of EFS2 for either BM relapse or isolated EM relapse. Outcome was equivalent with SCT or chemotherapy after early or late relapse of SR-ALL at any site.. Duration of first remission remains the most significant predictor of outcome after either BM or isolated EM relapse of SR-ALL. Prognosis after early BM relapse remains poor and is not improved with SCT in this cohort.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Female; Humans; Hydrocortisone; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Stem Cell Transplantation; Survival Analysis; Thioguanine; Treatment Outcome

Fifty-two infants with acute lymphoblastic leukemia (ALL) enrolled in the AIEOP ALL-91 and ALL-95 studies were treated with the intermediate or high risk protocols according to their presenting features and early response to treatment. The 5-year event-free survival was 33.3% (95% CI 12.1-54.5), 53.5% (95% CI 35.7-71.3) and 45.0% (95% CI 31.3-58.7) in the ALL-91 and ALL-95 studies and in the overall cohort, respectively. In the ALL-95 high-risk group (BFM therapy intensified by three blocks and double protocol II) nine of 17 patients treated with chemotherapy only and three of four transplanted patients were alive and in complete remission. The corresponding figures for patients treated in the ALL-91 high-risk protocol (reduced induction and nine blocks) were one of seven patients treated with chemotherapy only and none of two who were transplanted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Vincristine

There is conflicting information about the influence of body mass index (BMI) on the pharmacokinetics, toxicity, and outcome of chemotherapy. We compared pharmacokinetics, outcome, and toxicity data across 4 BMI groups (underweight, BMI < or = 10th percentile; normal; at risk of overweight, BMI > or = 85th and < 95th percentile; overweight, BMI > or = 95th percentile) in 621 children with acute lymphoblastic leukemia (ALL) treated on 4 consecutive St Jude Total Therapy studies. Chemotherapy doses were not adjusted to ideal BMI. Estimates of overall survival (86.1% +/- 3.4%, 86.0% +/- 1.7%, 85.9% +/- 4.3%, and 78.2% +/- 5.5%, respectively; P = .533), event-free survival (76.2% +/- 4.2%, 78.7% +/- 2.1%, 73.4% +/- 5.5%, and 72.7% +/- 5.9%, respectively; P = .722), and cumulative incidence of relapse (16.0% +/- 3.7%, 14.4% +/- 1.8%, 20.6% +/- 5.1%, and 16.7% +/- 5.1%, respectively; P = .862) did not differ across the 4 groups. In addition, the intracellular levels of thioguanine nucleotides and methotrexate polyglutamates did not differ between the 4 BMI groups (P = .73 and P = .74, respectively). The 4 groups also did not differ in the overall incidence of grade 3 or 4 toxicity during the induction or postinduction periods. Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P > .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Remission Induction; Retrospective Studies; Teniposide

Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine.. Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques.. Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations.. Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Infant, Newborn; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenomegaly; Thioguanine

6-mercaptopurine has been a standard component of long-term continuing treatment for childhood lymphoblastic leukaemia, whereas 6-thioguanine has been mainly used for intensification courses. Since preliminary data have shown that 6-thioguanine is more effective than 6-mercaptopurine, we compared the efficacy and toxicity of the two drugs for childhood lymphoblastic leukaemia.. Consecutive children with lymphoblastic leukaemia diagnosed in the UK and Ireland between April, 1997, and June, 2002, were randomly assigned either 6-thioguanine (750 patients) or 6-mercaptopurine (748 patients) during interim maintenance and continuing therapy. All patients received 6-thioguanine during intensification courses. We analysed event-free and overall survival on an intention-to-treat basis. We obtained toxicity data using an adverse-event reporting system, with follow-up questionnaires to seek detailed information for specific toxicities. This trial is registered with the International Standard Randomised Controlled Number 26727615 with the name ALL97.. After a median follow up of 6 years, there was no difference in event-free or overall survival between the two treatment groups. Although 6-thioguanine conferred a significantly lower risk of isolated CNS relapse than did 6-mercaptopurine (odds ratio [OR] 0.53, 95% CI 0.30-0.92, p=0.02), the benefit was offset by an increased risk of death in remission (2.22, 1.20-4.14, p=0.01), mainly due to infections during continuing therapy. Additionally, 95 patients developed veno-occlusive disease of the liver. Of these, 82 were randomly assigned 6-thioguanine, representing 11% of all 6-thioguanine recipients. On long-term follow-up, about 5% of 6-thioguanine recipients have evidence of non-cirrhotic portal hypertension due to periportal liver fibrosis or nodular regenerative hyperplasia.. Compared with 6-mercaptopurine, 6-thioguanine causes excess toxicity without an overall benefit. 6-mercaptopurine should remain the thiopurine of choice for continuing therapy of childhood lymphoblastic leukaemia.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Acute lymphoblastic leukaemia (ALL), and especially its treatment often leads to irreversible consequences in the central and peripheral nervous system. ALL and its treatment as well, may cause disturbances of central transmission of acoustic stimuli.. To establish, if testing of egzogenic provoked brain stem potentials can be useful for evaluation of complications of ALL treatment. The issue of analysis was the influence of past ALL and type of therapy on parameters of egzogenic potentials triggered by acoustic stimulus (BAEP) in patients after termination of treatment.. In the group of patients treated with NY program results of middle latencies of the wave I and III were normal, however latencies of wave V and interlatencies of waves I-III, I-IV and III-V were mildly elongated. Latencies and interlatencies elongated above the upper normal range were detected in 4 patients of this group: in one patient elongation of the wave V and interlatencies of waves I-IV and III-V was detected, while in the other one interlatencies of waves I-III and I-V and in the last two patients only interlatencies of waves I-III. In the group of patients treated with BFM 86/87 programs results were similar. Latencies of waves I and III were normal, while mean latencies of wave V and interlatencies of waves I-III, I-V and III-V were mildly elongated. In this group mild pathological elongation of BAEP interlatencies were detected in 5 patients. Non of them had elongation of latencies of waves I, III or V. In one patient elongated interlatencies of waves I-V and III-V were detected, in another one interlatencies of waves I-III, while in other 3 patients elongation of latencies of waves I-V. In the group of patients treated with BFM 95 program latencies of waves I, III and V were normal, while interlatencies of waves I-III, I-V and III-V were mildly elongated. In 2 patients of this group mild elongation of interlatencies of waves I-III or III-V were detected. In each patient of this group, similar as in the group BFM 86/87, latencies of waves I, III and V were normal.. (1) BAEP abnormalities in 22.4% of patients after the treatment of childhood ALL suggest that hearing monitoring in these patients is recommended. (2) Elongation of BAEP interlatencies and latency of wave V in patients after radiation OUN therapy warrant to develop new and less toxic therapies.

Topics: Acoustic Stimulation; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Evoked Potentials, Auditory, Brain Stem; Female; Hearing Disorders; Hearing Tests; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Reaction Time; Thioguanine; Vincristine

To compare outcomes of patients with NCI standard risk acute lymphoblastic leukemia (ALL) who relapsed after being randomized to receive either oral or intravenous 6-mercaptopurine (6MP) in the Children's Cancer Group study CCG 1922.. CCG 1922 accrued patients from March 1993 to August 1995. A total of 1,060 patients were randomly assigned to four treatment groups: oral 6MP plus prednisone (OP), intravenous 6MP plus prednisone (IP), oral 6MP plus dexamethasone (OD), and intravenous 6MP plus dexamethasone (ID). During the 2nd through 4th month of therapy groups OP and OD were treated with 75 mg/m(2)/day of oral 6MP for 70 days and groups IP and ID with 1,000 mg/m(2)/week of intravenous 6MP over 10 hr for 11 doses. All patients received a single delayed intensification and all received oral 6MP in maintenance.. Patients randomized to oral 6MP had significantly better 5-year overall survival (96 +/- 1% vs. 92 +/- 1%; P = 0.008). There was, however, no statistically significant difference in the event-free survival (EFS). Of the 179 patients who relapsed, 84 had a second or later event and 68 have died. Forty of the 84 second events were a death. Survival after relapse was significantly greater for patients randomized to oral 6MP during consolidation than those receiving intravenous 6MP (P = 0.002, log rank test) with 4-year survival post-relapse of 67 +/- 6% vs. 48 +/- 6%. The steroid randomization had no influence on outcome. Post-relapse therapy details are not available and if different between groups may have influenced the outcome.. Treatment with intravenous 6MP during a brief period of total therapy had a significant negative impact on the prognosis in childhood ALL even though oral 6MP was used during maintenance.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Humans; Infant; Infusions, Intravenous; Life Tables; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Survival Rate

6-Thioguanine (TG) was recently studied to determine whether TG in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCG-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TG on CCG-1952. We report a newly recognized pediatric complication of TG: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy.. Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m(2)/day of TG during maintenance phases. Actual TG dose ranged from 25 to 77 mg/m(2)/day (median 34 mg/m(2)/day).. The initial patient, a boy who had marked thrombocytopenia and intermittent splenomegaly during maintenance therapy, was evaluated for persistent pancytopenia and progressive splenomegaly 3 months after completion of therapy. Dilated splenic vein and collaterals consistent with PH were documented by MRI/MRA. Esophagogastroduodenoscopy found esophageal varices. Liver biopsy showed periportal fibrosis and marked dilatation of veins and venules. Of the other 12 patients, 9 patients studied had abnormal MRI/MRAs with evidence of varices in 4. Eight patients had splenomegaly on physical examination. Liver biopsies in a girl after 3.3 courses of TG and a boy after 4.6 courses of TG showed periportal fibrosis and dilatation of venules and sinusoids and minimal focal fatty changes. Subsequent MRI/MRAs have been stable or improved.. The evaluations of these 12 patients suggest that treatment with TG causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Child; Child, Preschool; Esophageal and Gastric Varices; Female; Humans; Hypertension, Portal; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Mercaptopurine; Pancytopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenomegaly; Thioguanine; Thrombocytopenia

Between November 1990 and November 1996, EORTC Children Leukemia Group conducted a randomized trial in de novo acute lymphoblastic leukemia and lymphoblastic non-Hodgkin's lymphoma patients using a Berlin-Frankfurt-Munster protocol to evaluate the monthly addition of intravenous 6-mercaptopurine (i.v. 6-MP) (1 g/m(2)) to conventional continuation therapy comprising per oral MTX weekly and 6-MP daily. Only during the first 18 months of the randomization period, 6-MP p.o. was interrupted for 1 week after each i.v. 6-MP. A total of 877 patients was randomized to either no i.v. 6-MP (Arm A) or additional i.v. 6-MP (Arm B). A total of 217 relapses (91 in Group A vs 128 in Group B) and 13 deaths in CR (5 vs 8) were reported; a total of 134 patients (55 vs 79) died. The median follow-up was 7.6 years. At 8 years, the disease-free survival rate was lower (P=0.005) in Arm B (69.1% (s.e.=2.2%)) than in Arm A (77.9% (s.e.=2.0%)), and the hazard ratio was 1.45 (95% CI 1.12-1.89). In conclusion, as delivered in this study, i.v. 6-MP was detrimental to event-free survival.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Evaluation Studies as Topic; Female; Humans; Infant; Injections, Intravenous; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reproducibility of Results; Treatment Outcome

To elucidate interpatient variability in thioguanine nucleotide (TGN) concentrations in acute lymphoblastic leukemia (ALL) cells, we determined the TGN concentrations in leukemic blasts from 82 children with newly diagnosed ALL after intravenous administration of mercaptopurine (MP). Patients treated with MP alone achieved higher TGN concentrations than those treated with the combination of methotrexate plus mercaptopurine (MTX + MP). Analysis of the expression of approximately 9600 genes in ALL cells obtained at diagnosis identified 60 gene probes significantly associated with TGN accumulation in patients treated with MP alone and 75 gene probes in patients treated with MTX + MP, with no overlap between the 2 sets of genes. Genes significantly associated with intracellular TGN accumulation after MP alone included those encoding MP metabolic enzymes and transporters (eg, SLC29A1). Inhibition of SLC29A1 by nitrobenzylmercaptopurine ribonucleoside (NBMPR) caused a 33% to 45% reduction of TGN in ALL cells in vitro (P < .006), consistent with the gene expression findings. Genes associated with TGN concentration after combination therapy included those involved in protein and adenosine triphosphate (ATP)-biosynthesis. Together, these in vivo and in vitro data provide new insight into the genomic basis of interpatient differences in intracellular TGN accumulation and reveal significant differences between treatment with MP alone and treatment with MP and MTX.

Topics: Adolescent; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Gene Expression Profiling; Genotype; Guanine Nucleotides; Humans; Mercaptopurine; Phenotype; Phylogeny; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Tissue Distribution

Mercaptopurine is an important antimetabolite for treatment of childhood acute lymphoblastic leukemia (ALL). It has been prescribed to be given daily without therapeutic monitoring of drug levels. After first-pass metabolism by hepatic xanthine oxidase (XO), mercaptopurine is converted into two major intracellular metabolites, thioguanine nucleotide (TGN) and methylated mercaptopurine metabolites (including methylated thioinosine nucleotides), which are cytotoxic in vitro. Its short plasma half-life and S-phase-dependent pharmacokinetics suggest that biologically active concentration and exposure duration may be critical to cell kill.. Pediatric Oncology Group (POG) 9605, a randomized, open label phase III study of standard-risk ALL, was designed to compare daily with twice-daily mercaptopurine during continuation therapy. Red blood cell (RBC) TGN and methylated mercaptopurine metabolite levels were measured as surrogates of leukemic cell levels in a randomly selected subset of patients. TGN and methylated mercaptopurine metabolites were analyzed quantitatively by high-performance liquid chromatography (HPLC) and reported in ng/8 x 10.8 RBC. Statistical inferences utilized multiple linear regression.. One hundred eighteen patients received mercaptopurine 75 mg/m(2) daily and 108 received 37.5 mg/m(2)/dose twice daily. Descriptive statistics for the daily group showed the median TGN was 42 ng (mean and standard deviation [SD] = 48 +/- 35, quartiles 29-64). For the twice daily group, it was 40 ng (mean and SD = 40 +/- 27, quartiles 26-53). For methylated mercaptopurine metabolites, the daily group median was 2,020 ng (mean and SD = 2,278 +/- 1,559, quartiles 1,247-3,162); the twice daily group median was 1,275 ng (mean and SD = 1,580 +/- 1,240, quartiles 599-2,369). When adjusted for the covariables: actual dosage, days on study, age at diagnosis, white blood cell count, gender, Black race compared with not, and Hispanic compared with not, daily dosing resulted in significantly higher average methylated mercaptopurine metabolites by 668 (standard error [SE] = 179, P = 0.001) and a trend toward higher average TGNs by 6.2 (SE = 4.2, P = 0.14).. Daily dosing of mercaptopurine resulted in higher mean red cell methylated mercaptopurine metabolites when compared to split (twice a day dosing). The data were inconclusive with respect to TGNs. The relationships of methylated mercaptopurine metabolites and TGNs to clinical outcomes will be elucidated as part of the maturing 9605 data.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Biological Availability; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Male; Mercaptopurine; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Regression Analysis

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Blood Cell Count; Child; Child, Preschool; Dexamethasone; Drug Administration Schedule; Female; Humans; Infant; Injections, Intravenous; Injections, Spinal; Karyotyping; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone

Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL).. A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group).. After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04).. Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Erythrocytes; Female; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sex Factors; Thioguanine

Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells.. We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m(2) over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m(2), or high dose, 1 g/m(2) intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia.. Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 +/- 14.7 micromol/L versus 23.5 +/- 18.0 micromol/L, P <.001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 +/- 0.66 pmol/5 x 10(6) cells versus 7.4 +/- 15.2 pmol/5 x 10(6) cells, P <.001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 +/- 13.5 micromol/L versus 3.8 +/- 2.5 micromol/L, P =.029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% +/- 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% +/- 35%) compared with those in patients receiving mercaptopurine alone (P <.0001).. These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine.

Topics: Antimetabolites, Antineoplastic; Bone Marrow Cells; Child; Chromatography, High Pressure Liquid; Humans; Hypoxanthine; Injections, Intravenous; Leukocyte Count; Mercaptopurine; Methotrexate; Nucleosides; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Xanthines

Between January 1989 and July 1995, a prospective study of the therapeutic efficacy of the LALA 87 protocol in adult acute lymphoblastic leukaemia (ALL) has been conducted.. A total of hundred and twelve patients with ALL have been analysed. The median age of the patients was 40 years (range: 15-65), the gender ratio (M/F) was 66/46, and the morphologic FAB (French-American-British) profile was L1 in 30 (26.9%) patients, L2 in 71 (63.3%) and L3 morphology in 11 (9.8%) of the patients. The LALA 87 protocol includes five phases: induction, consolidation, reinforcement, maintenance and central nervous system (CNS) prophylaxis with intrathecal methotrexate and irradiation. The induction phase comprised daunorubicin 50 mg/m(2) (days 1-3), cyclophosphamide 600 mg/m(2) (days 1 and 8), vincristine 1.5 mg/m(2) (on days 1, 8, 15 and 22) and daily oral prednisone on days 1-21. Maintenance therapy was given for 2 years and consisted of different drugs as reinforcement, daily 6-mercaptopurine and weekly methotrexate.. Complete remission (CR) was achieved in 81 (72.3%) of the patients. The causes of induction failure were partial response in 10 (8.9%), and hypoplastic death in 12 patients (10.7%), and 9 were non-responders (8.0%). Of the 81 patients who achieved CR, 62 relapsed (76%). Among the relapsed patients, 9 developed CNS disease in spite of CNS prophylaxis during induction chemotherapy. Median follow-up for the living patients was 110 months. Median disease-free survival (DFS) was 16 months; 19 patients are still in remission with an estimated 10-year DFS (24%). Adverse prognostic factors were >50 years of age, immunologic subtype and cytogenetic profile.. The results support the strategy of applying more effort and other treatment modalities in the therapy of ALL.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cyclophosphamide; Daunorubicin; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Treatment Outcome; Vincristine

Antineoplastic therapy may cause metabolic disturbances, which result in e.g. abnormal growth rate. The aim of the study was the assessment of IGF-1 and IGFBP-3 plasma concentrations in children after intensive therapy of ALL completed according to age, weight, height and therapy protocols (Methotrexate dose, Central Nervous System - CNS prophylaxis).. 63 children (43 boys) were involved in this study with mean age 10.95+/-4.73 years after ALL therapy according to BFM protocols. 35 patients were in maintenance therapy and 28 completely finished the therapy. 20 children had cranial irradiation as CNS prophylaxis (12 Gy). We assessed plasma levels of IGF-1 and IGFBP-3 in radioimmunoassay method and the obtained results were related to mean age values (SDScore).. 1. A) IGF-1 mean plasma levels in children (n=30) before puberty (Tanner I) was 151.48+/-75.75 ng/ml and was lower than compared to value in the puberty group (n=16, Tanner II-IV) - 222.06+/-96.61 ng/ml p=0.000008. After puberty (Tanner V) IGF-1 was 332.03+/-75.66 ng/ml. b) IGFBP-3 was highest after puberty (3837.4 ng/ml +/-598.49); before puberty it was 2899.68+/-656.57 ng/ml, and in puberty it was 3593.14+/-598,49 ng/ml. 2. IGF-1 SDS values were lower than mean age values. 3. IGFBP-3 SDS were insignificantly higher than mean age values. 4. There were no differences between IGF-1 SDS and IGFBP-3 SDS according to gender, prior CNS prophylaxis, methotrexate dose and phase of maintenance therapy and completed therapy. 5. IGF-1 and IGFBP-3 correlated to each other and to body mass index, height but IGF-1 SDS and IGFBP-3 SDS was independent on age, CNS prophylaxis, BMI SDS and height SDS.. 1. IGF-1 and IGFBP-3 values are dependent on puberty degree, body mass index and height. 2. IGF-1 SDS are lower and IGFBP-3 values higher, independent on gender, therapy protocol and CNS prophylaxis (12 Gy).

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Body Height; Body Mass Index; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Puberty; Radiotherapy, Adjuvant; Remission Induction; Vincristine

The German cooperative study group for childhood acute lymphoblastic leukemia (COALL-92) was designed to examine the clinical effectiveness of thioguanine (TG) versus mercaptopurine (MP) in maintenance treatment of childhood acute lymphoblastic leukemia (ALL) in a randomized multicenter trial. TG and MP are prodrugs and have to be converted intracellularly to 6-thioguanine nucleotides (TGNs) for cytostatic activity. TG is converted into TGN in fewer steps and has been shown to be more cytotoxic in equimolar doses in vitro compared with 6-MP. Therefore, a higher effectiveness of TG in maintenance treatment was postulated. Of 521 patients enrolled into the protocol, 474 were randomized to receive either MP or TG during maintenance therapy in a daily oral dose. After a median observation time of 6.6 years, the probability of event-free survival was 79% +/- 3% for the MP group (238 children) and 78% +/- 3% in the TG group (236 patients). In spite of TGN levels, exceeding those of the MP group 7 times, treatment with TG did not improve the outcome but was more complicated to handle due to a specific toxicity profile of prolonged myelosuppression with marked thrombocytopenia. Therefore, MP should remain the preferred drug for maintenance treatment of ALL, unless other studies demonstrate superiority of TG in larger trials or selected patient groups.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Immunophenotyping; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Risk; Thioguanine; Thrombocytopenia; Time Factors

Prognosis of children with acute lymphoblastic leukaemia (ALL)--the most common cancer in childhood, has improved remarkably over the last 40 years. The authors report the treatment outcome in children with ALL cured according to ALL-BFM 90 Study protocol in the Czech Republic during the first half of nineties.. Children aged 0-18 years were included into the study in 10 centers between 1990 to 1996. Patients were classified into standard-risk (SR), medium-risk (MR) and high-risk (HR) group according to initial leukaemic burden, early treatment response, and genotype of leukaemia. Duration of the chemotherapy was two years. Treatment results were evaluated in 352 children. With a median follow-up of 7.3 years, event-free-survival (EFS) was 71.3% and overall survival 76.4%. EFS was 80.3%, 74% and 28.2% in SR, MR and HR group, respectively. Relapse was diagnosed in 17.8% of the patients.. The treatment outcome of children with ALL improved significantly (p = 0.0045) compared to the previous study ALL-BFM 83 (EFS 62%). These results are comparable to those achieved by leading leukaemia study groups in the world.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Recurrence; Vincristine

The aim of this study was to compare leucocyte and erythrocyte thioguanine nucleotide (TGN) cytotoxic metabolite concentrations in children with lymphoblastic leukaemia taking mercaptopurine (MP) or thioguanine (TG) as part of their long-term remission maintenance chemotherapy.. Ten consecutive children treated on the MRC ALL97 protocol were studied. Six were randomized to TG and four to MP. Leucocyte and erythrocyte thiopurine nucleotide metabolites were measured after the children had been titrated to the standard thiopurine protocol dose, or higher.. Children taking TG accumulated significantly higher erythrocyte TGN concentrations than those taking MP (median difference 1171 pmol/8 x 10(8) erythrocytes, 95% CI 766 to 2169, P<0.02), but there was no significant difference in the concentration range of leucocyte TGNs generated from TG or MP. In those children taking TG, median TGN concentrations were 5142 pmol/8 x 10(8) leucocytes and 1472 pmol/8 x 10(8) erythrocytes (3.5-fold difference, median difference 3390 pmol/8 x 10(8) cells, 95% CI 1559 to 7695, P=0.005), compared to 5422 pmol/8 x 10(8) leucocytes and 261 pmol/8 x 10(8) erythrocytes (20-fold difference, median difference 5054 pmol/8 x 10(8) cells, 95% CI 2281 to 6328, P=0.03) in those taking MP.. Despite the accumulation of significantly higher erythrocyte TGN concentrations for TG compared with MP, the accumulation of leucocyte TGNs in children taking TG was similar to the range of leucocyte TGNs in children taking MP. Therefore, when correlating intracellular TGNs to clinical effect, the range of erythrocyte TGN metabolites will be higher for those children taking TG than in those taking MP.

Topics: Child; Child, Preschool; Erythrocyte Count; Erythrocytes; Female; Humans; Leukocyte Count; Leukocytes; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m(2)) or high-dose MTX (HDMTX: intravenous 1 g/m(2)) followed by intravenous MP; or intravenous MP alone (1 g/m(2)), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 +/- 189 vs 250 +/- 38 fmol/nmol/h; P =.001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P <.001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (-50% +/- 4%, -56% +/- 3%, and - 20% +/- 4%, respectively; P <.0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (-63% +/- 4% vs -37% +/- 4%; P <.0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 +/- 298 vs 1075 +/- 114 pmol/10(9) cells; P <.01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P <.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Burkitt Lymphoma; Child; Child, Preschool; Female; Humans; Infant; Leukemia-Lymphoma, Adult T-Cell; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines

The report deals with the results of application of an original protocol--the Berlin-Moscow-91 (BM-91)--for the treatment of acute lymphoblastic leukemia (ALL) in children. The researchers' major concern was to improve survival and cut down side-effects incidence as well as to prevent and successfully manage occult neuroleukemia as a potential source of relapse. Patients aged 5 months-15 years received the BM-91 and ALL BFM-90m treatment first at one clinic and later at several centers. Out of 852 children with primary diagnosis of ALL admitted to Russian hematological hospitals (March 2, 1991-November 3, 2000), 687 were included into the study; 329 received the MB-91 protocol. Nine-year recurrence-free survival was 73% while overall survival--80%. Toxic side-effects after L-asparaginase were reported in 27 (7.9%). It is concluded that good results in childhood ALL treatment can be achieved without resorting to high-dosage chemotherapy and radiation in most cases.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Data Interpretation, Statistical; Daunorubicin; Dexamethasone; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Moscow; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Russia; Survival Analysis; Time Factors; Vincristine

This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.

Topics: Adult; Age Factors; Antimetabolites, Antineoplastic; Azathioprine; Child; Drug Therapy, Combination; Erythrocytes; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioinosine; Thionucleotides

Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can successfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixty-seven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients >1 year of age at diagnosis unfavorable prognostic factors were male sex, >25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) >50 x 10(9)/l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain; Child; Child, Preschool; Disease-Free Survival; Female; Germany; Humans; Infant; Male; Mercaptopurine; Netherlands; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Treatment Outcome

Through inhibition of purine de novo synthesis and enhancement of 6-mercaptopurine (6MP) bioavailability high-dose methotrexate (HDM) may increase the incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytoxic metabolites of 6MP. Thus, coadministration of 6MP could increase myelotoxicity following HDM. Twenty-one children with standard risk (SR) and 25 with intermediate risk (IR) acute lymphoblastic leukemia (ALL) were studied. During consolidation therapy they received either three courses of HDM at 2 week intervals without concurrent oral 6MP (SR-ALL) or four courses of HDM given at 2 week intervals with 25 mg/m2 of oral 6MP daily (IR-ALL). During the first year of maintenance with oral 6MP (75 mg/m2/day) and oral MTX (20 mg/m2/week) they all received five courses of HDM at 8 week intervals. In all cases, HDM consisted of 5,000 mg of MTX/m2 given over 24 h with intraspinal MTX and leucovorin rescue. Erythrocyte levels of 6TGN (E-6TGN) and methotrexate (E-MTX) were, on average, measured every second week during maintenance therapy. When SR consolidation (6MP: 0 mg), IR consolidation (6MP: 25 mg/m2), and SR/IR maintenance therapy (6MP: 75 mg/m2) were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir <0.5 x 10(9)/l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir <100 x 10(9)/l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (beta = -0.017, P= 0.001), the average ANC level during maintenance therapy (beta = 0.82, P = 0.004), and E-6TGN (beta = -0.0029, P= 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (beta = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

In our previous studies, the outcome of high-risk ALL was still poor. In the present study, all children with ALL were classified into three groups and treated with a new regimen (AL90).. Between 1990 and 1996, 220 children with ALL, treated with the AL90 regimen, were classified into three risk groups: low, intermediate, and high: LR, IR, and HR, respectively. The protocol consisted of three- to five-drug induction, consolidation with intermediate-dose methotrexate and/or cytarabine, mercaptopurine and cyclophosphamide, four-drug intensification, and sequential maintenance therapies. Only intrathecal chemotherapy was used for CNS prophylaxis in the LR group, whereas cranial irradiation was added for the IR and HR groups.. The number of eligible patients was 91: LR group, 71: IR group, and 58: HR group. Complete remission (CR) was obtained in > 98% of the LR and IR groups, while only 88% achieved CR in the HR group. The 5-year event-free survival (EFS) rate was 67.4% in all patients: 70.4% in the LR group, 71.7% in the IR group, and 57.5% in the HR group. With respect to the previous study, EFS in the HR group who showed positive residual leukemia at 14 days was improved, whereas EFS in boys versus girls was significantly lower (48.8% : 85.7%, P = 0.02).. In high-risk ALL, the rate of induction failure was high and boys had a worse outcome, calling for improvements in induction therapy and a specific approach for boys.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Humans; Immunophenotyping; Infant; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Radiotherapy, Adjuvant; Remission Induction; Risk; Risk Factors; Severity of Illness Index; Sex Factors; Survival Analysis; Treatment Outcome; Vincristine

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythrocytes; Female; Genotype; Humans; Infant; Infections; Leukocyte Count; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

In study NHL-BFM 90 we investigated the efficacy of an ALL-type treatment without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). In particular, the prognostic impact of the speed of tumor regression was evaluated. From April 1990 to March 1995, 105 evaluable patients, 1.1-16.4 years of age, with T-LBL were enrolled into study NHL-BFM 90. Patients with stage I and II received an 8-drug induction followed by a consolidation including high-dose-methotrexate (MTX) and maintenance therapy up to a total therapy duration of 24 months. Patients with stage III and IV received an additional reinduction and cranial radiotherapy (CRT) (12 Gy for prophylaxis) between consolidation and maintenance. Residual tumor after completion of induction had to be resected. No local RT was applied. Patients received intensified chemotherapy if tumor regression on day 33 of induction was <70% or when vital residual tumor was present after the induction phase. With a median follow-up of 6.41 years, pEFS at 5 years is 91.4% (SE+/-2.7%). 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to <70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. Our data demonstrate that, with intensive ALL-type chemotherapy but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. Providing tumor regression within 5 weeks is sufficient, tumor remnants after induction have weak prognostic impact.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Austria; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Germany; Humans; Immunophenotyping; Infant; Life Tables; Lymphoma, T-Cell; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiotherapy, Adjuvant; Remission Induction; Thioguanine; Treatment Outcome; Vincristine

The purpose of our study was to investigate the efficacy of an acute lymphoblastic leukemia (ALL)-type treatment with moderate-dose, prophylactic cranial irradiation and without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). From April 1990 to March 1995, 105 evaluable patients, 1.1 to 16.4 years of age, with T-LBL were enrolled in study NHL-BFM 90 (non-Hodgkin's lymphoma-Berlin-Frankfurt-Munster 90). They received an 8-drug induction over 9 weeks followed by an 8-week consolidation including methotrexate (MTX) 5 g/m(2) x 4. Patients with stage I (n = 2) and II (n = 2) continued with maintenance therapy (6-mercaptopurine daily and MTX weekly, both orally) until a total therapy duration of 24 months. Patients with stage III (n = 82) and IV (n = 19) received an 8-drug intensification over 7 weeks and cranial radiotherapy (12 Gy for prophylaxis) after consolidation, followed by maintenance. Residual tumor after induction had to be resected. Patients received intensified chemotherapy if tumor regression on day 33 of induction was less than 70% or when vital residual tumor was present after the complete induction phase. With a median follow-up of 4.5 years, the estimated event-free survival at 5 years is 90% (95% confidence interval, 82%-100%). Events were 1 early death, 8 tumor failures, and 1 secondary acute myeloid leukemia. A total of 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to less than 70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. We conclude that, with intensive ALL-type chemotherapy including moderate cumulative doses of anthracyclines 240 mg/m(2) and cyclophosphamide (3 g/m(2)) and moderate-dose prophylactic cranial irradiation but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. (Blood. 2000;95:416-421)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cranial Irradiation; Disease-Free Survival; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Probability; Remission Induction; Time Factors

To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL).. Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m(2) plus IV MP 1,000 mg/m(2) (regimen A) or IV MTX 1,000 mg/m(2) alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years.. Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P =.5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen.. Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Survival Analysis

We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy.. Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis.. The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important.. Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Child, Preschool; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk Factors; Treatment Outcome

6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P =.006 and. 039, respectively). The occurrence of neutropenia was associated with worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020) was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with better outcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Proportional Hazards Models; Remission Induction; Survival Rate

The National Chilean Pediatric Oncology Group, PINDA, reports the first prospective, nonrandomized trial for acute lymphoblastic leukemia (ALL), using a modified version of the Berlin-Frankfurt-Munster protocol (ALL BFM 86). The aim of this study was to classify immunophenotypes, to decrease cranial irradiation, and to assess whether this protocol would improve the survival rate.. From June, 1987, to June, 1992, 444 unselected children were diagnosed with ALL. Of them, 425 were evaluable. Therapy was stratified by risk. Standard-risk (SR) and high-risk (HR) patients received protocols I, M, II, and maintenance therapy. Very-high-risk (VHR) patients received protocol E instead of protocol M. All patients received a prephase treatment consisting of prednisone and intrathecal methotrexate (MTX). HR and VHR patients received cranial irradiation (12-18 Gy). The following changes were made to the ALL BFM 86 protocol: in protocol M, MTX 1 g/m2 instead of 5 g/m2; in protocol E, citarabine 1 g/m2 instead of 2 g/m2; mithoxantrone and ifosfamide were substituted by teniposide and cyclophosphamide.. Immunophenotypes: pro-B-ALL, 14%; common ALL, 67.4%; pre-B-ALL, 4.3%; T-ALL, 10%; undifferentiated leukemia (AUL), 4.3%. The overall 5-year event-free survival (EFS) rate was 60% +/- 2% (SE). The 5-year EFS rate for each risk group was: SR 75%, HR 62%, VHR 28%, with a median follow-up of 6.5 years (range 4.5-9.5 years). The cumulative incidence of central nervous system (CNS) relapse was 5.4%.. We have been able successfully to perform a nationwide study. Our strategy to adapt the BFM protocol to our population of patients trial was effective in improving the EFS. The immunophenotype distribution is similar to that in other reported series.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Chile; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Developing Countries; Female; Humans; Immunophenotyping; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Survival Analysis; Vincristine

Intracellular concentrations of 6-mercaptopurine metabolites, i.e. of 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) were analysed in red blood cells (RBC) of 19 children with acute lymphoblastic leukemia (ALL), the subjects of a maintenance chemotherapy of their first remission. Interpatient variations in concentrations of both metabolites were high; concentrations of 6-TGN varied from <60 to 833 pmol/8x10(8) RBC (median value, 144) and those of 6-mMP metabolites from <150 to 19000 pmol/8x10(8) RBC (median value, 3250). In two patients, 6-TGN appeared at concentrations below the limits of assay sensitivity, and 6-mMP metabolites were not detected. In another child the concentrations of both metabolites were at the limit of the assay sensitivity. In three other children the concentrations of both metabolites were below the median value of the group. In the analysed group of children, significant correlations were found between the white cell count (WBC) and RBC 6-TGN (r(s)=-0.72, P<0. 005) as well as between the neutrophil count and RBC 6-TGN (r(s)=-0.60, P<0.01). No significant correlation was found between the concentrations of 6-TGN and 6-mMP metabolites. The monitoring of concentrations of 6-TGN as well as of 6-mMP metabolites allows an early identification of patients who are at an increased risk of the disease relapse as indicated by the low levels of either 6-TGN itself or of its two metabolites.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Erythrocytes; Female; Guanine Nucleotides; Humans; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

6-Mercaptopurine (6MP) has been regarded as nonleukemogenic, even though the cytotoxicity of 6MP depends on the incorporation of 6-thioguanine nucleotides (6TGN) into DNA. In hematopoietic cells this pathway competes with S-methylation catalyzed by thiopurine methyltransferase (TPMT). However, methylated 6MP metabolites inhibit purine de novo synthesis and thus may enhance incorporation of 6TGN into DNA. Approximately 10% of white individuals have low TPMT activity as a result of polymorphisms in the TPMT gene. The authors attempted to test the hypothesis that the degree of DNA damage during 6MP therapy might reflect variations in 6MP metabolism and pharmacokinetics.. The authors measured TPMT activity as well as erythrocyte levels of 6TGN (E-6TGN) and methylated 6MP metabolites (E-MeMP) during 6MP therapy in 439 children with acute lymphoblastic leukemia, 5 of whom later developed secondary myelodysplasia or acute myeloid leukemia (sMDS/AML).. The patients who developed sMDS/AML had significantly lower TPMT activity compared with the remaining patients (P = 0.03). The 55 patients with TPMT activity <14 U/mL red blood cells (RBC) (antimode of the bimodal distribution) had a 5-year risk of sMDS/AML of 9 +/- 6% versus 1 +/- 1% for the remaining patients (P = 0.002). Cox regression analysis identified TPMT activity and E-MeMP level as the strongest predictors of risk for sMDS/AML (global P value = 0.02). Patients with low TPMT activity and high E-MeMP levels had the highest risk. All 5 patients with sMDS/AML had E-6TGN and/or E-MeMP levels > the 90% percentiles or had TPMT activity < 14 U/mL RBC.. These data demonstrate an increased leukemogenic risk when 6MP is administered with other cytotoxic agents in patients with low TPMT activity, and indicate that not only high 6TGN levels but also high levels of methylated metabolites may lead to DNA damage.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Child; Child, Preschool; DNA Damage; Guanine Nucleotides; Humans; Immunophenotyping; Infant; Mercaptopurine; Methyltransferases; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Thionucleotides

Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes.. We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided.. Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations.. We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Child; Erythrocytes; Female; Guanine Nucleotides; Heterozygote; Humans; Male; Mercaptopurine; Methylation; Methyltransferases; Phenotype; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Thionucleotides

To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL).. Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years.. Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A.. Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.

Topics: Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child, Preschool; Female; Humans; Infusions, Intravenous; Leucovorin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Remission Induction; Sex Factors; Treatment Failure

The fluorescence-activated cell sorter (FACS) was utilized to phenotype lymphocyte compartments in children receiving intensive chemotherapy for acute lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation chemotherapy treatment were arbitrarily selected for study. All 16 patients had profound B cell lymphopenia. In contrast, T cell numbers were often normal or marginally low, and accounted for up to 98% of the lymphocyte populations. No abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts and lymphocyte percentages were not predictive of the underlying B cell lymphopenia. Patients were also tested for serum immunoglobulin levels and most had abnormally low IgG and IgM. None of four patients immunized with the 1996-1997 influenza virus vaccine seroconverted to at least two vaccine antigens as compared to 10 of 10 healthy, age-matched controls. In total, these data highlight for the first time the profound abnormality of the B/T lymphocyte ratio in patients during treatment for ALL, and argue for consideration of B cell-targeted immunotherapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; CD4 Lymphocyte Count; Child; Child, Preschool; Female; Flow Cytometry; Humans; Immunoglobulin G; Immunoglobulin M; Lymphocyte Subsets; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes

Mercaptopurine (6MP) has been the standard drug for maintenance therapy of acute lymphoblastic leukemia. In a multicenter study we investigated whether thioguanine (6TG), which is converted more directly to the cytotoxic thioguanine nucleotides (TGN), offers a therapeutic advantage over 6MP. In this study (COALL-92), 6TG was randomized versus 6MP in maintenance therapy, whereby the doses of both drugs had to be adjusted to a white blood cell (WBC) count of between 2 and 3/nl. In 19 children the plasma levels of both drugs and/or the accumulation of their metabolites in red blood cells (RBC) were measured during intensive treatment in two consecutive chemotherapy blocks, and in 54 children the metabolites in RBC were measured every 3 months during daily treatment in maintenance therapy. There was a marked interindividual difference in the plasma kinetics of the two drugs; after identical doses of 100 mg/m2 an about 4-fold higher peak concentration of the parent drug was reached with 6MP. The main metabolites of 6TG were thioguanine nucleotides (TGN), whereas during 6MP treatment, methylated thioinosine nucleotides (TIN) predominated in erythrocytes. In patients receiving 6TG during maintenance therapy (22 patients) the concentration of methylated TGN reached about 40% of that of unmethylated TGN; after 6MP administration (32 patients) the methylated TIN were concentrated about 26-fold higher in RBC than were TGN. In contrast to 6TG, for 6MP the pattern of metabolites shifted toward the methylated ones with increasing dose. The median TGN concentration was about 7-fold higher in the TG branch, although the median dose was only about 70% of that of 6MP. The WBC values were equivalent in the two treatment groups. Our results suggest that the cytotoxic effect of 6MP is not based solely on the formation of TGN.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Erythrocytes; Female; Guanine Nucleotides; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thioinosine; Thionucleotides

Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported.. From 1991 to 1995, 1194 children (< 15 years) with non-B ALL, were enrolled and assigned to the standard risk [SR: age > 1 year, non-T-ALL, BFM risk factor (RF) < 0.8], intermediate risk (IR: RF > or = 0.8 but < 1.7, or with RF < 0.8 and age < 1 year, or T-ALL), or high risk [HR: RF > or = 1.7, or t(9;22), or t(4;11) or prednisone poor response or late response or CNS involvement] groups. All patients received initially protocol Ia. Thereafter SR patients received HD-MTX 2 g/m2, a modified protocol II, and continuation therapy with triple intrathecal chemotherapy (TIT); IR patients received protocol Ib, HD-MTX 5 g/m2, protocol II and continuation therapy with TIT; HR patients received 9 polychemotherapy blocks, cranial irradiation and continuation therapy. Duration of treatment was 24 months. A randomized study was conducted to evaluate the impact of high-dose asparaginase in non high risk patients: the results of this study cannot be disclosed yet.. One thousand one hundred and fifty-two (96.5%) patients achieved CR. Overall EFS (SE) at 5-years was 71.0% (1.4), with a survival of 80.3% (1.3). Relapse occurred in 262 children (21.9%), either in the marrow (n = 192 isolated and 32 with other sites, 18.7%), in the CNS (n = 18, 1.5%), or elsewhere (n = 20, 1.7%). 5-year EFS (SE) was 83.3% (2.4) in SR, 74.7% (1.8) in IR, and 39.7% (3.5) in HR groups, respectively.. Overall cure rate was higher than in the previous AIEOP-ALL 88 study. Treatment intensification with polychemotherapy blocks did not improve results in HR. Cranial irradiation can be safely omitted in over 80% of children treated with BFM based chemotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Child, Preschool; Chromosome Aberrations; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Infant; Italy; Leucovorin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Risk; Thioguanine; Treatment Outcome; Vincristine

This study aimed to compare the therapeutic efficacy of two treatments for childhood acute lymphoblastic leukemia (ALL), and to evaluate the feasibility of intensive chemotherapy in a developing country.. The study was conducted at the National Cancer Institute in Bogota, Colombia. Untreated ALL patients under 16 years of age were divided into two groups: a historical control cohort (HC) of 141 patients treated with conventional chemotherapy and an intensive chemotherapy cohort (IC) of 130 patients treated with a modified Berlin-Frankfurt-Münster protocol (m-BFM). Patients were clinically classified into risk categories for relapse, and followed through July 31, 1995. Disease-free survival (DFS) curves were obtained using the Kaplan-Meier method and were compared by the log rank test.. Therapy groups had similar clinical baseline characteristics. Nonresponse rate to induction was higher in the HC group (16.3%) than in the IC cohort (7.6%) (P = 0.047), but deaths during induction were more frequent among m-BFM patients (13.8%) than in the HC group (6.4%) (P = 0.064). Bone marrow relapses after complete remission were less common in the IC group than in the HC group (19.4% and 45.9%, respectively; P = 0.0001), but central nervous system relapses showed no difference (12.8% in the HC and 16.3% under IC; P = 0.6). The DFS rates at 10 years were higher for the IC group, regardless of the baseline risk.. IC reduces the frequency of relapses in ALL children in developing countries, when compared to previous therapy. A highly effective therapy such as m-BFM seems to be the most important predictor of outcome in children.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Feasibility Studies; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Treatment Outcome; Vincristine

The cure rate of childhood acute lymphoblastic leukemia (ALL) has improved dramatically. Still there is a paucity of long-term data. With the improving cure rate, the quality of life and avoidance of second cancers have become important concerns. We evaluated 596 children and adolescents with ALL on Cancer and Leukemia Group B 7611 (CALGB 7611) who were randomized between 1976 and 1979 to receive intermediate-dose methotrexate (IDM) plus intrathecal methotrexate (IT MTX) or cranial radiation (CRT) plus IT MTX. After 10 additional years of follow-up, the pattern and significance of the results reported in 1983 are confirmed. IDM offered better hematologic protection (P < 0.0006), better testicular protection (P = 0.002), but CRT offered better central nervous system (CNS) protection (P < 0.0001). The retrieval rate for the 231 patients who relapsed while on therapy or within 6 months of elective cessation of therapy is 20 +/- 5%. For the 33 patients who relapsed more than 6 months after cessation of therapy, the retrieval rate is 49 +/- 10%. For all patients, the 12-year event-free survival was 37 +/- 3.6% and the overall survival was 49 +/- 3.5%. There were two cases of second malignancies reported in 3,502 person-years of survival. Both occurred following salvage therapy. There was no evidence of an excessive number of second primaries over the general population of children. There were no reported instances of clinical cardiopathy. After a median follow-up of 11 years, there have been no reports of cardiopathy and no evidence of an increased risk of second cancers in children treated on CALGB 7611. While the overall outcome is not what would be expected with modern therapy, one can conclude that CRT offered better CNS protection, but IDM offered better systemic and testicular protection. A small risk of second cancers or cardiac dys-function may be acceptable with therapies which produce long-term documented survival benefits.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Combined Modality Therapy; Cranial Irradiation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

A total of 119 children (1990-95) with acute lymphoblastic leukemia (ALL) B-lineage either CD10+ or CD10- were registered into a single non-randomized chemotherapy protocol. Only untreated patients with standard risk were included in the study. Their ages ranged from 1.8-10 years with a mean of 5.1 years. There were 82 (68%) children with early pre B-All, 35 (29%) with pre B-ALL and 2(1.6%) with transitional pre B-ALL (p < 0.00001). The patients were divided according to CD10 reactivity, either + (94 children) or -(25 patients). The event-free survival (EFS) at 60 months for the CD10+ children was of 78% (alive 73/94), while for the CD10- was 71% (alive 18/25) (p = 0.6) and 74% for both groups. The factors that influenced favorably the survival in the CD10+ group were the age between 3 to 5.99 years (p < 0.00001), sex (either male or female), leukocyte count between 10-24.9 x 10(9)/l (p < 0.00001), LDH under 300 U/I (p < 0.00001) and L1 bone marrow cytomorphology (p < 0.00001). In the CD10- patients, the EFS was favorably influenced by the female sex (p = 0.04), leukocyte count under 10 x 10(9)/l (p = 0.05) and LDH < 300 U/l (p = 0.02). CNS infiltration was documented in 4.2% (5/119). Mortality secondary to chemotherapy was seen in 7%. In conclusion, this is the first large series in Mexican children with B-lineage ALL published. Because of the relatively small number of patients in each group (pre B and transitional pre B), all the patients in the current series were treated alike. When the 119 patients were divided only on the basis of CD10 reactivity, the EFS for both groups (CD10+ and-) was similar; therefore, the reactivity to CD10 has no prognostic value in this type of ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Female; Humans; Immunophenotyping; Infant; Life Tables; Male; Mercaptopurine; Methotrexate; Neprilysin; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Risk Factors; Survival Analysis; Teniposide; Treatment Outcome; Vincristine

During 1984-86, 23 patients (5-37 years, median 16) with acute lymphoblastic leukemia (ALL) in first remission (n = 11) or beyond (n = 12) underwent autologous transplantation (ABMT) using marrow purged with the rat anti-CD52 monoclonal antibody Campath-1M after melphalan and total-body irradiation (TBI). Median time to 0.5 x 10(9)/L neutrophils and 50 x 10(9)/L platelets was 38 and 51 days respectively. Myeloid engraftment was significantly slower compared with ALL patients receiving unpurged marrow (P = .01). Eight patients died due to transplant-related causes 53-205 days after the procedure. Six of eight patients receiving 1150 cGy TBI died of toxicity compared with two of 15 receiving less than 1150 cGy (P = .006, Fisher's exact test). Nine patients relapsed at 45-195 days (median 97); eight died and one is alive at nine years in a chemotherapy-induced remission. Six patients are alive and well in continuous remission 9-10 years (median 10) after transplant. The 10-year probabilities of disease-free survival and relapse are 26% (95% CI: 11-45%) and 51% (95% CI: 37-59%) respectively. We conclude that it is feasible to purge marrow for autografting using Campath-1M without killing normal stem cells. Myeloid engraftment is slow but consistent, and long-term survival is seen in a proportion of patients. The role of CD52 monoclonal antibodies for purging in ALL still requires further study.

Topics: Adolescent; Adult; Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; CD52 Antigen; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Glycoproteins; Humans; Male; Melphalan; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Time Factors; Transplantation, Autologous; Whole-Body Irradiation

Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its poor prognosis. Forty patients with ALL, aged 55 years or older, and with good performance status (ECOG <3) were prospectively treated according to an age-adapted regimen: induction therapy was derived from the LALA87 protocol while the feasibility of treatment with interferon combined with chemotherapy was assessed during maintenance. Compared with younger adults treated according to the LALA87 protocol, elderly patients did not present with more adverse prognostic features, except for a lower incidence of T cell ALL (9 vs 31%, P=0.005). There were even less patients with a high leukocyte count (15 vs 38%, P=0.003), a characteristic associated with adverse prognosis while the incidence of Philadelphia-positive (Ph-positive) ALL was not significantly increased compared to younger adults (31 vs 20%, P=0.2). After completion of induction therapy, with or without salvage treatment, 85% (CI: 70-94%) obtained a complete response (CR) while treatment-related mortality during induction was 7.5% (CI: 2-20%). Median overall survival and disease-free survival were 14.3 months and 14 months, respectively, which, although inferior to results achieved in younger adults, compares favorably with available data in the elderly. Treatment with IFN proved feasible in most patients but had to be discontinued in eight patients because of toxicity. Age-adapted treatment improves the prognosis of ALL in the elderly even if, in most cases, a cure cannot be achieved.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Daunorubicin; Disease-Free Survival; Female; Humans; Interferons; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Steroids; Vincristine

The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881.. After 1 month of oral treatment at a dose of 50 mg.m-2.day-1, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g.m-2 (bolus dose of 0.2 g.m-2 followed by an 8-h infusion of 0.8 g.m-2) in 11 patients: systemic clearance was 23.02 1.h-1, volume of distribution was 0.75 l.kg-1, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol x 10(8) packed RBC) or within 24 h of infusion (223 pmol x 10(8) packed RBC). The CSF concentration was 3.78 mumol.1(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16). In patients receiving the oral dose of 50-165 mg.m-2.day-1 of 6-mercaptopurine, CSF concentrations were below 0.18 mumol.1(-1), 1-24 h after drug intake (n = 67), and the CSF to plasma ratio was not calculated.. Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n[symbol: see text]5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Erythrocytes; Humans; Injections, Intravenous; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Standard prophylaxis and treatment of malignancy-associated hyperuricemia in the USA has been allopurinol with vigorous hydration, urinary alkalinization and osmotic diuresis. Urate oxidase, the enzyme that converts uric acid to allantoin (a readily excreted metabolite that has 5- to 10-fold higher solubility than uric acid), is an alternative therapy; however, few published findings support this practice. Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both. Their blood levels of uric acid and other indicators of tumor lysis were measured at diagnosis and during treatment and then compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia. Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma. Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels than did the historical controls (median maximal level during treatment, 2.3 vs 3.9 mg/dl, P < 0.001). They also had lower creatinine (0.6 vs 0.7 mg/dl, P = 0.01) and blood urea nitrogen (11 vs 24 mg/dl, P < 0.001) levels. Similar findings were made in the eight cases of B cell ALL or non-Hodgkin lymphoma. None of the patients required dialysis for acute renal failure. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm and hypoxemia. Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy.

Topics: Allopurinol; Antimetabolites; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors; Urate Oxidase; Uric Acid

The response to 6-mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6-thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype.. Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children.. TPMT activities at diagnosis ranged from 5.5 to 18.5 units ml(-1) packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75 mg m(-2) ranged from 187 to 594 pmol 6TGNs, median 327, and 0.5 to 22.0 nmol MeMPs, median 4.5, per 8 x 10(8) RBCs. TPMT activity was not significantly related to the generation of MeMPs (r(s) = 0.06), but was negatively correlated to 6TGNs (r(s) = -0.44, P<0.025, n=29). TGNs were related to neutropenia at the point of dose reduction (r(s) = -0.5, P<0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal (r(s)= -0.41, P<0.05).. These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Dexamethasone; Erythrocytes; Etoposide; Female; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Vincristine

Infants with acute lymphoblastic leukemia (ALL) have a very poor prognosis. Since 1985, we have intensified therapy for infants with ALL by including a month of high dose multiagent chemotherapy after remission induction.. Between 1985 and 1995, we treated 23 infants (age < 12 months). We compared the presenting characteristics and outcomes of these infants with the 11 infants treated on our protocols between 1973 and 1985, an era prior to the intensification of therapy. Available bone marrow samples from infants treated since 1985 were analyzed for the presence of MLL gene rearrangements by Southern blot analyses and for TEL-AML1 gene fusion by reverse transcriptase-polymerase chain reaction.. With a median follow-up of 5.6 years, the 50-month event free survival (EFS) (+/- standard error) for the 23 infants was 54 +/- 11%, a significant improvement (P = 0.001) compared with the outcome for the 11 infants treated on our protocols prior to 1985 (EFS = 9 +/- 9%). Of the seven infants found to have a rearranged MLL gene, three (43%) remained in first complete remission. None of the nine infant bone marrow specimens tested had evidence of TEL-AML1 gene fusion. The intensified therapy was complicated by a high incidence of infections, including septicemia in 52% of patients and Pneumocystis carinii pneumonitis in 22% of patients. Late effects identified in the 13 long term survivors (median age, 6 years) included developmental delay and learning disabilities of varying severity (82% of evaluable patients), asymptomatic cataracts (67%), asymptomatic echocardiographic abnormalities (30%), obesity (27%), and short stature (18%).. Intensification of therapy significantly improved the EFS of infants with ALL compared with previous, less intensive regimens and with the experience of other investigators. Future treatment for infants should attempt to improve efficacy while minimizing toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Core Binding Factor Alpha 2 Subunit; Cytarabine; Disease-Free Survival; DNA-Binding Proteins; DNA, Neoplasm; Female; Histone-Lysine N-Methyltransferase; Humans; Infant; Infant, Newborn; Male; Mercaptopurine; Methotrexate; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Proto-Oncogenes; Remission Induction; Survival Rate; Transcription Factors; Treatment Outcome; Vincristine

Overall chemotherapeutic treatment results in pediatric acute lymphoblastic leukemia (ALL) are good, with event-free survival (EFS) rates over 70%. However, for a subset of patients characterized by high-risk (HR) features the outcome is less favorable, with EFS rates below 50%. Intensification of chemotherapy may improve the outcome for those patients, but increased toxicity, particularly myelosuppression, limits the escalation of dose intensity. Recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) is known to reduce myelosuppression after cancer chemotherapy in adults. The objective of this study was to examine the effect of r-metHuG-CSF on myelosuppression in HR pediatric ALL patients and on the overall response rate to chemotherapy. Patients with HR pediatric ALL were randomized to receive nine alternating cycles of chemotherapy according to the German ALL-Berlin-Frankfurt-Münster 90 protocol either alone or followed by r-metHuG-CSF administered prophylactically at a dose of 5 microg/kg/d subcutaneously. In both groups, the planned interval between chemotherapy courses was a minimum of 21 days. We report here interim results of 34 patients. The incidence of febrile neutropenia (absolute neutrophil count <0.5 x 10(9)/L and oral temperature > or = 38.5 degrees C) was 17% in children receiving r-metHuG-CSF, as compared with 40% in the control group (P = .007). In addition, the median total duration of febrile neutropenia was reduced from 20.3 to 6.2 days per patient (P = .02). Culture-confirmed infections occurred less frequently in the r-metHuG-CSF group (8% v 15%; P = .04), and the total duration of intravenous antibiotic use was significantly reduced from 32.2 days to 18.2 days per patient (P = .02). A tighter adherence to the planned treatment schedule was also facilitated by r-metHuG-CSF (P = .007). With a median follow-up of 3.3 years, the estimated EFS of 4 years is 41% +/- 12%. In conclusion, r-metHuG-CSF administered prophylactically in the interval between chemotherapy courses significantly reduced febrile neutropenia, culture-confirmed infections, and duration of intravenous antibiotic administration and allowed for tighter adherence to the treatment schedule.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Female; Fever; Filgrastim; Gastrointestinal Diseases; Germany; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Ifosfamide; Infant; Infection Control; Life Tables; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prospective Studies; Recombinant Proteins; Risk; Survival Analysis; Thioguanine; Vincristine; Vindesine

Methotrexate (MTX) infusions of 500--1,000 mg/m2 over 24 hours may improve survival and prevent relapse in children with acute lymphoblastic leukemia (ALL). Childrens Cancer Group (CCG) Study 139 compared weekly oral methotrexate 20 mg/m2/week (oral MTX) to MTX 500 mg/m2 infused over 24 hours (IV MTX) three times during consolidation and every 6 weeks during maintenance in 164 children with intermediate-risk ALL, i.e., those patients over age 1 year with white blood cell count 10,000 to 49,999/ml and no bulky extramedullary disease. Median follow-up for CCG-139 exceeded 75 months. Thirty-four events occurred among 80 patients receiving IV and oral MTX and 36 events among 84 patients receiving oral MTX. Two children died during induction and one did not enter remission. Remission induction rate is 98%. There have been 26 marrow relapses, 11 combined marrow and extramedullary relapses, 24 CNS relapses, and five testicular or other relapses. The frequency and distribution of relapses does not differ between the two regimens. For the entire group, overall event-free survival (EFS) at 6 years is 57.9% (standard deviation=4.0%) and actuarial survival is 80.0% (standard deviation =3.3%). Of the 29 patients with isolated extramedullary relapse, 18 survive free of a second event, a median of 42 months from relapse. In contrast to other trials, this trial does not show that IV MTX in this dose and schedule offers an advantage over standard therapy for this group of children.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Injections, Spinal; Leucovorin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Survival Analysis; Vincristine

In children with acute lymphoblastic leukemia (ALL), the level of minimal residual disease (MRD) at the end of induction strongly predicts outcome, presumably because it measures both drug sensitivity and the number of leukemic cells requiring elimination. Children with high levels (> 10(-3) leukemic cells per marrow cell) nearly always relapse, whereas those with low levels (<2 x 10(-5)) seldom do. However, the importance of MRD in adult ALL is unclear. We studied 27 patients aged 14 to 74 who were treated with a standard protocol and who attained morphological remission. MRD in the marrow at first remission was quantified by using the polymerase chain reaction (PCR), with the rearranged immunoglobulin heavy chain gene as a molecular marker. Levels of MRD varied from 3 x 10(-1) to <7 x 10(-7). The probability of long-term relapse-free survival was significantly related to the level of MRD and only one of nine patients with MRD >10(-3) did not relapse. For patients who did relapse, there was an inverse relationship between MRD level and the length of remission. Overall, MRD in adults in whom a translocation had not been identified was significantly higher than in comparably-treated children, suggesting that ALL in adults is more drug-resistant than in children.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Bone Marrow Transplantation; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Etoposide; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Humans; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm, Residual; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Survival Analysis; Treatment Outcome; Vincristine

A variety of oncogenes are activated by specific chromosomal translocations, which are associated with distinct subtypes of leukemia. The identification of these rearrangements provides critical diagnostic and prognostic information, which may contribute to the selection of specific anti-leukemic therapy. The translocation t(9;22), the equivalent of the BCR/ABL rearrangement, is associated with a poor prognosis. We therefore used RT-PCR to detect this molecular event in a prospective study including 890 children. 673 of them suffered from acute lymphoblastic leukemia (ALL) at primary diagnosis and a transcription of the chimeric gene was detected in 21 of 648 with a successful analysis (3.2%). All children were treated by one of the two German multicenter childhood ALL therapy studies ALL-BFM-90 or COALL-05-92, respectively. Comparison of clinical features between BCR/ABL-positive and -negative children showed no significant differences regarding WBC, percentage of blasts, splenomegaly, hepatomegaly and age. Immunophenotypic studies at diagnosis in 21 BCR/ABL-positive children identified common ALL in 16 patients (76.2%), pre-B-ALL in four (19.0%), and an early T-lineage ALL in one (4.8%). Coexpression of myeloid antigens (CD13 and/or CD33) was observed in six of 16 common ALL patients as well as in the one child with early T-lineage ALL phenotype. The type of breakpoint (m-BCR/ABL: n = 14; M-BCR/ABL: n = 7) showed no correlation with clinical parameters. A comparison of cytogenetic and molecular data was performed in 16 positive patients and was concordant in all of them. We analyzed the response to the prednisone pretreatment and found a higher incidence of poor responders among the BCR/ABL-positive children. Regarding the event-free survival (EFS) of BCR/ABL-positive (0.53) and -negative patients (0.79) after a follow-up of 2 years, significant differences (P < 0.05) between both groups could be demonstrated.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Base Sequence; Child; Child, Preschool; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Fusion Proteins, bcr-abl; Germany; Humans; Incidence; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mercaptopurine; Methotrexate; Molecular Sequence Data; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Transcription, Genetic; Translocation, Genetic; Vincristine

Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biogenic Amines; Biopterins; Brain Chemistry; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cytarabine; Dihydropteridine Reductase; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Infant; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Nerve Tissue Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Infection Control; Male; Mercaptopurine; Methotrexate; Middle Aged; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Recombinant Proteins; Remission Induction; Survival Analysis; Treatment Outcome

The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Synergism; Etoposide; Humans; Infant; Karyotyping; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone

To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy.. Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients.. Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group.. Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Regression Analysis; Remission Induction; Survival Analysis; Vincristine

A retrospective analysis was performed on forty nine elderly (34 males and 15 females) patients aged 65 years or more (median age 73, range 65-82) with acute non-lymphocytic leukemia (ANLL). Patients were studied to examine factors according to age group (65-69 years, 70-74, 75-79 and 80 or over), respectively. Patients were treated with either low dose Ara-C therapy or BHAC-DMP therapy according of the choice of their attending physicians. Complete remission (CR) was obtained in 20 of 49 patients (43%), and in 6 of 14 patients (43%) aged 65-69, in 8 of 18 (44%) aged 70-74, in 5 of 12 (42%) aged 75-79 years and in 1 of 3 (33%) aged 80 or over, respectively. The median survivals of these groups were 263, 298, 260, 168.5 and 38.5 days, respectively. Multivariate analysis revealed that the achievement of CR was associated with normal karyotype, and serum GOT level < or = 30 mu/ml and GPT < or = 40 mu/ml. Prolonged survival was related to the achievement of CR. The results indicated that liver function before chemotherapy was an important prognostic factor.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Survival Rate

The goal of this phase II multicenter clinical trial was to evaluate a new intensive chemotherapy program for adults with untreated acute lymphoblastic leukemia (ALL) and to examine prospectively the impact of clinical and biologic characteristics on the outcome. One hundred ninety-seven eligible and evaluable patients (16 to 80 years of age; median, 32 years of age) received cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase; 167 patients (85%) achieved a complete remission (CR), 13 (7%) had refractory disease, and 17 (9%) died during induction. A higher CR rate was observed in younger patients (94% for those < 30 years old, 85% for those 30 to 59 years old, and 39% for those > or = 60 years old, P < .001) and in those who had a mediastinal mass (100%) or blasts with a T-cell immunophenotype. Eighty percent of B-lineage and 97% of T-cell ALL patients achieved a CR (P = .01). The coexpression of myeloid antigens did not affect the response rate or duration. Seventy percent of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 84% of those without such evidence achieved a CR (P = .11). Patients in remission received multiagent consolidation treatment, central nervous system prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. After a median follow-up time of 43 months, the median survival for all 197 patients is 36 months; the median remission duration for the 167 CR patients is 29 months. Favorable pretreatment characteristics relative to remission duration or survival are younger age, the presence of a mediastinal mass or lymphadenopathy, a white blood cell count (WBC) less than 30,000/microL, L1 morphology, T or TMy immunophenotype, and the absence of the Ph chromosome. The estimates of the proportion surviving at 3 years are 69% for patients less than 30 years old, 39% for those 30 to 59 years old, 89% for those who had a mediastinal mass, 59% with WBC less than 30,000/microL, 63% with L1 morphology, 69% for T or TMy antigen expression, and 62% for those who lack the Ph chromosome. Fifteen patients (8%) had no unfavorable prognostic factors and have an estimated probability of survival at 5 years of 100% (95% confidence interval, 77% to 100%). This intensive chemotherapy regimen produces a high remission rate and a high proportion of durable remissions in adults with ALL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Female; Humans; Immunophenotyping; Life Tables; Male; Mercaptopurine; Methotrexate; Middle Aged; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Remission Induction; Risk Factors; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine

This trial evaluated the toxicity and preliminary efficacy of a repeated oral low dose (LD) methotrexate schedule with intravenous mercaptopurine infusions as intensification therapy for children with lower risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS. From December 1986 to January 1991, 96 children with newly diagnosed, lower risk ALL were enrolled. Vincristine, L-asparaginase, and prednisone were used for remission induction. Age-based methotrexate was administered intrathecally (IT) for central nervous system (CNS) prophylaxis. An outpatient-based intensification treatment included LD methotrexate 30 mg/M2 every 6 hours for 5 doses, followed by intravenous mercaptopurine 1000 mg/M2 for 6 hours every 2 weeks for 12 courses. Leucovorin rescue was administered 48 hours after methotrexate treatment was begun. Maintenance therapy included standard daily oral mercaptopurine, weekly intramuscular methotrexate, and IT methotrexate every 12 weeks, for 2 years.. All patients had disease remission. Thirty-two patients relapsed; there were 17 isolated bone marrow relapses, 10 isolated CNS relapses, 2 isolated testicular relapses, 1 marrow plus CNS relapse, 1 marrow plus testicular relapse, and 1 CNS plus testicular relapse. Event free survival (EFS) at 4 years was 66% (standard error, 7%) by Kaplan-Meier analysis. Complications associated with LD methotrexate/mercaptopurine courses were few and resulted in hospital readmissions in 2.4% of courses. Two patients were unable to comply with the oral LD methotrexate schedule and received intravenous methotrexate. Three patients were unable to complete scheduled maintenance because of hepatic or hematopoietic dysfunction.. Low dose methotrexate/mercaptopurine can be administered safely on an outpatient basis to children with lower risk B-lineage ALL. However, there was a higher than expected incidence of bone marrow and CNS relapse. The reasons for this outcome were not completely clear but raise the possibility that LD methotrexate therapy may be less effective in preventing relapse than are higher dose, parenteral methotrexate regimens.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Central Nervous System Neoplasms; Child; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Treatment Outcome; Vincristine

A multicenter prospective study was conducted in 114 children with acute lymphoblastic leukemia receiving 4 intravenous methotrexate (MTX) courses (5 g/m2 as a 24 hour-infusion) to determine the diffusion of MTX in cerebrospinal fluid (CSF) and to correlate the drug levels to central nervous system (CNS) relapse occurrence. Serum and CSF levels were measured at the end of 446 MTX courses. A significant correlation was found between CSF and serum MTX concentration. CSF MTX level was greater than 1 mumol/l in 66% of the courses. Twelve patients (11%) failed to achieve this potentially cytotoxic drug level at the end of the 4 consecutive MTX courses: only one CNS relapse was observed and the mean age of these children was lower than that of the others. To date 9 (7.8%) children had CNS relapse and no difference was observed in terms of CSF MTX levels when compared to data of children free of CNS relapse. With a median follow up of 32 months, pharmacokinetic data during high-dose MTX therapy do not seem to be an exclusive predictive factor of CNS relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Child; Child, Preschool; Cytarabine; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors

Sixty-one consecutive patients with acute lymphoblastic leukemia (ALL) (B-ALL excluded) were treated with the protocol described by Hoelzer et al. [15]. The complete remission (CR) rate was 85% (52/61 patients). Three patients died during induction therapy; six patients were refractory to treatment. The median duration of continuous complete remission (CCR), disease-free survival (DFS), and overall survival was 41.5, 41.4, and 40.8 months, respectively. At 5 years the probability of CCR was 49%, of DFS 43.5%, and of overall survival 41.6%. In the univariate analysis older age (> 35 years, p = 0.01), bcr-abl positivity (p = 0.007), and time to CR (> 4 weeks, p = 0.05) were significantly unfavorable prognostic factors. In the multivariate analysis only age (p = 0.006) and time to CR (p = 0.02) remained significant. Thus, our data confirm the high efficacy of this treatment regimen with regard to CR rate and remission duration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Austria; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Male; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Remission Induction; Vincristine

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Vincristine

Topics: Child; Drug Interactions; Female; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

The Children's Cancer and Leukemia Study Group (CCLSG) has conducted, since 1981, a series of protocols for treatment of acute lymphoblastic leukemia (ALL) in childhood. In a randomized control study of the 811 protocol (1981-1983) for standard-risk ALL, an intermittent cyclic regimen of an intermediate-dose of methotrexate (MTX) plus 6-mercaptopurine (6MP) showed significant superiority for maintenance chemotherapy as compared with conventional continuous administration of a low dose of the two drugs. The event-free survival (EFS) rate at 10 years was 65.4% for the intermittent cyclic regimen, while the EFS rate of continuous regimen was 36.1% (P < 0.01). The intermittent cyclic regimen may also be effective in preventing extramedullary relapses. In the 841 protocol (1984-1987), the three-drug induction therapy consisting of vincristine (VCR), prednisone (PDN) and L-asparaginase (L-ASP) improved the EFS rate (94.1% at 8 years) as compared with the two-drug therapy consisting of VCR and PDN (64.1%, P < 0.05). In the 874 protocol (1987-1990) two regimens with or without cranial irradiation for standard-risk patients were compared with respect to their ability to prevent central nervous system (CNS) leukemia and to improve overall outcome of ALL. The regimen with cranial irradiation showed a 79.9% EFS rate at 5 years, whereas the regimen without cranial irradiation demonstrated a 69.1% EFS rate (not significantly). Life-table analysis of serial CCLSG protocols for ALL in which the cyclic administration of intermediate-dose MTX plus 6MP has been standardized as maintenance therapy revealed that the outcome of allover ALL has gradually improved with increase of the EFS rate; 41.4% for the 811 protocol, 51.4% for the 841 protocol to 54.4% for the more recent 874 protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Japan; Life Tables; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate

This phase I/II study was designed to explore the feasibility, toxicity, and potential efficacy of administering high-dose continuous intravenous mercaptopurine (6MP) followed by intermediate-dose continuous intravenous cytarabine (Ara-C) to children with relapsed or unresponsive acute leukemia.. Twenty-three children with relapsed or unresponsive acute leukemia (13 myeloid, 10 lymphoid) were entered onto the study. After initial hydration and alkalinization, 1,000 or 1,250 mg/m2 of 6MP was administered by continuous intravenous infusion over 24 hours. Following another period of hydration, 500 mg/m2 of Ara-C was administered by continuous intravenous infusion daily for 4 days. In 17 children, plasma concentrations of 6MP were measured at hours 4, 24, and 27 of the 6MP infusions. Plasma concentrations of Ara-C were measured at hours 8, 24, 48, 72, and 96 of the Ara-C infusions. Intracellular Ara-C triphosphate (Ara-CTP) concentrations were measured in peripheral-blood leukemia cells of the five patients with sufficient cells for measurement. Children who developed remission received repeated courses of this regimen every 3 to 4 weeks until relapse or completion of 12 courses.. Of 13 children with acute myeloid leukemia (AML), six developed complete remissions (CRs) lasting 7 months to nearly 4 years. Two children remain in CR with normal growth, development, and health 3 years after cessation of treatment. Of 10 children with acute lymphoid leukemia (ALL), one had a CR of 2 months' duration. Dose-limiting toxicity consisted of severe hematosuppression with fever, neutropenia, and serious infection. There were two toxic deaths. The mean steady-state plasma concentrations of 6MP were approximately 4 mumol/L and of Ara-C approximately 3 mumol/L. The median Ara-CTP concentration in peripheral-blood leukemia cells was 308 mumol/L at hour 8 of the Ara-C infusion.. High-dose continuous intravenous 6MP followed by intermediate-dose intravenous Ara-C produced CRs of longer than 6 months in approximately half of children with relapsed or unresponsive AML. Further study of this drug regimen is justified.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Feasibility Studies; Female; Humans; Infusions, Intravenous; Leukemia, Myeloid; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Treatment Outcome

The MRC UKALL IX trial for patients with untreated ALL aged 14 years and over was open to new patients from July 1980 to April 1985. 266 patients were randomized between two induction schedules. M (involving intermediate dose methotrexate with folinic acid rescue) and D (involving daunorubicin). Schedule M resembled that used in the previous MRC adult ALL trial (UKALL VI), while schedule D was somewhat more intensive. No difference in disease-free survival was found between the treatment arms, but patients on the daunorubicin arm went into remission earlier. The overall remission rate was 87%, which is at least as good as in contemporary studies elsewhere; factors predictive of a lower remission rate were older age and higher WBC. For those who entered remission. WBC, age and sex were the most important prognostic factors. Time to achieve remission was not a significant factor after allowance was made for these. An historical comparison does not show any improvement over the preceding MRC adult trial, although the subsequent trial does show a modest improvement at present. Because the improved outlook seen in children is not apparent in adults, and no other randomized trial has demonstrated substantial benefit for any particular regimen, the next trial, UKALL XII, will be investigating the benefit or otherwise of bone marrow transplantation.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Daunorubicin; Female; Follow-Up Studies; Humans; Leucovorin; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Sex Factors; Vincristine

The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.

Topics: Adolescent; Child; Erythrocytes; Female; Humans; Kinetics; Male; Mercaptopurine; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thrombocytopenia; Time Factors

The evolution of 118 children treated for acute lymphoblastic leukemia between 1976 and 1984, and followed until 1991, was reviewed. Maintenance chemotherapy consisted of daily 6-mercaptopurine (6-MP), weekly methotrexate (MTX), and monthly vincristine and prednisone. Eighty-two children took 6-MP and MTX in the morning, and 36 took them in the evening. Disease-free survival, as determined by Kaplan-Meier analysis, was better for children on evening chemotherapy. Regression analysis (Cox proportional hazards model, with evening versus morning schedule as exposure variable, and age at diagnosis, leucocytosis at diagnosis, and sex as covariates) showed that for those surviving free of disease for longer than 78 weeks, the risk of relapse was 2.56 times greater for the morning schedule than for the evening one.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Circadian Rhythm; Drug Administration Schedule; Follow-Up Studies; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Proportional Hazards Models; Recurrence; Regression Analysis; Survival Analysis; Time Factors; Vincristine

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Mediastinum; Mercaptopurine; Methotrexate; Middle Aged; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Remission Induction; Survival Analysis; Teniposide; Vincristine

Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Infusions, Intravenous; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Survival Analysis; Vincristine

Ninety-five unselected patients with stage III and IV T cell lymphoblastic lymphoma were treated according to the United Kingdom Children's Cancer Study Group protocol 8503. This was a continuous, intensive leukaemia type regimen including cranial irradiation (18 Gy in 10 fractions) and continuing chemotherapy for 2 years identical to the concurrent Medical Research Council ALL protocol. Four-year event-free survival was 65% (95% CI 50-80%) with no significant difference between stage III and stage IV cases. 4.2% of patients died of infection or non-tumour related events. Following relapse salvage was unlikely without high dose chemotherapy and bone marrow rescue. These results show an improvement over previous U.K. studies but we need to continue to search for subsets of patients with resistant disease for whom even more intensive therapy possibly combined with bone marrow rescue is required.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Daunorubicin; Humans; Infant; Mercaptopurine; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Vincristine

Serum levels of IgG subclasses were measured in 18 children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy and in 36 age-matched controls in order to attempt to analyse the effects of chemotherapy. The IgG subclasses were measured by enzyme linked immunosorbent assay. Serum IgG1, IgG2 and IgG4 levels in the patients were significantly (p less than 0.01, p less than 0.005, p less than 0.005) lower than in the controls, but serum IgG3 levels in patients were as high as in controls. Suppression on IgG2 and IgG4 were more profound than IgG1. In six children, the levels of the IgG subclasses were measured at diagnosis, during maintenance chemotherapy and one year after cessation of chemotherapy. The levels of the four IgG subclasses at diagnosis and after cessation of chemotherapy were as high as those in control children except for the IgG4 levels in the post-chemotherapy group. IgG2 and IgG4 may be more susceptible to suppression by chemotherapy than IgG1 and IgG3 may not be suppressed by chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dysgammaglobulinemia; Female; Humans; IgG Deficiency; Immune Tolerance; Immunoglobulin Fragments; Immunoglobulin G; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6MP) in patients with refractory leukemia was performed. The dosing schedule, 50 mg m-2 h-1 for 48 h, was based on the results of a previous phase I trial of this approach. Among the 40 children treated for acute lymphoblastic leukemia (ALL), all of whom had received prior therapy with oral 6MP, 1 complete and 1 partial response were achieved. No response was observed in 17 patients with refractory acute nonlymphocytic leukemia (ANLL). Reversible hepatotoxicity, the primary dose-limiting toxicity, was observed in approximately 50% of cases. Mucositis was encountered infrequently and was usually not severe. 6MP given on the present continuous intravenous infusion schedule overcomes the limited and variable bioavailability of oral 6MP but shows limited activity as induction agent in children with recurrent ALL.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Plasma levels and the area under the plasma concentration-time curve (AUC) values of 6-mercaptopurine (6-MP) were determined in a balanced crossover study of oral (powder) and rectal (macrogol suppository) administration to 5 children with acute lymphoblastic leukaemia (ALL). The AUC (538.6 ng.h.ml-1) after the rectal dose of 30 mg/m2 was approximately 1.5-times of that (365.5 ng.h.ml-1) after the oral dose of 87.5 mg/m2. The coefficients of variation of interindividual variability of the AUCs were 21.5% and 32.3%, respectively. The relative bioavailability of the macrogol suppository compared to the powder was approximately 4.39. These findings indicate that rectal administration of 6-MP could avoid the first-pass effect of this drug in the alimentary canal and/or liver, resulting in a large AUC of 6-MP, and so could reduce interindividual variability in plasma 6-MP concentrations. Rectal administration of 6-MP may be more effective than empirical oral dosing for the treatment of children with ALL, especially for patients with nausea and/or vomiting.

Topics: Administration, Oral; Administration, Rectal; Adolescent; Biological Availability; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Using the CCLSG-S811 protocol for children with standard-risk acute lymphoblastic leukemia (ALL), late intensification therapy (LIT) with high-dose methotrexate (HD-MTX) was conducted without randomization. Of 118 eligible patients, 114 attained complete remission and 82 maintained continuous complete remission (CCR) for at least 3 years, completing the entire S811 regimen. Among the latter, 74 patients received LIT with HD-MTX between 2-3 years after CCR onset. MTX (2,000 mg/m2 per dose per week) was administered by 24 h infusion and three doses were given every 12 weeks. Leucovorin rescue (15 mg/m2 i.v.) every 6 h was initiated 12 h after the end of MTX infusion for seven doses. As regular maintenance chemotherapy, intermittent (Regimen A) or continuous (Regimen B) MTX plus 6-mercaptopurine (6MP) combined with pulses of prednisolone and vincristine was administered (Koizumi S, Fujimoto T, Takeda T, et al. Cancer 1988; 61: 1292-1300). Retrospective analysis revealed that patients on Regimen A who started LIT earlier (within 2 years of CCR onset (n = 23)) showed a higher rate of event-free survival (EFS) at 8 years (95.5% +/- 4.4%, mean +/- S.E.) than patients who started LIT later (2.5 years after CCR onset (n = 18, 66.2% +/- 11.3%, p less than 0.01)). In addition, the superiority of four or five courses of the LIT (n = 39) as compared to 2 or 3 courses (n = 35) was noted for both regimens. The data suggest that early and aggressive LIT with HD-MTX may improve the long-term survival of childhood ALL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cranial Irradiation; Humans; Infant; Leucovorin; Life Tables; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Survival Rate; Vincristine

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.

Topics: Asparaginase; Brain; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Infant; Injections, Spinal; Intelligence; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiation-Protective Agents; Radiation, Ionizing; Radiography; Radiotherapy; Regression Analysis; Vincristine

We report the safety and efficacy of 34 consecutive autologous bone marrow transplant (ABMT) procedures performed in adult patients with high-grade lymphoid malignancy after remission induction therapy. Fifteen patients with acute lymphoblastic leukemia (ALL) and six with high-grade non-Hodgkin's lymphoma (NHL) received pretransplant conditioning with intravenous (IV) melphalan and fractionated total body irradiation (TBI). Thirteen other patients with NHL were conditioned with melphalan alone, having previously received local involved field radiotherapy. Unmanipulated noncryopreserved autologous marrow was reinfused within 48 hours of harvesting. Engraftment occurred in all patients with medians of 10 days of neutropenia (neutrophils less than 0.5 x 10(9)/L), 4-day platelet transfusion requirement, 3 U packed RBC transfusion, and 18 days in hospital posttransplant. There were no procedure-related deaths. Actuarial disease-free survival in the 13 patients with ALL receiving autotransplant early in first remission is 48% with a median follow-up of 3 years. Two other ALL patients who had autotransplants after a period of maintenance therapy also remain in complete remission (CR). These results compare favorably with our 34% disease-free survival (DFS) in 15 allogeneic ALL transplant patients and 21% DFS in 19 patients on standard maintenance after a common induction schedule. No relapses have occurred in the 17 NHL patients transplanted in remission (median follow-up 2 years), but the two NHL patients who developed recurrent disease before ABMT died of progressive disease after temporary responses. We conclude that this method of ABMT results in rapid reengraftment with lack of toxicity and that the conditioning treatment used shows good efficacy against disease. It is applicable in high-grade lymphoid malignancy in first remission, and our results call into question the need for marrow purging in ALL and NHL patients transplanted in first remission.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cryopreservation; Female; Follow-Up Studies; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation, Autologous

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Brain Neoplasms; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Random Allocation; Recurrence; Remission Induction; Survival Rate; Testicular Neoplasms; Vincristine

During the 1970s, despite apparently similar treatment, the prognosis for children with lymphoblastic leukaemia (ALL) improved more in some countries, notably the United States and West Germany, than in others. To find out why, the first phase of the United Kingdom (UK) Medical Research Council (MRC) childhood ALL trial, UKALL VIII, was designed to see whether similar results to the United States Children's Cancer Study Group (CCSG) could be obtained in the U.K. using an identical protocol (CCG 162). Protocol 162 was one of a series of regimens devised by the American Children's Cancer Study Group in the 1970s and was used specifically for their average risk patients (all children with ALL with an initial white cell count up to 50 x 10(9)/l except those aged 3-6 years with white cell counts under 10 x 10(9)/l). One arm (1A) of their study was adopted by the MRC for all children in the U.K. aged 0-14 years with confirmed ALL. Eight hundred and twenty-nine consecutive patients were entered between 1980 and 1984. The first 199 patients formed a single arm study as per the original protocol 162 (arm 1A), but the subsequent 630 children were randomized to receive or not two doses of daunorubicin on the first 2 d of induction. This randomization was an attempt to answer the important question as to whether event-free survival was influenced by the use of four rather than three induction agents. A second randomization between 2 and 3 years continuing therapy was also introduced at this stage as it had been by the CCSG in their protocol. With a minimum follow up period of more than 5 years, disease-free survival for the whole group is 55%, a considerable improvement on all previous UKALL trials. Results for patients directly comparable with those in CCSG 162 ('average risk' patients) and their American counterparts were similar. Daunorubicin was associated with more early deaths but improved disease-free survival for those achieving remission. More children relapsed who stopped treatment after 2 years than those who continued for 3, but this was balanced by increased treatment mortality in the third year. The fact that for UKALL VIII the results were similar to those of the CCSG suggests that previous MRC protocols were not sufficiently sustained and intensive, particularly during the maintenance phase of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Random Allocation; United Kingdom; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cyclophosphamide; Daunorubicin; Dexamethasone; Doxorubicin; Germany, West; Humans; Leucovorin; Life Tables; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Randomized Controlled Trials as Topic; Risk; Survival Rate; Thioguanine; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Germany, West; Humans; Infant; Infant, Newborn; Leukocyte Count; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Randomized Controlled Trials as Topic; Risk; Survival Rate; Teniposide; Thioguanine; Vincristine

Eighty-five consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 24 years (range 10-69 years), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, Adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate and monthly intrathecal therapy, with drug intensification comprising either vincristine, Adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was obtained in 59 patients (69%) and only the French-American-British (FAB) L1 morphology was a significant predictive factor (P = 0.048). Twenty-three patients failed to achieve CR and of these 12 had primary drug resistance. Median follow-up is currently 260 weeks, median predicted survival of all patients is 58 weeks and for those who achieved CR it is 104 weeks. Median duration of CR is 70 weeks. Of the prognostic factors for survival, only FAB L1 subtype was significant. Bone marrow relapses occurred in 29 patients, and of these 9 (31%) achieved CR. There has been CNS relapse in two patients and both have died. Eleven patients continue in CR off therapy, with a median of 152 weeks. This regimen is effective, with acceptable toxicity, and a number of patients are potentially cured. The incidence of resistant and relapsing disease is an argument for further intensifying both induction and postinduction therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Combinations; Drug Evaluation; Humans; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; South Africa; Vincristine

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Child; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Radiotherapy Dosage; Random Allocation; Remission Induction; Sex Factors; Testis; Time Factors; Vincristine

Of 110 previously untreated patients who had entered the study of protocol TCL821, 96 were evaluable. The patients were divided into a standard risk group (Group I) and a high risk group (Group II) depending on their age and leukocyte count at the time of diagnosis. Treatment consisted of a 5-week induction therapy course with prednisolone (PRED), vincristine (VCR) and adriamycin (ADM) followed by central nervous system (CNS) prophylaxis. Maintenance therapy consisted of 6-mercaptopurine (6-MP) plus methotrexate (MTX) for 3 years and 6-MP alone for another 2 years, reinforced with dexamethasone, VCR and ADM or cytosine-arabinoside (Ara-C) or cyclophosphamide (CTX) every 16 weeks for Group I and 8 weeks for Group II for 3 years. Immunologic typing was done in 74 cases which revealed 60.9% of the common acute lymphoblastic leukemia (ALL) type, 14.9% null cell type, 4.0% undifferentiated type, 4.0% Pre-B cell type, 4.0% B cell type, 10.8% Pre-T cell type and 1.4% T cell type. In Group I the complete remission rate (CR) was 100% and the continuous complete remission rate (CCR) was 72.2% with a follow-up duration of 40-73 months. In Group II, both CR and CCR were 92.9% and 45.8% respectively. The incidence of patients with Pre-T cell type was higher in this study than in most other reports, and these patients responded favorably to treatment.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Dexamethasone; Doxorubicin; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Hydrocortisone; Infant; Male; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Taiwan; Vincristine

From 1984 to 1987, 144 previously untreated children with low (LR) or intermediate-risk (IR) acute lymphoblastic leukemia (ALL) were entered in the protocol L 841 or I 841, respectively. The patients in the LR group were randomized to receive regimen A (L 841 A) or B (L 841 B) and the patients in the IR group were randomized to receive regimen B (I 841 B) or C (I 841 C). L 841 A consisted of vincristine (VCR) + prednisone (PDN) for the remission induction phase and 18 Gy cranial irradiation combined with intrathecal methotrexate (MTX) for the central nervous system (CNS) leukemia prophylaxis. The maintenance phase consisted of MTX iv alternating 5-day course of VCR + PDN + 6-mercaptopurine (6MP) at 2 wk-interval. In L 841 B, I 841 B and I 841 C, asparaginase (ASP) was added as a third drug. Adriamycin (ADM) and high-dose MTX (100 mg/kg) were additionally employed in the intensive phase of I 841 C. Thirty-nine, 20, 25 and 49 eligible patients were entered in L 841 A, L 841 B, I 841 B and I 841 C, respectively. The event free survival rate in each regimen was 50.5% +/- 13.7% (M +/- SE), 100% +/- 6.0% (p less than 0.01), 72.7% +/- 9.8% and 40.7% +/- 13.2% (p less than 0.1) at 4 years, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Female; Humans; Infant; Japan; Male; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Randomized Controlled Trials as Topic; Remission Induction; Risk Factors; Vincristine

Plasma concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Ten children (nine with acute lymphatic leukemia) were studied on 2 consecutive days after oral intake of 6-MP. On one day the drug was administered in the fasting state and on the other (in random order) together with breakfast. The peak plasma concentrations of 6-MP after the dose intake with breakfast in percent of that in the fasting state (meal in % of fasting for each individual) varied between 33 and 181% (mean 111), and the area under the plasma concentration-time curve varied between 47 and 186% (mean 103). Thus, there were considerable variations among patients, but, for the group as a whole, there were no statistically significant differences between the two experimental conditions. This study cannot therefore form the basis for a recommendation as to whether 6-MP should be administered on an empty stomach or together with food.

Topics: Administration, Oral; Adolescent; Biological Availability; Child; Child, Preschool; Drug Administration Schedule; Fasting; Female; Food; Hodgkin Disease; Humans; Intestinal Absorption; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Four hundred thirty patients with high-risk acute lymphoid leukemia were entered on the acute leukemia in childhood protocol (AlinC 12) of the Pediatric Division of the Southwest Oncology Group (now the Pediatric Oncology Group) between 1976 and 1979. This study was a prospective randomized comparison of two regimens that had as their primary differences: (1) an intensification period with Cytoxan (cyclophosphamide) and asparaginase after induction; (2) a period of intravenous methotrexate before initiating maintenance; and (3) in the regimen that had those two additions, triple-drug chemoprophylaxis of the central nervous system (CNS) using methotrexate, hydrocortisone, and cytosine arabinoside as compared to cranial irradiation and intrathecal methotrexate. All patients received vincristine and prednisone induction, 6-mercaptopurine and methotrexate maintenance, and vincristine and prednisone pulse intensification. There was no significant difference in the rate of bone marrow relapse. However, overall disease-free survival favored the arm with intensification and chemoprophylaxis because of a lesser incidence of extramedullary relapse. Thus, for treatment 1 versus treatment 3 the two-sided P values were for overall disease-free survival 0.16; bone marrow relapses 0.13; all CNS relapses 0.04; and all extramedullary disease relapses 0.013. It is concluded that intensification as delivered in this protocol protects against testicular relapse and that chemoprophylaxis is adequate prophylaxis against isolated CNS relapse.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Humans; Hydrocortisone; Infant; Infant, Newborn; Infections; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prospective Studies; Random Allocation; Remission Induction; Vincristine

229 children with acute lymphoblastic leukaemia (ALL) and with clinical and laboratory features associated with a high risk of treatment failure entered a randomised study of three treatment regimens. Before 1981, such patients had a 3-year event-free survival (EFS) of 47%. Two intensive therapies, the Berlin-Frankfurt-Munster (BFM) 76/79 regimen and the New York (NY) regimen were compared with a control regimen that had achieved the best outcome in previous Trials. Data on 214 cases (93.4%) were analysed. The 3-year EFS was 78% for the BFM and NY regimens and 49% for the control regimen, a significant difference. The differences persisted after stratification by age at onset, sex, white blood cell count at diagnosis, and marrow blast morphology. Control patients were 2.7 times more likely to fail induction, to die, or to relapse than were patients on the intensive regimens.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Drug Combinations; Female; Humans; Infant; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Radiotherapy Dosage; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

This paper reports the results of a multicentric randomized clinical trial on the treatment of first hematological relapse in childhood ALL. Induction treatment consisted of vincristine, adriamycin, L-asparaginase, and prednisone. Patients achieving complete remission were randomized to two maintenance regimens (A and B). Regimen A consisted of five different drug associations including VM26 and IDMTX in a sequential schedule; Regimen B was essentially classical Spiers schedule for the first year, followed by a milder treatment. Eighty-four of 102 evaluable patients (82%) achieved second complete remission. The two maintenance regimens were similar as regards duration of second complete remission (median duration A, 32 weeks; B, 37 weeks) and toxicity. Better results were obtained in patients relapsing after 12 months from suspension of treatment in first complete remission than in those relapsing within the first year off therapy (82.8% vs. 31.4%). In group A fewer CNS relapses were reported. The two regimens produced results similar to those reported by other authors. The good prognosis in patients relapsing at least 1 year after treatment suspension in first complete remission must be emphasized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Combinations; Humans; Italy; Life Tables; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Survival Rate; Thioguanine; Vincristine

Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric patients with acute lymphoblastic leukemia (ALL). NUDT15 variants have emerged as major determinants of mercaptopurine intolerance, especially in the Asian population. Two variants, c.55_56insGAGTCG in exon 1 and c.415C > T in exon 3, were commonly detected in the same allele, named NUDT15*1/*2. Although rare, compound heterozygous mutations also occur, with the two variants on different alleles (NUDT15*3/*6), which may confer tolerance to considerably lesser mercaptopurine dosage. Sanger sequencing or pyrosequencing can determine the NUDT15 variants but not the phase. Here, we designed an allele-specific PCR (AS-PCR) with locked nucleic acid-modified primers. A cohort of 63 patients harboring heterozygous c.55_56insGAGTCG and c.415C > T NUDT15 variations was selected for haplotyping using AS-PCR. Of the 63 patients, 60 harbored the NUDT15*1/*2 variant and three harbored compound heterozygous mutations, including two NUDT15*3/*6 and one NUDT15*2/*7 variants. These findings suggest that AS-PCR can determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants, which may enable precise genetic diagnosis of NUDT15. Nevertheless, a larger clinical trial is required to understand the clinical significance of NUDT15*3/*6 in pediatric patients with ALL because of its low incidence rate and challenges in detecting this variant.

Topics: Alleles; Antimetabolites, Antineoplastic; Child; Humans; Mercaptopurine; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Female; Humans; Hypoglycemia; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine-dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine-associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio = 7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46-fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio = 8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype-guided dose adjustment to reduce toxicity.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Cohort Studies; Humans; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine is a crucial component in the treatment of acute lymphoblastic leukemia. It is associated with toxicities that can delay treatment. Mercaptopurine is metabolized into 6-thioguanine nucleotides and 6-methylomercaptopurine nucleotides (6MMPN). Accumulation of 6MMPN has previously been associated with hepatotoxicity, pancreatitis, and hypoglycemia. However, skin toxicity has rarely been reported. We report 5 cases of elevated 6MMPN levels associated with cutaneous manifestations.

Topics: Antimetabolites, Antineoplastic; Child; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Skin Diseases; Thioguanine

The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Topics: Child; Humans; Incidence; Mercaptopurine; Poverty; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

Topics: Chemical and Drug Induced Liver Injury; DNA Polymerase gamma; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Valproic Acid

Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Zimbabwe

The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation.. In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia.. A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase.. During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461-4.200, p = 0.001).. In conclusion, child's age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

Topics: Child; Cohort Studies; Ethiopia; Humans; Incidence; Mercaptopurine; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults. Historically, this patient group has been treated using adult-based regimens, which entails a high rate of treatment-related mortality and a poor overall survival (OS). The use of the CALGB 10403, a pediatric-inspired regimen, has been proven effective in this patient subgroup. Nonetheless, low- and middle-income countries (LMICs) may present limited access to standard care treatments implemented elsewhere, warranting the need for further research to improve outcomes among vulnerable populations. In this study, we present the outcomes in terms of safety and effectiveness of using a modified CALGB 10403 regimen to reflect drug and resource availability in LMICs. Modifications included the use of Escherichia coli asparaginase,6-mercaptopurine instead of thioguanine and the use of rituximab among patients with CD20+. A total of 95 patients with a median age of 23 (range, 14-49) years treated with this modified scheme were prospectively assessed at 5 centers in Mexico and 1 in Guatemala. Among these, 87.8% achieved a complete response after induction. During follow-up, 28.3% of patients relapsed. Two-year OS rate was 72.1%. Factors associated with worse OS included hyperleukocytosis (hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.81-10.10) and postinduction minimal residual disease (HR, 4.67; 95% CI, 1.75-12.44). Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation, respectively), and the treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.

Topics: Adolescent; Adult; Asparaginase; Humans; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Rituximab; Young Adult

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic-pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukocyte Count; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute lymphoblastic leukemia (ALL), the anti-inflammatory effect of mercaptopurine (6-MP) and the impact of gut microbiome changes caused by 6-MP on anti-inflammasome remain unclear.. We aimed to explore the association between 6-MP therapeutic effects and microbiome-involved inflammatory responses in ALL mice models.. ALL murine model was built by i.v. injecting murine L1210 cells into DBA/2 mice (model group). Two weeks after cell injections, 6-MP was orally administrated for 14 days (6-MP group). Fecal samples of mice were collected at different time points. Cecum short-chain fatty acids (SCFAs) concentrations were determined by LC-MS/MS method. Serum cytokines were measured using a cytometric bead array. Gut microbiota composition in mice was explored using 16S rRNA gene sequencing.. The anti-tumor effect of 6-MP was proved in ALL mice models. The levels of pro-inflammatory factors IL-6 and TNFα significantly decreased after the administration of 6-MP. Cecum contents' acetate, propionate, and butyrate levels were negatively correlated with IL-6 (correlation coefficient: acetate, -0.24; propionate, -0.26; butyrate, -0.17) and TNFα (correlation coefficient: acetate, -0.45; propionate, -0.42; butyrate, -0.31) changes. Relative abundance changes of f_Lachnospiraceae.g_ASF356 and f_Peptococcaceae.g_uncultured were in accordance with the changes of butyrate levels and opposite to the changes of pro-inflammatory levels.. The anti-inflammatory response of 6-MP influenced by intestinal microbiota and its metabolites SCFAs, especially butyrate, played an essential role in improving ALL progression.

Topics: Acetates; Animals; Anti-Inflammatory Agents; Butyrates; Chromatography, Liquid; Fatty Acids, Volatile; Interleukin-6; Mercaptopurine; Mice; Mice, Inbred DBA; Microbiota; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Propionates; RNA, Ribosomal, 16S; Tandem Mass Spectrometry; Tumor Necrosis Factor-alpha

High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain.. We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs.. Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3%. Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Topics: Asparaginase; Humans; Mercaptopurine; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Trisomy

Persistently elevated absolute neutrophil counts during maintenance for acute lymphoblastic leukemia is a risk factor for relapse and may be related to wild-type thiopurine methyltransferase activity and overly efficient shunting of 6-mercaptopurine to hepatotoxic metabolites (6-methylmercaptopurine nucleotides), leading to low 6-thioguanine nucleotides. 6-mercaptopurine is also metabolized by xanthine oxidase, and therefore allopurinol, an inhibitor of xanthine oxidase, allows for increased 6-thioguanine nucleotides and decreased 6-methylmercaptopurine nucleotide. Here, we report our experience with allopurinol for persistently elevated absolute neutrophil count or hepatotoxicity and suggest an algorithmic approach for checking thiopurine metabolites and initiating allopurinol in acute lymphoblastic leukemia maintenance.

Topics: Allopurinol; Child; Humans; Mercaptopurine; Nucleotides; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Xanthine Oxidase

Topics: Acute Disease; Antimetabolites, Antineoplastic; Factor V Deficiency; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antimetabolites, Antineoplastic; Child; China; Humans; Mercaptopurine; Methyltransferases; Multidrug Resistance-Associated Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

The cost-effectiveness of NUDT15 genetic testing-guided initial 6-mercaptopurine (6-MP) dosing in children with acute lymphoblastic leukemia (ALL) was evaluated.. A decision tree model was used to evaluate the cost to China's medical system per quality-adjusted life-year (QALY) gained and cost per case of severe leukopenia avoided of NUDT15 genetic testing using public clinical data.. Genetic testing-guided initial 6-MP dosing reduced overall costs by $518.61, and prevented 0.221 cases of Grade III-IV leukopenia and increased QALY by 0.00136 per patient. Results were robust in one-way analyses and probabilistic sensitivity analyses.. NUDT15 genetic testing prior to the initial administration of 6-MP in pediatric ALL patients in China is less expensive than standard dosing without genetic testing.

Topics: Antimetabolites, Antineoplastic; Child; China; Cost-Benefit Analysis; Genetic Testing; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Quality-Adjusted Life Years

In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Incidence; Infant; Japan; Male; Mercaptopurine; Osteonecrosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Retrospective Studies; Vincristine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15

Topics: Asian People; Child; Genotype; Humans; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

6-mercaptopurine is a chemotherapeutic drug that exhibits hepatotoxic effects due to its toxic metabolites. This report describes a case of suspected drug-induced liver injury exacerbated by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 16-year-old male with very high risk B-cell acute lymphoblastic leukemia was admitted for hyperbilirubinemia 2 months after a 6-mercaptopurine dosage increase and found to have an active SARS-CoV-2 infection. Liver function improved throughout hospitalization and the patient was discharged on allopurinol. Following liver function after a dosage increase of hepatoxic chemotherapy and in a pediatric oncology patient with an active SARS-CoV-2 infection undergoing treatment is vital due to potential liver impact.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; COVID-19; COVID-19 Drug Treatment; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; SARS-CoV-2

6-mercaptopurine is a mainstay of acute lymphoblastic leukemia treatment. It has a narrow therapeutic window, dictated by its metabolite, thioguanine and 6-methylmercaptopurine. Skin manifestations usually consist of mild facial rash or hypersensitivity exanthems. We report a child who developed a painful acral rash and mucositis while undergoing maintenance therapy for B-cell acute lymphoblastic leukemia without infectious or known drug etiology. Thiopurine metabolites were skewed toward 6-methylmercaptopurine. Two weeks after allopurinol was added and 6-mercaptopurine (6-MP) dose adjusted, the cutaneous manifestations and other constitutional symptoms resolved. We posit that the rash was because of 6-MP toxicity related to skewed metabolism, adding to the growing list of toxicity related to altered 6-MP metabolism.

Topics: Allopurinol; Burkitt Lymphoma; Child; Exanthema; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Topics: Acute Disease; Burkitt Lymphoma; Chemical and Drug Induced Liver Injury; COVID-19; COVID-19 Drug Treatment; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; SARS-CoV-2

Mercaptopurine (6-MP) is an indispensable, first-line, drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, 6-MP has several intrinsic drawbacks, such as large individual variability in the drug response, undesirable adverse reactions, and drug resistance in patients with release ALL, which requires therapeutic drug monitoring (TDM). Several studies analyzed the total concentration of thiopurine nucleotides in red blood cells (RBCs) after hydrolysis, and two studies detected them separately and accurately by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we developed a rapid and robust LC-MS/MS method for simultaneous quantitation of mono-, di-, and triphosphates of thioguanosine and methylthioinosine. Not only EDTA and DTT were added, but also EHT1864, a new Rac family small GTPases inhibitor, was innovatively added to ensure the stability of the analytes. Commercial availability and relatively low cost compound methotrexate-D3 was selected as internal standards. The linearity, accuracy, precision, recovery, matrix effect and stability of the method were all in line with the guidelines. This method provide an accurate and robust new solution for the determination of 6 metabolites of MP in RBCs from ALL patients with maintenance therapy.

Topics: Child; Chromatography, Liquid; Humans; Mercaptopurine; Methylthioinosine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tandem Mass Spectrometry

6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

Topics: Antibodies, Monoclonal; Child; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Thioguanine

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, β = -10.99, p = 3.7 × 10

Topics: Antimetabolites, Antineoplastic; Child; Genome-Wide Association Study; Humans; Japan; Mercaptopurine; Methyltransferases; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.. Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.

Topics: 5'-Nucleotidase; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Humans; Mercaptopurine; Methotrexate; Outpatients; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

To avoid toxicity, patients with inherited intolerance to thiopurines require major dose reductions of six mercaptopurine (6MP) for acute lymphoblastic leukaemia (ALL) maintenance treatment. Germline variants in the NUDT15 gene are emerging as the most common cause of 6MP intolerance in East Asian populations. New approaches are being developed to identify susceptibility to 6MP toxicity in order to appropriately tailor dosing schedules for at-risk patients. Commentary on: Tanaka et al. Prominence of NUDT15 genetic variation associated with 6-mercaptopurine tolerance in a genome-wide association study of Japanese children with acute lymphoblastic leukaemia. Br J Haematol 2022;199:260-269 and Yoshida et al. Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance. Br J Haematol 2022;199:270-276.

Topics: Asian People; Child; Genome-Wide Association Study; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

An 18-year-old male was admitted for his second induction chemotherapy treatment for an acute lymphoblastic leukaemia with cyclophosphamide, cytarabine, and mercaptopurine. He presented with high fever, abdominal pain, non-bloody diarrhoea, portal hypertension and leukopenia. Stool sample analysis, blood cultures and extensive work-up were negative. The only microbiologic evidence was the presence of cytomegalovirus DNA detected by PCR. A profound hypogammaglobulinemia was documented. Pathology material reported non-caseating granulomas in liver, bone marrow, duodenum and colon with negative cytomegalovirus immunostaining. What is your diagnosis?. Un varón de 18 años se internó para recibir el segundo ciclo de inducción por una leucemia linfoblástica aguda con ciclofosfamida, citarabina y mercaptopurina. Desarrolló fiebre alta, dolor abdominal, diarrea no sanguinolenta, hipertensión portal y leucopenia. El análisis de materia fecal, cultivos de sangre y una evaluación exhaustiva fueron negativas. La única evidencia microbiológica fue la detección de ADN de citomegalovirus en sangre por PCR. También se documentó una hipogamaglobulinemia profunda. El material de patología reportó granulomas no caseificantes en hígado, médula ósea, duodeno y colon con inmunohistoquímica negativa para citomegalovirus. ¿Cuál es su diagnóstico?

Topics: Adolescent; Cyclophosphamide; Cytarabine; Fever of Unknown Origin; Granuloma; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there is an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects are associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgamma

Topics: Adult; Animals; Humans; Mercaptopurine; Methotrexate; Mice; Mice, Inbred NOD; Panobinostat; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P<0.0001 for the standard- risk arm), cytarabine (P<0.0001 for the standard-risk arm), and mercaptopurine (P<0.0001 for the low-risk arm and P<0.0001 for the standardrisk arm). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than on T15 (P<0.0001 for both the low-risk and standard-risk arms), with higher dose-intensity for mercaptopurine in those with anti-asparaginase antibodies than in those without (P=5.62x10-3 for T15 standard risk and P=1.43x10-4 for T16 standard risk). Neutrophil count did not differ between protocols for low-risk patients (P=0.18) and was actually lower for standard-risk patients on T16 than on T15 (P<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase dose intensity had higher methotrexate dose intensity with no impact on prognosis. The only dose intensity measure predicting a higher risk of relapse on both studies was higher mercaptopurine dose intensity, but this did not reach statistical significance (P=0.03 T15; P=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing of other drugs for acute lymphoblastic leukemia, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Escherichia coli; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL).. A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software.. Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi. The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.

Topics: Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Child; Genotype; Humans; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously, six candidate gene variants associated with mercaptopurine intolerance were reported. Herein, we investigated the association between the mean tolerable dose of mercaptopurine and these genetic variants in Taiwanese patients.. In total, 294 children with ALL were treated at the National Taiwan University Hospital from April 1997 to December 2017. Germline variants were analyzed for NUDT15, SUCLA2, TPMT, ITPA, PACSIN2, and MRP4. Mean daily tolerable doses of mercaptopurine in the continuation phase of treatment were correlated with these genetic variants.. Mercaptopurine intolerance was significantly associated with polymorphisms in NUDT15 (P value < 0.0001). Patients with SUCLA2 variants received lower mercaptopurine doses (P value = 0.0119). The mean mercaptopurine doses did not differ among patients with TPMT, ITPA, MRP4, and PACSIN2 polymorphisms (P value = 0.9461, 0.5818, and 0.7951, respectively). After multivariable linear regression analysis, only NUDT15 variants retained their clinically significant correlation with mercaptopurine intolerance (P value < 0.0001).. In this cohort, the major genetic determinant of mercaptopurine intolerance was NUDT15 in Taiwanese patients.. NUDT15 causes mercaptopurine intolerance in children with ALL. The NUDT15 variant is a stronger predictor of mercaptopurine intolerance than TPMT in a Taiwanese cohort. This finding is similar with studies performed on Asian populations rather than Caucasians. Pre-emptive genotyping of the patients' NUDT15 before administering mercaptopurine may be more helpful than genotyping TPMT in Asians.

Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Neutropenia; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies; Risk Assessment; Risk Factors; Taiwan

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Down Syndrome; Female; Follow-Up Studies; Humans; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate

Thiopurines are cornerstone drugs in the treatment of acute lymphoblastic leukaemia (ALL), but their use can be complicated by the incidence of life-threatening leucopenia.. We describe a case of a 6-year-old Chinese boy with B-ALL receiving extremely low dose of 6-mercaptopurine (only 4% of recommended dose) during the ALL maintenance therapy phase.. Complex pharmacogenetic tests and TDM should be recommended in children with complicated ALL to highlight the large individual variability in the responses to 6-MP exposure and the associated adverse effects.

Topics: Administration, Oral; Child; Dose-Response Relationship, Drug; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antimetabolites, Antineoplastic; Asymptomatic Diseases; Child, Preschool; COVID-19; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; SARS-CoV-2

Mercaptopurine (6MP) and methotrexate (MTX) cause myelosuppression and interruptions in therapy in children with lymphoblastic leukemia (ALL). Length of time off of therapy is related to poorer outcomes. To date the dose at which most children tolerate these agents without drops in blood counts has not been identified. This study attempts to determine the maximum tolerated dose of both 6MP/MTX.. A retrospective chart review of 77 ALL children, median age 4.5 years. Time to first interruption and dose, along with total number of interruptions were collected. Absolute neutrophil and platelet counts recorded at time of interruption. Subgroup analysis of age, sex, diagnosis and risk stratification were also completed. REB approval was gained.. Of the 77 patients that were studied, 9 of them had no treatment interruptions. Descriptive statistics are reported using Strata software. The mean number of interruptions during maintenance was 3.2, the mean time to first interruption was 149.8 days. The mean dose percent of MTX and 6MP at first interruption was 94.4% and 106% respectively. Maintenance therapy was interrupted independent of age, sex, diagnosis or disease risk stratification.. Few patients complete maintenance therapy without interruptions at the current dose escalation schedules outlined by the Children's Oncology Group protocols. The interruptions are due in part to intolerance of dose escalations of MTX and 6 MP above 100%. Future research should investigate doses of 6MP and MTX in maintenance therapy in relation to leukemia outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL.. The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs.. The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129).. The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Neoplasm Recurrence, Local; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Retrospective Studies; Survival Rate

Topics: Alleles; Child; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP.. We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice.. The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity.. Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.

Topics: Administration, Oral; Animals; Apoptosis; Cell Proliferation; Female; Humans; Mercaptopurine; Mice; Mice, Inbred NOD; Mice, SCID; Nanomedicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.

Topics: Antimetabolites, Antineoplastic; Brain Infarction; Child, Preschool; Drug Hypersensitivity; Homozygote; Humans; Infections; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Mucositis; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrophosphatases; Sepsis

Hypoglycemia has been observed in children receiving acute lymphoblastic leukemia (ALL) therapy, and it can negatively affect patient outcomes. We documented a 4%-6% prevalence of hypoglycemia among patients in the two clinics in this study. We aim to reduce morning hypoglycemia in children on chemotherapy for ALL at two community pediatric oncology clinics (A and B) by 50% in 9 months.. We used the Institute for Healthcare Improvement (IHI) Model for Improvement as the framework. Prolonged hours of fasting for procedural sedation, gaps in the caregivers' knowledge of hypoglycemia risk, and a lack of awareness of the new mercaptopurine administration guidelines were the most likely contributing factors for hypoglycemia. We developed a hypoglycemia prevention educational program for staff and caregivers followed by a knowledge assessment tool.. Each month, the average number of patients seen in both clinics was 43. The monthly average of blood glucose tests in these patients was 94. After implementing the intervention, the percentage of caregivers who received hypoglycemia education reached 88%. Of those, 78% scored ≥ 75% in the knowledge reassessment resurvey. The combined average hypoglycemic episodes in the two clinics decreased by 46%. A higher reduction in hypoglycemic episodes was observed in clinic A (75%) compared with clinic B (17%).. Implementing hypoglycemia education led to a significant drop in hypoglycemic episodes among children on ALL therapy. Despite using a similar approach, one of the two clinics showed a more than fourfold improvement compared with the other.

Topics: Acute Disease; Child; Fasting; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine (6MP) is used to treat acute lymphoblastic leukemia (ALL) and is metabolized by hypoxanthine guanine phosphoribosal transferase to form 6-thioguanine nucleotide (6TGN). It is also metabolized by thiopurine methyl-transferase to produce 6-methylmercaptopurine (6MMP). Elevated levels of 6MMP have been associated with toxic effects that may interfere with therapy. Allopurinol is known to inhibit thiopurine methyl-transferase which reduces red cell 6MMP and increases 6TGN. Allopurinol has been utilized successfully in adult and pediatric patients with inflammatory bowel disease who have experienced 6MMP related gastrointestinal toxicity. Between August 2015 and August 2018 we started 25 patients with ALL in maintenance on allopurinol in combination with a reduced dose of 6MP. They all had unacceptable side-effects from elevated 6MMP, including abdominal pain, nausea, vomiting, decreased appetite, hypoglycemia, fatigue, and liver toxicity. In addition many had a facial rash. All patients showed resolution of symptoms within a few weeks after starting allopurinol. The red cell levels of 6MMP rapidly declined in the first month. The red cell levels of 6TGN transiently increased in spite of the lower 6MP dose. There was no decrease in absolute neutrophil count or hemoglobin. Platelets decreased slightly not requiring therapy modification. Elevated bilirubin normalized, and alanine aminotransferase decreased significantly with most normalizing. All patients continued on allopurinol with reduced dose 6MP until completing therapy. Allopurinol, in conjunction with a reduced dose of 6MP, effectively resolves 6MMP related side-effects in ALL patients on maintenance chemotherapy. This approach may lead to increased adherence to oral 6MP during ALL maintenance in patients with 6MMP induced side-effects.

Topics: Adolescent; Adult; Allopurinol; Antimetabolites, Antineoplastic; Child; Child, Preschool; Enzyme Inhibitors; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Young Adult

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Cyclophosphamide; Female; Genetic Markers; Humans; India; Male; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Reduced Folate Carrier Protein

6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008.. Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67).. TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; DNA; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methotrexate; Methyltransferases; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). IL6 rs13306435 carriers (N = 19) exhibited significantly lower DIP (48.0 ± 27.3%) than non-carriers (N = 209, 69.9 ± 29.0%; p = 0.0016 and 0.0028 by t test and multiple linear regression, respectively). Among 19 carriers, 7 with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7 ± 8.9%) than those with IL6 (N = 12, 61.6 ± 25.1%) or CRIM1 (N = 94, 68.1 ± 28.4%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact [relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50)]. Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.

Topics: Adolescent; Bone Marrow; Bone Morphogenetic Protein Receptors; Child; Child, Preschool; Ethnicity; Exome Sequencing; Female; Humans; Infant; Interleukin-6; Male; Mercaptopurine; Methyltransferases; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Republic of Korea; Young Adult

Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; DNA; Humans; Infant; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Young Adult

Poor mercaptopurine (6MP) adherence (mean adherence rate < 90%) increases the relapse risk among children with acute lymphoblastic leukemia (ALL). 6MP adherence remains difficult to measure in real time. Easily measured patient-level factors could identify patients at risk for poor adherence.. The authors measured 6MP adherence via electronic monitoring for 6 months per patient. Using data from month 3, they created a risk prediction model for 6MP nonadherence in 407 children with ALL (mean age, 7.7 ± 4.4 years); they used receiver operating characteristic analyses in the training set (n = 250) and replicated this in the test set (n = 157).. Age, race/ethnicity, 6MP dose intensity, absolute neutrophil count, 6MP ingestion patterns, and household structure were retained in the prediction model. The model yielded areas under the receiver operating characteristic curve (AUCs) of 0.79 (95% confidence interval [CI], 0.71-0.85) and 0.74 (95% CI, 0.63-0.85) in the training and test sets, respectively. The model performed better for those who were ≥12 years old (AUC, 0.79; 95% CI, 0.59-0.99) than those <12 years old (AUC, 0.70; 95% CI, 0.58-0.81). Using the predicted probability of nonadherence based on receiver operating characteristic analysis, the authors developed a binary risk classifier to classify patients with a high or low probability of nonadherence. The sensitivity and specificity of the binary risk classifier were 71% and 76%, respectively. Adjusted for clinical prognosticators, the risk of relapse was 2.2-fold higher (95% CI, 0.94-5.1; P = .07) among patients with a high probability of nonadherence in comparison with those with a low probability, as identified by the risk prediction model.. The risk prediction model identified patients with a high probability of nonadherence and could be used in real time to personalize recommendations and interventions in the clinic.. The vast majority of children with acute lymphoblastic leukemia, the most common childhood cancer, are cured. The treatment of acute lymphoblastic leukemia includes taking an oral chemotherapy medicine (mercaptopurine) for approximately 2 years. Children who miss doses of this medicine (specifically children who take the medicine less than 90% of the time that it is prescribed) are more likely to suffer leukemia relapse. The authors of this article have measured mercaptopurine adherence with electronic bottle caps to determine characteristics of patients that predict nonadherence, and they have created a prediction tool that could allow physicians to identify and intervene with patients at high risk of nonadherence.

Topics: Administration, Oral; Area Under Curve; Child; Child, Preschool; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

The hyper-CVAD/methotrexate-cytarabine (H-CVAD/ MTX-AraC) chemotherapy protocol has been one of the standard treatments for hematological malignancies, such as mantle cell lymphoma (MCL), Burkitt lymphoma (BL), and B-cell and T-cell acute lymphoblastic leukemia. Because results of this therapy are poor, it has been progressively replaced with new specific regimens with better efficacy profiles (GELA protocol for MCL, BURKIMAB for BL, and PETHEMA for B-cell and T-cell acute lymphoblastic leukemia [ALL]). The objective of this study was to analyze the response rates and survival of these therapeutic regimens. This retrospective and descriptive observational study of 81 patients compared 42 patients treated with hyper-CVAD/methotrexate-cytarabine (group A) with 39 patients treated with GELA/BURKIMAB/PETHEMA (group B). More patients in group B than in group A completed the treatment (89.7% vs. 47.6%, p < 0.001). In group A, 14.3% did not complete treatment because of death compared with 7.7% in group B, and 29% in group A had cycle delays versus 6.7% in group B (p < 0.001). In group A, 78.6% of group A achieved a complete response (CR) compared with 94.9% of group B (p = 0.050). Disease-free survival (DFS) and overall survival (OS) were significantly higher in group B (p < 0.001 in both cases). Data for current therapeutic protocols have indicated superior efficacy, with higher complete response rates, as well as better disease-free survival and overall survival results. This article provides the best results in terms of the efficacy of treatment of four hematological malignancies (MCL, BL, B-cell ALL, and T-cell ALL) with the most current specific therapeutic regimens (GELA for MCL, BURKIMAB for BL, and PETHEMA for B-cell ALL and T-cell ALL) with respect to a classic general protocol (H-CVAD/MTX-AraC for all four). These results may represent a great advance in the treatment of these blood cancers, achieving an important long-term benefit for these hematological patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Hematologic Neoplasms; Humans; Lymphoma, Mantle-Cell; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Treatment Outcome; Vincristine; Young Adult

A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Humans; Invasive Fungal Infections; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mucorales; Mucormycosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Triazoles; Vincristine

Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the. We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating. Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child; Child, Preschool; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Transcription Factors; Treatment Outcome; Tumor Cells, Cultured

To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL).. The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing.. TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P < .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia.. White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genetic Variation; Humans; Infant; Inosine Triphosphatase; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies; Sweden

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

6-mercaptopurine (6-MP) is the mainstay in pediatric acute lymphoblastic leukemia (ALL) maintenance treatment. Variants in genes coding for thiopurine S-methyl transferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are known to influence 6-MP metabolism. We determined TPMT and ITPA genotype and enzyme activity and the mean 6-MP doses during maintenance treatment in 40 children treated for ALL according to the Dutch Childhood Oncology Group (DCOG)-ALL11 protocol in the Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands. Patients with genetic variants in TPMT (N=3) had significantly lower TPMT enzyme activity (mean 0.46 vs. 0.72 µmol/mmol hemoglobin/h, P=0.005). Although the difference was not statistically significant, they were treated with lower mean 6-MP doses (28.1 mg/m [SD 25.5 mg/m] vs. 41.3 mg/m [SD 17.2 mg/m], P=0.375). In patients with genetic ITPA variants (N=21), ITPA enzyme activity was significantly lowered (mean 3.67 vs. 6.84 mmol/mmol hemoglobin/h, P<0.0005). The mean 6-MP doses did not differ between patients with and without variants in ITPA (40.0 mg/m [SD 20.3 mg/m] vs. 40.6 mg/m [SD 14.9 mg/m], P=0.663). The TPMT genotype, but not the ITPA genotype, should be considered as part of standard evaluation before starting ALL maintenance treatment.

Topics: Antimetabolites, Antineoplastic; Biomarkers, Tumor; Child; Ethnicity; Female; Follow-Up Studies; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrophosphatases; Retrospective Studies

Acute lymphoblastic leukemia maintenance chemotherapy includes mercaptopurine, a purine analog with uncommon side effects, that can be life-threatening. We describe a 7-year-old female patient with ALL that presented with altered state of consciousness after maintenance chemotherapy with methotrexate and 6-mercaptopurine, due to severe hypoglycemia with metabolic acidosis. She initiated metabolic corrections with rapid resolution of symptoms. Hypoglycemia secondary to 6-mercaptopurine is a rare and transient side effect. The cause effect relation is difficult to establish, leading to underdiagnosis. Hypoglycemia is preventable without compromising maintenance therapy efficacy.

Topics: Acidosis; Child; Female; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Severity of Illness Index

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Survival Rate; Vincristine

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1

Topics: Abnormal Karyotype; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Comparative Genomic Hybridization; Cyclophosphamide; Cytarabine; Daunorubicin; Genes, Neoplasm; Humans; Ikaros Transcription Factor; In Situ Hybridization, Fluorescence; Mercaptopurine; Methotrexate; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Risk Factors; RNA, Messenger; RNA, Neoplasm; Sequence Analysis, RNA; Transcriptome; Vincristine; Workflow

Pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma are prescribed a daily oral chemotherapy medication named 6-mercaptopurine. Adherence to this medication is vital for survival and decreased risk for disease relapse. Adaptive problem-solving strategies are important for adhering to this complex regimen. This manuscript examined ethnic and racial differences in social problem-solving domains (Social Problem-Solving Inventory) among patients aged 7-19 years old who were diagnosed with cancer; and, their caregivers (

Topics: Adolescent; Adult; Caregivers; Child; Female; Humans; Longitudinal Studies; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Problem Solving; Young Adult

Previous research suggests that children and adolescents with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) often have difficulty adhering to complex treatment regimens during the maintenance phase of therapy. Measurement of treatment adherence can be done via objective (e.g., electronic monitoring (EM), pharmacological assays) or subjective methods (patient, parent, or physician reports). This paper provides an illustration of recommended strategies for comparing discrepancies between two objective measures of medication adherence (e.g., behavioral adherence using electronic monitoring versus pharmacological adherence using 6-mercaptopurine (6MP) metabolite data) within a relatively large cohort of pediatric patients with ALL or LBL (

Topics: Adolescent; Child; Cohort Studies; Female; Humans; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil.. The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software.. Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world.. Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.

Topics: Antimetabolites, Antineoplastic; Brazil; Humans; Indigenous Peoples; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-based medicine.. By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0 software was used to conduct meta-analysis of the outcome indicators of the included literature.. This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical direction for clinical treatment.. The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals.. PROSPERO (registration number is CRD42020150466).

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Substitution; Humans; Infant; Mercaptopurine; Meta-Analysis as Topic; Neoplasm Metastasis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Recurrence; Research Design; Systematic Review as Topic; Thioguanine

Topics: Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antiviral Agents; Austria; Child; COVID-19; COVID-19 Drug Treatment; Female; Humans; Mercaptopurine; Methotrexate; Pancytopenia; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; SARS-CoV-2; Treatment Outcome

Topics: Allopurinol; Child; Humans; Maintenance; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rome

Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric acute lymphoblastic leukemia. Recently, NUDT15 variants were identified as a major determinant of mercaptopurine intolerance. Two NUDT15 variants, c.36_37insGGAGTC and c.415C > T, are located on exons 1 and 3, respectively. Patients with heterozygous c.36_37insGGAGTC and c.415C > T can be either compound heterozygous with two variants on different alleles or heterozygous with both variants on the same allele. Because patients with biallelic NUDT15 variants are extremely sensitive to mercaptopurine, clinical identification of NUDT15 diplotype would be advantageous. A cohort of 37 patients with c.36_37insGGAGTC and c.415C > T NUDT15 variants were selected for haplotyping by targeted sequencing. NUDT15 complementary DNA was amplified and sequenced by 300-bp paired-end sequencing on Illumina MiSeq. Of the 37 patients carrying NUDT15 variants, 35 had heterozygous NUDT15*1/*2 variants and two had compound heterozygous NUDT15*3/*6 and NUDT15*2/*7 variants. These two patients with compound heterozygous variants could only tolerate low doses of mercaptopurine, similar to patients with homozygous NUDT15 variants. Targeted sequencing of NUDT15 cDNA can be used to determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants.

Topics: Adolescent; Alleles; Antimetabolites, Antineoplastic; Child; Child, Preschool; Cohort Studies; Drug Resistance, Neoplasm; Exons; Female; Haplotypes; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Mercaptopurine; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Sequence Analysis, DNA; Taiwan

Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP.. Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy.. From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004).. Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.

Topics: Allopurinol; Antimetabolites; Bone Marrow Diseases; Child; Child, Preschool; Female; Follow-Up Studies; Gastrointestinal Diseases; Humans; Infant; Male; Mercaptopurine; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies; Survival Rate

Maintenance chemotherapy with oral 6-mercaptopurine and methotrexate remains a cornerstone of modern therapy for acute lymphoblastic leukaemia. The dosage and intensity of therapy are based on surrogate markers such as peripheral blood leukocyte and neutrophil counts. Dosage based leukocyte count predictions could provide support for dosage decisions clinicians face trying to find and maintain an appropriate dosage for the individual patient. We present two Bayesian nonlinear state space models for predicting patient leukocyte counts during the maintenance therapy. The models simplify some aspects of previously proposed models but allow for some extra flexibility. Our second model is an extension which accounts for extra variation in the leukocyte count due to a treatment adversity, infections, using C-reactive protein as a surrogate. The predictive performances of our models are compared against a model from the literature using time series cross-validation with patient data. In our experiments, our simplified models appear more robust and deliver competitive results with the model from the literature.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Child; Child, Preschool; Datasets as Topic; Drug Dosage Calculations; Female; Humans; Infant; Leukocyte Count; Leukocytes; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Models, Biological; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stochastic Processes

Fasting hypoglycemia is a known complication of mercaptopurine (6MP) maintenance therapy for acute lymphoblastic leukemia (ALL). It is associated with high levels of the methylated metabolite 6-methyl-mercaptopurine (6MMP). Symptoms of hypoglycemia include morning tremulousness, nausea and vomiting. We have previously shown that switching 6MP dosing from evening to morning resolved hypoglycemia by reducing 6MMP; however, the reduction of 6MMP was only transient, potentially resulting in return of hypoglycemia. In children and adults with Crohn's disease, co-prescribing allopurinol with 6MP blocks the activity of thiopurine methytransferase (TPMT), reducing 6MMP and improving its tolerance. As a consequence of inhibiting TPMT, 6MP is shunted toward the production of 6-thioguanine nucleotide (6TGN), which will result in pancytopenia if the dose of 6MP is not reduced. We demonstrate that allopurinol with a reduced dose of 6MP in two patients with ALL and 6MMP-associated hypoglycemia resulted in a complete and sustained suppression of 6MMP and rapid reversal of hypoglycemia and its symptoms.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Blood Glucose; Blood Glucose Self-Monitoring; Child; Child, Preschool; Enzyme Inhibitors; Female; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Acute lymphoblastic leukemia is the most common malignancy in childhood and requires prolonged oral maintenance chemotherapy to prevent disease relapse after remission induction with intensive intravenous chemotherapy. In maintenance therapy, drug doses of 6-mercaptopurine (6-MP) and methotrexate (MTX) are adjusted to achieve sustained antileukemic activity without excessive myelosuppression. However, uncertainty exists regarding timing and extent of drug dose responses and optimal dose adaptation strategies. We propose a novel comprehensive mathematical model for 6-MP and MTX pharmacokinetics, pharmacodynamics and myelosuppression in acute lymphoblastic maintenance therapy. We personalize and cross-validate the mathematical model using clinical data and propose a real-time algorithm to predict chemotherapy responses with a clinical decision support system as a potential future application.

Topics: Algorithms; Antimetabolites, Antineoplastic; Child; Drug Therapy, Combination; Humans; Leukocytes; Mercaptopurine; Methotrexate; Models, Theoretical; Outcome Assessment, Health Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Secondary Prevention

Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP).. RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated.. The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase.. In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Chromatography, Liquid; Erythrocytes; Female; Humans; Male; Mercaptopurine; Nucleotides; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tandem Mass Spectrometry; Thioguanine

The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management.. A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning.. The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649.. TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

Topics: Adolescent; Alleles; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Regression Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Density; Bone Marrow; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Fractures, Compression; Humans; Image Enhancement; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Spinal Fractures; Spine; Vincristine

We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea.. From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses.. The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05).. Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Genotype; Humans; Male; Mercaptopurine; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Republic of Korea; Retrospective Studies

6-Mercaptopurine (6-MP) is considered the backbone of therapy in the maintenance phase of acute lymphoblastic leukemia (ALL). Gene polymorphisms involved in thiopurine degradation are predictors of toxicity in patients treated with 6-MP. We investigated the effects of nucleoside diphosphate linked moiety X (nudix) type motif 15 (NUDT15) polymorphism NUDT15c.415C>T on neutropenia incidence, dose adjustment for 6-MP, and survival rates in Thai children with ALL.. Children diagnosed with ALL who received 6-MP in the maintenance phase of treatment, in 2005-2016, were retrospectively enrolled.. The subjects consisted of 102 patients (median age, 5.2 years; 58 boys). On genetic testing 78, 22, and two patients were normal (CC), heterozygous (CT), and homozygous (TT), respectively. The incidence of neutropenia at 3 months was significantly higher in the CT/TT than CC polymorphism groups (OR, 12; 95%CI: 3.781-38.085, P < 0.001). The mean dose of 6-MP at 3, 6, and 12 months was significantly lower in the CT/TT versus the CC group (P < 0.001). The 5 year overall survival (OS) rate for CC was 80.4%, and for CT/TT, 95.5% (P = 0.34). The 5 year event-free survival (EFS) for CC and CT/TT was 75.1% and 85.7%, respectively (P = 0.17). After adjusted risk classification, no significant differences were observed for OS or EFS between the CC and CT/TT groups.. Patients harboring the CT/TT polymorphism of NUDT15 had a significantly higher incidence of neutropenia during the first 3 months of maintenance, resulting in significantly lower doses of 6-MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Genetic Markers; Heterozygote; Homozygote; Humans; Incidence; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Neutropenia; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies; Survival Analysis

The standard treatment for adult acute lymphoblastic leukemia (ALL) is undefined. Patients with newly diagnosed standard-risk ALL at a single institution were retrospectively analyzed. From 2010 to 2017, 46 patients were treated using the modified Berlin-Frankfurt-Münster (BFM)-ALL-95 regimen. Hematologic and molecular complete remission (CR) rates of 91.3% and 76.1% were achieved. The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients in the cohort were 58.0% (95% confidence interval, 42.1-73.9%) and 66.7% (95% CI, 51.4-82.0%), respectively. No patient presented with central nervous system involvement after CR in this study. This condition could be related to four doses of high-dose methotrexate (MTX) every 3 months during the maintenance phase. Multivariate analysis revealed that minimal residual disease positive and time interval between induction IA and Protocol M of more than 70 days were independent adverse factors for EFS and OS. One or more instances of grade 4 myelosuppression occurred during induction therapy. Nonhematological side effects were mild. No toxicity-related deaths were observed in the entire cohort. The data indicated that the modified regimen is well tolerated and can produce the promising outcomes in Chinese adults with standard-risk ALL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asian People; Asparaginase; Cohort Studies; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Risk; Time Factors; Treatment Outcome; Vincristine

Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in

Topics: 5'-Nucleotidase; Cell Line, Tumor; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Kinetics; Mercaptopurine; Metabolomics; Models, Biological; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma

6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0.05). NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone. All patients with both the intermediate activity NUDT15 variant and the ABCC4 rs3765534 variant suffered from leukopenia, and 57.1% patients required 50% protocol dose by day 168. These data indicate that NUDT15 and ABCC4 are major factors for 6-MP intolerability and that the interaction between these variants enhances intolerability to 6-MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Asian People; Child; Child, Preschool; Female; Humans; Infant; Japan; Leukopenia; Male; Mercaptopurine; Multidrug Resistance-Associated Proteins; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients.. Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients.. Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01).. We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

Topics: Adolescent; Child; Child, Preschool; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Neutropenia; Odds Ratio; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sequence Analysis, DNA

We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL).. Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated.. A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group.. NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; Female; Guanine Nucleotides; Humans; Infant; Male; Mercaptopurine; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Republic of Korea; Retrospective Studies; Sequence Analysis, DNA; Thionucleotides; Young Adult

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2

Topics: 5'-Nucleotidase; Animals; Cell Proliferation; Clonal Evolution; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Gain of Function Mutation; Guanosine; HEK293 Cells; Humans; IMP Dehydrogenase; Male; Mercaptopurine; Mice; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Receptor, Notch1; Recurrence; Xenograft Model Antitumor Assays

Topics: Adolescent; Child; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Leukopenia; Mercaptopurine; Methyltransferases; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients.. A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated.. The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377-9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764-33.514, P = 3.75 × 10. NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Asian People; Child; Child, Preschool; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Pharmacogenomic Variants; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.

Topics: 5'-Nucleotidase; Allosteric Regulation; Animals; Antimetabolites, Antineoplastic; Catalytic Domain; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; HEK293 Cells; Humans; Jurkat Cells; Mercaptopurine; Mice, Inbred C57BL; Models, Molecular; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Conformation, alpha-Helical; Recurrence; Structure-Activity Relationship

The acute lymphoblastic leukemia (ALL) is a heterogenous rare malignant disease of lymphoblastic precursor cells. The peak of incidence lies in childhood (5.3/100 000), but the incidence rises again from the age of 50 onwards, showing a second peak at patients > 80 years old (2.3/100 000). The ALL is an acute life-threatening disease which untreated leads to death within a short time. The therapeutic objective is cure. By the characterization of subgroups, their targeted therapy and therapy optimization cure rates could be improved (from less than 10 % in the eighties) to more than 50 - 70 % (depending on the subgroup). To this achievement the approach has contributed with risk adapted therapy protocols, with improved supportive therapy and in particular with taking the minimal residual disease (the most important prognostic factor) as a basis for the therapy decision. Recently, with the new immunotherapies there exist further promising options of targeted therapies.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Chromosome Aberrations; Cyclophosphamide; Cytarabine; Dexamethasone; Female; Humans; Immunotherapy; Incidence; Infant; Male; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Risk Factors; Vincristine; Young Adult

Children with acute lymphoblastic leukemia (ALL) in low-income countries have disproportionately lower cure rates than those in high-income countries. At Butaro Cancer Center of Excellence (BCCOE), physicians treated patients with ALL with the first arm of the Hunger Protocol, a graduated-intensity method tailored for resource-limited settings. This article provides the first published outcomes, to our knowledge, of patients with ALL treated with this protocol.. This is a retrospective descriptive study of patients with ALL enrolled at BCCOE from July 1, 2012 to June 30, 2014; data were collected through December 31, 2015. Descriptive statistics were used to calculate patient demographics, disease characteristics, and outcomes; event-free survival was assessed at 2 years using the Kaplan-Meier method.. Forty-two consecutive patients with ALL were included. At the end of the study period, 19% (eight) were alive without evidence of relapse: three completed treatment and five were continuing treatment. Among the remaining patients, 71% (30) had died and 10% (four) were lost to follow-up. A total of 83% (25) of the deaths were disease related, 3% (one) treatment-related, and 13% (four) unclear. Event-free survival was 22% (95% CI, 11% to 36%), considering lost to follow-up as an event, and 26% (95% CI, 13% to 41%) if lost to follow-up is censored.. As expected, relapse was the major cause of failure with this low-intensity regimen. However, toxicity was acceptably low, and BCCOE has decided to advance to intensity level 2. These results reflect the necessity of a data-driven approach and a continual improvement process to care for complex patients in resource-constrained settings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cancer Care Facilities; Child; Cyclophosphamide; Developing Countries; Dexamethasone; Female; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Rwanda; Treatment Outcome; Vincristine

Although cure rates in pediatric acute lymphoblastic leukemia (ALL) are quite high with combined chemotherapy regimens, complete response (CR) and long-term survival rates in adults are 80-90 and 30-40%, respectively. Currently, combined chemotherapy regimens, such as Hyper-CVAD and PETHEMA, are used in patients with adult ALL. However, there has been no study comparing the results of Hyper-CVAD and PETHEMA ALL-93.. In this retrospective single-center study, we evaluated the results of Hyper-CVAD and PETHEMA ALL-93 in 51 ALL patients treated between September 2008 and March 2017 at the Department of Hematology, Faculty of Medicine, Karadeniz Technical University.. Thirty-eight patients were treated with Hyper-CVAD and 13 with PETHEMA ALL-93. CR was obtained in 90 and 100% of patients, respectively. Survival estimates were comparable between Hyper-CVAD and PE-THEMA ALL-93, with a median overall survival (OS) and a median disease-free survival (DFS) of 17.5 and 12.1 months, respectively, for Hyper-CVAD and of 18.6 and 12.9 months, respectively, for PETHEMA ALL-93. The 2-year OS rates for Hyper-CVAD and PETHEMA ALL-93 were 30 and 40%, respectively, and the 2-year DFS rates were 28 and 44%, respectively. PETHEMA ALL-93 resulted in more hepatotoxicity, hypofibrinogenemia, aspergillus infection, and skin rash than Hyper-CVAD.. Although Hyper-CVAD and PE-THEMA ALL-93 showed similar effects, Hyper-CVAD was tolerated better. Age and comorbidities should be taken into account before a chemotherapy regimen is determined for patients with ALL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacterial Infections; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Fever; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Survival Rate; Treatment Outcome; Vincristine; Young Adult

Topics: Female; Humans; Male; Mercaptopurine; Methyltransferases; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Uruguay

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

Topics: Administration, Oral; Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Child, Preschool; Dairy Products; Drug Administration Schedule; Drug Monitoring; Erythrocytes; Female; Food-Drug Interactions; Humans; Male; Medication Adherence; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thionucleotides; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Gene Deletion; Humans; Ikaros Transcription Factor; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome; Vincristine

Prolonged exposure to thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg,

Topics: Adolescent; Asian People; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Models, Molecular; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; White People

Topics: Adolescent; Antimetabolites, Antineoplastic; ATP-Binding Cassette Transporters; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Multidrug Resistance-Associated Protein 2; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reduced Folate Carrier Protein

Studies on children with Acute Lymphoblastic Leukemia (ALL) reported non-adherence in 2-54% of cases. The primary objective of this study was to assess rates of adherence to 6-MP using two different methods in children and adolescents with ALL. Secondary aim was to identify factors that influence adherence to 6-MP in children with ALL.. All eligible children with ALL who are (≤ 19) years old and receive 6-MP therapy for at least 1 month were approached to participate in the study. A total of 52 children with ALL and their primary caregivers were recruited. Adherence measures included an objective method (measuring 6-MP metabolites in packed Red Blood Cells (RBCs)) and a subjective method (using parent and child self-report via the Medication Adherence Report Scale; MARS; Adherence was defined as 90% or greater).. Rates of adherence varied across the measurement methods. Packed RBCs sample analysis indicated forty-four patients (84.6%) to be adherent. Using the MARS questionnaires, a total of 49 children (94.2%) were classified as being adherent according to the parental MARS questionnaire scores, while all the 15 children (100%) who answered the MARS (child) questionnaire were classified as adherent. Overall adherence rate was 80.8% within the studied population.. MARS scale was shown to overestimate adherence compared to measurement of 6-MP metabolites in the blood. A combination of both methods led to increased detection of non-adherence to thiopurine in children with ALL.

Topics: Adolescent; Child; Cluster Analysis; Demography; Female; Humans; Male; Medication Adherence; Mercaptopurine; Parents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Surveys and Questionnaires

Topics: Antimetabolites, Antineoplastic; Asian People; Child; Humans; Mercaptopurine; Multidrug Resistance-Associated Proteins; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Topics: Acute Disease; Allopurinol; Child; DNA, Neoplasm; History, 20th Century; Humans; Hyperuricemia; Mercaptopurine; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Lysis Syndrome; Uric Acid

Thiopurine methyltransferase (TPMT) gene polymorphism regulates thiopurine therapeutic efficacy and toxicity. The aim of this study was to determine the influence of TPMT gene polymorphism in Egyptian children with acute lymphoblastic leukaemia (ALL). Sixty-four patients with ALL, T lineage (27%) and pre-B phenotype (73%), who were treated with BFM 90 or CCG 1991 standard risk protocol, and who also experiencedmyleosuppresion toxicity and required interruption and/ormodification of thiopurine chemotherapy were recruited over a year period. Thirty-two patients were on maintenance and another 32 completed their chemotherapy. Seventy healthy age-matched and sex-matched children served as controls. They were subjected to clinical assessment, haematological panel investigations and TPMT gene polymorphism for G238C, G460A and A719G alleles assessment using PCRfollowed byRFLP analysis.Although none of the studied patients had themutantTPMTvariant alleles,myelosuppression toxicity in the form of different degree of neutropenia was detected in all patients. As a result of myelosuppression toxicity, most of the patients needed 6-MP dose modification either once (53.1%), twice (15.6%), or ≥ thrice (25.1%) during their maintenance course and 96.9% of the patients required to stop 6-MP for less than a week (62.5%), up to 2 weeks (28.1%), or > 2 weeks (6.3%). Patients also developed infection who mostly (71%) needed hospitalization. None of the studied G238C, G460A and A719G TPMT variant alleles were detected. Infections and febrile neutropenia were common causes of 6-PM dose modification and interruption.

Topics: Adolescent; Alleles; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Daunorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases.. The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per μl.. One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00-66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort.. This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect.

Topics: Adolescent; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Genotype; Heterozygote; Homozygote; Humans; Lebanon; Male; Mercaptopurine; Methyltransferases; Neoplasm Staging; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrophosphatases; Retrospective Studies; Survival Rate

We report the diagnostic and therapeutic challenges in an unusually fulminant presentation of measles, presenting as severe necrotizing bronchiolitis with secondary hemophagocytic lymphohistiocytosis (HLH) in the absence of classical clinical features in an immunocompromised host on maintenance chemotherapy. Our patient had presented with features of a viral pneumonitis without the classical exanthem, in combination with HLH. Although rhinovirus-induced HLH was highly unusual, the positive rhinovirus swab result had distracted us from the eventual diagnosis. This calls for greater impetus to increase awareness and public education to improve vaccination rates and herd immunity to curb outbreaks and protect the immunocompromised patients.

Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Antineoplastic Combined Chemotherapy Protocols; Cryptogenic Organizing Pneumonia; Diagnostic Errors; Extracorporeal Membrane Oxygenation; Fatal Outcome; Humans; Lymphohistiocytosis, Hemophagocytic; Maintenance Chemotherapy; Male; Measles; Mercaptopurine; Methotrexate; Multiple Organ Failure; Pancytopenia; Picornaviridae Infections; Plasma Exchange; Pneumonia, Viral; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhinovirus; Sepsis; Survivors

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.

Topics: Adolescent; Alanine Transaminase; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis

We report a case of a child with pre-B cell acute lymphoblastic leukemia undergoing maintenance chemotherapy with 6-mercaptopurine and methotrexate (MTX) who developed sinusoidal obstruction syndrome after being treated with ciprofloxacin for BK viremia. This case represents a rare complication of maintenance therapy with MTX and 6-mercaptopurine, and suggests a drug interaction between ciprofloxacin and MTX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Child; Drug Interactions; Hepatic Veno-Occlusive Disease; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Multimodal Imaging; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase (TPMT) mutant allele carriers are at high risk to develop severe and potentially fatal hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico.. We included 849 unrelated subjects, of which 368 ALL children and 342 non-ALL subjects were from Mexico City, and 60 ALL cases and 79 non-ALL individuals were from Yucatan. Genotyping of the rs1800462, rs1800460 and rs1142345 SNPs was performed by 5'exonuclease technique using TaqMan probes (Life Technologies Foster City, CA).. The mutant TPMT alleles were present in 4.8% (81/1698 chromosomes) and only 0.2% were homozygote TPMT*3A/TPMT*3A. We did not find statistically significant differences in the distribution of the mutant alleles between patients from Mexico City and Yucatan in either ALL cases or non-ALL. Nonetheless, the TPMT*3C frequency in ALL patients was higher than non-ALL subjects (p = 0.03). To note, the null homozygous TPMT*3A/TPMT*3A genotype was found in 2.5% of the non-ALL subjects.. TPMT mutant alleles did not exhibit differential distribution between both evaluated populations; however, TPMT*3C is overrepresented in ALL cases in comparison with non-ALL group. Assessing the TPMT mutant alleles could benefit the ALL children and those undergoing 6-MP and MX treatment.

Topics: Adolescent; Antimetabolites, Antineoplastic; Case-Control Studies; Female; Gene Frequency; Genotype; Heterozygote; Homozygote; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Mexico; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The aim of this questionnaire-based survey was to determine the 'acceptability' of Xaluprine®, a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia.. This was a single centre survey of children (aged 3 to 16 years) and their parents at a routine follow-up visit during the maintenance phase of acute lymphoblastic leukaemica treatment. The questionnaire probed for their views on overall acceptability such as taste, smell, incidences of vomiting, ease and willingness to take Xaluprine® on a daily basis, and utilised a 5-point facial hedonic scale (1 = bad, 5 = good) as well as open/closed questions.. Twenty-two children were recruited; 17 (77%) scored taste between 3 and 5 ('okay' to 'good') and 20 (91%) scored smell between 3 and 5. Only four children (18%) reported an aftertaste. Of the five children (23%) who scored taste as 1 or 2 ('bad'), three found taking all oral medicines difficult. Six children (27%) reported vomiting, but this was not considered related to Xaluprine®. Seven children (32%) sometimes complained that they did not want to take Xaluprine®; 15 (68%) never complained. In response to the question, 'How easy is it for you to take Xaluprine®?' 18 children (82%) reported that it was 'Easy all the time.' This was more favourable than other oral liquid medicines that they were taking concurrently.. The results of this survey show that Xaluprine® has good overall acceptability in the paediatric population and suggests that Xaluprine® is an important, alternative, age-appropriate formulation of mercaptopurine.

Topics: Adolescent; Antimetabolites, Antineoplastic; Chemistry, Pharmaceutical; Child; Child, Preschool; Drug Compounding; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Surveys and Questionnaires; Suspensions; Taste; Vomiting

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Risk Factors

A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m

Topics: Age Factors; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Gene Frequency; Genetic Association Studies; Heterozygote; Homozygote; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Mercaptopurine; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Pyrophosphatases; Risk Factors; Taiwan; Time Factors; Treatment Outcome

6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

Topics: Adolescent; Allopurinol; Antimetabolites; Antimetabolites, Antineoplastic; Child; Humans; Liver; Maintenance Chemotherapy; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We describe a 4-year-old female with pre-B-cell acute lymphoblastic leukemia on maintenance chemotherapy, who developed hemophagocytic lymphohistiocytosis (HLH) secondary to Epstein-Barr virus (EBV) infection, complicated by an aggressive lymphoproliferative disorder. Although there was no history of bone marrow transplant or underlying immunodeficiency, EBV triggered a post-transplant lymphoproliferative disease (PTLD)-like lymphoma. Multiple regimens of chemotherapy failed to induce remission and patient developed multiorgan failure. The association of HLH with EBV-related PTLD-like lymphoproliferative disorder is rare. We present this case to highlight this unusual association so that this highly fatal disease can be recognized and promptly addressed.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Cyclosporine; Dexamethasone; Epstein-Barr Virus Infections; Etoposide; Female; Humans; Immunocompromised Host; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Methotrexate; Multiple Organ Failure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rituximab; Treatment Failure; Vincristine; Viral Load

The aim of the present study is to determine the correlation of hepatitis C virus (HCV) infection and polymorphisms in different genes with toxicity of either methotrexate (MTX) or 6-mercaptopurine (6-MP) administered to children with acute lymphoblastic leukemia (ALL).. One hundred children with low-risk ALL, who were treated according to the St. Jude Total therapy XV, were recruited. The recruited children were receiving MTX and 6-MP during maintenance phase. Patients were excluded from the study if they had other types of leukemia. Genotyping analyses for the thiopurine methyltransferase (TPMT), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferase (GST) genes were performed using a combination of polymerase chain reaction (PCR) and PCR-RFLP (where RFLP is restriction fragment length polymorphism) protocols. Relevant clinical data on adverse drug reactions were collected objectively (blinded to genotypes) from the patient medical records.. There was a significant correlation between the combined presence of HCV and TPMT*3B G460A gene polymorphisms and grades 2-4 hepatotoxicity as aspartate aminotransferase (AST) elevation (P < 0.04). The same observation was seen when comparing either the presence of HCV alone or the presence of the gene polymorphism alone. A significant association between the combined presence of HCV and MTHFR C677T polymorphism and grades 2-4 hepatotoxicity as alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) elevation was observed (P values <0.001, 0.02, and 0.001, respectively). The presence of HCV infection had a significant negative effect on hepatic transaminases.. The present data support a role for combining analysis of genetic variation in drug-metabolizing enzymes and the presence of HCV in the assessment of specific drugs toxicities in multiagent chemotherapeutic treatment regimens.

Topics: Child; Child, Preschool; Female; Genotype; Hepacivirus; Humans; Liver; Male; Mercaptopurine; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

Topics: Adolescent; Age Factors; Alleles; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.

Topics: Child, Preschool; Female; Homozygote; Humans; Mercaptopurine; Mutation, Missense; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.

Topics: Adaptor Proteins, Signal Transducing; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Ferredoxin-NADP Reductase; Folic Acid; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Mercaptopurine; Metabolic Networks and Pathways; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

A median of 22 (range 8-27) 6MP/MTX metabolite samples and 100 (range 25-130) blood counts during therapy and 10 (range 2-15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2-6 glutamate residues (ery-MTXpg. On-therapy WBC was correlated with ANC and ALC (r. Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.

Topics: Adolescent; Aging; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Child; Child, Preschool; Female; Genotype; Humans; Leukocyte Count; Leukopenia; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; PTEN Phosphohydrolase; Risk Assessment

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

Individualized therapy is a recent approach aiming to specify dosage regimen for each patient according to its genetic state. Cancer chemotherapy requires continuous monitoring of the plasma concentration levels of active forms of cytotoxic drugs and subsequent dose adjustment. In order to attain optimum therapeutic efficacy, correlation to pharmacogenetics data is crucial. In this study, a specific, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for determination of methotrexate (MTX), 6-mercaptopurine (MP) and its metabolite 6-thioguanine nucleotide (TG) in human plasma. Based on the basic character of the studied compounds, solid phase extraction using a strong cation exchanger was found the optimum approach to achieve good extraction recovery. Chromatographic separation was carried out using RP-HPLC and isocratic elution by acetonitrile: 0.1% aqueous formic acid (85:15v/v) with a flow rate of 0.8mL/min at 40°C. The detection was performed by tandem mass spectrometry in MRM mode via electrospray ionization source in positive ionization mode. Analysis was carried out within 1.0min over a concentration range of 6.25-200.00ng/mL for the studied analytes. Validation was carried out according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the monitoring of the MTX, MP and TG and subsequent application to personalized therapy was demonstrated in a clinical study on children with acute lymphoblastic leukemia (ALL). Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.

Topics: Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Humans; Limit of Detection; Mercaptopurine; Methotrexate; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Solid Phase Extraction; Tandem Mass Spectrometry; Thioguanine

Both tumour suppressor and oncogenic functions have been ascribed to the atypical zeta isoform of protein kinase C (PKCζ), whereas its constitutively active form PKMζ is almost exclusively expressed in the brain where it has a role in long-term memory. Using primers unique for either isoform, we found that both PKCζ and PKMζ were expressed in a subset of paediatric acute lymphoblastic leukaemia (ALL) cases carrying a TCF3 (E2A) chromosomal rearrangement. Combined PKCζ and PKMζ (PKC/Mζ) protein as well as phosphorylation levels were elevated in ALL cases, especially TCF3-rearranged precursor B-ALL cases, compared with normal bone marrow (P<0.01). Furthermore, high PKC/Mζ expression in primary ALL cells was associated with increased sensitivity to 6-thioguanine and 6-mercaptopurine (P<0.01), thiopurines used in ALL treatment. PKCζ is believed to stabilize mismatch-repair protein MSH2, facilitating thiopurine responsiveness in T-ALL. However, PKC/Mζ knockdown in a TCF3-rearranged cell line model decreased MSH2 expression but did not induce thiopurine resistance, indicative that the link between high PKC/Mζ levels and thiopurine sensitivity in paediatric precursor B-ALL is not directly causal. Collectively, our data indicate that thiopurine treatment may be effective, especially in paediatric TCF3-rearranged ALL and other patients with a high expression of PKC/Mζ.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Leukemic; HEK293 Cells; Humans; Isoenzymes; Lentivirus; Leukocytes, Mononuclear; Mercaptopurine; Phosphorylation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase C; Thioguanine

We evaluated the clinical, laboratory, and prognostic factors in adolescent and adult patients with acute lymphoblastic leukemia (ALL).. In this observational, retrospective, cross-sectional study, we examined the medical records of all consecutive patients with ALL admitted to a public hospital in Brazil from 1990 to 2005.. Of the 102 patients included, 88 were treated with 2 protocols of chemotherapy (Berlin-Frankfurt-Münster [BFM] 86 modified [BFM-86M] and UCLA [University of California, Los Angeles] protocol). The complete remission (CR), disease-free survival, and overall survival (OS) rate was 70.6%, 27%, and 30.5%, respectively (median follow-up, 49 months). Age < 18 years and no leukemic infiltration in the central nervous system (CNS) at diagnosis were positively associated with CR (P = .03); no bleeding and hepatomegaly at diagnosis and age < 35 years were associated with better OS on multivariate analyses of the whole population (P = .01). OS at 4 years was superior with BFM-86M than with UCLA (49.5% vs. 16%; P = .004), especially in young adults without risk factors.. We identified age as the most important prognostic factor in patients with ALL. CNS infiltration, hepatomegaly, and bleeding were associated with lower OS but must be validated in future research with South American populations and worldwide. The BFM-86M protocol can be considered a therapeutic option for young adults (age < 35 years) without adverse prognostic factors. For other patients with ALL, we emphasize the need for different therapeutic approaches.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Consolidation Chemotherapy; Cross-Sectional Studies; Cyclophosphamide; Cytarabine; Female; Humans; Induction Chemotherapy; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Retrospective Studies; Treatment Outcome; Vincristine; Young Adult

Methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia is challenged by treatment-related hepatotoxicity, failure to achieve the myelosuppressive target, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low thiopurine methyltransferase (TPMT) activity have lower levels of hepatotoxic methylated thiopurine metabolites (MeMPs), higher levels of thioguanine nucleotides (TGNs), and reduced relapse rates. Addition of 6-thioguanine to maintenance therapy of a child with ALL and high TPMT activity increased the TGN/MeMP index in erythrocytes 5.5-fold, mimicking the more favorable thiopurine metabolism seen in patients with low TPMT activity.

Topics: Antimetabolites, Antineoplastic; Child; Erythrocytes; Female; Humans; Mercaptopurine; Methyltransferases; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Thioguanine

Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT.. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy.. The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses).. For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heterozygote; Humans; Leukopenia; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Myelopoiesis; Nucleic Acid Synthesis Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk; Scandinavian and Nordic Countries; Survival Analysis

Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30-50 mg m(-2) in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m(-2), P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

Topics: Alleles; Antimetabolites, Antineoplastic; Child, Preschool; Dose-Response Relationship, Drug; Female; Genetic Variation; Genotype; Humans; Japan; Male; Mercaptopurine; Multidrug Resistance-Associated Proteins; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

For children with precursor B (pre-B) acute lymphoblastic leukemia (ALL) with TCF3-PBX1 fusion gene, their prognosis has been a controversial topic. From January 2008 to December 2012 in our hospital, 450 patients were diagnosed as ALL. Clinical characteristics of 20 patients with TCF3-PBX1 fusion gene were analyzed retrospectively, which were classified to the intermediate-risk (IR) group according to Chinese Children Leukemia Group-2008 (CCLG-2008) risk-stratification criteria and protocol based on the backbone of BFM 95 trails. Eighty five cases without TCF3-PBX1 in the same IR group were regarded as the comparison group. There were no differences in age, gender, initial white blood cell (WBC) count, status of central nerves system (CNS) at diagnosis and complete remission (CR) rates of bone marrow (BM) between the two groups (P > .05). The 5-year probability of event-free survival (EFS) rates were 84.4 ± 15.6% and 73.5 ± 15.6% in the TCF3-PBX1 group and the comparison group (P = .35), respectively. The 5-year probability of overall survival (OS) rates were 86.0 ± 17.6% and 81.8 ± 17.6% (P = .46), respectively. Relapse rates were 10.5% and 12.9% (P = 1.00), respectively. There were not cases with CNS relapse in the TCF3-PBX1 group. When intensive chemotherapy was used, the TCF3-PBX1 was associated with a favorable outcome in childhood pre-B ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asian People; Asparaginase; Child; Child, Preschool; China; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Infant; Karyotyping; Male; Mercaptopurine; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Retrospective Studies; Vincristine

Topics: Antimetabolites, Antineoplastic; Genetic Variation; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythrocytes; Female; Guanine Nucleotides; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Thrombocytopenia

Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.

Topics: Adolescent; Child; Child, Preschool; Exome; Feedback, Physiological; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Leukemia, B-Cell; Male; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Recurrence; Ribose-Phosphate Pyrophosphokinase; Tetrahydrofolates

Mutations in the de novo purine biosynthesis enzyme PRPS1 drive thiopurine resistance in relapsed ALL.

Topics: Drug Resistance, Neoplasm; Humans; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Ribose-Phosphate Pyrophosphokinase; Thioguanine

Topics: Antimetabolites, Antineoplastic; Female; Humans; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Variability in prescribed doses of 6-mercaptopurine (6MP) and lack of adherence to a 6MP treatment regimen could result in intra-individual variability in systemic exposure to 6MP (measured as erythrocyte thioguanine nucleotide [TGN] levels) in children with acute lymphoblastic leukemia (ALL). The effect on relapse risk of this variability is unknown.. To determine the effect of high intra-individual variability of 6MP systemic exposure on relapse risk in children with ALL.. We used a prospective longitudinal design (Children's Oncology Group study [COG-AALL03N1]) to monitor 6MP and disease relapse in 742 children with ALL in ambulatory care settings of 94 participating institutions from May 30, 2005, to September 9, 2011. All participants met the following eligibility criteria: (1) diagnosis of ALL at 21 years or younger; (2) first continuous remission in progress at the time of study entry; (3) receiving self-, parent-, or caregiver-administered oral 6MP during maintenance therapy; and (4) completion of at least 6 months of maintenance therapy at the time of study enrollment. The median patient age at diagnosis was 5 years; 68% were boys; and 43% had National Cancer Institute-based high-risk disease.. Daily 6MP regimen adherence was measured over 68 716 person-days using an electronic system that recorded the date and time of each 6MP bottle opening; adherence rate was defined as the ratio of days that a 6MP bottle was opened to days thata 6MP bottle was prescribed. Average monthly 6MP dose intensity was measured over 120 439 person-days by dividing the number of 6MP doses actually prescribed by the number of planned protocol doses (75 mg/m2/d). Monthly erythrocyte TGN levels (pmol/8 × 108 erythrocytes) were measured over 6 consecutive months per patient (n = 3944 measurements). Using intra-individual coefficients of variation (CV%), patients were classified as having stable (CV% <85th percentile) vs varying (CV% ≥85th percentile) indices. Median follow-up time was 6.7 years from the time of diagnosis.. Adjusting for clinical prognosticators, we found that patients with 6MP nonadherence (mean adherence rate <95%) were at a 2.7-fold increased risk of relapse (95% CI, 1.3-5.6; P = .01) compared with patients with a mean adherence rate of 95% or greater. Among adherers, high intra-individual variability in TGN levels contributed to increased relapse risk (hazard ratio, 4.4; 95% CI, 1.2-15.7; P = .02). Furthermore, adherers with varying TGN levels had varying 6MP dose intensity (odds ratio [OR], 4.5; 95% CI, 1.5-13.4; P = .01) and 6MP drug interruptions (OR, 10.2; 95% CI, 2.2-48.3; P = .003).. These findings emphasize the need to maximize 6MP regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.

Topics: Adolescent; Age Factors; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Monitoring; Female; Humans; Infant; Logistic Models; Longitudinal Studies; Male; Medication Adherence; Mercaptopurine; Multivariate Analysis; Odds Ratio; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; United States; Young Adult

We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia.. Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt.. We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse.. Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Topics: Adolescent; Child; Child, Preschool; Egypt; Female; Genotype; Hematologic Diseases; Humans; Male; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction

6-Mercaptopurine (6-MP) plays an important role in treatment of childhood acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphohydrolase (ITPA) is an enzyme involved in 6-MP metabolic pathway that convert the inosine triphosphate (ITP) to inosine monophosphate (IMP) and prevents the accumulation of the toxic metabolite ITP. Our objective was to evaluate the ITPA 94C>A, IVS2+21A>C polymorphisms in patients with ALL treated with 6-MP and prediction of its clinical outcomes. Our study population consisted of 70 patients diagnosed with ALL in the Division of Hematology-Oncology of Tehran Mofid Hospital. PCR was carried out to amplify exon 2, exon 3, intron 2, and intron 3 of ITPA gene then, all the amplified fragments were subjected to directional sequencing and then association between genotype and 6-MP toxicity was studied. In this study two exonic variants including 94C>A and 138G>A showed a prevalence of 8.5% and 36.4%, respectively. Two intronic variants, IVS2+21A>C and IVS3+101G>A were found in 13.5% and 7% of the samples, respectively. The rate of myelosuppression in the presence of mutant homozygote and heterozygous alleles (94C>A, 138G>A, IVS2+21A>C and IVS3+101G>A) was higher than that of wild type alleles during the use of 6-MP. Hepatotoxicity in patients with mutant homozygous and heterozygous 94C>A and IVS3+101G>A during the treatment 6-MP was higher than before treatment with 6-MP. Our results showed that patients with aberrant ITPase genotype (mutant homozygous or heterozygous), more likely to be myelosuppressed and show liver toxicity after treatment with 6-MP. Our results suggest that pre-therapeutic screening of patients for ITPA 94C>A, IVS2+21A>C and IVS3+101G>A can help in minimizing the adverse effects of 6-MP in ALL patients.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genotype; Humans; Infant; Iran; Male; Mercaptopurine; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Reverse Transcriptase Polymerase Chain Reaction

In the United States, doctors generally develop new cancer chemotherapy for children by testing innovative chemotherapy protocols against existing protocols in prospective randomized trials. In the Netherlands, children with leukemia are treated by protocols that are agreed upon by the Dutch Childhood Oncology Group. Periodically, the Dutch Childhood Oncology Group revises its protocols. Sometimes, these revisions are categorized as research, sometimes as treatment. In this Ethics Rounds, we analyze whether enrollment in a new protocol ought to be considered research and, if so, we discuss the implications of that designation. Our discussion highlights the different ways different countries approach complex issues of research ethics.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Clinical Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Evidence-Based Medicine; Humans; Leucovorin; Mercaptopurine; Methotrexate; Netherlands; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Assessment; Therapeutic Human Experimentation; United States; Vincristine

Parvovirus B19 is a small single-stranded DNA virus of the Parvoviridae family. Depending on host factors, it may produce a wide array of clinical disease states. Disease severity can range from self-limited to severe, requiring significant supportive care. Immunocompromised patients are generally affected more severely but rarely develop prolonged and persistent infections. Here, we describe a patient who was diagnosed with parvovirus during maintenance therapy for acute lymphoblastic leukemia and required therapy with intravenous immunoglobulin; the patient remained parvovirus positive according to a polymerase chain reaction testing but had no clinical symptoms for 27 months off chemotherapy.

Topics: Antineoplastic Agents; Asymptomatic Infections; Child; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Parvoviridae Infections; Parvovirus B19, Human; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Viremia

6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture.. TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27).. A threefold increase of TPMT gene expression was obtained during maintenance therapy, modulated by the architecture of the VNTR region.. The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Bone Marrow; Child; Child, Preschool; Female; Gene Expression Regulation, Neoplastic; Humans; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Minisatellite Repeats; Monocytes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic

Acute lymphoblastic leukemia (ALL) is the most common form of paediatric cancer. Maintenance therapy as last treatment phase includes oral chemotherapy with methotrexate (MTX) and mercaptopurine (6-MP), self- or parent-administered at home, given for about 1 ½ years, and qualified as decisive for an optimum therapy outcome. The aim of our study was to analyze factors influencing the adherence of patients with ALL undergoing maintenance therapy and their families.. A multi-method study was undertaken between 11/2011 and 10/2014 with patients surveyed by the Hannover Medical School outpatient clinic, including a questionnaire survey and qualitative interviews with parents as well as blood samples of the patients.. 33 questionnaires, 27 interviews and blood samples of 26 patients could be analyzed. Only one third of the blood samples showed concentrations of the 6-MP active metabolite within the therapeutic reference range. Parents named the clinical doctor as their main advisor on medication intake. 36% (12/33) of the participants stated that medication intake has not always occurred the way medication was prescribed. Drug formulation and drug intake information could be identified as determinants of adherence. Parents' problems to obtain information are partly caused by different study results concerning the correct timing of the drug intake and drug interactions with milk products.. Parents' information on drug therapy should be more consistent and the pharmaceutical formulations have to be adapted to patients' needs to improve adherence and thereby the chance of long-term remission.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Female; Food-Drug Interactions; Humans; Infant; Maintenance Chemotherapy; Male; Medication Adherence; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Surveys and Questionnaires

Topics: Antimetabolites, Antineoplastic; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacterial Infections; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Encephalitis, Herpes Simplex; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Induction Chemotherapy; Infant; Male; Mercaptopurine; Methotrexate; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Simplexvirus; Stomatitis, Herpetic; Vincristine; Virus Activation

To compare the relapse-free survival (RFS) in Vietnamese (n=141) and white (n=94) children living in Vietnam and Belgium, respectively, and treated in their own country for acute lymphoblastic leukemia according to the same FRALLE 2000 protocol.. RFS was significantly worse in Vietnamese children (hazards ratio=4.48; 95% confidence interval [CI], 2.16-9.3; P<0.01). The 5-year RFS was 83.8% (95% CI, 76.3%-92.0%) and 47.8% (95% CI, 35.6%-64.2%) for white and Vietnamese children, respectively. In the latter group, relapses occurred in bone marrow and cerebrospinal fluid at a much earlier stage. The outcome was compared at first relapse only because of different treatments afterward, according to the country. Both series were similar for sex, age at diagnosis, initial white blood cell count, cytogenetic abnormalities, and corticosensitivity at day 8. Higher frequency of L2-acute lymphoblastic leukemia (P<0.001) but lower frequency of T-acute lymphoblastic leukemia (P=0.004) were observed in Vietnamese children.. Several factors may contribute to the poor RFS in Vietnamese children, which include the time interval before the first intrathecal therapy and differences in the management of drug-related toxicity. However, additional contribution of socioeconomic factors and/or variations in pharmacogenetic polymorphisms in Vietnamese patients cannot currently be ruled out.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asian People; Belgium; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Treatment Outcome; Vietnam; White People; Young Adult

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL.

Topics: Adolescent; Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Evaluation; Female; Guanine Nucleotides; Humans; Hyperbilirubinemia; Hypoxanthine Phosphoribosyltransferase; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Xanthine Oxidase

Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.. We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype.. The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03).. This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT).

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cohort Studies; Cytogenetic Analysis; DNA, Neoplasm; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Genotype; Humans; Infant; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Pharmacogenetics; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Risk Factors

Acute lymphoblastic leukaemia (ALL) has posed challenges to the clinician due to variable patients' responses and late diagnosis. With the advance in metabolomics, early detection and personalised treatment are possible.. Metabolomic profile of 21 ALL patients treated with 6-mercaptopurine and 10 healthy volunteers were analysed using liquid chromatography/mass spectrometry quadrupole-time of flight (LC/MS Q-TOF). Principal components analysis (PCA), recursive analysis, clustering and pathway analysis were performed using MassHunter Qualitative and Mass Profiler Professional (MPP) software.. Several metabolites were found to be expressed differently in patients treated with 6-mercaptopurine. Interestingly, 13 metabolites were significantly differently expressed [p-value <0.01 (unpaired t-test) and 2-fold change] in 19% of the patients who had relapses in their treatment. Down-regulated metabolites in relapsed patients were 1-tetrahexanoyl-2-(8-[3]-ladderane-octanyl)-sn-GPEtn, GPEtn (18:1(9Z)/0:0), GPCho(O-6:0/O-6:0), GPCho(O-2:0/O-1:0), methyl 8-[2-(2-formyl-vinyl)-3-hydroxy-5-oxo-cyclopentyl]-octanoate and plasma free amino acids (PFAA). Characterizing the subjects according to their ITPA 94C>A genotypes reveal differential expression of metabolites.. Our research contributes to identification of metabolites that could be used to monitor disease progress of patients and allow targeted therapy for ALL at different stages, especially in preventing complication of relapse.

Topics: Adolescent; Amino Acids; Case-Control Studies; Female; Humans; Male; Mercaptopurine; Metabolome; Metabolomics; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Principal Component Analysis

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Computer Simulation; Drug Interactions; Humans; Infant; Infant, Newborn; Mercaptopurine; Methotrexate; Models, Biological; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tissue Distribution; Young Adult

Thiopurines are used for many cancers, including acute lymphoblastic leukemia (ALL). Patients with an inherited host defect in thiopurine methyltransferase (TPMT) are at high risk for life-threatening toxicity if treated with conventional dosages, but the impact on antileukemic efficacy is less clear.. We treated thiopurine-sensitive BCR-ABL+Arf-null Tpmt+/+ ALL in Tpmt+/+, +/-, or -/- recipient mice to test the impact of the host polymorphism on antileukemic efficacy.. Median survival was similar in untreated mice of different Tpmt genotypes (16-18 days). However, in mice treated with low-dose mercaptopurine (such as tolerated by TPMT-/- patients), the difference in 30-day leukemia-free survival by Tpmt genotype was profound: 5% (±9%) for Tpmt+/+ mice, 47% (±26%) for Tpmt+/- mice, and 85% (±14%) for Tpmt-/- mice (P=5×10), indicating a substantial impact of host Tpmt status on thiopurine effectiveness. Among Tpmt+/+ recipient mice, leukemia-free survival improved with higher doses of mercaptopurine (similar to doses tolerated by wild-type patients) compared with lower doses, and at higher doses was comparable (P=0.6) to the survival of Tpmt-/- mice treated with the lower dose.. These findings support the notion that germline polymorphisms in Tpmt affect not only host tissue toxicity but also antitumor effectiveness.

Topics: Animals; Fusion Proteins, bcr-abl; Germ Cells; Humans; Male; Mercaptopurine; Methyltransferases; Mice; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); however, interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. We determined the prevalence of the major genetic polymorphisms in 6-MP metabolizing enzymes in Chilean children with ALL.. 103 Chilean pediatric patients with a confirmed diagnosis of ALL were enrolled. DNA was isolated from whole blood and genetic polymorphism in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) coding genes were detected by polymorphism chain reaction-restriction fragment length (PCR-RFLP) assay.. The total frequency of variant TPMT alleles was 8%. TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively. For ITPA, the frequency of P32T allele was 3%. We did not observe any homozygous variant for TPMT and ITPA alleles. We also analyzed a subgroup of 40 patients who completed the maintenance phase of ALL treatment, and we found that patients carrying a TPMT gene variant allele required a significantly lower median cumulative dosage and median daily dosage of 6-MP than patients carrying wild type alleles.. TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

Topics: Adolescent; Alleles; Child; Child, Preschool; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

To explore 6-mercaptopurine (6-MP) treatment-related adverse reactions in children with acute lymphoblastic leukemia (ALL), and to assess the association between the polymorphisms of thiopurine methyltransferase (TPMT) gene and these 6-MP related toxicities.. Total RNA was extracted from bone marrow samples of 46 children with ALL and was then reversed to cDNA. TPMT(*)1S and (*)3C were screened by denaturing gradient gel electrophoresis (DGGE) combining with DNA sequencing. Drug toxicities were classified according to national cancer institute-common toxicity criteria version 3.0 (NCI CTC 3.0). The relationship between TPMT gene polymorphisms and the adverse reactions of 6-MP treatment was analyzed.. During the maintenance treatment period, 22% (10/46) of children discontinued 6-MP treatment because of serious adverse reactions. Two children with TPMT(*)3C genotypes presented severe adverse reactions, including 1 child with homozygotic mutation who had 6-MP dose-related myelosuppression and hepatotoxicity. The main side effects of 6-MP were myelosuppression, hepatotoxicity and gastrointestinal reaction. And there were no significant differences between TPMT(*)1S genotypes and severe myelosuppression or hepatotoxicity caused by 6-MP (P>0.05).. TPMT(*)3C may correlate with severe adverse reactions caused by 6-MP.

Topics: Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Dramatic progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has been achieved during the last two decades in Western countries, where the 5-year event-free survival (EFS) rate has risen from 30 to 85 %. However, similarly high cure rates have not always been achieved in all centers in developing countries due to limited sources. We evaluated the treatment results of the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol as used between 1995 and 2009 in the pediatric hematology departments of two university hospitals. A retrospective analysis of 343 children newly diagnosed with ALL (M/F 200/143, median age 6.8 years) was performed. The overall survival (OS) and EFS according to age, initial leukocyte count, immunophenotype, chemotherapy responses (on days 8, 15, and 33), and risk groups were analyzed by Kaplan-Meier survival analysis. Median follow-up time was 6.4 years. Complete remission was achieved in 97 % of children. Five-year EFS and OS were found to be 78.4 and 79.9 %, respectively. Children younger than 6 years old had significantly better EFS and OS (83.7 and 85.2 %) than children aged ≥6 years (71.4 and 72.8 %). Adolescents achieved 63 % EFS and 65 % OS. Patients who had initial leukocyte counts of <20 × 10(9)/L had better EFS and OS (82.2 and 84.6 %) than children with higher initial leukocyte counts (72.6 and 72.6 %). EFS for B-cell precursor and T-cell ALL was 81.5 and 66.7 %, respectively. Children with a good response to prednisolone on day 8 (87 %) achieved significantly better EFS and OS (81.2 and 81.9 % vs. 55.3 and 60.5 %). Children whose bone marrow on day 15 was in complete remission had higher EFS and OS (83.7 and 86.6.1 % vs. 56.4 and 61.5 %). Children in the standard-risk and medium-risk groups obtained statistically significantly higher EFS (95.5 and 82.7 %) and OS (97.7 and 82.3 %) compared to the high-risk group (EFS 56.3 %, OS 63.4 %). The relapse rate was 14.8 %. The median relapse time from diagnosis was 23.2 months. Death occurred in 69 of 343 patients (20.1 %). The major causes of death were infection and relapse. None of the patients died of drug-related toxicity. The ALL-BFM 95 protocol was applied successfully in these two centers. In developing countries in which minimal residual disease cannot be monitored, this protocol can still be used with high survival rates.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Evaluation; Follow-Up Studies; Humans; Immunophenotyping; Infant; Kaplan-Meier Estimate; Leukocyte Count; Mercaptopurine; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome; Turkey; Vincristine

Viral-associated trichodysplasia spinulosa is an unusual condition with distinctive clinical and histopathological features. Initially described in patients immunosupressed as a result of solid organ transplantation, it has also been reported in patients treated with immunosuppressive drugs other than cyclosporine or being treated for hematological malignancies. Patients presented with disseminated follicular, hyperkeratotic papules, and variable degrees of alopecia. Histopathological examination revealed shaftless bulbous and dilated hair follicles with keratotic plugging of the infundibulum. The authors reported a case of viral-associated trichodysplasia in a 5-year-old boy treated for a lymphoblastic leukemia. Eruption persisted, although treated with emollients and keratolytics, but resolved spontaneously after completing the antineoplastic medication.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Hair Diseases; Humans; Ichthyosis; Immunocompromised Host; Male; Mercaptopurine; Methotrexate; Polyomavirus Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance.. This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude's Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase.. Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 µmol/l (β=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (β=-4.905; 95% CI: -9; -0.809 and β=-5.770; 95% CI: -10.138; -1.403), respectively.. Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Child, Preschool; Female; Genotype; Humans; Infant; Lebanon; Liver-Specific Organic Anion Transporter 1; Male; Mercaptopurine; Methotrexate; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reduced Folate Carrier Protein; Retrospective Studies; Treatment Outcome

Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen.. Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes.. The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively.. ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cohort Studies; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Female; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Thioguanine; Treatment Outcome; Vincristine; Young Adult

Genetic polymorphisms are important factors in effects and toxicity of chemotherapeutics. This study aimed to investigate whether there was a correlation between genotype or haplotype of inosine triphosph pyrophosphohydrolase(ITPA) and toxicities during maintenance therapy with mercaptopurine (6-MP) in Chinese patients with acute lymphoblastic leukemia (ALL). 95 ALL children who hospitalized between October 2004 and September 2007,were retrospectively analyzed. 6-MP toxicity was documented according to Common Toxicity Criteria, Version 2.0. ITPA sequencing was undertaken. Correlation between genotype/haplotype and 6-MP toxicity was analyzed. The results indicated that 50 cases (52.6%) had grade III-IV of bone marrow inhibition. These children had long-term disease-free survival (DFS), without hepatic and other organs' dysfunction and secondary tumors. Three variations were observed in ITPA exon 2 (94 C → A), exon 3 (138 G → A), and exon 8 (561 G → A), the 94A carriers (CA and AA) had a lower risk of developing 6-MP toxicity when compared with carriers of the CC genotype (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12-0.98, P = 0.039). The risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but with no significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with wild-type haplotype 94C-138G-561G (OR: 0.26, 95% CI 0.07-0.94 P = 0.043). In conclusion, the risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but without significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with the wild-type haplotype 94C-138G-561G.

Topics: Adolescent; Antimetabolites, Antineoplastic; Asian People; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Male; Mercaptopurine; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies

Medication errors occur universally. Inappropriate administration of chemotherapy drugs can have adverse effects in cancer patients. Our objective was to assess the rate and type of medication errors in children with acute lymphoblastic leukemia (ALL) receiving oral chemotherapy in outpatient setting.. Prescription and administration of oral chemotherapy drugs in children with ALL were evaluated prospectively to determine rate and type of medication errors. Errors were defined as prescription (physician) level or administration (patient) level errors.. Two hundred eighty-nine drugs were prescribed to 121 patients. Medication errors occurred in 36 (12.5%) prescriptions; 21(7.3%) were administration errors, 13 (4.5%) were prescribing errors, and two errors occurred at both levels. Mercaptopurine (6-MP) was significantly associated with higher rates of errors (Odds ratio [OR] = 2.1, 95% CI [confidence interval] 1-4.1) whereas lapses were less with dexamethasone (OR = 0.25, 95% CI 0.09-0.67). As a result of medication errors 28 (23.1%) patients received inappropriate doses. Twenty five (21%) patients received sub-optimal doses whereas three got higher doses of chemotherapy. On univariate analysis, socioeconomic status, education status of the caregiver, 6-MP and methotrexate were significantly associated with errors (P ≤ 0.05). On multivariate analysis, ≤ primary school education of the caregiver and prescription of methotrexate were independent predictors of errors.. Medication errors affected nearly one fourth of the children receiving oral chemotherapy. Future studies are needed to look at effective interventions to avoid chemotherapy associated errors especially amongst the lower strata of society.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cross-Sectional Studies; Developing Countries; Dexamethasone; Drug Prescriptions; Female; Follow-Up Studies; Humans; Infant; Male; Medication Errors; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Factor V; Female; Hemostasis; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

In this issue of Blood, Bhatia et al demonstrate the critical importance of an adherence to oral chemotherapy regimens in attaining cure for children with acute lymphoblastic leukemia (ALL) and identify race-specific determinants of adherence.

Topics: Female; Humans; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Racial Groups

Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects.

Topics: Antimetabolites, Antineoplastic; Child; Erythrocyte Indices; Humans; Leukopenia; Mercaptopurine; Patient-Specific Modeling; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors

Herein, we report the first case of kaposiform haemangioendothelioma (KHE) associated with acute B-lymphoblastic leukemia (B-ALL).. A five-month-old infant presented a plaque of angiomatous appearance on the forearm that had increased in volume since birth, as well as pallor and cutaneous haematomas. Kasabach-Merritt syndrome (KMS) was evoked despite hepatomegaly and considerable splenomegaly. Laboratory tests revealed severe anaemia and thrombocytopenia as well as major hyperleukocytosis with 90% blasts. Skin biopsy revealed vast vascular lobules containing cohesive fusiform endothelial cells not expressing Glut1, bound up in a dense infiltrate of B-lymphoblast cells. It was in fact KHE associated with B-ALL confirmed by the myelogram. The child was treated with the INTERFANT 2006 protocol followed by allograft of haematopoietic stem cells, which resulted in complete haematological remission. At the same time, almost total regression of KHE was noted.. In this infant, KHE had an inflammatory appearance and was associated with thrombocytopenia, evocative of KMS. Analysis of blood and marrow samples resulted in a diagnosis of B-ALL. Histopathological examination of the angioma revealed a typical appearance of KHE associated with dense lymphoblastic proliferation. This appearance could have resulted either from passive contamination by circulating blast cells or from active recruitment of tumor cells at the KHE site.. HK mimicking KMS may reveal B-ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Diagnostic Errors; Hemangioendothelioma; Hemangioma; Humans; Infant, Newborn; Kasabach-Merritt Syndrome; Leukemia, B-Cell; Male; Mercaptopurine; Methotrexate; Neoplasms, Multiple Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Skin Neoplasms; Transplantation, Homologous

Topics: 5'-Nucleotidase; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Europe; Germany; History, 20th Century; History, 21st Century; Humans; Medical Oncology; Mercaptopurine; Methotrexate; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Randomized Controlled Trials as Topic; Vincristine

The BFM studies for relapsed childhood acute lymphoblastic leukemia (ALL) were started in 1983, at a time when cure rates for ALL were still lower and the number of children with ALL relapse equaled about the number of children with newly diagnosed neuroblastoma. Today, relapses have become relatively rare events in ALL although, because of the frequency of ALL, they are still a significant cause of death in children and adolescents. With currently used treatment modalities, cure rates of about 50% after relapse can be achieved, and, together with the improved results of front-line therapy, the survival rate of childhood ALL is now about 90%. Most children with extramedullary and late bone marrow (BM) relapses achieve a second CR; remission rates in patients with high-risk features, however, remain still unsatisfactory. With improved techniques allogeneic hematopoietic stem cell transplant (HSCT) has become a relatively safe treatment but is not necessary for all patients as postremission therapy. HSCT is not required in children with isolated extramedullary and late BM relapses with rapid response to induction therapy measured by molecular techniques (minimal residual disease, MRD) but absolutely indicated in patients with early BM relapses and systemic relapses of T-cell ALL. For patients with insufficient response innovative therapies such as small molecules or targeted immunological or pharmacological approaches are urgently required. Efforts have to be made, therefore, in order to detect potential biological or molecular targets, which can be used for individualized, more effective and hopefully less toxic therapies in the future.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Europe; Hematopoietic Stem Cell Transplantation; Humans; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Retreatment; Survival Rate; Vincristine

We describe a 5-year-old female with acute lymphoblastic leukemia (ALL) who suffered from cytomegalovirus (CMV) retinitis during maintenance therapy consisting of 6-mercaptopurine (6-MP) and methotrexate (MTX) with pulses of vincristine (VCR) and dexamethasone (DEX). Administration of anticytomegaloviral drugs led to a complete regression of active retinitis. Her low CD4 positive T cells and serum immunoglobulin G (IgG) recovered when maintenance therapy was resumed without VCR and DEX. The patient has been in complete remission (CR) for more than 5 months after completion of maintenance therapy without recurrence of CMV retinitis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Cytomegalovirus Retinitis; Dexamethasone; Female; Humans; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Two children with acute lymphoblastic leukemia/lymphoma developed recurrent acute pancreatitis during treatment; the etiology was presumed to be secondary to 6-mercaptopurine (6MP). Both had no further attacks after discontinuation of 6MP. Acute pancreatitis secondary to 6MP is extremely rare in acute leukemia/lymphoma although it has been reported in patients with other conditions like inflammatory bowel disease; the reason for this difference is not clearly understood.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Acute lymphoblastic leukemia (ALL) maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH), attributed to purine analog (mercaptopurine [6-MP]). This hypoglycemia has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver.. An overweight 5-year-old boy with ALL was evaluated for SH (lethargy and vomiting) that occurred 8-10 h after fasting while receiving daily 6-MP. Hypoglycemic episodes (>20 episodes per month) occurred predominantly around midmorning but not during the 5-day dexamethasone pulse. The adrenocorticotropic hormone test yielded a normal cortisol response, which ruled out pituitary adrenal suppression. A 12-h overnight fasting glucose was 49 mg/dL, with suppressed insulin response <2 IU/mL, low C-peptide of 0.5 ng/mL, high insulin-like growth factor-binding protein >160 ng/mL, high free fatty acid of 2.64 mmol/L, and negative glucagon stimulation test (change in blood glucose [BG] <5 mg/dL). These results ruled out hyperinsulinism. The patient was placed on cornstarch therapy 5 h prior to dosing with 6-MP. This treatment reduced the SH events to fewer than two episodes per month. To study the efficacy of cornstarch, the patient was fitted with the iPro™ professional continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA) with a preset low alarm at 70 mg/dL, which was worn for a period of 5 days while the patient was on cornstarch. With 1,000 sensor reading the BG range was 65-158 mg/dL, and the percentage mean absolute difference between sensor and finger-stick BG readings (the parent monitored his BG four times a day) was 9.4%. There were no hypoglycemic episodes detected by the CGMS while the patient was on cornstarch. After the cessation of chemotherapy, a 15-h fasting study was performed, and the CGMS was placed. Results showed resolution of hypoglycemia.. The CGMS helped us devise an effective management plan for our patient. CGMS proved useful as an adjunct to characterize the pattern of hypoglycemia and to validate the benefit of cornstarch in hypoglycemia associated with 6-MP treatment of ALL.

Topics: Antimetabolites, Antineoplastic; Blood Glucose; Blood Glucose Self-Monitoring; Child, Preschool; Fasting; Humans; Hypoglycemia; Male; Mercaptopurine; Monitoring, Ambulatory; Precursor Cell Lymphoblastic Leukemia-Lymphoma

A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. The method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 × 10⁸ RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 °C for 8 h after sampling.

Topics: Adult; Analytic Sample Preparation Methods; Antimetabolites, Antineoplastic; Azathioprine; Biotransformation; Chromatography, High Pressure Liquid; Drug Monitoring; Erythrocytes; Female; Humans; Indicators and Reagents; Male; Mercaptopurine; Nucleic Acid Synthesis Inhibitors; Pilot Projects; Potassium Permanganate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Quaternary Ammonium Compounds; Thioguanine; Thionucleotides

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

Topics: 5'-Nucleotidase; Antineoplastic Agents; Arabinonucleosides; Base Sequence; Cell Line; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sequence Analysis, DNA; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Cyclophosphamide; Cytarabine; Doxorubicin; Eye Neoplasms; Fatal Outcome; Female; Humans; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Vincristine

Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA 94C>A) contribute to variable responses, including fatal adverse effects, among subjects treated with 6-mercaptopurine (6-MP). Our objectives were to investigate the distribution of specific TPMT and ITPA genotypes in healthy subjects and patients with acute lymphoblastic leukaemia (ALL) from the three main ethnic groups (Malays, Chinese and Indians) in Malaysia and the association of the polymorphisms with adverse effects of 6-MP.. Patients with ALL and healthy controls were recruited and genotyped for genetic variants of TPMT and ITPA 94C>A. The relationship between genotypes and clinical outcomes was investigated.. Acute lymphoblastic leukaemia patients with allele ITPA 94A were more likely to develop fever and liver toxicity with 6-MP. The prevalence of TPMT variants was low and this makes it unlikely that testing for them would be useful in our populations. Only patients heterozygous for TPMT*3C were detected.. Our results suggest that ITPA 94C>A testing, but not TPMT testing, may help in minimizing the adverse effects of 6-MP in Malaysian patients. However, whether this is true in clinical practice requires a larger study and formal randomized controlled evaluation.

Topics: Adolescent; Antimetabolites, Antineoplastic; Case-Control Studies; Child; Child, Preschool; Ethnicity; Female; Genotype; Humans; Infant; Inosine Triphosphatase; Malaysia; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Young Adult

Methotrexate (MTX) and 6-mercaptopurine (6MP) are the most commonly used drugs in the therapy of childhood acute lymphoblastic leukaemia (ALL). The main genotoxic effect of MTX resulting from inhibition of thymidylate synthase is mis-incorporation of uracil into DNA, which is considered essential for the effectiveness of the Protocol M in ALL IC BFM 2002/EURO LB 2002 regimens. In this study, we investigated the level of basal and induced DNA damage as well as the effectiveness of DNA repair in lymphocytes of children with ALL at four time-points during therapy with MTX and 6MP. To assess DNA damage and the efficacy of DNA repair we used the modified alkaline comet assay with uracil DNA glycosylase (Udg) and endonuclease III (EndoIII). In addition, we examined the induction of apoptosis in the lymphocytes of the patients during treatment. Finally, we compared the activity of base-excision repair (BER), involved in removal of both uracil and oxidized bases from DNA in lymphocytes of children with ALL and lymphocytes of healthy children. BER efficiency was estimated in an in vitro assay with cellular extracts and plasmid substrates of heteroduplex DNA with an AP-site. Our results indicate that there is a significant decrease in the efficacy of DNA repair associated with an increased level of uracil in DNA and induction of apoptosis during therapy. Moreover, it was found that the BER capacity was decreased in the lymphocytes of ALL patients in contrast to that in lymphocytes of healthy children. Thus, we suggest that an impairment of the BER pathway may play a role in the pathogenesis and therapy of childhood ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Child; Child, Preschool; Comet Assay; DNA Damage; DNA Repair; Humans; Hydrogen Peroxide; Lymphocytes; Male; Mercaptopurine; Methotrexate; Oxidation-Reduction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Uracil; Young Adult

Topics: Antimetabolites, Antineoplastic; Female; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Thiopurines are S-substituted antimetabolites that are widely used in the treatment of hematological malignancies and as immunosuppressants. Because of extensive inter-individual variation in drug disposition and the significant toxicity associated with thiopurine therapy, there is a need for improved individualized treatment. We here present a fast and sensitive method for quantifying the pharmacological end-point of thiopurines, 6-thioguanine (TG) in chromosomal DNA. Purine nucleobases are released from DNA, etheno-derivatized with chloroacetaldehyde, separated by HILIC and quantified by tandem mass spectrometry using endogenous chromosomal guanine as internal standard. The method is linear up to at least 10 pmol TG/μg DNA and the limit of detection and quantification are 4.2 and 14.1 fmol TG/μg DNA, respectively. The matrix (DNA) had no effect upon quantification of TG. SPE recovery was estimated at 63% (RSD 26%), which is corrected for by the internal standard resulting in stable quantification. The TG levels found were above the LOQ in 18 out of 18 childhood leukemia patients on 6-mercaptopurine/methotrexate maintenance therapy (median 377, range 45-1190 fmol/μg DNA) with intra- and inter-day RSDs of less than 11%. The method uses 2 μg DNA/sample, which can easily be obtained from these patients.

Topics: Calibration; Child; Chromatography, Liquid; DNA; DNA, Neoplasm; Guanine; Humans; Jurkat Cells; Leukocytes; Limit of Detection; Linear Models; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry; Thioguanine

Cryptosporidium species is considered to be an important cause of significant morbidity in immunocompromised individuals. A prospective case-control study of sporadic diarrhea due to Cryptosporidium infection was conducted on children with acute lymphoblastic leukemia (ALL).. Forty children with ALL on maintenance chemotherapy according to the Berlin-Frankfurt-Munster (BFM-90) protocol and 45 sex- and age-matched controls were studied. The ALL group included 25 patients with acute diarrhea and 15 without diarrhea, and the control group included 30 children with acute diarrhea and 15 without. Collected stool specimens were examined using modified Ziehl-Neelsen (MZN) and modified trichrome stains. Serum Cryptosporidium Parvum immunoglobulin G (IgG) antibodies were detected by enzyme-linked immunosorbent assay.. Cryptosporidium oocysts, pathogenic Gram-negative organisms, Giardia lamblia, and Entamoeba histolytica were identified in the stool samples (fecal specimens) of six (24%), eight (32%), four (16%), and two (8%), respectively, of the 25 patients with ALL and actute diarrhea and in one (3%), two (6.5%), six (20%), and five (16.5%), respectively, of the 30 control patients with diarrhea. Serum IgG antibodies were positive in four of the six ALL patients and in one of the control group patients with Cryptosporidium diarrhea who tested positive for oocysts in the stool. Diarrhea duration and severity were greater in ALL patients with stool-positive Cryptosporidium oocysts than in those with non-Cryptosporidium-positive diarrhea (p < 0.000).. Cryptosporidium infection should be considered in children with ALL presenting with prolonged or severe watery diarrhea during chemotherapy, especially those treated with methotrexate and 6-mercaptopurine. Since Cryptosporidium is not routinely tested for in stool examination, a MZN stain is recommended.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Cryptosporidiosis; Cryptosporidium parvum; Diarrhea; Egypt; Entamoeba histolytica; Feces; Female; Gastroenteritis; Giardia lamblia; Gram-Negative Bacteria; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies

TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. MATERIALS, METHODS & RESULTS: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP.. These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients.

Topics: Alleles; Genotype; Humans; K562 Cells; Mercaptopurine; Methyltransferases; Minisatellite Repeats; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Protein Binding; Transcription, Genetic; Tumor Cells, Cultured

This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Biotransformation; Brazil; Gene Frequency; Genetic Loci; Genetic Markers; Genotype; Glucocorticoids; HapMap Project; Humans; Mercaptopurine; Methotrexate; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Racial Groups; Regression Analysis

Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.. A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed.. After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites.. Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence-an observation currently under investigation.

Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Female; Hispanic or Latino; Humans; Infant; Male; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk; Surveys and Questionnaires; Time Factors; United States

The rationale of this study was to explore the contribution of genetic variants of the folate pathway to toxicity of 6-mercaptopurine (6-MP)-mediated hematological toxicity in children with acute lymphoblastic leukemia (ALL) and to explore the interaction of these variants with TPMT and ITPA haplotypes using multifactor dimensionality reduction analysis.. Children with ALL (n = 96) were screened for GCPII C1561T, RFC1 G80A, cSHMT C1420T, TYMS 5´-UTR 2R3R, TYMS 3´-UTR ins6/del6, MTHFR C677T, MTR A2756G polymorphisms using PCR-RFLP and PCR-amplified fragment length polymorphism techniques.. GCPII C1561T showed independent association with toxicity. The following synergetic interactions appeared to increase the toxicity of 6-mercaptopurine: TPMT*12 × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A × TYMS 2R3R. The genetic variants of thiopurine and folate pathway cumulatively appeared to increase the predictability of toxicity (r(2) = 0.41) in a multiple linear regression model. For the observed toxicity grades of 1, 2, 3 and 4, the respective predicted toxicity grades were 1.65 ± 0.29, 1.68 ± 0.24, 2.56 ± 0.58 and 2.99 ± 1.03, p(trend) < 0.0001.. Gene-gene interaction between thiopurine and folate pathways inflate the 6-MP-mediated toxicity in Indian children with ALL illustrating the importance of ethnicity in the toxicity of 6-MP.

Topics: Adolescent; Biomarkers, Pharmacological; Child; Child, Preschool; Female; Folic Acid; Genetic Association Studies; Glutamate Carboxypeptidase II; Haplotypes; Humans; Male; Mercaptopurine; Metabolic Networks and Pathways; Methotrexate; Methyltransferases; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Although the outcome of patients with acute lymphoblastic leukemia (ALL) has been improved continuously by chemotherapy and tyrosine kinase inhibitors, prognosis of patients with Philadelphia chromosome positive (Ph(+)) ALL still remains poor. Since further intensification of chemotherapy is limited by toxic side effects and patients with high risk of transplant-related mortality are not eligible for allogeneic stem cell transplantation new treatment strategies are urgently needed for the prevention of Ph(+) ALL relapse. There is increasing evidence that the immune system plays an essential role for the eradication or immunologic control of remaining leukemia cells. We developed several DNA-based vaccines encoding a BCR-ABL(p185) specific peptide and GM-CSF, and CD40-L, IL-27 or IL-12 and evaluated the preventive and therapeutic efficacy against a lethal challenge of syngeneic Ph(+) ALL in Balb/c mice. In vivo cell depletion assays and cytokine expression studies were performed and the efficacy of the DNA vaccine was compared with 6-mercaptopurine (6-MP) alone and the combination of the DNA vaccine and 6-MP. Preventive immunization with the vaccine BCR-ABL/GM-CSF/IL-12 and the TLR-9 agonist dSLIM induced an innate and adaptive immune response mediated by NK-cells, CD4(+) T-cells and CD8(+) T-cells leading to a survival rate of 80%. Therapeutic vaccination resulted in a significantly longer leukemia-free survival (40.7 days vs. 20.4 days) and a higher survival rate (56% vs. 10%) compared to chemotherapy with 6-MP. Remarkably, in combination with the vaccine 6-MP acted synergistically and led to 100% survival. These results demonstrate that minimal residual disease of Ph(+) ALL can be significantly better controlled by a combined treatment approach of immunotherapy and chemotherapy. This provides a rationale for improving maintenance therapy in order to reduce the relapse rate in patients with Ph(+) ALL.

Topics: Animals; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD40 Ligand; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Female; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Colony-Stimulating Factor; Immunity, Innate; Interleukin-12; Interleukin-17; Killer Cells, Natural; Lymph Nodes; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Messenger; Vaccination; Vaccines, DNA

Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.

Topics: Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Tract; Gene Expression; Genome-Wide Association Study; Genotype; HapMap Project; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

This study was aimed to analyze the thiopurine S-methyltransferase (TPMT) gene sequence in acute lymphoblastic leukemia (ALL) children severely intolerant to 6-mercaptopurine (6-MP) and to investigate the causes resulting in tolerance difference to 6-MP in ALL children so as to provide evidence for safe and rational use of 6-MP. The adverse reactions of drug was evaluated in ALL children treated with BCH-2003-ALL chemotherapeutic protocol during 2004-10-1 to 2007-9-30 according to NCI-CTC V2.0. The TPMT gene sequences of ALL children with 3-4 grade of severe toxicity during the maintenance therapy were analyzed by PCR and direct DNA sequencing. To assure the accuracy of sequencing, the 738 bp fragment of coding region in TPMT gene (NM_000367) was divided into 3 subfragments and bidirectionally sequenced. The results indicated that among 133 ALL children, 61 were severely intolerant to 6-MP. The direct DNA sequencing showed that among 59 patients (excluding 2 cases without RNA samples), the simple myelotoxicity was found in 37 cases, hepato-myelotoxicity was observed in 9 cases, hepatotoxicity along appeared in 12 cases, 1 case showed skin rash. Out of 59 ALL children, the C474T mutation was found in 57 cases, with mutation rate 96.6%, including 21 cases with heterozygous mutation and 36 cases with homozygosis mutation. The TPMT gene sequencing of 10 cases tolerant to 6-MP indicated that C474T mutation was detected in 8 cases which was homozygous mutation. It is concluded that the C474T mutation in 738 bp fragment of coding region in TPMT gene is very frequent, but it is not related with tolerance to 6-MP, suggesting that severe intolerance to 6-MP in ALL children may be not related with the mutation of coding region in TPMT gene.

Topics: Adolescent; Child; Child, Preschool; Drug Tolerance; Female; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sequence Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Combined Modality Therapy; Dexamethasone; Erythroblasts; Erythropoiesis; Female; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients.. A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers.. The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A, 1 TPMT*3A/*3A) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A, TPMT*1 (wild-type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004).. The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Poland; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Young Adult

A 4-year-old boy with acute lymphoblastic leukemia who was receiving 6-mercaptopurine during the maintenance chemotherapy experienced prolonged generalized tonic nocturnal seizures because of severe hypoglycemia after his evening dose by a 12-hour period of fasting. Investigations ruled out all causes of these seizures other than the 6-mercaptopurine-induced severe hypoglycemia.

Topics: Anti-Infective Agents; Antimetabolites, Antineoplastic; Child, Preschool; Humans; Hypoglycemia; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Seizures; Trimethoprim, Sulfamethoxazole Drug Combination

An increased understanding of the genetic basis of disease creates a demand for personalized medicine and more genetic testing for diagnosis and treatment. The objective was to assess the incremental cost-effectiveness per life-month gained of thiopurine methyltransferase (TPMT) genotyping to guide doses of 6-mercaptopurine (6-MP) in children with acute lymphoblastic leukemia (ALL) compared to enzymatic testing and standard weight-based dosing.. A cost-effectiveness analysis was conducted from a health care system perspective comparing costs and consequences over 3 months. Decision analysis was used to evaluate the impact of TPMT tests on preventing myelosuppression and improving survival in ALL patients receiving 6-MP. Direct medical costs included laboratory tests, medications, physician services, pharmacy and inpatient care. Probabilities were derived from published evidence. Survival was measured in life-months. The robustness of the results to variable uncertainty was tested in one-way sensitivity analyses. Probabilistic sensitivity analysis examined the impact of parameter uncertainty and generated confidence intervals around point estimates.. Neither of the testing interventions showed a benefit in survival compared to weight-based dosing. Both test strategies were more costly compared to weight-based dosing. Incremental costs per child (95% confidence interval) were $277 ($112, $442) and $298 ($392, $421) for the genotyping and phenotyping strategies, respectively, compared to weight-based dosing.. The present analysis suggests that screening for TPMT mutations using either genotype or enzymatic laboratory tests prior to the administration of 6-MP in pediatric ALL patients is not cost-effective.

Topics: Antimetabolites, Antineoplastic; Bone Marrow Diseases; Child, Preschool; Clinical Enzyme Tests; Cost-Benefit Analysis; Decision Trees; Drug Dosage Calculations; Genetic Testing; Genotype; Humans; Mercaptopurine; Methyltransferases; Models, Econometric; Ontario; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sensitivity and Specificity; Survival Analysis

6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response.. Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis.. During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity.. In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

Topics: Age Factors; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythrocytes; Genotype; Humans; Liver; Mercaptopurine; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Statistics as Topic; Thioguanine

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL.. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files.. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy.. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Turkey

This study aimed to investigate whether there was a correlation between the genotype or haplotype of the methylenetetrahydrofolate reductase gene (MTHFR) and toxicities during consolidation therapy or plasma methotrexate (MTX) levels at 48 h after the first dose of MTX infusion. We retrospectively genotyped 181 children with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated with the Chinese Children's Leukemia Group protocol. In standard- and medium-risk treatment branches, the 677T carriers (CT + TT) had a higher risk of developing thrombocytopenia when compared with carriers of the CC genotype (odds ratio [OR] 5.21, 95% confidence interval [CI] 1.18-23.01, p = 0.017). The 1298AC/CC genotypes were associated with a decrease in skin toxicity, as compared with the common AA genotype (p = 0.037). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. A lower frequency of anemia (OR 0.44, 95% CI 0.21-0.90, p = 0.025) and lower MTX level (p = 0.044) were observed in patients with the 677C-1298C haplotype than in those without. High plasma MTX level was correlated with anemia (p = 0.011) and neutropenia (p = 0.044). In the high-risk group, the polymorphisms or plasma MTX levels were not correlated with any toxicity. Taken together, our data demonstrate that genotyping of MTHFR and measurement of plasma MTX levels might be useful to optimize MTX therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asian People; Child; Child, Preschool; China; Drug-Related Side Effects and Adverse Reactions; Female; Gene Frequency; Genotype; Haplotypes; Humans; Infant; Linkage Disequilibrium; Logistic Models; Male; Mercaptopurine; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neutropenia; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Skin Diseases; Thrombocytopenia

Topics: Antimetabolites, Antineoplastic; Clinical Enzyme Tests; Genetic Testing; Humans; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adolescent; Age Factors; Antineoplastic Agents; Case-Control Studies; Child; Dexamethasone; Female; Humans; Male; Mercaptopurine; Methotrexate; Muscle Strength; Muscle Stretching Exercises; Muscle Weakness; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Sex Factors; Time Factors; Vincristine

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Cerebral Ventricles; Cyclophosphamide; Female; Fusion Proteins, bcr-abl; Humans; Hydrocephalus; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

Genetic variations of the enzymes involved in chemotherapy metabolism in cancer patients may play a role in determining relapse and toxicity risks. Methotrexate is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5,10 methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is central to folate metabolism and has two common functional polymorphisms (C677>T and A1298>C). The present study aimed to assess the prevalence of MTHFR polymorphisms C677>T and A1298>C in Egyptian children with ALL and the relation to the frequency of drug-induced complications and relapse rate. Forty ALL patients were included in the study. They were treated according to modified ALL-BFM 90 protocol, and were followed up for 3.1-6.5 years. The severity and duration of hepatic, mucosal and infectious complications during therapy were reported. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay. The MTHFR C677>T polymorphic allele frequencies were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively among the studied ALL patients. The MTHFR A1298>C polymorphic allele frequencies were 40, 35, and 25% for AA, AC, and CC genotypes, respectively. Methotrexate therapy was significantly associated with increased grade III/IV toxicity in TT genotype: diarrhea in 81.3%, oral mucositis in 81.3%, elevated transaminases in 87.5%, neutropenia in 78.7% compared to values of 7.7, 7.7, 15.3, and 7.7% in CC genotype, respectively (P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.03). The 677 TT genotype was significantly associated with relapse in 5 years in 56.3%, compared to 18.2% in CT and 0% in CC alleles. The overall 5 years survival was significantly lower in 677 TT (50%) compared with CC genotypes (92.3%) (P = 0.001). No significant relation was found between MTHFR A1298C polymorphism and the risks of therapy induced complications or relapse rate in the studied ALL patients. MTHFR TT genotype is significantly associated with increased mucosal and hepatic toxicity during methotrexate therapy as well as increased relapse rate in childhood ALL. Because of the relatively high prevalence of the TT genotype in the studied Egyptian children with ALL, MTHFR gene polymorphisms should be studied in large multicenter studies; and dosage modification of methotrexate in the ALL treatment protocols should be considered based on the MTHF

Topics: Alleles; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Egypt; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Mercaptopurine; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neoplasm Proteins; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Stomatitis; Vincristine

To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT).. We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy.. DNA-6TGN levels were significantly correlated to E-6TGN (r (p) = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r (p) = -0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r (p) = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites.. DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytosol; DNA; Drug Monitoring; Erythrocytes; Female; Guanine Nucleotides; Humans; Infant; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Thionucleotides

The antimetabolite mercaptopurine is commonly used as part of treatment regimens for acute lymphoblastic leukemia and as treatment for inflammatory bowel diseases. Adverse effects associated with mercaptopurine include myelosuppression, hepatotoxicity, and hyperpigmentation. We describe a 36-year-old man with Philadelphia chromosome-negative pre-B-cell acute lymphoblastic leukemia who experienced a serious mercaptopurine-induced hypersensitivity reaction requiring prolonged hospitalization and extensive laboratory testing and imaging. He was treated with a multiagent chemotherapy regimen. Mercaptopurine 60 mg/m(2)/day orally was started as part of his third course of chemotherapy. On day 9 of mercaptopurine therapy, the patient developed persistent fevers, skaking chills, and rigors that persisted in the absence of documented infection, consistent with drug fever. All symptoms and signs resolved after discontinuation of mercaptopurine. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient's development of fever and mercaptopurine therapy. Mercaptopurine-induced fever has been reported in patients with inflammatory bowel diseases, but this case report is the first, to our knowledge, in a patient with acute lymphoblastic leukemia. Health care professionals should be aware of the possible development of fever as a hypersensitivity reaction in patients with acute lymphoblastic leukemia treated with mercaptopurine.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Hypersensitivity; Fever; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts.. To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m(2) over 24 h) with daily oral 6-MP (25 mg/m(2)) during interval therapy in 20 children with ALL.. HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease -21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis-Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period.. HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Biotransformation; Child; Child, Preschool; Drug Interactions; Erythrocytes; Female; Humans; Inactivation, Metabolic; Injections, Intravenous; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Bone impairment is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors but less is known about bone dynamics during ALL therapy. We longitudinally assessed by Quantitative Ultrasound (QUS) skeletal modifications during this treatment.. Forty-four newly diagnosed ALL children underwent bone measurement by QUS parameters BTT (Bone Transmission Time) and AD-SoS (Amplitude-Dependent Speed of Sound), mainly reliant on bone density and cortical thickness, respectively. Measurements were performed at diagnosis, and 6, 12, and 24 months thereafter. The occurrence of skeletal complications such as fractures, vertebral collapse, osteonecrosis, and osteopenia was related to measurement outcome.. A rapid deterioration of bone properties measured by BTT and AD-SoS was evident in the first semester of therapy (p<0.001). Subsequently, the next measurements were characterized by progressive uncoupling of the two QUS parameters (p<0.001). These were both significantly reduced at the end of therapy (p<0.001). Twelve subjects with in-treatment skeletal complications displayed an almost two-fold decrease of both parameters (p<0.001). BTT decreasing more than 1 Standard Deviation (SD) over 6 months of therapy was able to predict skeletal complication occurrence (p<0.001).. This report represents the largest longitudinal cohort systematically submitted to bone condition assessment from the beginning to the end of therapy for childhood ALL. Bone deterioration occurs early and persists throughout therapy, consistent with bone properties uncoupling. This pattern possibly reflects an initial impairment of both mineral density and cortical thickness with a subsequent recovery of this latter. QUS permits an early detection of bone deterioration and related skeletal complications in childhood ALL.

Topics: Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Density; Chi-Square Distribution; Child; Child, Preschool; Cyclophosphamide; Cytosine; Female; Fractures, Bone; Humans; Male; Mercaptopurine; Methotrexate; Osteonecrosis; Osteoporosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Time Factors; Ultrasonography; Vincristine

Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.

Topics: Algorithms; Antimetabolites, Antineoplastic; Child; Dose-Response Relationship, Drug; Erythrocyte Indices; Humans; Mercaptopurine; Models, Biological; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Sensitivity and Specificity; Treatment Outcome

The prevalence of thiopurine S-methyltransferase (TPMT) polymorphism and its association with clinical and hematological toxicities was retrospectively analyzed in 71 Indian children with acute lymphoblastic leukemia (ALL). Only heterozygous TPMT alleles were observed (10%, 7/71) with relative frequencies being *1/*3C (4.2%), *1/*2 (4.2%) and *1/*3A (1.4%). The median 6-mercaptopurine dose administered during the maintenance therapy was 31% lower among patients with heterozygous TPMT alleles versus the rest (32.1mg/m(2)/day and 46.2mg/m(2)/day, p=0.005), though the myelosuppression and toxicities were similar in both the groups. Identification of TPMT genotype appears to be important in making the ALL treatment more effective and less toxic.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; India; Infant; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Survival Rate; Treatment Outcome

In a group of newly diagnosed acute lymphocytic leukemia (ALL) children we evaluated a number of hemostatic and inflammatory markers at diagnosis and at different time points during chemotherapy for the remission induction to identify alterations in the plasma levels of prothrombotic markers before and during the course of chemotherapy. The following plasma markers were evaluated: thrombin-antithrombin complex (TAT), D-Dimer, plasminogen activator inhibitor 1 (PAI-1), antithrombin, fibrinogen, von Willebrand factor (VWF) antigen and high molecular weight VWF (HMW-VWF) multimers, P-selectin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6). Plasma samples were collected at the following time points: at T0 (baseline) and T1 (+24 days of therapy), T2 (+36 days therapy), and T3 (+64 days therapy). The results show that, at diagnosis, ALL children presented with laboratory signs of increased thrombin generation and fibrin formation (i.e. high TAT and D-dimer levels), fibrinolysis inhibition (i.e. high PAI-1 level), endothelial activation (i.e., high HMW-VWF and soluble P-selectin levels) and inflammation (i.e. high TNF-alpha and IL-6 levels). After starting induction therapy, the thrombin generation markers and inflammatory cytokines significantly decreased. To the opposite, PAI-1 and P-selectin significantly increased, suggesting an insult by chemotherapy on the vascular endothelium. These effects were more evident during steroid administration. Symptomatic venous thromboembolism (VTE) episodes developed in two cases during induction therapy, which did not allow the evaluation of the predictive value for VTE of laboratory markers.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Antithrombins; Asparaginase; Case-Control Studies; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Fibrin Fibrinogen Degradation Products; Humans; Infant; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; P-Selectin; Plasminogen Activator Inhibitor 1; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Risk Factors; Thrombin; Thrombophilia; Venous Thromboembolism; Vincristine; von Willebrand Factor

Central nervous system (CNS) complications during treatment of childhood acute lymphoblastic leukemia (ALL) remain a challenging clinical problem. Outcome improvement with more intensive chemotherapy has significantly increased the incidence and severity of adverse events. This study analyzed the incidence of neurological complications during ALL treatment in a single pediatric institution, focusing on clinical, radiological, and electrophysiological findings. Exclusion criteria included CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy, late-onset encephalopathy, or long-term neurocognitive defects. During a 9-year period, we retrospectively collected 27 neurological events (11%) in as many patients, from 253 children enrolled in the ALL front-line protocol. CNS complications included posterior reversible leukoencephalopathy syndrome (n = 10), stroke (n = 5), temporal lobe epilepsy (n = 2), high-dose methotrexate toxicity (n = 2), syndrome of inappropriate antidiuretic hormone secretion (n = 1), and other unclassified events (n = 7). In conclusion, CNS complications are frequent events during ALL therapy, and require rapid detection and prompt treatment to limit permanent damage.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System; Central Nervous System Diseases; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Electroencephalography; Female; Humans; Infant; Leukemic Infiltration; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Tomography, X-Ray Computed; Vincristine

There is limited data about the long-term treatment outcome and prognosis of childhood acute lymphoblastic leukemia (ALL) in developing countries. Our study was designed to assess survival data and identify risk factors. Data of 142 children with ALL who were treated with a modified BFM 95 protocol between 1997 and 2007 were evaluated. The median age was 4.3 years. Complete remission (CR) rate after induction phase was 93.5%; with 2.1% induction-related mortality and 0.7% having resistance disease. Of complete responders, 67.1% are in continuous CR with a median follow-up of 63 months (range: 24 to 153 mo). Treatment-related mortality was 17.7% and the total rate of treatment abandonment was 3.5%. The probability of event-free survival was 67.3% (95% confidence interval 59.3-75.3) at 4 years and 63.2% (95% confidence interval 54.4-72.0) at 8 years. This report examines children with ALL treated with a modified ALL-BFM 95 protocol in a tertiary care center in Turkey with adequate follow up and demonstrates the need for improvements especially for patients with unfavorable risk group and strategies to reduce deaths from infection in CR to keep pace with cure rates in developed countries.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Recurrence; Retrospective Studies; Risk Factors; Turkey; Vincristine

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child, Preschool; Cytarabine; Humans; Injections, Intramuscular; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Tuberculosis, Pulmonary; Vincristine

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.

Topics: Adolescent; Child; Child, Preschool; Female; Gastrointestinal Diseases; Humans; Infant; Male; Mercaptopurine; Neutropenia; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Drug-Related Side Effects and Adverse Reactions; Female; Hematopoietic Stem Cell Transplantation; Heterozygote; Humans; Male; Mercaptopurine; Methylenetetrahydrofolate Reductase (NADPH2); Methyltransferases; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Down Syndrome; Female; Guideline Adherence; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Patient Compliance; Physician's Role; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome

There has been a steady improvement in cure rates for children with advanced-stage lymphoblastic non-Hodgkin's lymphoma. To further improve cure rates whereas minimizing long-term toxicity, we designed a protocol (NHL13) based on a regimen for childhood T-cell acute lymphoblastic leukemia, which features intensive intrathecal chemotherapy for central -nervous system-directed therapy and excludes prophylactic cranial irradiation. From 1992 to 2002, 41 patients with advanced-stage lymphoblastic lymphoma were enrolled on the protocol. Thirty patients had stage III and 11 had stage IV disease. Thirty-three cases had a precursor T-cell immunophenotype, five had precursor B-cell immunophenotype and in three immunophenotype was not determined. Out of the 41 patients, 39 (95%) achieved a complete remission. The 5-year event-free rate was 82.9+/-6.3% (s.e.), and 5-year overall survival rate was 90.2+/-4.8% (median follow-up 9.3 years (range 4.62-13.49 years)). Adverse events included two induction failures, one death from typhlitis during remission, three relapses and one secondary acute myeloid leukemia. The treatment described here produces high cure rates in children with lymphoblastic lymphoma without the use of prophylactic cranial irradiation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; T-Lymphocytes; Treatment Outcome; Vincristine

Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Infant; Karyotyping; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Risk Factors; Stem Cell Transplantation; Survival Rate; Treatment Outcome

The study analyzed the characteristics and prognostic significance of additional chromosomal abnormalities in 110 Chinese adults with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL). Secondary aberrations were present in 60.9% of the cases. All chromosomes were involved in secondary aberrations, and chromosomes 9, 7, 21, 18, and 14 were most frequently abnormal. Fifty of 110 patients (45.5%) had at least one normal metaphase cell in their chromosome preparations at diagnosis. Patients with additional aberrations had shorter disease-free survival (DFS) and overall survival (OS) in chemotherapy combined with imatinib (ICT) group and only shorter DFS in conventional chemotherapy (CT) group. The existence of normal metaphase cells was associated with a superior survival in CT group, but not in ICT group. Patients with loss of chromosomes 7, 7p, 9, and 9p had inferior outcome compared to patients with other secondary aberrations and those without secondary aberrations, in both CT and ICT group.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Benzamides; Chromosome Aberrations; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Pyrimidines; Salvage Therapy; Vincristine; Vindesine; Young Adult

Six-mercaptopurine (6-MP) is a pro-drug widely used in treatment of various diseases, including acute lymphoblastic leukaemia (ALL). Side-effects of thiopurine therapy have been correlated with thiopurine methyltransferase (TPMT) activity. We propose a novel TPMT-mediated mechanism of S-adenosylmethionine (SAM)-specific effects on 6-mercaptopurine (6-MP) induced cytotoxicity in a model cell line for acute lymphoblastic leukemia (MOLT). Our results show that exogenous SAM (10-50microM) rescues cells from the toxic effects of 6-MP (5microM) by delaying the onset of apoptosis. We prove that the extent of methylthioinosine monophosphate (MeTIMP) induced inhibition of de novo purine synthesis (DNPS) determines the concentrations of intracellular ATP, and consequently SAM, which acts as a positive modulator of TPMT activity. This leads to a greater conversion of 6-MP to inactive 6-methylmercaptopurine, and thus lower availability of thioinosine monophosphate for the biotransformation to cytotoxic thioguanine nucleotides (TGNs) and MeTIMP. We further show that the addition of exogenous SAM to 6-MP treated cells maintains intracellular SAM levels, TPMT activity and protein levels, all of which are diminished in cells incubated with 6-MP. Since TPMT mRNA levels remained unaltered, the effect of SAM appears to be restricted to protein stabilisation rather than an increase of TPMT expression. We thus propose that SAM reverses the extent of 6-MP cytotoxicity, by acting as a TPMT-stabilizing factor. This study provides new insights into the pharmacogenetics of thiopurine drugs. Identification of SAM as critical modulator of TPMT activity and consequently thiopurine toxicity may set novel grounds for the rationalization of thiopurine therapy.

Topics: Cell Line, Tumor; Drug Antagonism; Humans; Lymphocytes; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Messenger; S-Adenosylmethionine

Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.

Topics: Adolescent; Alleles; Amino Acid Substitution; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Gene Frequency; Genotype; Humans; Male; Mercaptopurine; Methotrexate; Multidrug Resistance-Associated Proteins; Mutation, Missense; Pilot Projects; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Retrospective Studies; Survival Rate

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cranial Irradiation; Humans; Hypoxanthine Phosphoribosyltransferase; Immunoenzyme Techniques; Karyotyping; Mercaptopurine; Methotrexate; Methyltransferases; Mutation; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Risk Factors; Stem Cell Transplantation; Survival Rate; Treatment Outcome

Modified BFM-90 regimen has significantly improved the outcome of lymphoblastic lymphoma in children and adolescents. Infection is the main side effect of this regimen, which may affect the treatment efficacy and prognosis without proper intervention. This study was to summarize the characteristics of the modified BFM-90 regimen related infection, and explore effective approaches to treat the infection.. The infection rate, site, pathogen were reviewed for the infections of 104 children and adolescents suffering from lymphoblastic lymphoma at different phases of the modified BFM-90 regimen. The relationship between chemotherapy, bone marrow suppression and infection was analyzed. The value of procalcitonin (PCT) in identifying the infection type and the outcome of anti-infection treatment was evaluated.. The infection rates in reduction phases Ia, Ib and re-reduction phases IIa, IIb were 52.5%, 60.7% and 48.6%, 28.2%, respectively. The infection rate in consolidation chemotherapy for patients with low to intermediate risk and high risk were 17.2% and 100%, respectively. In total 302 infections occurred. One hundred and sixty-seven cases (55.3%) had documented infection sites, most of which happened to the respiratory tract. Ninety-five cases (31.5%) had documented pathogens, most of which were Gram-negative bacteria. Infections of 262 cases (86.8%) were secondary to bone marrow suppression. The sensitivity and specificity of PCT in diagnosing sepsis were 83.3% and 70.2%, but it failed to identify the infection type. After the anti-infection treatment, 296 cases were cured, four cases gave up further treatment due to financial difficulties, two cases died of sepsis.. Infections caused by modified BFM-90 regimen for lymphoblastic lymphoma in children and adolescents are closely correlated to bone marrow suppression. The positive diagnosis rate of the pathogen is too low to identify most of the infection type. The treatment still mainly depends on experience.

Topics: Adolescent; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacterial Infections; Cephalosporins; Child; Child, Preschool; Cross Infection; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Female; Humans; Itraconazole; Male; Mercaptopurine; Methotrexate; Mouth Diseases; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Remission Induction; Respiratory Tract Infections; Vincristine

To develop a method that prospectively assesses adherence rates in paediatric patients with acute lymphoblastic leukaemia (ALL) who are receiving the oral thiopurine treatment 6-mercaptopurine (6-MP).. A total of 19 paediatric patients with ALL who were receiving 6-MP therapy were enrolled in this study. A new objective tool (hierarchical cluster analysis of drug metabolite concentrations) was explored as a novel approach to assess non-adherence to oral thiopurines, in combination with other objective measures (the pattern of variability in 6-thioguanine nucleotide erythrocyte concentrations and 6-thiouric acid plasma levels) and the subjective measure of self-reported adherence questionnaire.. Parents of five ALL patients (26.3%) reported at least one aspect of non-adherence, with the majority (80%) citing "carelessness at times about taking medication" as the primary reason for non-adherence followed by "forgetting to take the medication" (60%). Of these patients, three (15.8%) were considered non-adherent to medication according to the self-reported adherence questionnaire (scored > or = 2). Four ALL patients (21.1%) had metabolite profiles indicative of non-adherence (persistently low levels of metabolites and/or metabolite levels clustered variably with time). Out of these four patients, two (50%) admitted non-adherence to therapy. Overall, when both methods were combined, five patients (26.3%) were considered non-adherent to medication, with higher age representing a risk factor for non-adherence (P < 0.05).. The present study explored various ways to assess adherence rates to thiopurine medication in ALL patients and highlighted the importance of combining both objective and subjective measures as a better way to assess adherence to oral thiopurines.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Male; Medication Adherence; Mercaptopurine; Parents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Uric Acid

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Development of DNA-based tests for TPMT/DPD polymorphisms can help clinicians and patients to make important decisions about cancer treatment. Also, due to lack of Indian data, we aimed at the development and validation of these tests in Indian patients.. Molecular assays were used for identifying TPMT/DPD variations; validated by DNA sequencing.. Molecular assays have been used for screening TPMT*2, *3A, *3B, *3C alleles and IVS14+1(G-->A) in DPD gene. A patient, exhibiting neutropenia on 6-MP was observed to be G460A-homozygote, while, two Acute Lymphoblastic Leukemia (ALL) patients with side-effects exhibited wild-type alleles. Two patients showing 6-MP side-effects and responding well to the same drug at later stage also carried wild-type alleles.. G460A homozygosity in a patient allowed clinicians to stop 6-MP treatment, improving patient's health status. Two ALL patients showing side-effects were wild-type, indicating presence of unidentified rare variations. Two patients with wild-type allele showed side-effects during 6-MP treatment, but responded well to same drug at later stage, suggesting side-effects to be attributable to multiple biological and environmental processes. Absence of IVS14+1(G-->A) in DPD gene will not exclude possibility of another mutation.. Molecular assays for determining common TPMT/DPD variations, can provide accurate diagnosis and efficient therapies in future clinical studies.

Topics: Antineoplastic Agents; Base Sequence; Dihydrouracil Dehydrogenase (NADP); DNA Primers; Fluorouracil; Humans; India; Mercaptopurine; Methyltransferases; Polymerase Chain Reaction; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Dexamethasone; Humans; Hydrocortisone; Injections, Spinal; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Middle Aged; Paraparesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiculopathy; Sacrum; Spinal Nerve Roots; Vincristine

To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD).. Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94-->A and IVS2+21A-->C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined.. Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A-->C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A-->C variants with thrombocytopenia (P = 0.012). CONCLUSIONS; Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Female; Gene Frequency; Genotype; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Treatment Outcome

Through interruption of maintenance treatment with 6-mercaptopurine (6MP), toxicity after high-dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene and coadministration of antimetabolites on post-HDMTX toxicity.. Toxicity was retrospectively analysed after 656 HDMTX courses administered to 88 paediatric ALL patients at a single treatment centre.. High-dose methotrexate with high-intensity co-treatment (6MP 75 mg/m(2)/d + MTX 20 mg/m(2)/wk) was found associated with increased odds of haematological toxicity (OR's: 3.47-7.88; P's: <0.001), hepatic toxicity (OR = 6.91; P < 0.001), hospitalization with fever (OR = 2.2; P = 0.004) and interruption maintenance treatment (OR = 15.9; P < 0.001) compared to HDMTX with low-intensity co-treatment (6MP 25 mg/m(2)/d). Addition of cytarabine to the low-intensity co-treatment increased the odds of neutropenia (OR = 3.51; P = 0.002), thrombocytopenia (OR = 6.56; P < 0.001), hepatic toxicity (OR = 3.84; P = 0.012) and interruption of maintenance treatment (OR = 4.25; P = 0.002). Alterations in 6MP dose were associated with significant changes in toxicity. Dose reduction reduced the odds of haematological toxicity (OR's: 0.22-0.34; P's: <0.001-0.020), while dose increase increased the odds of haematological toxicity (OR's: 2.72-7.42; P's: 0.006-0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity.. Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated antimetabolites, and modifiable by alterations in 6MP dose. Prevention of toxicity related withdrawals through 6MP dose reduction could be a way of increasing total dose intensity.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Cytarabine; Female; Humans; Male; Mercaptopurine; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neutropenia; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Thrombocytopenia

Chemotherapy-induced oral mucositis is a frequent therapeutic challenge in cancer patients. The purpose of this retrospective study was to estimate the prevalence and risk factors of oral mucositis in 169 acute lymphoblastic leukaemia (ALL) patients treated according to different chemotherapeutic trials at the Darcy Vargas Children's Hospital from 1994 to 2005. Demographic data, clinical history, chemotherapeutic treatment and patients' follow-up were recorded. The association of oral mucositis with age, gender, leucocyte counts at diagnosis and treatment was assessed by the chi-squared test and multivariate regression analysis. Seventy-seven ALL patients (46%) developed oral mucositis during the treatment. Patient age (P = 0.33), gender (P = 0.08) and leucocyte counts at diagnosis (P = 0.34) showed no correlation with the occurrence of oral mucositis. Multivariate regression analysis showed a significant risk for oral mucositis (P = 0.009) for ALL patients treated according to the ALL-BFM-95 protocol. These results strongly suggest the greater stomatotoxic effect of the ALL-BFM-95 trial when compared with Brazilian trials. We concluded that chemotherapy-induced oral mucositis should be systematically analysed prospectively in specialized centres for ALL treatment to establish the degree of toxicity of chemotherapeutic drugs and to improve the quality of life of patients based on more effective therapeutic and prophylactic approaches for prevention of its occurrence.

Topics: Adolescent; Age Factors; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brazil; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prevalence; Retrospective Studies; Risk Factors; Sex Factors; Stomatitis; Vincristine

Immunosuppression is a major side effect of cancer chemotherapy. The process of immune reconstitution can be dissimilar according to the nature of the disease, type and doses of drugs, and age of the patients. Recently, several studies have examined immune reconstitution in children and young adults after intensive chemotherapy for solid tumours or stem cell transplantation. The aim of the present study is to evaluate immune reconstitution (cellular and humoral) in children with acute lymphoblastic leukemia during the maintenance phase of therapy and to correlate between the complicating infections and the abnormalities in immune system during reconstitution. To achieve this goal, 36 children with acute lymphoblastic leukemia (24 females and 12 males) in the maintenance phase of therapy with 12 healthy children of matched age and sex served as a control group were recruited in this study. The patients were taken consecutively from the Hematology/Oncology Outpatient Clinic of Mansoura University Children's Hospital (MUCH). They were subjected to thorough history taking, clinical examination and laboratory investigations in the form of: complete blood count, serum creatinine, liver function tests and evaluation of the immune system by estimation of CD3, CD4, CD8, CD19 and CD56 (cellular immunity) by flow cytometry and immunoglobulins A, M and G (humoral immunity) at the first and the third month of maintenance therapy. The results of the study documented presence and persistence of leucopenia and lymphopenia during maintenance therapy with decreased medians of CD3, CD4 and CD8 from the first to the third month of therapy and in comparison to the control group. The other markers CD19, CD56, IgA, IgM, IgG and CD4/CD8 ratio showed increasing median from the first to the third month of therapy. Also we detect a significant correlation between infection and CD19 and serum IgM at the first month and between infection and CD19, IgM and CD4/CD8 ratio at the third month of therapy. In conclusion, persistent immunosuppression is documented in children with acute lymphoblastic leukemia during maintenance therapy. Reconstitution of B lymphocytes and Natural killer cells occurs early while T cell reconstitution shows delayed recovery of both T helper and T suppressor cells. Immunosupression during maintenance therapy has no major clinical impact in terms of increased incidence or severity of systemic infections.

Topics: Adolescent; Adrenal Cortex Hormones; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Case-Control Studies; CD4-CD8 Ratio; Child; Child, Preschool; Female; Humans; Immunoglobulins; Infections; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

We report a 13-year-old male patient with Charcot-Marie-Tooth disease (CMT) type 2 who developed severe neuropathy because of vincristine (VCR) for his acute lymphoblastic leukemia. A clumsy gait, muscle weakness in his fingers, and inverted champagne bottlelike muscle in the lower limbs were noticed after remission induction treatment for acute lymphoblastic leukemia, which included VCR at a total dose of 8 mg/m. An electrophysiologic study showed an almost normal median motor nerve conduction velocity (approximately 50 m/s), markedly reduced M-wave amplitude and sensory disturbance. He was diagnosed as CMT type 2 based on his symptoms and electrophysiologic findings. His symptoms gradually worsened, and even after VCR was discontinued, he could not walk alone for 7 months. VCR has previously been considered to be relatively safe in CMT type 2, however, some patients with CMT type 2 might show severe neurologic toxicities, as seen in patients with CMT type 1.

Topics: Adolescent; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Charcot-Marie-Tooth Disease; Contraindications; Cytarabine; Daunorubicin; Etoposide; Gait Disorders, Neurologic; Humans; Male; Mercaptopurine; Methotrexate; Muscle Weakness; Neural Conduction; Peripheral Nervous System Diseases; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites.. Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m(-2) day(-1)). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites.. The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model.. The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genotype; Humans; Male; Mercaptopurine; Metabolic Clearance Rate; Methyltransferases; Models, Biological; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

The frequency of allele variants of gene TPMT*2, *3A, *3B, and *3C was estimated in a population of 116 Brazilian children with acute lymphoblastic leukemia. The association between genotype and clinical and laboratory data obtained during chemotherapy maintenance phase and the correlation of intraerythrocyte concentration of 6-mercaptopurine metabolites (6-tioguanine nucleotide nucleotides and methylmercaptopurine) were analyzed. A multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used in DNA amplification. Twelve patients presented TPMT gene mutation, all in heterozygous form. The most frequent allele variation was TPMT*3A (3.9%), followed by *3C (0.9%), *2 (0.4%), and *3B (0%). There was no significant association between clinical and laboratory data and the presence of mutation in TPMT gene. Of the 36 patients who were monitored for 6-mercaptopurine metabolite levels, only 1 had the mutation. In this patient, high 6-tioguanine nucleotide and low methylmercaptopurine concentrations were found. Event-free survival (EFS) for the whole group was 73.4%. There was no significant difference in event-free survival in the comparison between the groups with and without mutation (P = 0.06).

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To evaluate the treatment results of central nervous system preventive therapy (CNSP) with triple intrathecal therapy (TIT) alone in children with acute lymphoblastic leukemia (ALL).. We retrospectively studied a cohort of 59 patients with median follow-up time 50.6 months (range: 27-80 months) at a single institution in Taiwan. Patients with ALL were classified in risk groups at diagnosis. TPOG-ALL-93 protocols and TPOG-ALL-2002 protocols were used. Both protocols were for multicenter studies in Taiwan and contained protocols for standard-risk (SR), high-risk (HR), and very-high-risk (VHR) patients. In this study, we used TIT alone for CNSP. In all ALL patients, methotrexate, hydrocortisone, and cytarabine were given at age-dependent doses.. As of October 2006, patients had a 3-year event-free survival and an overall survival 89.4 +/- 4.1% (S.E.) and 93.1 +/- 3.3%, respectively. Under TIT no patients had complications such as seizure, encephalitis, or infection, and no morbidities like those caused by cranial irradiation. In this study, we used TIT alone for CNSP and had no CNS relapse.. In the context of effective systemic therapy, TIT alone appears to be effective CNSP for most patients with ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Epirubicin; Female; Follow-Up Studies; Humans; Hydrocortisone; Infant; Injections, Spinal; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Retrospective Studies; Risk; Survival Analysis; Vincristine

We investigated preliminarily whether methylenetetrahydrofolate reductase (MTHFR) 677C/T or reduced folate carrier 1 (RFC1) 80G/A polymorphisms were associated with toxicities during maintenance chemotherapy with mercaptopurine (6MP) and methotrexate (MTX) in children with acute lymphoblastic leukemia or lymphoblastic lymphoma. The clinical records of 20 children (2 to 15-y old) who had received maintenance chemotherapy were reviewed retrospectively and their genomic DNA was genotyped to identify polymorphisms at MTHFR 677C/T, RFC1 80G/A, and thiopurine methyltransferase 719A/G. Maintenance chemotherapy with 6MP and MTX was repeated on a weekly basis, and any week during which 6MP and/or MTX dosing was withheld was counted as an interrupted episode. Associations between the risk of interruptions and polymorphisms were studied using a generalized estimating equation analysis. Patients with an increasing number of T alleles at MTHFR 677C/T experienced interruptions in both 6MP (P<0.01) and MTX (P=0.03) more frequently. Patients with an increasing number of A alleles at RFC1 80G/A experienced interruptions in 6MP (P=0.04) more frequently. This preliminary study does not prove but suggests that MTHFR 677C/T and RFC1 80G/A polymorphisms may serve as predictors of toxicity during maintenance chemotherapy.

Topics: Adolescent; Antineoplastic Agents; Carbon-Nitrogen Ligases; Child; Child, Preschool; Genotype; Humans; Mercaptopurine; Methotrexate; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reduced Folate Carrier Protein

A 21-year-old white male with relapsed acute lymphoblastic leukemia (ALL) developed an invasive Zygomycosis infection 3 weeks after beginning re-induction chemotherapy. Because of the high risk of fatal recurrence of the fungal infection, neither long-term maintenance chemotherapy nor allogeneic hematopoietic stem cell transplant (HSCT) was considered appropriate. Because his ALL blasts expressed CD34 but lacked CD133, he received a CD133 selected autologous graft following high-dose consolidation chemotherapy. The patient survives in remission 19 months after HSCT.

Topics: AC133 Antigen; Amphotericin B; Antifungal Agents; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Caspofungin; Child; Combined Modality Therapy; Contraindications; Dexamethasone; Drug Therapy, Combination; Echinocandins; Glycoproteins; Humans; Immunomagnetic Separation; Lipopeptides; Male; Mercaptopurine; Methotrexate; Peptides; Peptides, Cyclic; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Recurrence; Remission Induction; Salvage Therapy; Transplantation, Autologous; Transplantation, Homologous; Triazoles; Vincristine; Voriconazole; Zygomycosis

Adolescents with acute lymphoblastic leukaemia (ALL) have languished in the shadow of success of the outcome of therapy in childhood ALL. Their treatment has always been incorporated into either paediatric or adult clinical trials depending on the mode of referral and hence there is a need to address an age and risk specific strategy for improving the outcome of this neglected group of patients. This article has summarised the recent and updated retrospective comparative analysis of adolescents treated on the Medical Research Council (MRC) trials. This analysis adds further emphasis to the treatment approach and the merits and limitations of treatment of adolescents on paediatric and adult trials.. A retrospective comparative analysis of adolescents aged 15-17 years, treated on either MRC ALL97/revised 99 (n = 61), a randomised paediatric trial or UKALLXII/E2993 (n = 67), an adult trial, between 1997 and 2002 was undertaken.. Results suggest a trend towards a superior outcome on paediatric trials. The 5-year EFS on ALL97 was 65% (95% CI = 52-78%) and on UKALLXII/E2993 was 49% (95% CI = 37-61%; P = 0.01). Multivariate analysis allowing for age and Ph status, diminished the EFS difference, but confirmed a reduced rate of death in remission in patients managed on the paediatric protocol.. Despite limitations in the methodology, comparative studies including our MRC study suggest a consistent advantage for adolescents managed intensively on paediatric trials. Redefining age limits with risk-based strategy and multi-centre collaboration should be considered to improve the survival of young adults.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Female; Humans; Male; Mercaptopurine; Methotrexate; Patient Selection; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Research Design; Survival Analysis; Thioguanine; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vincristine

The thiopurine antimetabolite 6-mercaptopurine (6MP) is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL). 6MP is mainly catabolized by both hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and xanthine oxidase (XOD) to form thioinosinic monophosphate (TIMP) (therapeutically active metabolite) and 6-thiouric acid (6TUA) (inactive metabolite), respectively. The activity of both the enzymes varies among ALL patients governing the active and the inactive metabolite profile within the immature lymphocytes. Therefore, an attempt was made to study the kinetic nature of the branched bi-enzyme system acting on 6MP and to quantitate TIMP and 6TUA formed when the two enzymes are present in equal and variable ratios. The quantification of the branched kinetics using spectrophotometric method presents problem due to the closely apposed lambda(max) of the substrates and products. Hence, employing an HPLC method, the quantification of the products was done with the progress of time. The limit of quantification (LOQ) of substrate was found to be 10nM and for products as 50 nM. The limit of detection (LOD) was found to be 1 nM for the substrate and the products. The method exhibited linearity in the range of 0.01-100 microM for 6MP and 0.05-100 microM for both 6TUA and TIMP. The amount of TIMP formed was higher than that of 6TUA in the bi-enzyme system when both the enzymes were present in equivalent enzymatic ratio. It was further found that enzymatic ratios play an important role in determining the amounts of TIMP and 6TUA. This method was further validated using actively growing T-ALL cell line (Jurkat) to study the branched kinetics, wherein it was observed that treatment of 50 microM 6MP led to the generation of 12 microM TIMP and 0.8 microM 6TUA in 6 h at 37 degrees C.

Topics: Adolescent; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Humans; Hypoxanthine Phosphoribosyltransferase; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry; Xanthine Oxidase

In a multicenter study the authors prospectively investigated neurocognitive function in childhood ALL patients. Sixty-six patients (mean age at diagnosis 7.9 +/- 3.6 years, 34 female), treated with repeated intrathecal and systemical methotrexate administrations without cranial irradiation, underwent psychometric testing for intelligence, concentration, and visual-motor integration postdiagnosis and after reinduction therapy. Although there was a statistically significant decline of intellectual function after reinduction therapy for younger patients and girls (IQ scores still within normative data range), there were no differences in visual-motor performance and concentration over the time of induction therapy. Thus, neurocognitive examination should focus on younger ALL patients and girls.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cognition Disorders; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Injections, Spinal; Intelligence Tests; Longitudinal Studies; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prospective Studies; Psychomotor Performance; Risk Factors; Vincristine

Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Clone Cells; Cytotoxins; Hematopoietic Stem Cells; Humans; Immunophenotyping; In Vitro Techniques; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

6-Mercaptopurine (6MP) is an essential anticancer drug used in the treatment of childhood acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe toxicity or efficacy of 6MP. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C, are responsible over the 80% of low or undetectable enzyme activity. The frequencies of these variants were investigated among 106 children with ALL in Turkish population. TPMT*3A and TPMT*3C were the only deficiency alleles detected in Turkish population with an allele frequency of 0.9% for both. While *3C allele frequency in Turkish population was found to be very similar to Asian and other Caucasian populations, *3A allele frequency was significantly (P < 0.05) lower. So far, studies showed that the genetic polymorphisms of other drug metabolizing enzymes like CYP2E1, CYP1A1, GSTM1/ T1 in Turkish population were similar to Caucasian populations. However, we found that the distribution of TPMT polymorphisms in Turkish population was significantly lower than those in other Caucasians like British, French, and Italian whereas the distributions of TPMT variants were found to be very similar to Kazak population which is also Caucasian in ethnic origin. In this study, the clinical histories of the patients in the sample population were also examined, retrospectively. The patients with heterozygous or homozygous mutant genotypes had developed severe neutropenia and infection during 6MP therapy. The study provides the first data on the frequency of common TPMT variants in the Turkish population, based on analysis of pediatric patients with ALL.

Topics: Adolescent; Alleles; Amino Acid Substitution; Antimetabolites, Antineoplastic; Child; Child, Preschool; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Inactivation, Metabolic; Male; Mercaptopurine; Methyltransferases; Neutropenia; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Retrospective Studies; Turkey

Topics: Antimetabolites, Antineoplastic; Child; Exanthema; Excipients; Humans; Hypersensitivity; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Starch; Tablets

Between January 2001 and December 2003, 67 patients with acute leukemia were evaluated prospectively for hemostatic abnormality at presentation, of which 43 (64.2%) had acute lymphoblastic leukemia and 24 (35.8%) had acute myelogenous leukemia. At presentation, 27 patients (40.3%) had bleeding manifestations. Thrombocytopenia was present in 57 patients (85%), and 33(49.3%) had some abnormality of global coagulation markers. Disseminated intravascular coagulation was defined by International Society of Thrombosis and Hemostasis criteria. Disseminated intravascular coagulation was more often associated with bleeding manifestations in acute myelogenous leukemia cases than in acute lymphoblastic leukemia cases. Two patients presented disseminated intravascular coagulation on day 7 of chemotherapy, without any bleeding manifestations. Four of 15 evaluated cases who had a bleeding or infection complication after day 7 of induction therapy also had disseminated intravascular coagulation. It is recommended that all patients with leukemia be investigated for disseminated intravascular coagulation at presentation.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Partial Thromboplastin Time; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Remission Induction; Vincristine

The activity of thiopurine S-methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter-subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time-consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype.. We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL).. Eighty-nine per cent of the children had a homozygous wild-type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0.001) but inter-group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6-methylmercaptopurine derivative/6-thioguanine nucleotides (6-TGN)] and TPMT activity at the end of 6 months' maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6-mercaptopurine monitoring.. Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Erythrocytes; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Pharmacogenomics of acute lymphoblastic leukemia (ALL) evolved rapidly in the past few years. Majority of recent findings concerns knowledge on key components of ALL treatment, 6-mercaptopurine and methotrexate. Leukemia is the most common cancer affecting children, with ALL comprising 80 % of all leukemia cases. Introduction of treatment protocols composed of several chemotherapeutic agents improved importantly survival in patients with ALL. Nevertheless, ALL is still the leading cause of cancer-related death in children. Interindividual differences in drug responses are an important cause of resistance to treatment and adverse drug reactions. Identifying pharmacogenomic determinants of drugs used in ALL treatment may allow for prospective identification of patients with suboptimal drug responses allowing for complementation of traditional treatment protocols by genotype-based drug dose adjustment.

Topics: Antineoplastic Agents; Humans; Mercaptopurine; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Symptomatic hypoglycemia is an unusual complication in children receiving oral purine analogues for treatment of childhood acute lymphoblastic leukemia (ALL). The exact mechanism of the hypoglycemic effect of the antimetabolic therapy remains unclear. Reduced hepatic glycogen stores or impaired hepatic glyconeogenesis may partly explain the hypoglycemia. To prevent hypoglycemia, food containing complex carbohydrates is recommended before sleep. In severe cases of hypoglycemia due to 6-mercaptopurine (6-MP), the dose can be given in the morning and if this fails 6-MP can be discontinued for a short period of time. We report a 3-year-old child who developed severe early morning hypoglycemia episodes that resolved after decreasing 6-MP while receiving non-high risk ALL therapy.

Topics: Administration, Oral; Child, Preschool; Follow-Up Studies; Humans; Hypoglycemia; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Treatment Outcome

To group patients receiving treatment for acute lymphoblastic leukemia (ALL) according to their oral mercaptopurine (6-MP) metabolite levels and to establish cut-off points to screen for potential poor clinical outcome.. Methodological study using 6-MP metabolite levels from 48 adolescent ALL patients enrolled in a multicenter adherence study. Cluster analysis was the primary analytical technique. We used two validation methods (a split-sampling and a simulation technique) for validating the results.. Four clusters were retained in our initial analysis using our first group of patients (n = 27). Three clusters (labeled 1, 2, and 4) exhibited the expected negative correlation between the two metabolites, that is, "high" values of one were associated with "low" values of the other. One cluster (labeled 3) had "low" levels for both TGN and MMP. Five of the 27 adolescents had their 6-MP "held" during the study. Post-hoc examination of the results revealed that all five grouped in Cluster 3 during the time that their medications were stopped, but grouped in other clusters at other times. The median ANC was highest in Cluster 3, consistent with low therapeutic drug levels. Parameters were reproducible with both validation methods. Values below the respective 75th centile for both TGN and MMP in Cluster 3 for the complete sample (n = 48) are suggested as representing a potentially higher risk for relapse.. This study provides an objective method for identifying patients at risk for treatment failure due to suboptimal 6-MP therapy; the clinical significance of this approach should be examined in future studies.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Cluster Analysis; Dose-Response Relationship, Drug; Female; Humans; Male; Mercaptopurine; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk Factors; Treatment Failure

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Cluster Analysis; Dose-Response Relationship, Drug; Female; Humans; Male; Mercaptopurine; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk Factors; Treatment Failure

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Infusions, Intravenous; Mercaptopurine; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Salvage Therapy

The antimetabolite mercaptopurine (MP) is widely used to treat childhood acute lymphoblastic leukaemia (ALL). To study the dynamics of MP on the cell cycle, we incubated human T-cell leukaemia cell lines (Molt-4 sensitive and resistant subline and P12 resistant) with 10 microM MP and measured total cell count, cell cycle distribution, percent viable, percent apoptotic, and percent dead cells serially over 72 h. We developed a mathematical model of the cell cycle dynamics after treatment with MP and used it to show that the Molt-4 sensitive controls had a significantly higher rate of cells entering apoptosis (2.7-fold, P<0.00001) relative to the resistant cell lines. Additionally, when treated with MP, the sensitive cell line showed a significant increase in the rate at which cells enter apoptosis compared to its controls (2.4-fold, P<0.00001). Of note, the resistant cell lines had a higher rate of antimetabolite incorporation into the DNA of viable cells (>1.4-fold, P<0.01). Lastly, in contrast to the other cell lines, the Molt-4 resistant subline continued to cycle, though at a rate slower relative to its control, rather than proceed to apoptosis. This led to a larger S-phase block in the Molt-4 resistant cell line, but not a higher rate of cell death. Gene expression of apoptosis, cell cycle, and repair genes were consistent with mechanistic dynamics described by the model. In summary, the mathematical model provides a quantitative assessment to compare the cell cycle effects of MP in cells with varying degrees of MP resistance.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Cell Cycle; DNA Repair; Drug Resistance, Neoplasm; Gene Expression Profiling; Humans; Mercaptopurine; Models, Theoretical; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease.. Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease.. No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX.. Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL.

Topics: Adolescent; Antimetabolites, Antineoplastic; Biomarkers; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Monitoring; Erythrocytes; Female; Humans; Liver Cirrhosis; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Statistics, Nonparametric

Topics: Erythrocytes; Humans; Mercaptopurine; Methyltransferases; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Protein C, protein S, and antithrombin III were measured in 35 patients with acute leukemia (13 with AML and 22 with ALL). Low levels of proteins C and S were present in 15 (42.9%) and 20 (57.1%) patients, respectively, and 6 patients had low levels of antithrombin (ATIII). Seven patients also had DIC at presentation. There were no significant differences in the levels of protein C, protein S, and ATIII in patients with or without DIC. Twenty patients were available for re-evaluation at the end of induction therapy. The low levels of protein C and ATIII found at diagnosis had risen to normal levels at the end of the induction therapy, while low =levels of protein S remained in 75% of the patients. One patient with low protein C at presentation developed myocardial infarction on day 15, and another patient died of progressive neuropathy. No other thrombotic manifestations were seen. Whether the low protein C, protein S, or antithrombin levels predispose patients with acute leukemia to thrombosis in the absence of DIC is not known.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antithrombin III; Asparaginase; Cyclophosphamide; Cytarabine; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Myocardial Infarction; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prednisone; Protein C; Protein S; Thrombosis; Vincristine

Patients with Philadelphia chromosome-positive (Ph+) and/or BCR-ABL+ acute lymphoblastic leukemia (ALL) have extremely poor prognoses. Most of these patients have additional, heterogenous karyotype abnormalities, the majority of which have uncertain clinical significance. In this study we analyzed the clinical characteristics, karyotype abnormalities, and outcome of 77 patients with Ph+ and/or BCR-ABL+ ALL registered in Poland in 1997-2004. In 31/55 patients with known karyotype, the sole t(9;22)(q34;q11) abnormality had been diagnosed; in one patient, variant translocation t(4;9;22)(q21q31.1;q34;q11), and additional abnormalities in 23 (42%) patients, had been diagnosed. The characteristics of the patients with Ph chromosome and additional abnormalities were not significantly different when compared with the entire analyzed group. Out of 77 patients, 54 (70%) achieved first complete remission (CR1) after one or more induction cycles. The overall survival (OS) probability of 2 years was 63, 43, and 17% for patients treated with allogeneic stem cell transplantation (alloSCT), autologous SCT, and chemotherapy, respectively (log rank p=0.002). Median OS from the time of alloSCT was significantly longer for patients transplanted in CR1 compared with alloSCT in CR >1 (p=0.032). There were no significant differences in CR rate, disease-free survival (DFS), and OS for patients with t(9;22) and additional abnormalities compared with the whole group. Only WBC >20 G/l at diagnosis adversely influenced OS probability (log rank p=0.0017). In conclusion, our data confirm poor outcome of Ph+ and/or BCR-ABL+ ALL. Only patients who received alloSCT in CR1 had longer DFS and OS. We have shown that additional karyotype abnormalities did not influence the clinical characteristics of the patients; however, their influence on treatment results needs to be further assessed.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Female; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation; Humans; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mercaptopurine; Methotrexate; Middle Aged; Philadelphia Chromosome; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Retrospective Studies; Treatment Outcome

Mechanisms of resistance to thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were investigated in human leukemia cell lines. We developed two 6-MP- and 6-TG-resistant cell lines from the human T-lymphoblastic cell line (MOLT-4) by prolonged exposure to these drugs. The resistant cells were highly cross resistant to 6-MP and 6-TG, and exhibited marked reduction in cellular uptake of 6-MP (70% and 80%, respectively). No significant modification of the activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase was observed. Real-time PCR of concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2) of resistant cells showed substantial reductions in expression of messenger RNAs. Small interfering RNA designed to silence the CNT3 and ENT2 genes down-regulated the expression of these genes in leukemia cells. These decreases were accompanied by reduction of transport of 6-MP (47% and 21%, respectively) as well as its cytocidal effect (30% and 21%, respectively). Taken together these results show that CNT3 and ENT2 play a key role in the transport of 6-MP and 6-TG by leukemia cells. From a clinical point of view determination of CNT3 and ENT2 levels in leukemia cells may be useful in predicting the efficacy of thiopurine treatment.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Cell Line, Tumor; Drug Resistance, Neoplasm; Equilibrative Nucleoside Transporter 1; Equilibrative-Nucleoside Transporter 2; Gene Silencing; Humans; Hypoxanthine Phosphoribosyltransferase; IMP Dehydrogenase; Membrane Transport Proteins; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Thioguanine

The authors present a case where the simultaneous administration of 6-mercaptopurine (6-MP) and cow's milk during maintenance treatment for acute lymphoblastic leukemia led to elevated full blood counts resistant to increasing doses of chemotherapy. The blood counts returned to the expected range after milk intake with chemotherapy was discontinued.

Topics: Animals; Antineoplastic Agents; Biological Availability; Child, Preschool; Humans; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Milk; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The purpose of this pilot study was to measure physical activity (PA) levels in children undergoing treatment for acute lymphoblastic leukemia (ALL) and to compare the results with those from age-matched healthy children. We used the MTI Actigraph accelerometer to determine PA (during a 1 week period) in children (n = 7; age = 4-7 y) undergoing maintenance treatment for ALL and in age-matched controls (n = 7). The number of children accumulating at least 60 min of moderate-to-vigorous physical activity (MVPA) for 5 or more days of the week was 3 for the control group, whereas no children with ALL met this criterion. Significantly lower levels of total weekly time of MVPA were seen in children being treated for ALL (328 +/- 107 min) than in controls (506 +/- 175 min) (p < 0.05). When weekday data was analyzed, the ALL patients also had significantly lower mean daily times of MVPA (49 +/- 23 min vs. 79 +/- 25 min). It is thus important that young ALL sufferers are encouraged to participate in appropriate sports, games, and physical activities both in the family and school environments that will prime them with positive attitudes to PA during the critical early years of life.

Topics: Antineoplastic Agents; Child; Child, Preschool; Exercise; Female; Humans; Male; Mercaptopurine; Methotrexate; Motor Activity; Oxygen Consumption; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors

Although medication errors are 1 of the most common types of medical errors, their frequency in pediatric patients receiving oral outpatient chemotherapeutic agents is unknown. The prescribing, dispensing, and parental administration of these medications to children receiving treatment for acute lymphoblastic leukemia (ALL) were systematically reviewed to determine the rate and types of medication errors occurring in these patients.. During a 2-month study period, parents of children with ALL were contacted and asked to participate in the study before a regularly scheduled clinic appointment. At the visit, the parent demonstrated how each medication was administered. A pediatric oncologist reviewed the medical record to determine the correct treatment regimen for study patients. After comparing the correct treatment regimen with what was administered, a classification of "no medication error," "medication error," or "cannot determine" due to insufficient information was made for each indicated drug. Identified medication errors were subclassified as prescribing, dispensing, or administration errors.. Data on 172 chemotherapeutic medications for 69 patients were analyzed. One or more errors occurred with 17 of the 172 (9.9%) medications; a classification of "cannot determine" was made for 12 (7.0%) medications. Among the 17 medication errors there were 12 (7.0%) administration errors and 5 (2.9%) prescribing errors. There were no pharmacy dispensing errors. All errors were due to incorrect dosing or failure to administer an indicated medication. At least 1 medication error occurred in 13 of the 69 (18.8%) study patients.. Prescribing and administration medication errors occurred with nearly 10% of chemotherapeutic drugs administered to outpatient children with ALL. Systematic changes, including computerized physician order entry and simplification of treatment protocols, should be considered.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Dexamethasone; Humans; Infant; Medication Errors; Mercaptopurine; Methotrexate; Outpatients; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Thioguanine

A 28-year-old woman with acute lymphoblastic leukemia developed fever and unilateral pleural based pulmonary infiltrate during prolonged chemotherapy induced neutropenia. CT-guided lung biopsy confirmed the diagnosis of pulmonary mucormycosis and liposomal amphotericin B therapy was started. A few days after the initial symptoms, the patient developed convulsions and a brain abscess was detected in computerized tomography and magnetic resonance imaging. Fungal hyphae detected in histopathological examination of a brain biopsy had identical morphology with those seen in previous lung biopsies. The patient was treated with liposomal amphotericin B for five months and cytotoxic chemotherapy was successfully completed during antifungal therapy. Pulmonary infiltrates and the brain abscess resolved and the patient received an allogeneic bone marrow transplantation from a matched, unrelated donor. Antifungal therapy was continued for one additional month after bone marrow transplantation to prevent a relapse of invasive mucormycosis. Follow-up of the patient revealed no signs of relapse of invasive mucormycosis but two months after successful bone marrow transplantation the patient developed lethal cytomegalovirus pneumonitis which was confirmed by autopsy. No signs of mucormycosis were detected at post-mortem.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Brain Abscess; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Cytomegalovirus Infections; Daunorubicin; Dexamethasone; Etoposide; Fatal Outcome; Female; Humans; Immunocompromised Host; Liposomes; Lung Diseases, Fungal; Mercaptopurine; Mitoxantrone; Mucormycosis; Pneumonia, Viral; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation, Homologous; Vincristine

Topics: Child; Factor V; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors

Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments.. To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL.. We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols.. Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively.. A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Prognosis; Recurrence; Risk Factors; Survival Rate; Time Factors; Vincristine

Topics: Antimetabolites, Antineoplastic; Child; Disease-Free Survival; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Thioguanine

Avascular necrosis (avn) is a complication of treatment for malignancies in children and adolescents. The authors present a two-center retrospective of experiences with avn in children treated for acute lymphoblastic leukaemia or non-Hodgkin lymphoma (8 from 191 patients with newly diagnosed disease in total of 19 sites). The median age at diagnosis was 16.6 years. Avn was observed in 4.1% of the group, higher among males than females (7/1), both during and after therapy. Early diagnosis of the process has enabled 7 patients to avoid surgical intervention. The increased incidence of avn, the multimodal character of symptoms, but unknown late consequences of avn showed that prospective studies of early recognition and proper therapy are needed.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Female; Humans; Incidence; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Osteonecrosis; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Retrospective Studies; Vincristine

Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT*2, 3.2% for TPMT*3A, and 0.5% for TPMT*3B. A rare TPMT*3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P < 0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.

Topics: Child; Drug Tolerance; Humans; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Yugoslavia

Treatment of acute leukemia is based on the general measures and specific treatment in accordance to the protocols. In the Europe and in Bosnia and Herzegovina BFM protocols are used, and they were developed by German pediatricians- hematologist. Protocols are based on the combination of the medicines (corticosteroids and some citostatics, which are given to the patient according to the exact scheme. These protocols use classification of the diseased according to the risk group diseased belong to.. The aim of this work is to establish which of the protocols, protocol BFM 90 or protocol BFM 95, have more influence in the treatment of the diseased children with lymphoblast leukemia.. Patient which were examined were children with ALL and treated on the pediatric clinic in Sarajevo in accordance to the protocols BFM 90 and 95 in the period between 1997 and year 2004. Method used in this study was descriptive analyses based on the inside we had into the available documentation.. In the study there were 117 children with ALL included. 54 (46,1%) of the children were treated in accordance to the protocol BFM 90, and 63 (53,85 %) of the children were treated in accordance to the protocol BFM 95. There was noticed significant difference of the survival of the diseased children, based on the statistical testing. Children treated in accordance to the protocol BFM 90 there were 24 % of the children who died, and 12,6 % of the children who were treated in accordance to the protocol 95 died.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Survival Rate; Vincristine

To analyse the clinical features of patients with B cell lymphoblastic lymphoma(BCLL) and the outcomes after modified BFM-90 protocol therapy.. The clinical features of 14 patients with BCLL were analysed, and compared with that of T cell lymphoblastic lymphoma in the same period. The efficacy and toxicity of modified BFM-90 protocol were analysed.. The 14 patients were aged 3 to 18 and diagnosed as BCLL by morphology and immunohistology. One case was in stage I , 2 stage III and 11 stage IV. Most common involved sites were lymph nodes (70% ), skin (50% ) and bone marrow (64% ). One patient received CHOP + HD-MTX, and 13 received modified BFM-90 protocol chemotherapy. Twelve patients (92.3%) achieved complete remission( CR) , 1 patient(7. 7% ) partial remission( PR). The median follow-up duration was 19. 5 months (2 to 44 months). At present 13 patients are alive except one PR patient who gave up treatment and died of disease. The major toxicity of the protocol was myelosuppression, but could be tolerated.. The most common involvement sites of BCLL were lymph nodes, skin and bone marrow. The effectiveness is improved as treated with modified BFM-90 protocol.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lymphoma, B-Cell; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Infusions, Intravenous; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Survival Rate

In Hungary children (from 1 to 18 years of age) with de novo acute lymphoblastic leukemia were treated from January 1996 to October 2002, according to protocol ALL-BFM-95.. The aim of this study was to evaluate the experience with this protocol, the treatment results according to the risk groups and to compare the Hungarian data with the international results.. Patients were stratified into 3 risk groups, based on initial white blood cell count, age, immunology, cytogenetics and response to treatment: standard, medium and high risk group.. Three hundred sixty eight children entered the study (male-female ratio was 1.27:1, median age 6 years and 4 months). 110 (29.9%) children were in the standard, 210 (57.1%) in the medium and 48 (13%) in the high risk group. Duration of the chemotherapy was 2 years, except of the boys in the standard risk group, their maintenance therapy was 1 year longer. The overall complete remission rate was 93.2%. 20 (5.4%) children died in induction and 5 (1.4%) were non-responders. The 5-year overall survival for all patients was 78.5%, in the standard risk group 93.2%, in the medium risk group 78.4% and in the high risk group 44.5% with a minimum follow up of 1.19 years and median follow up of 4.85 years. From the 368 patients 272 (73.9%) are still in their first complete clinical remission and other 18 children are alive after relapse. In 14.7% of the patients relapse was diagnosed; the most common site was the bone marrow. In one patient second malignancy occurred. The 5-year event free survival for all patients was 72.6%, in the standard risk group 87.6%, in the medium risk group 72.1% and in the high risk group 39.9%.. The treatment outcome of children with acute lymphoblastic leukemia improved remarkably over the last decades. 78% of children suffering from acute lymphoblastic leukemia could be cured with the ALL-BFM-95 protocol. The Hungarian results are comparable to those achieved by other leukaemia study groups in the world regarding the ALL-BFM-95 protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Risk Assessment; Survival Analysis; Treatment Outcome; Vincristine

Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity.. To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL.. TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses.. Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10(-4) were defined as negative.. Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86).. TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Genotype; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis

Surface-enhanced Raman spectroscopy (SERS) has been applied to characterize the interaction of 6-mercaptopurine-ribose (6MPR), an active drug used in chemotherapy of acute lymphoblastic leukemia, with a model biological substrate at therapeutic concentrations and as function of the pH value. Therefore, a detailed vibrational analysis of crystalline and solvated (6MPR) based on Density Functional Theory (DFT) calculations of the thion and thiol tautomers has been performed. 6MPR adopts the thion tautomeric form in the polycrystalline state. The SERS spectra of 6MPR and 6-mercaptopurine (6MP) recorded on silver colloid provided evidence that the ribose derivative shows different adsorption behavior compared with the free base. Under acidic conditions, the adsorption of 6MPR on the metal surface via the N7 and possibly S atoms was proposed to have a perpendicular orientation, while 6MP is probably adsorbed through the N9 and N3 atoms. Under basic conditions both molecules are adsorbed through the N1 and possibly S atoms, but 6MP has a more tilted orientation on the silver colloidal surface while 6MPR adopts a perpendicular orientation. The reorientation of the 6MPR molecule on the surface starts at pH 8 while in the case of 6MP the reorientation starts around pH 6. Under basic conditions, the presence of the anionic molecular species for both molecules is suggested. The deprotonation of 6MP is completed at pH 8 while the deprotonation of the riboside is finished at pH 10. For low drug concentrations under neutral conditions and for pH values 8 and 9, 6MPR interacts with the substrate through both N7 and N1 atoms, possibly forming two differently adsorbed species, while for 6MP only one species adsorbed via N1 was evidenced.

Topics: Adsorption; Antimetabolites, Antineoplastic; Colloids; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Mercaptopurine; Molecular Structure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Silver; Spectrum Analysis, Raman; Thioinosine

Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting crossresistance to prednisolone, vincristine, asparaginase, and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS).

Topics: Age Factors; Antineoplastic Agents; Asparaginase; Cell Survival; Child; Cluster Analysis; Core Binding Factor Alpha 2 Subunit; Daunorubicin; Disease-Free Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Mercaptopurine; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prednisolone; Principal Component Analysis; Proportional Hazards Models; Translocation, Genetic; Treatment Outcome; Tumor Cells, Cultured; Vincristine

The determination of the thiopurine S-methyltransferase activity (TPMT; EC 2.1.1.67) has become an important issue during thiopurine therapy due to its known genetic polymorphism resulting in a wide range of TPMT activity. Therefore, the standard thiopurine drug regimen is associated with increased hematopoetic toxicity in patients with low or absent TPMT activity, whereas patients with high activity may be insufficiently treated. However, presently available methods are labour intensive and time consuming and tend towards too high or too low enzyme activity due to their methodological approach. The use of instable substrate solutions (6-MP or 6-TG), organic solvents like dimethyl sulfoxide and too high substrate and co-substrate saturation concentrations contribute to this phenomenon. We therefore, established an optimized and fast isocratic HPLC linked TPMT assay based on the enzymatic methylation of mercaptopurine or thioguanine in RBC lysates with S-adenosyl-l-methionine as methyl donor. Unspecific non-enzymatic methylation was not detectable. The recovery of 6-methyl-mercaptopurine was 97-102%, the intra- and interday variation between 1.0 and 5.0%, respectively. The assay dispenses with a time consuming extraction procedure with organic solvents, a heating step, and a gradient elution and is therefore, favourable for clinical routine application. The TPMT activity was measured in 62 untreated children with acute lymphoblastic leucemia at the time of diagnosis (activity = 34.0+/-10.6 nmol/g Hb/h, range: 11.5-55.4 nmol/g Hb/h) and in 12 adult healthy volunteers (62.8+/-7.7 nmol/g Hb/h, range: 48-82 nmol/g Hb/h) reflecting the wide measurable TPMT activity found in erythrocytes.

Topics: Adult; Child; Chromatography, High Pressure Liquid; Erythrocytes; Humans; Kinetics; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reproducibility of Results; Thioguanine

We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.

Topics: Adult; Antineoplastic Agents; Asparaginase; Benzamides; Cell Survival; Cytarabine; Daunorubicin; Drug Interactions; Drug Screening Assays, Antitumor; Fluorometry; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Immunosuppressive Agents; Mercaptopurine; Philadelphia Chromosome; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Pyrimidines; Tumor Cells, Cultured; Vincristine

This study describes approaches for stacking a large volume of sample solutions containing a mixture of mercaptopurine monohydrate, 6-methylmercaptopurine, thioguanine, thioguanosine, and thioxanthine in capillary electrophoresis (CE). After filling the run buffer (60 mM borate buffer, pH 8.5), a large sample volume was loaded by hydrodynamic injection (2.5 psi, 99.9 s), followed by the removal of the large plug of sample matrix from the capillary using polarity switching (-15 kV). Monitoring the current and reversing the polarity when 95% of current recovered, the separation of anionic analytes was performed in a run buffer < 20 kV. Around 44- to 90-fold improvement of sensitivity for five analytes was achieved by large-volume stacking with polarity switching when compared with CE without stacking. This method was feasible for determination of the analytes spiked in plasma. Removing most of electrolytes from plasma is a key step for performing large-volume sample stacking. Solid-phase extraction was used for pretreatment of biological samples. To our knowledge, this study is one of few applications showing the possibilities of this stacking procedure to analyze biological samples by large-volume sample stacking with polarity switching (LVSSPS) in CE.

Topics: Electrophoresis, Capillary; Guanosine; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sensitivity and Specificity; Thioguanine; Thionucleosides; Xanthines

Thiopurines are used for treatment of several diseases. Cytotoxicity is caused by the derived compounds 6-thioguanine nucleotides (TGNs) and methyl-6-thioinosine monophosphate (methylthio-IMP). The 6-thiopurine mononucleotides 6-thio-IMP (thio-IMP), 6-thio-GMP (thio-GMP) and methylthio-IMP can be catabolized by purine 5'-nucleotidase. It has been shown that the various 5'-nucleotidases are key enzymes for (6-thio)-purine metabolism. We aimed to investigate whether the overall 5'-nucleotidase (5'NT) activity is correlated with the efficacy and toxicity of 6-thiopurine nucleotides. Substrate affinity of 5'NT for IMP, GMP, AMP, thio-IMP, thio-GMP and methylthio-IMP was studied in human lymphocytes. For each of the substrates, the pH for optimal overall enzyme activity has been determined at a pH range between 6 and 10. At the optimal pH, assays were performed to establish Km and Vmax values. Optimal pH values for the various substrates were between 7 and 8.5. Km values ranged from 33 to 109 microM, Vmax ranged from 3.99 to 19.5 nmol/10(6) peripheral mononuclear cells (pMNC) h, and Vmax/Km ratios ranged from 105 to 250. The results did not show a distinct preference of 5'NT activity for any of the tested thiopurine nucleotides. The enzyme kinetic studies furthermore revealed substrate inhibition by thio-IMP and thio-GMP as a substrate. Inhibition by thio-GMP also seems to occur in patients treated with 6-mercaptopurine (6 MP); subsequently, this may lead to toxicity in these patients.

Topics: 5'-Nucleotidase; Child; Chromatography, High Pressure Liquid; Guanosine Monophosphate; Humans; Hydrogen-Ion Concentration; Kinetics; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Substrate Specificity; Sulfhydryl Compounds; Thioguanine

Topics: Antimetabolites, Antineoplastic; Apoptosis; Child, Preschool; Humans; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

West Nile Virus (WNV) infection is an important cause of encephalitis. Although the medical literature contains examples of WNV encephalitis in susceptible, mainly elderly, immunocompromised hosts, few case reports have described pediatric cases. The authors describe an adolescent with acute lymphocytic leukemia and WNV encephalitis. Surveillance studies indicate an increase in WNV activity. Physicians need to be aware of WNV activity in their community and consider WNV as a potential source of infection.

Topics: Acyclovir; Adolescent; Animals; Antibodies, Viral; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Brain; Ceftazidime; Ceftriaxone; Culicidae; Diagnosis, Differential; Encephalitis, Viral; Fatal Outcome; Humans; Immunoglobulins, Intravenous; Insect Bites and Stings; Magnetic Resonance Imaging; Male; Mercaptopurine; North Carolina; Persistent Vegetative State; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vancomycin; Vincristine; Virginia; West Nile Fever; West Nile virus

The authors describe a 7-year-old boy with TEL/AML1-positive pre-B acute lymphoblastic leukemia, with hemizygous 9p21 deletion at presentation and no p16(INK4A) protein expression. Despite an initial response to a standard chemotherapy regimen, the patient suffered two hematologic relapses and died 34 months after diagnosis. The authors discuss the possibility that complete p16(INK4A) gene inactivation may adversely modify the prognostic significance of TEL/AML1 fusion in childhood acute lymphoblastic leukemia, and present evidence from clinical and in vitro observations in favor of this assumption.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 9; Combined Modality Therapy; Core Binding Factor Alpha 2 Subunit; Cyclin-Dependent Kinase Inhibitor p16; Cyclophosphamide; Cytarabine; Daunorubicin; Fatal Outcome; Gene Deletion; Genes, p16; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Proteins; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Recurrence; Vincristine

Several studies have suggested a role of bone marrow stroma injury in long-term chemotherapy-induced hematopoietic failure. To evaluate whether bone marrow microenvironment is altered by chemotherapy for acute lymphoblastic leukemia (ALL) and to determine its contribution to postchemotherapy anemia, we investigated the ability of stroma from children receiving maintenance chemotherapy for ALL to support hematopoiesis. Long-term bone marrow cultures (LTBMC) were established with bone marrow cells either from ALL children under therapy (n = 24) or from control subjects (n = 19). Nonadherent cells and colony forming units-granulocytic monocytic (CFU-GM) output in LTBMC did not differ between patients and controls. In contrast, burst forming unit-erythroid (BFU-E) numbers were lower in patient LTBMC (p = 0.013). Co-cultures of normal CD34+ cells and preformed patient or control stromas showed significantly reduced hematopoietic supportive capabilities of patient stromas: both CFU-GM and BFU-E were reduced (p = 0.002 and 0.046, respectively). In addition, supernatants (SN) of patients' LTBMC inhibited normal BFU-E growth compared with SN of normal LTBMC. Transforming growth factor (TGF)-beta1 levels were increased in patient cultures (p = 0.0039) and inversely correlated with BFU-E produced in LTBMC (r = -0.36, p = 0.04). Neutralization of TGF-beta1 significantly increased the BFU-E output of patient LTBMC (p = 0.0078). In contrast, macrophage inflammatory peptide (MIP)-1alpha levels were lower in SN of patients compared with controls (p = 0.015). Thus, chemotherapy for ALL induces functional deregulation within bone marrow stromal cells with an increase in the growth-inhibiting factor TGF-beta1, together with a decrease in MIP-1alpha, which might contribute to hematopoietic toxicity.

Topics: Antibodies; Antigens, CD34; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cells, Cultured; Chemokine CCL3; Chemokine CCL4; Child; Chronic Disease; Coculture Techniques; Cytokines; Erythroid Precursor Cells; Humans; Macrophage Inflammatory Proteins; Mercaptopurine; Methotrexate; Myeloid Progenitor Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stromal Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hepatotoxicity with elevation of aminotransferase levels is common during combined methotrexate and thiopurine therapy. However, the mechanism of hepatotoxicity induced by these drugs remains obscure. We have investigated the relationship of a rise in aminotransferase levels to erythrocyte levels of methotrexate and its polyglutamates, 6-thioguanine nucleotides, the major cytotoxic metabolites of 6-mercaptopurine, and methylated metabolites of 6-mercaptopurine generated by thiopurine methyltransferase in competition with the formation of 6-thioguanine nucleotides.. Weighted means of alanine aminotransferase levels and metabolites of methotrexate and 6-mercaptopurine were calculated from a total of 929 blood samples from 43 patients with acute lymphoblastic leukemia during maintenance therapy with methotrexate and 6-mercaptopurine.. Weighted means of aminotransferase levels were significantly related to the average doses of 6-mercaptopurine (r(s) = 0.60, P <.001), erythrocyte levels of methylated metabolites of 6-mercaptopurine (r(s) = 0.63, P <.001), and thiopurine methyltransferase activity (r(s) = 0.32, P =.03). Weighted means of aminotransferase levels were negatively correlated with erythrocyte levels of 6-thioguanine nucleotides and were not related to the average doses of methotrexate or erythrocyte levels of methotrexate and its polyglutamates.. It was found that 6-mercaptopurine and its methylated metabolites are correlated with the degree of hepatotoxicity during methotrexate and 6-mercaptopurine maintenance therapy. Further studies are needed to explore whether aminotransferase levels could be used as a surrogate marker for methylated metabolites of 6-mercaptopurine and thus to evaluate 6-mercaptopurine treatment compliance.

Topics: Alanine Transaminase; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Activation; Female; Humans; Liver; Liver Function Tests; Male; Maximum Tolerated Dose; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Probability; Risk Assessment; Severity of Illness Index

A procedure is described for the rapid determination of the intra-erythrocyte concentration of 6-mercaptopurine (6-MP) and its metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Erythrocytes (8 x 10(8) cells) in 350 microl Hanks solution containing 7.5 mg dithiothreitol were treated with 50 microl 70% perchloric acid. The precipitate was removed by centrifugation (13,000 g) and the supernatant hydrolyzed at 100 degrees C for 45 min. After cooling, 100 microl was analyzed directly by HPLC using a Radialpack Resolve C18 column eluted with methanol-water (7.5:92.5, v/v) containing 100 mM triethylamine. 6-TG, 6-MP and the hydrolysis product of 6-MMP, 4-amino-5-(methylthio)carbonyl imidazole, were monitored at 342, 322 and 303 nm using a Shimadzu SPD-M10A diode array UV detector. The analytes eluted at 5.3, 6.0 and 10.2 min, respectively. The calibration curves were linear (r(2) > 0.998), and the analytical recoveries were 73.2% for 6-TG, 119.1% for 6-MP and 97.4% for 6-MMP. The intra- and inter-assay variations were highest for 6-MP (9.6 and 14.3%, respectively). The lowest detectable concentrations were 3, 3 and 25 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The quantification limits (coefficients of variation <15%) were 8, 10 and 70 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The method was applied to the analysis of 183 samples from 36 children under chemotherapy for acute lymphoblastic leukemia. The concentrations of the metabolites in the red cells of the patients ranged from 0 to 1934 pmol/8 x 10(8) erythrocytes for 6-TGN, and from 0 to 105.8 and 0 to 45.9 nmol/8 x 10(8) erythrocytes for 6-MP and 6-MMP, respectively. The procedure gave results that were in agreement with those obtained with other methods designed to detect cases of non-compliance with treatment, including patient interviews and medical evaluation, among others, demonstrating its applicability to monitoring the treatment of leukemic children.

Topics: Biomarkers; Child; Chromatography, High Pressure Liquid; Dithiothreitol; Erythrocytes; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

We report two cases of accidental ingestion of large quantities of 6-mercaptopurine (6-MP) in siblings of patients with acute lymphoblastic leukemia (ALL). These cases reinforce the need for thorough anticipatory guidance to families in order to prevent the incidence of potentially life-threatening accidental ingestions.

Topics: Child, Preschool; Female; Humans; Infant; Mercaptopurine; Poisoning; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Siblings

To evaluate compliance in children with acute lymphoblastic leukaemia (ALL).. Compliance was assessed through specific interviews, annotations from medical charts, and erythrocytic determination of 6-mercaptopurine metabolites.. A total of 39 patients who had concluded maintenance phase of chemotherapy were included in the study. Mothers were responsible for delivering 6-MP in 87% of cases. Thirty five interviewees said that medical prescription was well understood and that the main reason for non-compliance was forgetfulness. Non-compliance was detected through interviews (33.3% of the cases), reports from medical charts (30.7%), and drug determination (16.6%); 53.8% of children were found to be non-compliant. Non-compliance was significantly associated with chronic undernourishment. Although not statistically significant, there was a trend for the group of non-compliant children to be associated with low per capita family income. No significant associations of non-compliance with age at diagnosis, gender, parents' schooling level, number of family members, power consumption, and medians of absolute leucocyte or neutrophil blood counts were detected. A short follow up period precluded valid analysis on outcome. In the non-compliant group (n = 21), seven children relapsed, contrasting with three relapses in the compliant group (n = 18).. Results suggest that non-compliance is one of the mechanisms which underlies the adverse influence of socioeconomic factors on the outcome of children with ALL. Additional studies are necessary to confirm this hypothesis. Comprehensive approaches to the problem of non-compliance are urgently needed.

Topics: Adolescent; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Blood Cell Count; Child; Child, Preschool; Chronic Disease; Female; Humans; Infant; Interviews as Topic; Male; Mercaptopurine; Mothers; Nutrition Disorders; Patient Compliance; Poverty; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

This study was designed to assess the predictive value of an MTT (3-[4,5-dimethylthiazol-2,5-diphenyl] tetrazolium bromide) in vitro assay for the evaluation of leukemic cell resistance/sensitivity to cytotoxic drugs, and to compare these results with clinical and laboratory parameters in cases of childhood acute lymphoblastic leukemia (ALL).The chemoresistance of leukemic cells was ascertained by means of an MTT assay in 32 previously untreated children with ALL. The children were treated using the protocol ALL-BFM 90. Statistical correlations were made between in vitro drug resistance to anti-cancer drugs: prednisolone (PRED), vincristine (VCR),daunorubicin (DNR), etoposide (VP-16) and cytosine arabinoside (ARA-C) and in vivo clinical and laboratory parameters: age, sex, risk factor (RF), leukocytes (WBC)and absolute number of blast cells (BC) at diagnosis (BC0), BC at day 8 (BC8), the percentage of blast cells in bone marrow at day 15 (BM15) and at day 33 (BM33),and leukocyte surface antigens CD3, CD4, CD5, CD8, CD10, CD19, CD20, HLADR.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Coloring Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Female; Humans; In Vitro Techniques; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prednisone; Remission Induction; Sex Factors; Tetrazolium Salts; Thiazoles; Vincristine

Angiogenesis is an important mechanism in morbility of malignant tumor, vascular endothelial growth factor (VEGF) is the key factor. This study was to investigate the serum level of VEGF in children and adolescent patients with non-Hodgkin's lymphoma (NHL).. The serum levels of VEGF(sVEGF) in 24 pretreated NHL patients were detected by ELISA. sVEGF in 10 of the 24 patients who received complete response after treatment were also detected by ELISA.. The average serum VEGF level was 745.79 ng/L (40.64-3623.09 ng/L)in 24 NHL patients. It was higher than normal [(294.20+/-23.40) ng/L]. sVEGF in 18 of the patients were higher than the standard, while in 6 of the patients were lower than the standard. The average serum VEGF level was 289.54 ng/L (35.11-826.8 ng/L) in 10 of The CR patients, 8 cases of them had a high VEGF level before treatment but a nearly normal level after first CR. And 2 cases of them had normal level during the course.. The serum level of VEGF in NHL patients was higher than normals. The high serum level of VEGF has a tendency to drop to the normal standard after receiving CR. From the clinical data, a high serum level was not found associated with stage, gender, PS. score, IPI score, serum LDH and "B" symptoms et al.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Vascular Endothelial Growth Factor A; Vincristine

Topics: Child; Female; History, 20th Century; Humans; Male; Mercaptopurine; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

T-cell lymphoblastic lymphoma in childhood and adolescence is an aggressive malignant disease with higher mortality. BFM-90 regimen for lymphoblastic lymphoma is one of the most effective regimens. This study was designed to evaluate efficacy and toxicities of modified BFM-90 regimen on Chinese children and adolescents with lymphoblastic lymphoma.. A total of 20 naive children and adolescents with T cell lymphoblastic lymphoma were enrolled, 7 in stage III, and 13 in stage IV. Eighteen (90%) patients suffered from mediastinal mass with superior vena obstruction syndrome,10(50%) suffered from marrow invasion. All patients received modified BFM-90 regimen consisting of induction, consolidation and central nervous system prophylaxis, reinduced alleviation, and maintenance therapy. Total treatment duration was 2 years. Kaplan-Meier method was used to evaluate long-term survival rate.. After induction remission,18 patients (90%) achieved complete remission (CR), 1 had partial remission (PR), and 1 had progressive disease (PD), overall response rate was 95%. The 2 patients with PR or PD died of tumor progression. Of 2 patients at CR1 received APBSC, 1 relapsed after transplantation, but achieved CR and survived after salvage chemotherapy;1 survived all along. Of other patients achieved CR, 5 relapsed; of these 5 patients, 1 survived after allogeneic stem cell transplantation, 1 survived after autologous stem cell transplantation, 3 died of progressive disease after chemotherapy. The overall 3-year survival rate was 74%. All patients had myelosuppression of grade III-IV during the induction and reinduction phases, but the hemotologic toxicity was manageable.. Modified BFM-90 regimen is feasible for Chinese children and adolescent patients with lymphoblastic lymphoma, and may improve survival rate of these patients. The major side effect is myelosuppression, but it is manageable.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Stem Cell Transplantation; Survival Rate; Treatment Outcome; Vincristine

Since 01.07.1993 to 30.09.2002, 640 children (48.2% girls and 51.8% boys) with ALL-SR were diagnosed and treated according to the modified ALL-BFM 90 protocol. In 29 children the treatment was intensified because of poor corticosteroid response. Subject to statistical analysis (Kaplan-Meier method) were thus 611 children with ALL-SR. Among them, 89 patients failed to respond to therapy: 10 (1.6%) early deaths, 15 (2.5%) deaths during I complete remission, 64 (10.5%) relapses. Relapses occurred: 45 (7.4%) in bone marrow, 11 (1.8%) in central nervous system, 4 (0.7%) in testicular and in 4 (0.7%) children combined relapses were observed. Probability rates for 9-year event free survival (EFS) and relapse free survival (RFS) for all patients were 0.77 (0.02) and 0.79 (0.02), respectively. Application of high dose of methotrexate is effective in prevention of relapses, especially meningeal and testicular involvement.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Bone Neoplasms; Central Nervous System Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Infant, Newborn; Male; Mercaptopurine; Methotrexate; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Retrospective Studies; Risk Factors; Secondary Prevention; Survival Analysis; Testicular Neoplasms; Time Factors; Treatment Outcome; Vincristine

The frequency of dental abnormalities, such as delayed dental development, microdontia, hypoplasia, agenesis, V-shaped root and shortened root was evaluated in 76 acute lymphoblastic leukemia (ALL) pediatric patients who had been off chemotherapy for 6 months. These children had been subjected to one of the three Brazilian Protocols or the BFM86 Protocol. The patients were divided into three groups: Group I (GI; high risk) treated with one of the three Brazilian Protocols who received high-dose chemotherapy, intensive maintenance and cranial radiotherapy; Group II (GII; low risk) who were also treated with one of the three Brazilian Protocols using low-intensive chemotherapy with no radiotherapy; and Group III (GIII) based on the BFM86 Protocol. Of 76 children, 13 showed no dental abnormalities (8 were at the age of tooth formation). The remaining 63 children (82.9%) showed at least one dental anomaly. The abnormalities were probably caused by the type, intensity, frequency of the treatment and age of the patients at ALL diagnosis and this might have important consequences for the children's dental development.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Dental Enamel Hypoplasia; Dexamethasone; Doxorubicin; Etoposide; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Odontogenesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Teniposide; Tooth Abnormalities; Tooth Diseases; Tooth Eruption; Tooth Root; Vincristine

Topics: Acetazolamide; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chlorthalidone; Cyclophosphamide; Cytarabine; Daunorubicin; Diagnosis, Differential; Headache; Humans; Intracranial Hypertension; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Sinus Thrombosis, Intracranial; Vincristine; Vomiting

Low-dose methotrexate (MTX) is used as disease-modifying therapy in severe rheumatoid arthritis and as maintenance treatment in patients with complete remission of acute lymphoblastic leukemia (ALL). It is generally well tolerated, but in 27% of patients acute pneumonitis leads to discontinuation of treatment. We describe a 56-year-old female patient with newly diagnosed pre-B-ALL. She was treated with induction chemotherapy in July 1999 which lead to complete remission. Maintenance treatment with low-dose MTX and 6-mercaptopurine (6-MP) was started in December 1999. In April 2000 she was hospitalized because of fever, cough, and rapidly progressive dyspnea. No pathogens could be cultured from blood or bronchoalveolar lavage fluid. Computed tomography of the lungs revealed interstitial infiltration and ground-glass opacities. Acute pneumonitis was diagnosed, and MTX was stopped. Prednisone therapy lead to rapid clinical amelioration of dyspnea and hypoxemia. Since for this patient there was no alternative leukemia therapy, MTX was successfully reintroduced in August 2000 without reappearance of any respiratory symptoms. We discuss risk profile, clinical and histological presentation, and therapy of MTX-induced pneumonitis. To our knowledge, this is the first patient with ALL in whom successful reintroduction of MTX after severe pneumonitis has been reported.

Topics: Acute Disease; Female; Humans; Mercaptopurine; Methotrexate; Middle Aged; Pneumonia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Tomography, X-Ray Computed

To evaluate the activity and genotype of thiopurine methyltransferase (TPMT) and the concentration of thioguanine nucleotides (TGNs) as parameters for individualizing mercaptopurine (6-MP) therapy.. Erythrocyte TPMT activity was measured by means of radiochemical assay. Sequence specific primer (SSP) PCR and restriction fragment length polymorphism (RFLP) were used to determine the mutations in TPMT genomic DNAs. Erythrocyte TGNs concentration in acute lymphoblastic leukemia (ALL) patients after 6-MP treatment was detected by high-performance liquid chromatography (HPLC).. The erythrocyte TPMT activity in Han population was 16.6 +/- 4.5U/ml pRBCs (man 16.8 +/- 5.0 U/ml pRBCs, woman 16.5 +/- 4.4 U/ml pRBCs), the activity in 8.1% of the samples was lower than 10 U/ml pRBCs. There was no difference for TPMT activity by gender, age, and between healthy donors and ALL patients. For TPMT genotypes, there were 5 cases of TPMT * 2, 4 TPMT * 3A, 6 TPMT * 3B, 10 TPMT * 3C and 5 unknown in 30 subjects who had low TPMT activity. In children with ALL, the TGNs level did show a negative correlation with TPMT activity at diagnosis and 7 approximately 14 days after 6-MP therapy and with WBC count 14 days after the determination of TGNs.. Detection of TPMT activity before 6-MP therapy and TGNs level during 6-MP therapy may be helpful for preventing side effects from antipurine metabolic drug overdose, and individualizing 6-MP chemotherapy in children with ALL.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Middle Aged; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleotides; Time Factors

To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Profiling; Humans; Mercaptopurine; Methotrexate; Oligonucleotide Array Sequence Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

THE AIM of the study was the longitudinal assessment of physical development of children treated for acute lymphoblastic leukemia (ALL) in the past. A total group of 76 children (51 girls), from whom 63 get ill before puberty, were included in the study. Therapy was managed according to BFM protocols in which central nervous system (CNS) prophylaxis was used in 27 children in dose 12 Gy, methotrexate in dose 5 g/m(2) was used in 63 children and 1g/m(2) in 13 children. Height and body mass index expressed as standard deviation score (SDS) in the time of diagnosis (H1 SDS, BMI1 SDS), after intensive therapy (H2 SDS, BMI2 SDS) and after 1.7+/-3.13 years from therapy (H3 SDS, BMI3 SDS) were assessed.. 1. BMI2 SDS values increased in relation to BMI1 SDS (p=0.0000001) and BMI3 SDS values insignificantly decreased, but they were higher than at the time of diagnosis. 2. We affirmed increase of BMI2 SDS in the group of boys directly after the treatment (p=0.00006) and later decrease (p=0.04), so there were no differences between BMI1 SDS and BMI3 SDS. 3. The increase of BMI2 SDS in comparison with BMI1 SDS (p=0.007) was kept until the treatment completed in the group of girls (p=0.05 between BMI1 SDS and BMI3 SDS). 4. The increase and next decrease of BMI SDS values was observed among children who get ill before puberty. But we noticed intermittent increase of BMI SDS in the puberty children at the time of diagnosis. 5. We affirmed increase of BMI SDS after the treatment completed in the group of children treated with only cytostatics. The increase of BMI SDS (p=0.02) and next decrease of BMI3 SDS (p=0.007) was noticed in the group with CNS prophylaxis, there were no differences between BMI1 SDS and BMI3 SDS. 6. We observed increase of BMI2 SDS and BMI3 SDS in comparison with BMI1 SDS (p=0.00001 and p=0.0004) in the group treated with 5 g/m(2) methotrexate. BMI3 SDS values were decreased in comparison with BMI2 SDS (p=0.01) and BMI1 SDS (p=0.006) in the group treated with 1 g/m(2) methotrexate. 7. There were no significant changes in the growth rate during the treatment and after therapy.. 1. ALL treatment contributes to the increase of body mass, which is kept until therapy completed, especially in the group of girls. 2. Growth rate including children with CNS prophylaxis does not submit significantly disturbances.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Body Mass Index; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Female; Growth; Humans; Longitudinal Studies; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiotherapy, Adjuvant; Retrospective Studies; Risk Factors; Sex Factors; Thioguanine; Vincristine

Topics: Child, Preschool; Family Health; Humans; Male; Mercaptopurine; Methyltransferases; Mutation, Missense; Pedigree; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Multidrug resistance is an important mechanism responsible for refractoriness of leukemia and worse outcome of patients. Overexpression of the multidrug resistance gene, MDR1, is of prognostic relevance in acute myeloid leukemia, while its role in acute lymphoblastic leukemia (ALL) is still under debate. Single nucleotide polymorphisms (SNP) have been detected in the MDR1 gene. The C3435T polymorphism in this gene seems to have functional and clinical consequences. In the present investigation, we have analyzed the role of the C3435T SNP for drug resistance and prognosis of human ALL. The C3435T SNP was analyzed in 20 T-ALL cell lines and in blood samples from 53 ALL patients and 7 healthy donors. The cell line panel consisted of cell lines not prior exposed in vitro to cytostatic drugs as well as of drug-resistant lines which were selected in vitro by exposure to doxorubicin, vincristine, methotrexate, or hydroxyurea. We have developed a highly sensitive matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based genotyping approach to survey the C3435T SNP. Furthermore, mRNA expression was determined by real time reverse-transcribed polymerase chain reaction and doxorubicin sensitivity by a growth inhibition assay. Surprisingly, we did not find a significant correlation between C3435T homo- or heterozygote genotypes and MDR1 mRNA expression of cell lines or blood samples from patients and healthy donors. Furthermore, there was no relationship between the response of the cell lines to doxorubicin and the C3435T genotypes. Homo- or heterozygosity did not correlate to survival of patients in the Kaplan-Meier analysis. In conclusion, we do not have reason to assume that the C3435T SNP contributes to drug resistance of ALL and prognosis of ALL patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Case-Control Studies; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Genes, MDR; Humans; Hydroxyurea; Male; Mercaptopurine; Methotrexate; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tumor Cells, Cultured; Vincristine

The case records of 99 consecutive children with acute lymphoblastic leukaemia who received either 6-thioguanine (6-TG) or 6-mercaptopurine (6-MP) as maintenance therapy for at least 1 year were reviewed for hepatic veno-occlusive disease (VOD). Overall, 12% of those on 6-TG developed VOD (all boys). Isolated persistent thrombocytopenia appeared to be the earliest indicator of incipient VOD. Multivariate analysis identified male sex and 6-TG as risk factors. In all cases, VOD was mild and reversible on withdrawing 6-TG or replacing it with 6-MP. The data implicate a sex-linked polymorphic variation in xenobiotic pathways of thiopurine metabolism in the pathogenesis of VOD.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Hepatic Veno-Occlusive Disease; Humans; Logistic Models; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sex Factors; Thioguanine; Xenobiotics

Topics: Advisory Committees; Azathioprine; Child; Drug Labeling; Drug Utilization; Genetic Testing; Humans; Inflammation; Mercaptopurine; Methyltransferases; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; United States; United States Food and Drug Administration

Early treatment response is a strong predictor for treatment outcome in childhood acute lymphoblastic leukemia (ALL), treated within the protocols of the Berlin-Frankfurt-Münster (BFM) study group. In the ALL-BFM trials, early treatment response is assessed by in vivo response to glucocorticoids (prednisone response), the molecular background of which is unknown. Initial in vivo resistance to glucocorticoid (GC) treatment in childhood ALL (prednisone-poor response) is associated with a dramatically shorter event-free survival than that found in GC-sensitive patients (prednisone-good responders). The intracellular effects of glucocorticoids are mediated by the glucocorticoid receptor (GR). The protein expression of the GR has been linked to in vivo and in vitro GC resistance in various diseases treated with GC. However, existing data are conflicting.. We performed a case-control study for prednisone response to investigate the association of in vivo GC resistance and GR protein expression in childhood ALL. GR expression was assessed using Western blot technology.. The median relative GR protein expression of all patients was 0.87. Overall, we did not find different GR protein expression in PPR and PGR patients. GR protein expression was 0.91 in PGR patients versus 0.85 in PPR ones of in vivo GC resistance and GR expression.. We conclude that the expression of GR is of minor importance for in vivo GC resistance in childhood ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Case-Control Studies; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Protein Isoforms; Receptors, Glucocorticoid; Treatment Outcome; Vincristine

Veno-occlusive disease (VOD) is an entity described as a triad of pathologic findings including ascites, tender hepatomegaly, and elevated liver enzymes. The prognosis of patients suffering from VOD is highly variable, ranging from slow resolution to the need for liver transplant. The histopathology of VOD has been described by light and electron microscopy. However, the pathogenesis of VOD is still largely unclear. In the present case study, we report the significant findings in a case of pediatric VOD following chemotherapy. We studied the liver biopsy by light and electron microscopes. In addition to previous reported findings of occlusion of the central vein with endothelial cell damage, proliferation and activation of stellate cells, and collagen deposition in the central vein wall, there were prominent activated macrophages within the lumen and wall of central veins. The following mechanism of VOD was proposed: Tissue damage activates monocytes through monocyte chemoattractant protein-1. The secretory macrophages release TGF-beta, which promotes proliferation of stellate cells to cause collagenous thickening of the central vein. The activated stellate cells produce collagen. The normal drainage of the Space of Disse and sinusoids draining into the central vein are blocked by the fibrosis. This leads to extravasated RBCs trapped within the thickened central vein wall and impaction of RBCs in the sinusoids.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Female; Hepatic Veno-Occlusive Disease; Humans; Liver; Macrophages; Mercaptopurine; Methotrexate; Microscopy, Electron; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

Antimetabolite-based continuation therapy is commonly used for childhood acute lymphoblastic leukemia (ALL) and hypoglycemia after prolonged fasting has been recently reported. We have found that spontaneous, symptomatic hypoglycemia (SH) may also occur in such patients.. Between 1995 and 1999, patients treated according to the AIEOP-ALL-95 study received BFM-type intensive chemotherapy; mercaptopurine (6-MP) was given (60 mg/m(2)/days, orally for 14 days) during the second part of induction and during consolidation therapy (25 mg/m(2)/day, orally for 8 weeks); thioguanine (6-TG) was given during reinduction therapy with protocol II (60 mg/m(2)/day, orally for 14 days); continuation therapy consisted of a combination of 6-MP (50 mg/m(2)/day orally) and methotrexate (MTX, 20 mg/m(2)/weekly, i.m.). We reviewed the charts of all patients treated for childhood ALL at our two centers. This was done to assess the incidence and the characteristics of all episodes of SH: sweating, pallor, nausea, abdominal pain with or without transient alterations of alertness, in the presence of blood glucose level of under 60 mg/dl.. Six of 86 patients (6.9%) developed 18 episodes of SH. Five were male, none was older than 5 years, and four were only 3 years old. SH episodes occurred during consolidation (n = 2), reinduction (n = 7), and continuation (n = 9) phases.. SH is a rare complication associated with administration of the purine analogues, mercaptopurine and thioguanine to children with reduced fat storage and young age.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Glucose; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Hypoglycemia; Italy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Purines; Retrospective Studies; Time Factors; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Cyclophosphamide; Cytarabine; Cytogenetic Analysis; Daunorubicin; DNA Primers; Female; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Translocation, Genetic; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Factor VIII; Humans; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiography; Risk Factors; Sagittal Sinus Thrombosis; Vincristine

We describe a 69-year-old Japanese male with acute leukemia with a CD7+ and CD56+ immunophenotype presenting with multiple lymphadenopathy. He was treated with idarubicin and cytosine arabinoside. Although the leukemia showed partial response, the patient did not achieve complete remission. He died of sepsis due to severe neutropenia after the third course of chemotherapy. His autopsy revealed blast infiltration in the lymph nodes, liver, spleen and vertebral bone marrow. Recently, CD7+ and CD56+ myeloid/natural killer precursor acute leukemia has been associated with a poor prognosis. Our case illustrates that myeloid/natural killer cell precursor acute leukemia shows some response to intensive chemotherapy for acute myeloid leukemia, but such therapy is insufficient to effect a cure. To overcome the resistance of this disease to chemotherapy, further studies should explore other treatment strategies.

Topics: Acute Disease; Aged; Antigens, CD; Antigens, CD7; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD56 Antigen; Cytarabine; Daunorubicin; Diagnosis, Differential; Etoposide; Fatal Outcome; Humans; Idarubicin; Killer Cells, Natural; Leukemia, Myeloid; Leukemic Infiltration; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Mitoxantrone; Myeloid Cells; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sarcoma, Myeloid; Sialic Acid Binding Ig-like Lectin 3

Extending the principle of conventional acute lymphoblastic leukemia (ALL) therapy to transplantation, 77 adult patients receiving autografts in first remission after melphalan with or without total body irradiation were scheduled to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years after transplantation to reduce relapse. Seventy-one percent of patients received 6MP, 57% received MTX, and 38% received VP. Thirty patients had a relapse at 1.5 to 80 months (median, 12.5 months), 15 in the first year and 7 beyond 3 years. The cumulative incidence of relapse at 10 years was 42% (95% CI, 31%-55%). The 10-year probabilities of disease-free survival (DFS) and overall (OS) survival were 50% (95% CI, 38%-62%) and 53% (95% CI, 41%-65%), respectively. Age older than 30 years, more than 4 weeks to attain remission, and high-risk karyotypes, for example, t(9;22) or t(4;11), were adverse features contributing to the identification of 3 prognostic risk groups with 0, 1, and 2 adverse features, respectively: standard (47%), intermediate (36%), and high (17%). The 10-year cumulative incidences of relapse (20%, 48%, 85%; P <.0001) and probabilities of DFS (72%, 41%, 10%; P =.0003) were significantly different among these groups. In Cox analysis of the 71 patients alive and well 120 days after transplantation, those receiving 2 or 3 maintenance chemotherapy agents had significantly lower relapse rates and superior DFS compared with those receiving 0 or 1 agent. Our data suggest that maintenance chemotherapy improves the outcome of patients with ALL undergoing autografting. However, it is unlikely that autograft-based strategies are optimal for the high-risk group of patients who should be considered for alternative-donor allograft procedures.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Secondary Prevention; Survival Analysis; Transplantation, Autologous; Vincristine

Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10-44) and 58% (42-75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; DNA, Neoplasm; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA-A Antigens; HLA-B Antigens; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Infant; Living Donors; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Registries; Remission Induction; Survival Rate; Time Factors; Transplantation, Homologous; Treatment Outcome; Vincristine

Mercaptopurine is a prodrug requiring intracellular activation to thiopurine nucleotides to exert antileukemic effect. We developed a reversed-phase liquid chromatographic assay for the quantification of mercaptopurine, thioguanine, and methylmercaptopurine nucleoside and nucleotide concentrations in the target tissue, the leukemic lymphoblast.. Leukemic blasts were isolated from peripheral blood and bone marrow by a standard Ficoll-hypaque procedure. Proteins were removed by ultrafiltration in the presence of dithiothreitol. Thiopurine ribonucleotides were converted into their respective ribonucleosides by treatment of ultrafiltrate with acid phosphatase. Thiopurine nucleosides and bases were measured by direct injection of ultrafiltrate into the chromatographic system. Thiopurine nucleotide concentrations were calculated by subtracting the thiopurine nucleoside concentrations measured after treatment with acid phosphatase from those measured after direct injection of ultrafiltrate in the chromatographic system. Analytes were separated on a C18 Supelco column with ammonium phosphate-methanol eluent coupled with ultraviolet detection.. CVs for intra- and interday precision were 1.1-14% (median, 4.9%), and recovery of added analyte was 89-126% (median, 105%) at low and high concentrations of analytes, except for mercaptopurine riboside. The median signal for each of the five metabolites in lymphoblast samples was 98% (range, 80-106%) of that in water. Detection limits for thiopurine bases and nucleosides ranged from 0.5 to 4.5 pmol/5 x 10(6) cells.. This method is suitable for measurement of thiopurine metabolite concentrations in lymphoblasts in children with acute lymphoblastic leukemia following a single dose of intravenous mercaptopurine.

Topics: Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Humans; Lymphocytes; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Purine Nucleosides; Purine Nucleotides

Topics: Acute Disease; Adolescent; Antimetabolites, Antineoplastic; Child; Female; Humans; Male; Mercaptopurine; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.

Topics: Algorithms; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Child; Drug Administration Schedule; Erythrocytes; Humans; Hypoxanthine Phosphoribosyltransferase; Inactivation, Metabolic; Injections, Intravenous; Inosine Monophosphate; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasm Proteins; Nucleotides; Polyglutamic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Thioguanine; Thionucleotides; Xanthine Oxidase

To study, using serial neuropsychological assessment and evaluation of school achievement, persistent neuropsychological late effects in children treated for acute lymphoblastic leukemia (ALL) at a young age with chemotherapy only.. Twenty consecutive patients underwent three evaluations, including 12 psychometric measures beside IQ. The authors applied strict methodology and a prospective-longitudinal design that started at diagnosis and extended to a median follow-up of 7 years. This report focuses on the outcome of the last evaluation. Test results were compared with healthy controls and to patients with ALL treated on a previous chemotherapy-only protocol. School achievement was evaluated in patients and their siblings.. At the last evaluation, significantly lower test scores in patients compared with controls were found for only 2 of 14 cognitive measures (1 intelligence and 1 attention measure). No great differences were seen between school achievement of patients and siblings. Compared with the previous chemotherapy protocol, a better outcome was seen in the current study group on two measures (one memory and one attention measure).. Children surviving ALL have no major cognitive impairment after chemotherapy, including intrathecal and high-dose intravenous methotrexate. The slightly better outcome in the current group may indicate possible adverse effects of more dexamethasone treatment in the previous group.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Attention; Child, Preschool; Cognition Disorders; Cyclophosphamide; Cytarabine; Dexamethasone; Female; Follow-Up Studies; Humans; Ifosfamide; Injections, Spinal; Learning Disabilities; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Netherlands; Neuropsychological Tests; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Survivors; Teniposide; Treatment Outcome; Vincristine

We examined the pre-treatment bone marrow samples from 200 consecutive adult patients with acute lymphoblastic leukemia (ALL) treated on various protocols at the University of Texas, M.D. Anderson Cancer Center between 1986 and 1998. Standard MFC techniques were used to determine CD56 expression on the leukemia blasts cells. The expression of CD56 was correlated with clinical characteristics at diagnosis, response to therapy, survival and disease-free survival. Blast expression of CD56 (> or = 20% of leukemic blasts) was seen in 16 (8%) of patients, with a median expression of 67% (range 20-99%). CD56 expression was associated with a higher incidence of central nervous system (CNS) disease at diagnosis (19% versus 4%; P=0.016). Incidence of CNS disease at any time was higher in patients with CD56+ disease (31% versus 14%; P=0.057). Among the 109 patients uniformly treated with the hyperCVAD regimen, CD56 expression was associated with a statistically significant higher incidence of CNS disease (33% versus 9%; P=0.026). CD56 expression in ALL is uncommon but may predict a higher risk for CNS disease. If these results are confirmed, CD56 expression could be used in combination with other high-risk features (e.g. lactate dehydrogenase (LDH), S-phase fraction, mature B-cell phenotype) to design a risk-oriented approach to CNS prophylaxis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow Cells; CD56 Antigen; Cell Adhesion; Central Nervous System; Chemotaxis, Leukocyte; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Gene Expression; Humans; Incidence; Leukemic Infiltration; Life Tables; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm Proteins; Neoplastic Stem Cells; Neurons; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prednisone; Risk; Survival Analysis; Treatment Outcome; Vincristine

To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL).. Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above.. Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01).. Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk Factors; Treatment Outcome; Vincristine

To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used antileukemic agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSalpha) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing deoxythioguanosine (G(S)) within either G(S).T or G(S).C pairs, resulted in formation of a DNA-protein complex distinct from the DNA-MutSalpha complex and unaffected by ATP. Isolation and sequence analysis of proteins involved in this DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a component. Western blot analysis of nuclear extracts from a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p = 0.001). Confocal analysis revealed markedly different intracellular distribution of GAPDH between nucleus and cytosol in six human ALL cell lines. Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment. These findings indicate that a new DNA-protein complex containing GAPDH and distinct from known MMR protein-DNA complexes binds directly to thioguanylated DNA, suggesting that this may act as a sensor of structural alterations in DNA and serve as an interface between these DNA modifications and apoptosis.

Topics: Antimetabolites, Antineoplastic; Base Pair Mismatch; Cell Nucleus; DNA Primers; DNA Repair; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thionucleosides; Tumor Cells, Cultured

Nineteen of 35 children (54%) with acute lymphoblastic leukemia receiving maintenance therapy consisting of daily oral 6-mercaptopurine and weekly oral methotrexate developed hypoglycemia (blood glucose level <2.7 mmol/L [50 mg/dL] or <2.9 mmol/L [54 mg/dL] with symptoms) during 16 hours of overnight fasting. In 15 of 15 re-studied children, fasting tolerance had improved, and in 67% (10/15), it had become normal a few months after cessation of therapy.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Fasting; Female; Finland; Humans; Hypoglycemia; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Statistics, Nonparametric

Viral hepatitis is a cause of hepatic dysfunction in children with ALL in remission during maintenance therapy is debated. The aims of the current study were (1) to explore the incidence of hepatic dysfunction in a group of children (Egyptian and Saudi) with ALL under maintenance therapy, (2) to study the prevalence of hepatitis B (HBV) and/or C (HCV) infection and their contributions to chronic liver disease that might be induced by maintenance therapy.. The current study included 105 children with ALL (54 Egyptian and 51 Saudi). All eligible patients had been on maintenance therapy for at least 12 months and all had serial assessments of liver function. These included determination of total bilirubin, AST, ALT, and alkaline phosphatase. Markers for HBV and HCV including HBsAg, anti-HBC, and anti-HCV and for some patients HCV RNA by PCR were studied. Percutaneous liver biopsy was performed for a group of children.. The prevalence of hepatitis infection (HBV and/or HCV) among Egyptian children was found to be high (43/54-80%). Only five Saudi children had evidence of exposure to HBV (5/51-9.8%), P<0.0001. During the period of study, 22 Egyptian patients vs. four Saudi patients (41 vs. 7.8%, P<0.0001) experienced at least one episode of elevation of liver enzymes, three times the upper limit of normal or more. Twenty-six of the 48 patients (54%) with HBV and/or HCV infection had episodes of elevated liver enzymes, while there was no occurrence among the patients negative for HBV and HCV. In patients with HBV infection, the presence of HBsAg was strongly associated (100%) with elevated liver enzymes. Histopathologic examination of liver biopsies obtained from 35 patients revealed that all five patients negative for HBV and HCV had normal liver biopsies in spite of being under maintenance therapy.. In children undergoing treatment for ALL, elevations in liver enzymes may be primarily due to hepatitis viruses. However, maintenance therapy using known hepatotoxic drugs, may have additive deleterious effects. Liver enzymes are normalized in affected patients when maintenance therapy is temporarily suspended.

Topics: Antimetabolites, Antineoplastic; Case-Control Studies; Chemical and Drug Induced Liver Injury; Child; Egypt; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Incidence; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Saudi Arabia

Topics: Adolescent; Antimetabolites, Antineoplastic; Bone Marrow; Child; Child, Preschool; Female; Heterozygote; Humans; Japan; Male; Mercaptopurine; Methyltransferases; Polymerase Chain Reaction; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The purpose of this study was to determine the frequency with which magnetic resonance (MR) imaging detects avascular necrosis of the bone (AVNB) in children with acute lymphoblastic leukemia (ALL) or advanced-stage non-Hodgkin lymphoma (NHL) who receive prednisone during remission induction, reinduction, and maintenance chemotherapy; to assess the clinical significance of these findings; and to identify factors predictive of AVNB. We prospectively obtained MR imaging of the hips and knees of 116 children who had completed at least 1 year of treatment for ALL or advanced-stage NHL on identical prednisone-containing regimens between December 1991 and October 1994. MR imaging findings of AVNB were compared with clinical outcomes, and the effect of therapeutic and patient factors on the frequency of AVNB was analyzed. The MR imaging findings of 17 of the 116 participating patients were consistent with AVNB. The most common clinical manifestation was joint pain (11 patients). Only one patient had progressive joint deterioration that necessitated surgical replacement. Only age 10 years or more at the time of the primary diagnosis was significantly associated with the development of AVNB (P = 0.004). MR imaging showed changes consistent with AVNB in approximately 15% of this patient population. However, most patients in this study who had MR imaging signs of AVNB did not experience progressive joint destruction, even with continued prednisone therapy. Therefore, the clinical usefulness of MR imaging as a screening tool for AVNB in this set of patients remains uncertain.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Arthralgia; Arthroplasty, Replacement, Hip; Asparaginase; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Femur Head Necrosis; Humans; Lymphoma, Non-Hodgkin; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Osteonecrosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Treatment Outcome; Vincristine

Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Dexamethasone; Humans; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Time Factors; Vincristine

We report a childhood case that showed the repeated appearance and disappearance of various kinds of cytogenetic abnormalities (CA) for 5.5 years after allogeneic bone marrow transplantation (BMT). The patient underwent allogeneic BMT from an HLA-matched unrelated donor during the second complete remission of acute lymphoblastic leukemia. The conditioning regimen for BMT consisted of etoposide, cyclophosphamide, anti-human thymocyte immunoglobulin, and total body irradiation. There were no leukemic relapses or secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) since the BMT. The CA occurred from residual recipient cells, which were damaged by chemotherapy or radiation prior to BMT. Although previous studies about post-BMT CA had reported the continuous emergence of identical clones, the present case showed the appearance of one different type of clone after another. Although the appearance of different types of CA may mean that these clones did not obtain any growth advantages, it may be a sign of genomic instability, which is probably a risk factor for the development of secondary AML/MDS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Clone Cells; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; DNA Damage; Female; Follow-Up Studies; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Mercaptopurine; Methotrexate; Methylprednisolone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Vincristine

To evaluate the clinical implications of CD45 expression in acute childhood lymphoblastic leukemia (ALL), we measured the CD45 expression of blast cells from 133 untreated patients with childhood B-precursor ALL (n = 118) or T-ALL (n = 15). CD45 expression (> or = 20%) was detected in all 15 cases (100%) of T-ALL, and 101 cases (86%) of B-precursor ALL. In 122 cases, the fluorescence intensity of the CD45 expression was measured as a relative value; the ratio of average linear values (RALV) of CD45 on the blasts to that on CD3-positive T-lymphocytes from the same specimen. The expression was more intense in the T-ALL cases than in the B-precursor ALL cases (RALV, mean +/- SE: T-ALL 0.230 +/- 0.04 vs. pro-B ALL 0.150 +/- 0.012/pre-B ALL 0.153 +/- 0.019, p < 0.05). However, the intensity of the CD10, CD19, CD20 and CD34 antigen immunoreactivity did not correlate with the CD45 expression. Patients with hyperdiploidy (chromosome number > 50) showed significantly lower levels of CD45 expression than patients with t(1;19) or normal karyotypes (RALV, mean +/- SE: 0.081 +/- 0.022 vs. 0.133 +/- 0.03/0.143 +/- 0.019, p < 0.05). Other clinical features such as age, gender and WBC count did not correlate with CD45 expression. The prognostic implications of CD45 expression were studied in non-high-risk (low-risk + intermediate-risk) (n = 60) and high-risk patients (n = 52) with B-precursor ALL who had been treated with the risk-directed protocol of ALL-941 trial. Although CD45 expression did not correlate with the event-free survival (EFS) of the non-high-risk patients, there was a significant correlation between the expression levels and the EFS of the high-risk patients: the 3-year EFS rate of the CD45low group (n = 26, RALV = 0.017-0.132) was 88 +/- 7% versus the CD45high group (n = 26, RALV = 0.133-0.450) at 34 +/- 24% (p < 0.05). These results show that the levels of expression of the CD45 antigen on leukemic lymphoblasts are significantly correlated with the clinical features and prognosis of childhood ALL.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Child; Disease-Free Survival; Doxorubicin; Humans; Immunophenotyping; Leukocyte Common Antigens; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Remission Induction; Time Factors; Vincristine

The poor absorption of orally administered 6-mercaptopurine (6MP) causes a wide variation in its cytotoxic efficacy. An i.v. dosage form would eliminate this problem. Our objective was to compare the pharmacokinetics of 6MP administered orally with those of an i.v. dosage form 6-mercaptopurine riboside (6MPR), in children with acute lymphoblastic leukemia or malignant lymphoma.. A total of 10 children were treated with oral 6MP, 50 mg/m(2) per day, while five children were treated with 6MPR, 50 mg/m(2) per day, administered by rapid i.v. injection. The plasma concentrations of 6MP and of 6MPR were measured on day 0, while the concentrations of 6-thioguanine nucleotides (6TGN) in red blood cells (RBC) were measured on day 2. The area under the plasma concentration-time curve (AUC1-5) was calculated from 1 to 5 h after drug administration.. With the intravenously administered 6MPR, the AUC1-5 ranged from 124 to 186 (1.5-fold range, median 145) microM min; only two samples were obtained for the RBC concentration of 6TGN, and were 121 and 273 pmol per 25 mg hemoglobin. With the orally administered 6MP, the AUC1-5 ranged from 23 to 65 microM min (2.8-fold range, median 56); the RBC concentration of 6TGN ranged from 18 to 152 pmol per 25 mg hemoglobin (median 75).. The i.v. administration of 6MPR showed less interindividual variation in the AUC1-5 coupled with a higher RBC level of 6TGN as compared with those by oral 6MP. We conclude that the i.v. administration of 6MPR achieves stable blood levels of active drug in children undergoing cancer chemotherapy.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Area Under Curve; Child; Child, Preschool; Female; Humans; Injections, Intravenous; Lymphoma; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioinosine

THE CURRENT STATE: Children with curable cancer are potentially at risk of long-term renal sequelae. The nephrotoxicity is considered dose related and includes a variable reduction of glomerular filtration rate along with tubular dysfunction.. The aims of the present study were: to analyse kidney damage as well as the clinical course in children treated for ALL, to determine what type of nephrotoxic damage is most frequent in relation with the used treatment, to determine possible risks of acute and chronic nephropathy of anticancer therapy, to standardise evaluation of kidney function in children after their complex antitumourous treatment has finished.. We examined a group of 36 children (21 boys, 15 girls, average age at diagnosis of ALL 6.9 years)) treated for ALL using the therapeutical protocol ALL BFM 90. The average period after the treatment had finished was 48 month. The following parameters were examined: urinalysis and urine sediment, clearance of creatinine, tubular resorption, ultrasound of kidneys, 24 hrs proteinuria (PU) and urine concentration of albumine, transferine, alpha-1-microglobuline and Tamm-Horsfall protein. Concentration function of kidneys was examined by test with DDAPV.. After finish of cytostatic therapy had 19 patients (52.8%) PU. Glomerular PU was found in 3 children (15.8%), in 3 children (15.8%) was found mixed PU and 13 children (68.4%) had tubular PU. Reduction of GFR had 5 patients (13.9%) and 19 patients (52.8%) had reduction of DDAPV test.. Sensitive laboratory analysis of proteinuria is required for timely detection of the most frequent type of kidney damage in the course of treatment with cytostatics but also other concurrently administered drugs. Thus we can reliably detect mainly patients with glomerular/mixed proteinuria who are potentially imperilled by the risk of the development of chronic renal failure. If there is higher level of glomerular/mixed proteinuria even after the treatment has finished, the patients have to undergo another nephrological monitoring. (Tab. 3, Ref. 20.)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Kidney; Kidney Function Tests; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

Early response to therapy is an independent prognostic factor in childhood acute lymphoblastic leukemia. Although most patients have rapid early responses, as detected by morphology, 15% to 20% of patients have relapses. The authors evaluated residual disease by molecular methods on day 15 of minimal residual disease (MRD) therapy and compared these data with their recently established MRD-based risk stratification, defined by MRD levels 5 weeks after induction treatment and before consolidation. All 68 children treated according to current Berlin-Frankfurt-Münster (BFM) protocols went into morphologically complete remission after induction. There was a significant difference in outcome between children with rapid disease clearance and those with high levels of day-15 MRD (P =.035). Among patients with high levels of day-15 MRD, only the MRD-based risk stratification was predictive of the outcome. All patients with negative or low day-15 MRD had excellent prognoses and were in the MRD-based low-risk group. Thus, after only 2 weeks of treatment, the authors were able to identify a patient population of 20% who may benefit from the least intensive treatment.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Gene Rearrangement; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk; Time Factors; Treatment Outcome; Vincristine

Topics: Antimetabolites, Antineoplastic; Azathioprine; Child; Genotype; Humans; Mercaptopurine; Methyltransferases; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Nineteen pediatric patients affected by acute lymphoblastic leukemia (ALL) were examined weekly with respect to 6-mercaptopurine nucleotide (6-MPN) and 6-thioguanine nucleotide (6-TGN) levels in erythrocytes during the course of maintenance treatment with 6-MP 50 mg/m2 per d and results were related to various parameters of bone marrow function to assess, in the same individual, the level of reliability of 6-MP metabolites in predicting a later change in peripheral blood cell counts. Median values for 6-MPN and 6-TGN were 57 and 200 pmol/8 x 10(8) erythrocytes, respectively, as measured by reversed-phase high-performance liquid chromatography (HPLC). 6-TGN levels in erythrocytes were inversely related with white blood cell count (r = -0.463, p < 0.0001, n = 361), absolute neutrophil count (r = -0.386, p < 0.0001, n = 347), erythrocyte (r = -0.354, p < 0.0001, n = 287), and platelet counts (r = -0.24, p < 0.0001, n = 319) in the majority of patients (n = 10-12), while no correlation was found for 6-MPN. In the remaining children, no evidence of correlation was demonstrated between 6-TGN levels and myelotoxicity. The results confirm the role of 6-TGN as the reference cytotoxic metabolite for evaluating the exposure to 6-MP and identifying treatment compliance in ALL children but indicate the limits of a follow-up based solely on metabolite levels and suggest that a more correct approach remains the double monitoring of 6-TGN and blood cell count with differential.

Topics: Adolescent; Antimetabolites, Antineoplastic; Bone Marrow; Child; Child, Preschool; Drug Monitoring; Erythrocytes; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides

S-Methylation by thiopurine methyltransferase (TPMT) is an important route of metabolism for the thiopurine drugs. About one in 300 individuals are homozygous for a TPMT mutation associated with very low enzyme activity and severe myelosuppression if treated with standard doses of drug. To validate the use of molecular genetic techniques for the detection of TPMT deficiency, we have determined red blood cell TPMT activity in 240 adult blood donors and 55 normal children. Genotype was determined by restriction fragment length analysis of polymerase chain reaction products in a cohort of 79 of the blood donors and five cases of azathioprine-induced myelosupression, and this confirmed a close relationship between genotype and phenotype. In 17 of the 24 cases in which mutations were found, DNA was also available from remission bone marrow. In one of these cases, DNA from the remission marrow sample indicated the presence of a non-mutated allele that had not been seen in the blast DNA sample obtained at presentation. These results indicate that polymerase chain reaction-based assays give reliable and robust results for the detection of TPMT deficiency, but that caution should be exercised in relying exclusively on DNA obtained from lymphoblasts in childhood leukaemia.

Topics: Adolescent; Adult; Azathioprine; Blood Donors; Child; Child, Preschool; DNA Mutational Analysis; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Methyltransferases; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reference Values; Sensitivity and Specificity; Thioguanine

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 10(4) normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, > or = 0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (> or = 1%) or at week 14 of continuation therapy (> or = 0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% +/- 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% +/- 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD(+) patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients. (Blood. 2000;96:2691-2696)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Etoposide; Female; Flow Cytometry; Humans; Hydrocortisone; Immunophenotyping; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Neoplastic Cells, Circulating; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Remission Induction; Treatment Outcome; Vincristine

The difference in the current cure rates between adult and childhood acute lymphoblastic leukaemia (ALL) may be caused by differences in drug resistance. Earlier studies showed that in vitro cellular drug resistance is a strong independent adverse risk factor in childhood ALL. Knowledge about cellular drug resistance in adult ALL is still limited. The present study compared the in vitro drug resistance profiles of 23 adult ALL patients with that of 395 childhood ALL patients. The lymphoblasts were tested by the MTT assay. The group of adult ALL samples was significantly more resistant to cytosine arabinoside, L-asparaginase, daunorubicin, dexamethasone and prednisolone. The resistance ratio (RR) was highest for prednisolone (31.7-fold) followed by dexamethasone (6.9-fold), L-asparaginase (6. 1-fold), cytosine arabinoside (2.9-fold), daunorubicin (2.5-fold) and vincristine (2.2-fold). Lymphoblasts from adult patients were not more resistant to mercaptopurine, thioguanine, 4-HOO-ifosfamide, mitoxantrone and teniposide. There were no significant differences in drug resistance between adult T-cell (T-) ALL (n = 11) and adult common/pre-B-cell (B-) ALL (n = 10). Additionally, adult T-ALL did not differ from childhood T-ALL (n = 69). There were significant differences between adult common/pre-B-ALL and childhood common/pre-B-ALL (n = 310) for prednisolone (RR = 302, P = 0.008), dexamethasone (RR = 20.9, P = 0.017) and daunorubicin (RR = 2.7, P = 0.009). Lymphoblasts from adults proved to be relatively resistant to drugs commonly used in therapy. This might contribute to the difference in outcome between children and adults with ALL.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Agents; Asparaginase; Bone Marrow Cells; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Idarubicin; Ifosfamide; Infant; Leukemia, Prolymphocytic; Leukemia, T-Cell; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Statistics, Nonparametric; Teniposide; Thioguanine; Vincristine

The use of pharmacogenomics to individualize drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. However, the combinations of disease, drug, and genetic test characteristics that will provide clinically useful and economically feasible therapeutic interventions have not been clearly elucidated. The purpose of this paper was to develop a framework for evaluating the potential cost-effectiveness of pharmacogenomic strategies that will help scientists better understand the strategic implications of their research, assist in the design of clinical trials, and provide a guide for health care providers making reimbursement decisions. We reviewed concepts of cost-effectiveness analysis and pharmacogenomics and identified 5 primary characteristics that will enhance the cost-effectiveness of pharmacogenomics: 1) there are severe clinical or economic consequence that are avoided through the use of pharmacogenomics, 2) monitoring drug response using current methods is difficult, 3) a well-established association between genotype and clinical phenotype exists, 4) there is a rapid and relatively inexpensive genetic test, and 5) the variant gene is relatively common. We used this framework to evaluate several examples of pharmacogenomics. We found that pharmacogenomics offers great potential to improve patients' health in a cost-effective manner. However, pharmacogenomics will not be applied to all currently marketed drugs, and careful evaluations are needed on a case-by-case basis before investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions.

Topics: Anticholesteremic Agents; Anticoagulants; Antimetabolites, Antineoplastic; Cardiovascular Diseases; Carrier Proteins; Child; Cholesterol Ester Transfer Proteins; Cost-Benefit Analysis; Drug Therapy; Genotype; Glycoproteins; Hepatitis C; Humans; Interferons; Mercaptopurine; Methyltransferases; Pharmacogenetics; Pharmacology, Clinical; Phenotype; Pravastatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ribavirin; Warfarin

Topics: Alleles; Antimetabolites, Antineoplastic; Child; Female; Genetic Testing; Genotype; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Infants diagnosed with acute lymphoblastic leukemia (ALL) are considered the patient subgroup at the highest risk for central nervous system (CNS) disease, both at presentation and as an isolated extramedullary relapse. In addition, they are highly vulnerable to adverse developmental sequelae from CNS-directed therapy.. Thirty patients younger than 12 months at diagnosis (12 males, 18 females) in first hematologic remission were evaluated after completion of ALL therapy (mean age = 62.1 months; standard deviation = 17.2 months; range = 38-102 months). CNS-directed treatment included very high dose infusions of methotrexate (MTX) and intrathecal cytarabine and MTX. Three patients had meningeal leukemia that required additional therapy. Children were administered the McCarthy Scales of Children's Abilities, and parents completed a sociodemographic questionnaire to obtain information about occupation and education.. Mean scores on all 6 cognitive and motor indices of the McCarthy Scales were in the average range (Verbal = 52.0; Perceptual = 53.6; Quantitative = 49.6; General Cognitive Index [GCI] = 102.1; Memory = 49.2; Motor = 51.0). Score distributions for each neurodevelopmental index were comparable to age-based population standards. One patient obtained a GCI that exceeded 2 standard deviations above the mean; none scored more than 2 standard deviations below. There was no report of developmental disabilities or neurologic disorders for any of the patients. Risk factors, including age at diagnosis, gender, additional CNS-directed treatment, and family socioeconomic status, were not associated with developmental outcome.. Test findings indicated a generally positive neurodevelopmental outcome for ALL patients diagnosed in infancy who were treated with very high dose MTX as CNS-directed therapy. Combined with the reduction in the isolated CNS relapse rate achieved by the Children's Cancer Group (CCG) clinical trial CCG-107, the results of this study represent a substantial improvement in neurodevelopmental outcome for very young patients compared with infants treated for ALL in the past.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Damage, Chronic; Cognition Disorders; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Developmental Disabilities; Female; Follow-Up Studies; Humans; Infant; Injections, Spinal; Leucovorin; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Movement Disorders; Neuropsychological Tests; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Psychomotor Performance; Remission Induction; Risk; Socioeconomic Factors; Survivors; Vincristine

The role of 6-mercaptopurine (6MP) in the treatment of childhood acute lymphoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP is significantly influenced by inactivation by the polymorphic enzyme thiopurine methyltransferase (TPMT). In the general population 89-94% have high TPMT activity, 6-11% have intermediate activity, and approximately 0.3% have low activity. Individuals with low-activity experience severe or fatal toxicity with standard 6MP doses. Prospective identification of this group of patients might prevent this problem. Recent identification of the molecular basis for low TPMT activity enabled rapid assessment of altered 6MP metabolism by PCR methods. This study evaluated the frequency of mutant TPMT alleles in 147 children with ALL. One patient was homozygous mutant (0.7%), and 16 patients were heterozygous for variant TPMT alleles (10.9%). The majority of mutant alleles were TPMT*3A. Both the allele frequency and the pattern of TPMT mutations were similar to that observed in an adult British population. The number of weeks when 6MP therapy was administered at full dose was determined in patients on MRC UKALL X and XI. The 94 patients spent a median 11% of the maintenance period receiving no therapy as a result of haematological toxicity. There was no significant difference in the number of weeks when no therapy could be administered among patients with a wild-type or heterozygous genotype. However, the one patient with a homozygous mutant genotype had severe haematological toxicity and no therapy could be administered for 53% of the maintenance period. This study demonstrates that 11.6% of the children had variant TPMT alleles. Prospective identification of TPMT genotype may be a promising tool for decreasing excessive haematological toxicity in individuals with low activity.

Topics: Adult; Antimetabolites, Antineoplastic; Child; Gene Frequency; Humans; Mercaptopurine; Methyltransferases; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Child; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Lung Neoplasms; Lymphoma, B-Cell; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

Expression of the Wilms' tumour gene (wt1) has been demonstrated in a large proportion of human acute leukaemias and is thought to play a role in leukaemogenesis. Recent observations in adult patients with acute leukaemia suggest that wt1 gene expression is a poor prognostic factor. In childhood acute leukaemia, the clinical role of wt1 gene expression has not been established. We have therefore investigated bone marrow samples from 50 children with acute lymphocytic leukaemia at the time of diagnosis for the presence of wt1 transcripts to determine whether wt1 gene expression is associated with specific characteristics of leukaemic cells and whether it is predictive of response to treatment. All patients were treated according to the ALL-BFM 90 protocol. The median observation time was 30 months. Wt1 transcripts were detected by RT-PCR in 60% of the diagnostic samples. Wt1 PCR positive patients showed a higher median leukocyte and peripheral blast cell count than wt1 negative patients. High and intermediate risk patients more frequently displayed wt1 transcripts than low risk patients. No correlation between wtl gene expression and FAB type, immunophenotype, co-expression of myeloid antigens or karyotype has been observed. Furthermore, there was no correlation between wt1 gene expression at diagnosis and achievement of complete remission (CR) and no difference in disease-free survival (DFS) or overall survival (OS) between wt1 positive and negative patients (p > 0.1). These data indicate that (1) wt1 gene expression at diagnosis is detected more frequently in patients with high leukocyte and peripheral blast cell counts, but is not associated with specific characteristics of leukaemic cells, (2) wt1 gene expression is not an independent prognostic factor for CR, DFS or OS in childhood ALL treated by an intensive therapy protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; DNA-Binding Proteins; Female; Gene Expression Regulation, Leukemic; Genes, Wilms Tumor; Humans; Life Tables; Male; Mercaptopurine; Methotrexate; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transcription Factors; Vincristine; WT1 Proteins

Topics: Alleles; Antimetabolites; Central Nervous System Neoplasms; Child; Germany; Humans; Incidence; Mercaptopurine; Methyltransferases; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Two cases of young patients, Jehova Witnesses (JW), diagnosed as having acute lymphoblastic leukaemia are presented. In one case a complete remission (CR) was obtained, lasting until now, 20 months after diagnosis; the other one died 11 months after diagnosis without achieving a CR. Three important questions can be raised in JW: 1) the absolute respect to patients' wishes; 2) to treat or not to treat; and 3) the pertinent therapy. The answer is yes to 1) and 2), and a slight myelotoxic therapy for the last one.

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Transfusion; Christianity; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Fatal Outcome; Female; Humans; Male; Mercaptopurine; Methotrexate; Personnel, Hospital; Physician-Patient Relations; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Refusal to Treat; Remission Induction; Right to Die; Treatment Refusal; Vincristine

Twenty-four pediatric patients with acute lymphoblastic leukemia (ALL) on maintenance therapy were evaluated for their compliance with taking their prescribed doses of oral mercaptopurine (6-MP).. We utilized the Medication Event Monitoring System (MEMS; Aprex Corporation, Fremont, CA) for the study. Compliance was defined as the number of days doses were taken as a percentage of the total number of days doses were prescribed during the study period. The mean age of the patients was 7.3 years (range 2.6-17.2 (years). Patients were evaluated for a mean of 44 days (range 15-94 days). Thirty-three percent of patients (8) took less than 90% and 17% (4) took less than 80% of their prescribed pills. Eight patients were also evaluated for a difference in compliance between morning and evening administration. For the comparison of compliance between a morning vs. an evening schedule a tren toward improved compliance in the evening was found. Five patients had an increase and one patient a decrease in compliance with an evening schedule (differences ranged from 0.2% to 51.3%), with two patients having 100% compliance on both schedules.. Our data raise concern that a significant proportion of pediatric patients are non-compliant with pill taking and demonstrate that the timing of administration of 6-MP in children with ALL may be crucial in some patients and supports the hypothesis that evening administration of 6-MP is associated with a lower risk of relapse.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Computers; Female; Humans; Male; Mercaptopurine; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma

This paper describes a specific and sensitive reversed-phase HPLC assay for the measurement of 6-methylthioguanine (methyl-TG) and methyl-TG nucleotides (methyl-TGNs) in red blood cells (RBCs), which is suitable for routine clinical use. Briefly, an ethyl acetate extract of RBCs is evaporated and reconstituted in 0.1 M HCl. The methyl-TG is separated from other thiopurines by reversed-phase HPLC and quantitated using UV detection. For the measurement of methyl-TGNs the free base (methyl-TG) is obtained by acid hydrolysis of the nucleotide back to the parent thiopurine. The intra-assay C.V. over the concentration range of 0.055-1.10 nmol methyl-TG per 4x10(8) (100 microl) RBCs ranged from 2.8 to 8.5%, and the mean recovery of methyl-TG over the calibration range was 61.6% (coefficient of variation, C.V., 3.8%). The lower limit of reproducibility was 0.055 nmol extracted from 100 microl RBCs. Analysis of blood samples from children with leukaemia receiving 6TG chemotherapy, revealed RBC methyl-TGNs at concentrations ranging from 323 to 1365 pmol per 8x10(8) RBCs. No methyl-TG was detected in any of the patient samples.

Topics: Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Erythrocytes; Humans; Hydrogen-Ion Concentration; Hydrolysis; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Thioguanine

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold above the population median, but without unacceptable bone-marrow toxicity. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia followed high-dose MTX infusions. Due to the risk of fatal myelosuppression we recommend up-front determination of TPMT activity in patients treated with 6MP or azathioprine.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Follow-Up Studies; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

A retrospective analysis was performed on 76 consecutive elderly patients with acute leukemia aged 60 years or more (48 men, 28 women). Forty patients were 60-69 years old, 28 were 70-79 years old and 8 were > or = 80 years old. There were 55 patients with acute myelogenous leukemia (AML), 13 acute lymphoblastic leukemia (ALL) and 8 AML from myelodysplastic syndrome (MDS/AML). Patients were treated with the JALSG protocol, CAG regimen, or low-dose Ara-C regimen for AML, and DVP/M-CHOP protocol for ALL. The complete remission (CR) rates were 52.7% (29 of 55) in AML, 61.5% (8 of 13) in ALL, and 0% in MDS/AML. The median CR durations were 226, 85, 0 days, and the median survivals were 204, 177, 99 days, respectively. CR rates were 65.3% for the JALSG protocol, 62.5% for the CAG regimen and 25.0% for low-dose Ara-C regimen. According to age, CR was obtained 62.5% in patients aged 60-69 years and 33.3% in patients over 70 years old. Our results indicated that patients aged 60-69 years should be treated with intensive chemotherapy.

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; DNA; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Retrospective Studies; Vincristine

The dental health of 41 children aged 4-16 years who were in maintenance therapy from acute lymphoblastic leukemia (ALL) was examined in relation to the period of time in maintenance. There was no significant difference in dental experience and salivary flow rate between the control group and patients with leukemia. Performed treatment index (PTI) and required treatment index (RTI) scores reflected that children, who were in maintenance therapy had insufficient dental care and needed more dental treatments. A statistically significant difference in salivary pH was found between the children, who were in maintenance therapy for 12-24 months and less than 12 months and also the control group; but the pH scores of all groups were observed in normal limits.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Case-Control Studies; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dental Care for Chronically Ill; Dental Caries; DMF Index; Female; Humans; Male; Mercaptopurine; Methotrexate; Oral Hygiene; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Vincristine

As a prelude to a nationwide randomized trial of thioguanine (TG) versus mercaptopurine (MP) for childhood lymphoblastic leukaemia we compared a pilot group of 23 children taking TG with a matched group taking MP. We assessed drug tolerance based on haematological toxicity and measured erythrocyte (RBC) concentrations of thioguanine nucleotides (TGN). The median tolerated dose of TG was 30 mg/m2 compared to 55 mg/m2 for MP. There was no difference in the pattern of anaemia or neutropenia between the two groups, but dose-limiting thrombocytopenia was more evident in the TG children (P< 0.001), four of whom had a decrease in platelet count to <20 x 10(9)/l compared to only one on MP. The median RBC TGN concentration for those on 40 mg/m2 TG was 1726 pmol/8 x 10(8) RBCs compared with 308 pmol/8 x 10(8) RBCs for those on 75 mg/m2 MP (P< 0.0001). There was an inverse correlation between RBC TGNs and neutrophil count in the MP group but not in those on TG. No correlation between metabolite concentration and thrombocytopenia was found in either group. These results provide further evidence that TG has a selective effect on platelets. They also showed that RBC TGN were, on average, 5-fold higher in those taking TG but did not obviously relate to myelotoxicity as found in children on MP. The higher concentrations seen may partly reflect the erythrocyte's ability to metabolize TG directly to TGN by pathways not open to MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Infant; Lymphocyte Count; Male; Mercaptopurine; Neutropenia; Neutrophils; Nucleotides; Platelet Count; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thrombocytopenia

Topics: Adult; Aged; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Cytarabine; Daunorubicin; Female; Heart; Heart Failure; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

Children with acute lymphoblastic leukaemia (ALL) typically gain weight at excessive rates during and after therapy, and a high proportion of young adult survivors are obese. Previous studies have failed to identify the abnormalities in energy balance that predispose these children to obesity. The aim of this study was to determine the cause of excess weight gain in children treated for ALL by testing the hypothesis that energy expenditure is reduced in these patients. Twenty children [9 boys, 11 girls; mean age 10.9 (3.2) y] treated for ALL who had shown excess weight gain, but were not obese [mean body mass index SD score 0.70 (1.04)], were closely and individually matched with 20 healthy control children [9 boys, 11 girls; mean age 10.7 (3.0) y; mean body mass index SD score 0.27 (0.91)]. In each child we measured total energy expenditure by doubly-labeled water method, resting energy expenditure, energy expended on habitual physical activity, and energy intake. Total energy expenditure was significantly higher in control subjects than in patients: mean paired difference 1185 kJ/d (282 kcal/d), 95% confidence interval (CI) 218-2152. This difference was largely due to reduced energy expended on habitual physical activity in the patients. Resting energy expenditure was lower in the patients: mean paired difference 321 kJ/d (76 kcal/d), 95% CI 100-541. Energy intake was also lower in the patients: mean paired difference 1001 kJ/d (238 kcal/d), 95% CI 93-1909. Children treated for ALL are predisposed to excess weight gain, and subsequently obesity, by reduced total energy expenditure secondary to reduced habitual physical activity. Prevention of obesity in ALL should focus on modest increases in habitual physical activity, modest restriction of dietary intake, and monitoring of excess weight gain.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Child; Energy Metabolism; Female; Humans; Male; Mercaptopurine; Methotrexate; Obesity; Physical Exertion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Reference Values; Survivors; Vincristine; Weight Gain

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Asparaginase; Biological Availability; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; DNA Adducts; Erythrocytes; Female; Guanosine Triphosphate; Humans; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Proportional Hazards Models; Recurrence; Thionucleotides; Treatment Outcome; Vincristine

Methods of assaying 6-mercaptopurine (6MP) and its methylated and non-methylated metabolites are essential for the therapeutic dose in treating patients with acute lymphoblastic leukemia. However, previous methods are technically complicated and unsuitable for clinical use. Thus, we have now developed a method utilizing reversed-phase high-performance liquid chromatography (HPLC) in order to quantify these compounds in human red blood cells (RBCs) in a single sample to serve as an index of cytotoxic activity. The agents 6MP, 6-thioguanine (6TG) and 6-methylmercaptopurine (6MMP) were well separated by this assay. Linear relationships were observed between the peak areas and the RBC concentrations of 6MP, 6TG and 6MMP over the range of 20-2000, 18-1800 and 18-1800 pmol per 25 mg hemoglobin (Hb), respectively. The limit of quantitation of the assay is 20, 18 and 18 pmol per 25 mg Hb, respectively. This assay system is suitable for routine clinical use.

Topics: Antimetabolites, Antineoplastic; Chromatography, High Pressure Liquid; Erythrocytes; Hemoglobins; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality Control; Reproducibility of Results; Thioguanine

To report the survival and event-free survival of children with acute lymphoblastic leukaemia treated in Auckland between 1985-1991, using an international protocol, ANZCCSG ALL Study V.. The data were collected prospectively as part of the study. The analysis was carried out using standard survival methods.. At a median follow up of 7.5 years, the overall survival is 75% and event-free survival 60%.. For an unselected series, these outcomes are comparable to overseas series. The survival for children diagnosed in the 1990's is likely to be similar.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Humans; Infant; Mercaptopurine; Methotrexate; New Zealand; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Proportional Hazards Models; Prospective Studies; Radiotherapy, Adjuvant; Survival Analysis; Treatment Outcome; Vincristine

Between years 1993 and 1998, 113 children aged from 6 months to 18 years (41 girls and 72 boys) with first relapse of acute lymphoblastic leukaemia (ALL) were included in the study. All children were treated according to BFM-90 relapse protocol. Thirty-two cases were classified as very early relapses, 56 as early and 25 as late relapses. Sixty-one children had isolated bone marrow relapse, in 30 children extramedullary relapse occurred (in 21 children in central nervous system and in 16 children in testes). There were 23 combined relapses. Remission was achieved in 12 children with very early relapse (78.12%), 32 children with early relapse (85.71) and 19 children with late relapse (96%). Event-free survival in 30 months of follow-up was 29.2%, 59.0% and 73.2% for very early, early and late relapses, respectively. Sixteen children with relapsed ALL after chemotherapy according to BFM-90 relapse protocol underwent high-dose therapy with hematopoietic stem cell transplantation (in 3 cases autologous and in 13 cases allogeneic). In 6 children isolated bone marrow relapse occurred after transplantation, all of them died during subsequent chemotherapy. Ten children is alive and well from 2 to 43 months after transplantation. The results obtained with BFM-90 chemotherapy in children with first early relapses are not acceptable. Such patients require high-dose chemotherapy and transplantation of hematopoietic progenitor cells.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Survival Rate; Treatment Outcome; Vincristine

The aim of the study was to evaluate the results of treatment of 46 children with non B non-Hodgkin's Lymphoma registered in 7 centers of Polish Paediatric Leukaemia/Lymphoma Study Group from 1993 to 1998. The patients were treated according to BFM-90 protocol based on German regimen. The overall probability of event-free survival for the all children after 4 years of follow-up was 71%, for patients in stage III--65%, stage IV--70%. The achieved results were not as positive as in the BFM Study Group, what was related to: the great number of children with advanced stage of disease (54.3%), the late final diagnosis, the great number of recurrences (22.5%) and deaths caused by the toxicity of medication (6.5%) (infections, drug toxicity).

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Infant; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Survival Rate; Treatment Failure; Vincristine

Topics: Animals; Antimetabolites, Antineoplastic; Azathioprine; Cloning, Molecular; Genotype; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Mice; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Structure-Activity Relationship; Thioguanine

Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2-3 years with intensive maintenance therapy blunted growth resulted in a significant loss of -1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI.. (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied.

Topics: Adolescent; Age Factors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Combined Modality Therapy; Cranial Irradiation; Dose-Response Relationship, Radiation; Female; Growth; Growth Disorders; Humans; Longitudinal Studies; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Puberty

A nationwide study of intracellular drug metabolite concentrations in children prescribed 6-mercaptopurine for the treatment of lymphoblastic leukaemia was carried out to assess interpatient variability at a standardised dose. Nine children (2% of the total) had completely undetectable metabolites, indicative of non-compliance. Five were adolescents, but otherwise they had no obvious distinguishing characteristics. Not taking any 6-mercaptopurine at all is uncommon, but the problem cannot be predicted. The total number of children who do not comply cannot be determined from this study, but the nine children described represent only a fraction of these.

Topics: Adolescent; Antimetabolites; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The objective of the study was to determine if children with high risk acute lymphoblastic leukemia (ALL) exhibit higher frequency of alterations in nutritional state during the phases of induction and consolidation of chemotherapy than children with low risk ALL, based on the arm muscle area. The design was concurrent comparative cohorts. It was performed at pediatric hematology service of the Hospital General del Centro Médico Nacional "La Raza" and hematology service of the Hospital de Pediatría del Centro Médico Nacional "Siglo XXI". One hundred-five patients were incorporated into the study: 53 with high risk (HR) ALL and 52 with low risk (LR) ALL. Basal measurements of arm circumference and tricipital skinfold were surveyed monthly (for 3 months) by standardized personnel. Altered nutritional state during follow-up was defined as the loss of 10% or more of the arm muscular area (AMA) measured at diagnosis. Statistics of proportion analysis with a significance level of 0.05 and relative risk (RR) with confidence intervals (CI) were calculated. In the first month the RR was 0.77 (CI 0.31-1.87); the LR group was the most affected. In the second month the RR was 7.31 (CI 1.41-38.03); the most affected group was the HR. In the third month the RR was 1.77 (CI 0.60-4.92); the HR group was the most affected. High-risk patients show a higher frequency of nutritional state alterations reflected in AMA during the second month after diagnosis. This may be caused by the more aggressive chemotherapy received by these patients.

Topics: Adolescent; Anthropometry; Antineoplastic Combined Chemotherapy Protocols; Arm; Asparaginase; Body Constitution; Child; Child, Preschool; Cohort Studies; Cytarabine; Drug Administration Schedule; Energy Metabolism; Epirubicin; Female; Gastrointestinal Diseases; Hospitals, General; Hospitals, Pediatric; Humans; Infant; Male; Mercaptopurine; Methotrexate; Nutrition Disorders; Nutritional Status; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk; Skinfold Thickness; Vincristine

Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m2 6MP produced TGNs of 2348 pmol/8 x 10(8) red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m2 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m2 daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity.

Topics: Antimetabolites, Antineoplastic; Child; Drug Administration Schedule; Erythrocytes; Female; Guanine Nucleotides; Humans; Mercaptopurine; Methyltransferases; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Thrombocytopenia

Measurement of red cell 6-mercaptopurine (MP) derived 6-thioguanine nucleotide (TGN) and methylmercaptopurine metabolites (MeMPs) can be used to monitor therapy in children who are administered MP for childhood lymphoblastic leukemia. Red cell TGNs are not influenced by the time of blood sampling in relation to the last MP dose. The purpose of this study was to find out whether the same is true for the MeMPs. Plasma MP and red cell MP metabolite pharmacokinetics were studied in seven children immediately before and for 4 hours after a protocol standardized dose of MP. Duplicate blood samples were taken, one was processed immediately whereas one was left at an ambient temperature for 24 hours. The variation in TGN and MeMP metabolites over the 0- to 4-hour period (10 time points per child) was within the error of the assays used. The coefficients of variation for the TGNs ranged from 2.7% to 7% and for the MeMPs, 4% to 10.7%. There was no difference in the TGN and MeMP concentrations measured when the blood samples were left for 24 hours. If a child takes a MP tablet immediately before a clinic appointment, it has no major influence on MeMP measurements.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Child; Child, Preschool; Erythrocytes; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Time Factors

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Cholestasis, Intrahepatic; Female; Humans; Liver; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

6-Mercaptopurine, a hypoxanthine antimetabolite, is used in the treatment of acute lymphoblastic leukemia (ALL) in children. Extensively metabolized before it exerts cytotoxic action, it is catabolized into 6-mercapto-2,8-dihydroxypurine (thiouric acid), which is excreted by the kidneys. We describe a metabolite of 6-mercaptopurine, 6-methylmercapto-8-hydroxypurine, whose presence has not been previously reported in plasma. This compound was found in high concentrations in plasma during high-dose 6-mercaptopurine infusions (1300 mg/m2 in 24 h). This previously unknown compound was identified by reversed-phase HPLC with absorbance detection and by gas chromatography-mass spectrometry. The pathways leading to 6-methylmercapto-8-hydroxypurine in vivo are not yet fully understood. In a group of 17 patients treated with four courses of high-dose 6-mercaptopurine infusions according to the ALL-8 treatment protocol of the Dutch Childhood Leukemia Study Group, the steady-state concentrations of 6-methylmercapto-8-hydroxypurine in plasma were one-fifth of the parent drug concentrations, with wide interindividual variation. The formation of high concentrations of 6-methylmercapto-8-hydroxypurine in plasma, especially during the infusion, probably indicates another catabolic pathway of high-dose 6-mercaptopurine, apart from its conversion into thiouric acid.

Topics: Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Infusions, Intravenous; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL) in remission received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml(-1). Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 micrograms/ml of MTX. The present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in the plasma Cmax and AUC of 6-MP in humans and animals.

Topics: Adolescent; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Biotransformation; Child; Child, Preschool; Drug Interactions; Female; HL-60 Cells; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Rats, Wistar; Time Factors

The autosomal recessive trait of thiopurine S-methytransferase (TPMT) deficiency is associated with severe hematopoietic toxicity when patients are treated with standard doses of mercaptopurine, azathioprine, or thioguanine. To define the molecular mechanism of this genetic polymorphism, we cloned and characterized the cDNA of a TPMT-deficient patient, which revealed a novel mutant allele (TPMT*3) containing two nucleotide transitions (G460-->A and A719-->G) producing amino acid changes at codons 154 (Ala-->Thr) and 240 (Tyr--> Cys), differing from the rare mutant TPMT allele we previously identified (i.e., TPMT*2 with only G238-->C). Site-directed mutagenesis and heterologous expression established that either TPMT*3 mutation alone leads to a reduction in catalytic activity (G460-->A, ninefold reduction; A719-->G, 1.4-fold reduction), while the presence of both mutations leads to complete loss of activity. Using mutation specific PCR-RFLP analysis, the TPMT*3 allele was detected in genomic DNA from approximately 75 percent of unrelated white subjects with heterozygous phenotypes, indicating that TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in Caucasians.

Topics: Amino Acid Sequence; Base Sequence; Child, Preschool; Cloning, Molecular; DNA, Complementary; DNA, Neoplasm; Enzyme Stability; Erythrocytes; Gene Frequency; Humans; Kinetics; Male; Mercaptopurine; Methylation; Methyltransferases; Molecular Sequence Data; Point Mutation; Polymorphism, Restriction Fragment Length; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; RNA, Messenger; S-Adenosylmethionine; White People; Yeasts

6-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-L-methionine (AdoMet), produced from methionine and ATP, is converted into S-adenosyl-L-homocysteine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMet: AdoHcy ratio and DNA methylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-dose 6MP on the methylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5' g.m-2 in 24 hr) immediately followed by high-dose 6MP (1300 mg.m-2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg.m -2 daily for 8 weeks). Leucovorin rescue was started at 36 hr in both groups. In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 muM (6MP steady state levels: 11.6 muM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13.1 nmol/10(8)). AdoHcy levels (10 pmol/10(8)) remained constant in both groups and AdoMet was not detectable ( < 20 pmol/10(8)). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result of an increased demand on methyl groups during 6MP infusion.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Erythrocytes; Homocysteine; Humans; Mercaptopurine; Methionine; Methotrexate; Methylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleotides; S-Adenosylhomocysteine; S-Adenosylmethionine

True histiocytic lymphomas (THLs) are rare tumors in which the malignant cells show morphologic and immunophenotypic evidence of histiocytic differentiation. We describe THLs that arose after therapy for one case of T-lineage lymphoblastic lymphoma (LyL) and two cases of acute lymphoblastic leukemia (ALL) (both CD10+, one pre-B phenotype). The lymphoblastic neoplasms were not unusual in any way, and responded well to standard therapy. The THLs arose 10 to 20 months after complete remission was achieved for the lymphoblastic neoplasms, at which time there was still no clinical or pathologic evidence of the lymphoblastic neoplasms. All three THLs exhibited clinical and morphologic features of malignancy. Neoplastic cells in the THLs had abundant eosinophilic vacuolated cytoplasm and pleomorphic nuclei, and expressed histiocytic antigens in the absence of lymphocyte-specific lineage markers. Because THLs are rare neoplasms, their occurrence after otherwise successful therapy for lymphoblastic neoplasms in these three cases may constitute a distinct clinicopathologic entity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Neoplasms; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Etoposide; Fatal Outcome; Humans; Ifosfamide; Lymphoma, Large B-Cell, Diffuse; Male; Mediastinal Neoplasms; Mercaptopurine; Methotrexate; Methylprednisolone; Neoplasms, Second Primary; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Remission Induction; Scapula; Spinal Neoplasms; Vincristine

Extramedullary relapse outside the testes and CNS is rare in children with acute lymphoblastic leukemia (ALL). We describe a case of a recurrence of ALL in the uterine cervix during hematopoietic remission.. Primary recurrence in the uterine cervix was diagnosed by cytology with immunochemistry 43 months after initial diagnosis. She was successfully treated with systemic chemotherapy, without hysterectomy or irradiation. She remains in second complete remission 54 months after relapse.. Immunocytochemistry using monoclonal antibodies against cell surface antigens made the cytologic diagnosis of leukemic relapse in the uterine cervix possible. Systemic chemotherapy is the first treatment of choice for ALL recurrence in the genital tract in a patient without poor prognostic factors in order to spare gonadal function and reproductive potential.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Cyclophosphamide; Daunorubicin; Female; Follow-Up Studies; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Ultrasonography; Uterine Cervical Neoplasms; Vaginal Smears; Vincristine

Forty-four adults with AML (n = 18) or ALL (n = 26) beyond first remission underwent unpurged (n = 39) or purged (n = 5) autografting after 110-140 mg/m2 melphalan and 1050 cGy TBI. ALL patients were eligible to receive maintenance chemotherapy with 6-mercaptopurine and methotrexate for 2 years after hematologic recovery. The duration of first remission was 1-167 months (median 11). The median time to 50 x 10(9)/I platelets was 76 days, and that to 0.5 x 10(9)/I neutrophils 31 days. Eight patients died of transplant-related toxicity; seven within 1 year. Twenty-two patients relapsed at 1-20 months (median 2.5 months). The 3-year probabilities (95% CI) of relapse and disease-free survival are 58% (43-75%) and 31% (17-45%), respectively. The duration of the first remission (< 1 year vs > or = 1 year) and the stage of transplant (second remission vs other) had no effect on relapse or disease-free survival. There was a trend towards higher relapse rates (76 vs 34%) and poorer disease-free survival (19 vs 49%) among ALL patients compared with AML which did not reach significant levels due to small patient numbers. We conclude that melphalan-TBI is a suitable conditioning regimen for autografting in advanced leukemia. The outcome of AML patients is comparable to standard regimens, but the outcome of ALL patients is poor and measures to enhance the anti-leukemic efficacy are necessary.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Leukemia; Leukemia, Myeloid; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

The use of peripheral blood as a source of hematopoietic precursors is an alternative to the bone marrow in allogeneic transplantation. Although pediatric allogeneic PBPC experience is limited, there is no reason to believe that the outcome and benefit with PBPC should be different than adults. We describe our initial experience in two children who received PBPC allogeneic transplantation in whom the donors were mobilized with filgrastim. Hematopoietic recovery was achieved on days 14 and 16, and the patients did not develop severe GVHD.

Topics: Adolescent; Bone Marrow; Bone Marrow Cells; Child; Combined Modality Therapy; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukapheresis; Leukemia, Myelomonocytic, Chronic; Male; Mercaptopurine; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Homologous

We report a 13-year-old boy with Lennox-Gastaut syndrome (LGS) associated with leukoencephalopathy. He was diagnosed with unclassified acute lymphocytic leukemia at the age of 3 years. After initial chemotherapy, he received intravenous methotrexate (total dosage 1,035 mg), intrathecal methotrexate (total dosage 221 mg), and whole brain irradiation (2,400 cGy). From about the age of 8 years, he developed slurred speech, hyperactivity, and mental deterioration. Cranial CT revealed calcification of the subcortical white matter. At age 9 years, he exhibited tonic seizures and atonic seizures. EEG showed diffuse slow spike-wave discharges, which are characteristic of LGS. Although multiple antiepileptic drugs have been prescribed, the frequency of seizures remains unchanged and his mental state is becoming progressively worse.

Topics: Adolescent; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Brain Damage, Chronic; Calcinosis; Cranial Irradiation; Cytarabine; Dementia; Doxorubicin; Electroencephalography; Epilepsy, Absence; Epilepsy, Generalized; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Movement Disorders; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Radiation Injuries; Syndrome; Vincristine

To describe the use of combination chemotherapy, including divided-dose oral methotrexate (dMTX), for children with B-precursor acute lymphoblastic leukemia (ALL). dMTX produced prolonged MTX exposure on an outpatient basis.. Two hundred forty-three patients were treated from January 1986 to May 1992. dMTX was given weekly during consolidation and biweekly for the first 16 months of continuation therapy with mercaptopurine (6-MP) and asparaginase (L-ASP). Initially, etoposide (VP-16) and cytarabine (Ara-C) pulses were included. Treatment continued for 30 months with single-dose weekly MTX replacing dMTX during continuation, part 2. Unexpected acute neurotoxicity was eliminated by the addition of leucovorin. VP-16 and Ara-C were omitted in the face of acute myelogenous leukemia (AML).. Two hundred thirty-nine patients entered remission: 16 had a lymphoid marrow relapse, two each with testicular or CNS relapse; 19 a CNS relapse; 16 secondary AML; three other second malignancies; two withdrew for transplant; three died in remission; 16 withdrew because of noncompliance, and nine withdrew with toxicity. Event-free survival (EFS) at 4 years was 73 +/- 4%; 81 +/- 4% for 150 patients with better risk features and 60 +/- 7% for 93 with high-risk features. Lymphoid marrow relapse-free survival in the standard- and high-risk patients was 94 +/- 3% and 86% +/- 6%, respectively. The most common adverse event was secondary AML in the standard-risk group and isolated CNS relapse in the high-risk group.. This therapy produced an overall EFS similar to other published regimens, but the pattern of failures is very different, with few patients having a lymphoid marrow relapse. These data suggest that highly effective therapy for children with ALL can be delivered on an outpatient basis using a regimen featuring repetitive dMTX.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

The current U.K. trial protocol (UKALL XI) for childhood lymphoblastic leukaemia demands mercaptopurine (MP) dose escalation in children who tolerate daily 75 mg/m2 MP (100% dose) without cytopenias. The previous trial (UKALL X) did not. MP metabolism was studied in a group of UKALL XI children (n = 21) who tolerated 100% dosages and who were matched in this respect with a similar group of UKALL X children. Red blood cell MP derived thioguanine nucleotide (TGN) concentrations were measured in both groups under comparable conditions; at 75 mg/m2 MP there was no significant difference. MP dose escalation in the UKALL XI children produced higher TGN concentrations (TGNs at 100% vs 125% dosages, median difference 90 pmol/8 x 10(8) RBCs, 95% CI 25 to 165 pmol, P < 0.02). Assayed at the time of cytopenia induced dose reduction, the UKALL XI children had accumulated significantly higher TGN concentrations than the UKALL X children (median difference 78 pmol/8 x 10(8) RBCs, 95% CI 20 to 144, P < 0.02). These findings indicate that dose escalation in children tolerant of 100% MP dosages produces higher peak TGN concentrations.

Topics: Antimetabolites, Antineoplastic; Child; Dose-Response Relationship, Drug; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

During maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX polyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN]) accumulate intracellularly, including in erythrocytes (E-MTX and E-6TGN) with large interindividual variations. In the present Nordic Society for Pediatric Hematology and Oncology (NOPHO) study, the relation of E-MTX and E-6TGN to relapse risk was explored.. Two hundred ninety-seven patients with non-B-cell ALL, aged 1 to 14 years, on oral MTX and 6MP had E-MTX and E-6TGN levels measured three to 35 (median, eight) and three to 75 (median, nine) times, respectively. For each patient, a mean of all E-MTX (mE-MTX) and E-6TGN (mE-6TGN) measurements was calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX-6TGN), since MTX and 6MP may have synergistic action.. For patients in remission, the median mE-MTX and mE-6TGN values were 4.7 nmol/mmol hemoglobin (Hgb) (range, 0.4 to 10.3) and 173 nmol/mmol Hgb (range, 58 to 846). With a median follow-up duration of 66 months for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX-6TGN and sex to be the most significant parameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who had a mE-MTX-6TGN less than the product of the median mE-MTX and median mE-6TGN (813 [nmol/mmol Hgb]2) had a significantly poorer event-free survival (EFS) than did patients with higher values (5-year probability of EFS [pEFS5y], 0.70 v 0.86; P = .001).. The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Erythrocytes; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Infant; Male; Mercaptopurine; Methotrexate; Polyglutamic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence; Regression Analysis; Remission Induction; Risk; Thionucleotides; Time Factors

As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studied. All were on the same therapeutic schedule of mercaptopurine. All had been on an unattenuated full protocol-directed dose (at least 75 mg m-2) for a minimum of 7 days before assay. There was a very wide variation in the concentration of the two metabolites measured; the thioguanine nucleotides ranged from 0 to 1255 pmol per 8 x 10(8) red cells (median 289, lower quartile 210, upper quartile 377) and the methylmercaptopurine metabolites ranged from 0 to 46.3 nmol per 8 x 10(8) red cells (median 5.18, lower quartile 2.31, upper quartile 11.59). The anticipated negative correlation was not apparent, but the ratio between the two was not randomly distributed. No child had both metabolite concentrations in the upper quartiles, but in 32 (10%) children the concentration of both metabolites was in the lower quartile. Of the 32, only one metabolite was detected in four and none at all in six. The most likely explanation for these findings is that a minority of children with lymphoblastic leukaemia fail to take oral mercaptopurine either totally or intermittently. The extent of the problem is unknown, but we suspect it may be clinically important in at least 10% of patients.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma

In children treated for acute lymphoblastic leukemia (ALL), catch-up growth occurs after cessation of therapy and not during maintenance therapy. In this study we investigated whether this inhibition of catch-up growth during maintenance treatment is attributable to the influence of chemotherapy or to the influence of corticosteroids.. Forty-six children treated for ALL were included in the study. In 27 patients maintenance therapy comprised vincristine (VCR), prednisone (Pred), or dexamethasone (Dexa) alternated with 6-mercaptopurine (6-MP) and methotrexate (MTX) and 19 patients received maintenance therapy with 6-MP and MTX only. Treatment did not include cranial irradiation.. Statural growth during maintenance treatment was comparable in both groups over the study period of 1.5 years.. Chemotherapy with 6-MP and MTX, and not corticosteroids, is the main factor that prevents catch-up growth from occurring during maintenance therapy for ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Growth; Growth Disorders; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Although central nervous system (CNS) leukemic relapse is frequent in adult acute lymphocytic leukemia (ALL), the need for prophylaxis in different risk groups for CNS relapse, the value of high-dose systemic and intrathecal (IT) chemotherapy, and the timing of prophylaxis are not well defined. This analysis was conducted to investigate these questions and to assess the value of a risk-oriented CNS prophylaxis approach. We analyzed the incidence of CNS leukemia after initiation of therapy in patients treated on 4 consecutive trials for adult ALL including different CNS prophylactic modalities. The treatment groups included (1) the program preceeding the vincristine-Adriamycin-dexamethasone (VAD) regimen, with no CNS prophylaxis; (2) the VAD regimen with prophylaxis using high-dose systemic chemotherapy; (3) the modified VAD program with high-dose systemic chemotherapy to all patients and IT chemotherapy for high-risk patients after achieving complete remission; and (4) the hyperCVAD program with early high-dose systemic and IT chemotherapy starting during induction to all patients, with more IT injections (16IT) administered to the high-risk group for CNS relapse compared with the low-risk group (4IT). A total of 391 patients were included, 73 of whom were treated with preVAD, 112 with VAD, 114 with modified VAD, and 92 with hyperCVAD. The overall CNS relapse rates were 31%, 18%, 17%, and 3%, respectively for the 4 groups (P < .001). For the high-risk group for CNS relapse, they were 42%, 26%, 20%, and 2%, respectively (P < .001). The differences in CNS relapse rates in the low-risk group were not statistically significant. At 3 years, the overall CNS leukemia event-free rates were 48%, 76%, and 98%, respectively (P < .001). In the high-risk group, the CNS event-free rates were 38%, 66%, 75%, and 98%, respectively (P < .001); however, there was no difference in the low-risk group. We conclude that (1) high-dose systemic chemotherapy is a useful prophylactic measure; (2) early IT chemotherapy is necessary to reduce the incidence of CNS leukemia overall and in the high-risk group; and (3) a risk-oriented approach is appropriate to tailor the intensity of CNS prophylaxis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Humans; Infusions, Intravenous; Injections, Spinal; Life Tables; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Risk Factors; Survival Rate; Vincristine

The activity of thiopurine methyltransferase (TPMT) exhibits genetic polymorphism, with approximately 1 in 300 individuals inheriting TPMT deficiency as an autosomal recessive trait, and about 11% having intermediate activity (ie, heterozygotes). Patients with TPMT deficiency accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and develop severe toxicity when treated with standard dosages of mercaptopurine. High TPMT activity has been associated with lower concentrations of TGNs, yielding a higher risk of treatment failure in children with acute lymphoblastic leukemia (ALL). As the biochemical basis of these pharmacodynamic relationships has not been fully elucidated, we investigated the variability and relationship of TPMT activity in erythrocytes and lymphoblasts from children with ALL. A 58-fold range of erythrocyte TPMT activity was found among 119 patients receiving ALL chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low intrapatient variability (coefficient of variation, 13.5%) was observed over 1 year. A 27-fold range in TPMT activity was observed in leukemic blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x 10(9) cells). TPMT activity in leukemic blasts at diagnosis was significantly correlated with TPMT in erythrocytes before therapy (rs = .75, P < .0001, N = 13). These data document extensive interpatient variability of TPMT activity in ALL blasts and establish its linkage to polymorphic TPMT activity in erythrocytes, providing a new mechanism by which erythrocytes serve as prognostic markers of mercaptopurine metabolism and TPMT activity in children with ALL.

Topics: Adolescent; Aneuploidy; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Child; Child, Preschool; Cytarabine; Erythrocytes; Female; Humans; Lymphocytes; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasm Proteins; Neoplastic Stem Cells; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Teniposide; Treatment Failure

The antimetabolite 6-mercaptopurine is widely utilized in maintenance therapy for childhood acute lymphoblastic leukemia. Following p.o. administration, this prodrug undergoes extensive biotransformation, resulting in the generation of a plethora of metabolites including 2'-deoxy-6-thioguanosine triphosphate. Incorporation of 6-thioguanine (6-TG) bases into DNA is generally considered to be central to thiopurine-mediated cytotoxicity. We have developed a novel precolumn derivatization HPLC technique for quantifying 6-TG base accumulation into leukocyte DNA obtained from acute lymphoblastic leukemia patients receiving 6-mercaptopurine maintenance therapy. The method is based on enzymatic degradation of DNA to 2'-deoxyribonucleosides and the derivatization of released 2'-deoxy-6-thioguanosine with a thiol-reactive reagent containing a 7-amino-4-methylcoumarin-3-acetic acid fluorophore. The 2'-deoxy-6-thioguanosine-7-amino-4-methylcoumarin-3-acetic acid adduct is resolved by reversed-phase HPLC and quantified fluorometrically. Assay response is linear from 15 pmol to 60 fmol 6-TG bases/microgram DNA with a limit of quantitation corresponding to the incorporation of 1 6-TG residue per 50,000 bases. In a small cohort of acute lymphoblastic leukemia patients receiving p.o. 6-mercaptopurine-based maintenance therapy, significant interindividual variation in the accumulation of 6-TG bases into leukocyte DNA was revealed. The determined levels of drug base incorporation ranged from 95 to 710 fmol 6-TG bases/microgram DNA (6-TG base:nucleotide ratio 1:32,000 to 1:4,000). The assay may provide a novel methodology for pharmacological monitoring of thiopurine therapy either in the routine clinical setting or during studies of alternative routes of drug delivery.

Topics: Cell Line; Child; Chromatography, High Pressure Liquid; DNA; DNA, Neoplasm; Humans; Leukocytes; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Tumor Cells, Cultured

Sister chromatid exchanges (SCE) and lymphocyte subsets of children with acute lymphoblastic leukemia (ALL) were investigated during chemotherapy. The treatment followed protocol ALL-BFM-90. Children with ALL at the time of diagnosis showed statistically significant higher SCE frequencies (4.9 +/- 0.77) than healthy controls (3.6 +/- 0.93; P = 0.002). The in vivo effects of cyclophosphamide (CP) resulted in a dramatic increase of the SCE frequency (20.5 +/- 3.76). This increased SCE level of lymphocytes might reflect an instability of DNA or a deficiency of DNA repair. One could suggest that lymphocytes of children with ALL might have a higher susceptibility to harmful influences; and this could be a co-factor towards the development of the malignant disease. However, immediately 1 week after the administration of CP, the SCE rate decreased. This decline of SCE frequency correlated with a severe reduction of the absolute number of T lymphocytes. The observed reduction of SCE frequency may be due to a loss of T lymphocytes, or SCE became repaired during 1 week.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Chromosomes, Human; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Immunophenotyping; Infant; Lymphocyte Count; Lymphocyte Subsets; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Sister Chromatid Exchange; Time Factors; Vincristine

Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was used to analyze a 50-microliters sample of cerebrospinal fluid from leukaemic children treated with high doses of methotrexate. Free amino acids and primary amines are labelled with fluorescein isothiocyanate prior to analysis. Electropherograms containing more than 50 peaks were obtained in less than 22 min. Twenty-one peaks were identified, and 19 were quantitated. Observed differences in individual amino acid levels are compared with healthy reference values. The results indicate that CE-LIF is useful as a selective, rapid and sensitive tool for the determination of free amino acids and amines in clinical biology studies.

Topics: Adolescent; Amines; Amino Acids; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Electrophoresis, Capillary; Female; Humans; Lasers; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Spectrometry, Fluorescence

Topics: Aged; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Fatal Outcome; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Mucormycosis is a rare fungal infection that has been described mainly in oncologic and diabetic patients. We here report the cases of two leukaemic patients in whom pulmonary mucormycosis was diagnosed. Prompt diagnosis, therapy with amphotericin B and surgery when possible, are the cornerstones in the treatment of this fungal infection. Although infrequent, this infection must be suspected in oncohaematological patients with lung infiltrates.

Topics: Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Itraconazole; Leukemia, Promyelocytic, Acute; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Mucormycosis; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Child; Erythrocytes; Humans; Infusions, Intravenous; Leucovorin; Leukocytes, Mononuclear; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Pyrimidines

Many months' treatment with daily oral mercaptopurine is an important part of therapy for nearly all children with lymphoblastic leukaemia (ALL). Even when prescribed the same dose based on body surface area, patients have widely different intracellular concentrations of drug metabolites. Whether this variation matters in terms of disease control is not yet clear. To find out, we followed up a large group of children with ALL in whom mercaptopurine-derived thioguanine nucleotides in the red cells were measured during treatment with an identical dose of mercaptopurine early in first remission. 172 unselected children (100 boys, 72 girls) were recruited between 1980 and 1992. At median follow-up of 5 years from diagnosis 42 (24%) had relapsed; 30 had erythrocyte thioguanine nucleotide concentrations below the group median (284 pmol per 8 x 10(8) erythrocytes) and 12 had values above the median. The actuarial relapse-free survival at 5 years was 63% in the below-median group and 84% in the above-median group (difference 21% [95% CI 3-39%], p = 0.0018). Multivariate analysis showed that erythrocyte thioguanine nucleotide concentration was independent of other prognostic variables including age, leukaemia immunophenotype, white-blood-cell count at diagnosis, trial protocol, and sex. Whatever the cause, in childhood ALL variable formation of intracellular mercaptopurine metabolites seems to be clinically important. Therapeutic schedules that include long-term daily oral mercaptopurine might be more effective if such metabolites are monitored.

Topics: Actuarial Analysis; Adolescent; Child; Child, Preschool; Erythrocytes; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence; Regression Analysis; Remission Induction; Survival Analysis; Thionucleotides

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.

Topics: Apoptosis; Cell Differentiation; Cell Division; Drug Screening Assays, Antitumor; Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Promyelocytic, Acute; Lymphoma, Large B-Cell, Diffuse; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Transfer; Thioguanine; Tumor Cells, Cultured

The use of mercaptopurine (MP) rather than thioguanine (TG) in the treatment of childhood acute lymphoblastic leukemia (ALL) has occurred for historical reasons, but does not have a pharmacologic basis. The purpose of this study was to begin to address whether TG would be more efficacious than MP in the treatment of childhood ALL. Preclinical cytotoxicity studies were performed using human leukemic cell lines and leukemic cells from patients with ALL. First, the concentration-survival curves for MP and TG in three human leukemic cell lines (MOLT-4, CCRF-CEM and Wilson) were determined. The second group of experiments determined the concentration-time dependence for cytotoxicity of MP and TG. The final group of experiments compared the in vitro cytotoxicity of MP to TG in leukemic cells from patients with ALL. The thiopurines displayed classical anti-metabolite cytotoxicity profiles, exhibiting a cytotoxicity threshold concentration and demonstrating an increase in cell kill with prolongation of exposure to the drug. For MP, the cytotoxicity threshold was approximately 1 microM, with maximum cytotoxicity occurring with 10 microM concentrations. For TG, the threshold was only 0.05 microM with maximum cytotoxicity occurring at 0.5 microM. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas exposures as short as 4 h were required for TG. Leukemic cells from children with ALL were also more sensitive to TG than to MP. The median IC50 for TG (20 microM) was significantly lower than that for MP (> or = 206 microM). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childhood ALL. The more direct intracellular activation pathway, higher potency, and shorter duration of drug exposure necessary for cytotoxicity all suggest that TG may have an advantage over MP.

Topics: Adolescent; Adult; Cell Survival; Child; Child, Preschool; Drug Screening Assays, Antitumor; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Time Factors; Tumor Cells, Cultured

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were > or = 1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective major cytotoxic metabolites of MTX and 6MP). For each patient, E-MTX and E-6TGN levels were measured 2-15 (median, 6) and 2-17 (median, 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX x 6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (mWBCshift). The mean WBCs measured on therapy (mWBC(on)) and off therapy were highly correlated (r = 0.48, P = 0.009). The median mWBCshift was 2.7 x 10(9)/l (range, 1.4-4.8 x 10(9)/l). In a multivariate regression analysis, the best-fit model to predict the mWBCshift included mE-MTX x 6TGN, age at drug withdrawal, and mWBC in the order given [mWBCshift = 4.3 + 0.00089 x (mE-MTX x 6TGN) - 0.097 x age - 0.41 x mWBC(on); global rs = 0.66, P = 0.0002]. Thus, the patients with higher mE-MTX x 6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronounced degree of myelosuppression as measured by mWBCshift. These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment intensity than do the WBCs alone.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Platelet Count; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To determine the potential efficacy and toxicity of intravenous (i.v.) methotrexate (MTX) and mercaptopurine (MP) as postremission intensification treatment for children with B-lineage acute lymphoblastic leukemia (ALL) at higher risk to relapse.. Eighty-three patients (age 1 to 20 years) with higher-risk B-lineage ALL were entered onto this protocol. Following standard four-drug remission induction, 80 patients received 12 intensive 2-week cycles of MTX/MP: MTX 200 mg/m2 i.v. push, then 800 mg/m2 i.v. 24-hour infusion on day 1; MP 200 mg/m2 i.v. in 20 minutes, then 800 mg/m2 i.v. 8-hour infusion day 2; MTX 20 mg/m2 intramuscularly day 8; and MP 50 mg/m2 by mouth days 8 to 14. Age-based triple intrathecal therapy (MTX, hydrocortisone, and cytarabine) was administered for CNS prophylaxis. Continuation therapy was weekly MTX/MP (as on days 8 to 14) for 2 years.. Eighty-one patients (98%) entered remission. There were 28 relapses (marrow, n = 11; marrow and CNS, n = 2; isolated CNS, n = 9; testes, n = 5; ovaries, n = 1). No overt relapse occurred during the intensive phase of therapy. The event-free survival (EFS) rate at 4 years is 57.4% +/- 9.1% (SE). Hematologic, mucosal, and infectious toxicities were seen in 12%, 9%, and 5% of intensive MTX/MP courses, but were generally mild.. Combined data from this and our previous trial suggest that intensive MTX/MP may produce long-term disease-free survival in 70 to 75% of children with B-lineage ALL. In comparison to other intensive regimens, intensive MTX/MP is easy to administer, effective, and relatively nontoxic. If patients at risk for failure of MTX/MP can be identified prospectively, more aggressive regimens could be restricted to this smaller (25% to 30%) cohort.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Analysis; Treatment Outcome

Fifty consecutive adult patients with acute lymphoblastic leukemia (ALL) were treated with an intensive cyclical chemotherapy and the mean received dose of individual cytotoxic drug was retrospectively studied. The median age was 28 years. Twenty-one (43%) had white blood cell (WBC) count over 30 x 10(9)/l. Of the 26 patients with successful cytogenetic studies, ten (28%) had unfavorable clonal chromosomal abnormalities (four Philadelphia chromosome, six others). A high complete remission (CR) rate (86%) was achieved. This was associated with delivery of 100% of the planned dosage of vincristine, prednisone, and daunorubicin at induction. Dose reduction of asparaginase, the fourth drug in the induction protocol, was recorded in 20 (40%) patients. The CR rate of these patients was not adversely affected. Dose reduction was recorded during consolidation (38 of 43 remitters) and maintenance (18 of 20 remitters) as a result of treatment toxicity. The mean received dose of teniposide, Ara-C, asparaginase, mercaptopurine, and methotrexate was 73% (SD 7%), 73% (SD 7%), 62% (SD 41%), 65% (SD 15%) and 73% (SD 17%) of the planned dosage, respectively. The 5-year overall survival and leukemia-free survival (LFS) were 11% (95% CI: 0-27%) and 13% (95% CI: 0-26%), respectively. Even standard-risk patients had 4-year LFS of only 26% (95% CI: 0-57%). Among 36 remitters not withdrawn from consolidation, there were 29 treatment failures after a median follow-up of 42 months; 25 (86%) of these were leukemia relapse, three (10%) were toxic death during consolidation, and one patient (4%) died from therapy-related myelodysplastic syndrome. We postulate inadequate drug delivery during postremission therapy contributed to the high relapse rate in the whole group as well as the standard-risk patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Leucovorin; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Recurrence; Remission Induction; Retrospective Studies; Survival Rate; Teniposide; Vincristine

Disturbances in dental development were studied with the use of radiography and histology in a patient with acute lymphoblastic leukemia who was treated with induction chemotherapy at 2.3 years of age and bone marrow transplantation at 4.3 years of age. The follow-up 9.5 years after bone marrow transplantation showed evidence of short tapered roots, enamel hypoplasia, microdontia, and aplasia. A histologic examination of two extracted permanent teeth showed that the crown of the maxillary lateral incisor exhibited numerous incremental lines that corresponded closely to the treatment periods with cytotoxic drugs. The maxillary second premolar exhibited regularly spaced incremental lines in the enamel and dentine. A gross hypoplasia was seen in the cervical part of the crown corresponding to the time of administration of 10 Gy total body irradiation. The results indicate that chemotherapy mainly induces qualitative disturbances in dentine and enamel, whereas total body irradiation induces both qualitative and quantitative changes.

Topics: Abnormalities, Radiation-Induced; Amelogenesis; Antineoplastic Agents; Asparaginase; Bone Marrow Transplantation; Child, Preschool; Cyclophosphamide; Cytarabine; Dental Arch; Dental Enamel Hypoplasia; Dentinogenesis; Doxorubicin; Female; Humans; Immunosuppressive Agents; Maxillofacial Development; Mercaptopurine; Methotrexate; Odontogenesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tooth Eruption; Tooth Root; Vincristine; Whole-Body Irradiation

A 3 1/2 year old girl with cystic fibrosis who underwent successful treatment for acute lymphoblastic leukemia remains in complete remission 36 months after diagnosis. We also report high clearance rates of three antineoplastic agents in this patient. Drug doses were adjusted to achieve optimal systemic exposure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cystic Fibrosis; Cytarabine; Daunorubicin; Female; Humans; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Teniposide; Vincristine

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.

Topics: Adolescent; Adult; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Child; Daunorubicin; Follow-Up Studies; Humans; Liver; Mercaptopurine; Methotrexate; Nervous System Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

Bone marrow granulocytic-macrophagal precursors (GMP) and fibroblastic precursors (FP) were measured in 235 children with acute lymphoblastic leukemia (ALL) receiving polychemotherapy (PCT) in progression of the disease. A total of 408 culture investigations were conducted. PCT proved to exert different effects on hemopoiesis during the first acute ALL period and remission. In the former period the target for PCT were blast cells, the course of induction therapy increased the number of GMP, FP and early granulocytic cells. In recurrent ALL the sensitivity of GMP to PCT grew, while FP remained intact. PCT performed in remission resulted in gradual suppression of granulocytopoiesis, GMP beginning from the second remission year. The treatment discontinuation on remission year 3-5 produced enhancement of granulocytosis by all parameters.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Female; Hematopoiesis; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Time Factors; Vincristine

In this study we used the radiolabeled selective ligand (3H-NECA) of A2-types purine receptors in order to investigate specific NECA binding with human blood lymphocytes and bone marrow lymphoblasts. Relative affinity of 6-mercaptopurine and azathioprine for purine receptors was determined. One type of high affinity NECA binding sites have been shown on the lymphocytes (Kd = 0.57 mkM, Bmax = 0.63 pmol/10(6) cells), which selectively interacted with AZT, but not 6-MP. Relative potencies of substance in competitive radioassay: adenosine > AZT > 6-MP. Two classes NECA binding sites on the lymphoblasts have been identified. One of them corresponds to lymphocyte receptors. The second type of NECA binding sites is characterised by following parameters: Kd = 6.5 mkM and Bmax = 1.5 pmole/10(6) cells. They are selective sensitized to 6-MP. Relative affinity changes in the line: 6-MP > adenosine > AZT.

Topics: Azathioprine; Bone Marrow; Bone Marrow Cells; Humans; Lymphocytes; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Stem Cells

A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cyclophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adrenal Gland Neoplasms; Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Cyclophosphamide; Diseases in Twins; Female; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Mercaptopurine; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects; Thyroid Neoplasms; Time Factors; Twins, Dizygotic; Vincristine

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose.

Topics: Bone Marrow; Child; Child, Preschool; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reference Values; Thionucleotides; Vincristine

Thirty-four children with diagnosed cases of acute leukemias and being treated with cytotoxic chemotherapy at St James' Hospital, Leeds, were followed for between 6 months and 1 year to determine the changes in their oral microflora. They were examined before treatment commenced and then at monthly intervals. Swabs were taken from the oral cavity to test for the presence or absence of bacteria and Candida. Saliva samples were also used to assess the levels of Streptococcus mutans in the mouth. Sensitivity tests were carried out to assess the effect of the cytotoxic agents on the oral flora. All children received prophylactic nystatin and chlorhexidine gluconate mouthrinses four times daily for the whole period of the study. There was significant difference (p < 0.0001) for counts of S. mutans at different treatment stages. Sensitivity tests showed that S. mutans was sensitive to the cytotoxic drug daunorubicin, and this drug was probably responsible for the fall in S. mutans counts. A significant difference was also found in the types of bacteria isolated between the study and reference groups, but there was no change in the composition of the flora in the study group during treatment. These bacteria were also found to mirror those cultured from routine blood samples in children with acute leukemia.

Topics: Adolescent; Analysis of Variance; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacterial Infections; Candida albicans; Candidiasis, Oral; Chi-Square Distribution; Child; Child, Preschool; Chlorhexidine; Colony Count, Microbial; Cytarabine; Daunorubicin; Etoposide; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Mouth; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Streptococcus mutans; Thioguanine; Trimethoprim, Sulfamethoxazole Drug Combination; Vincristine

Analysis was made of ALL treatment results according program POG 8493 in 9 infants. In 4 children WBC exceeded 100.0 G/l, and in 5 children CNS was affected. Eight infants had remission, six had relapse (mainly BM): early up to 8 month in 5, late--in 52 month in one girl. Four children died after relapse, four are still living: 2 I RC (2 and 23 months), 2 in II RC (1 month and 23 month). Probability of 4-year EFS was 0.25 and that survival--0.44. In view of continuing poor ALL prognosis, in infants it is necessary to look for more effective methods of treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cortisone; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Drug Administration Schedule; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Survival Rate; Vincristine

6-Mercaptopurine (6MP) cytotoxicity was studied in Molt F4 cells, a T-cell acute lymphoblastic leukemia (ALL) cell line. The effects on cytotoxicity were concentration-dependent. Measurements of intracellular thionucleotide intermediates of 6MP demonstrated a rapid rise of thio-IMP (tIMP) levels, and subsequently a rapid decrease. Thio-GMP (tGMP) and methyl-thio-IMP (Me-tIMP) appeared later in time, and persisted longer. Mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase (IMPDH), was used to inhibit the conversion of tIMP into tGMP, thereby decreasing the incorporation of 6MP into DNA. A synergistic effect on cell viability and cell growth was observed when cells were treated with a combination of 2 microM 6MP and 0.5 microM MPA. Also, intracellular Me-tIMP increased 5 times with the combination. Based on the increase of Me-tIMP concentration and the observed synergism between 6MP and MPA, we conclude that methylation of tIMP into Me-tIMP is an important alternative route for 6MP cytotoxicity.

Topics: Cytotoxins; Drug Synergism; Humans; Mercaptopurine; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured

To prevent drug resistance, the authors designed a protocol that featured early intensive rotating drug pairs as part of the therapy for acute lymphoblastic leukemia (ALL).. After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were given in 30 weeks: A--intermediate-dose methotrexate (IDMTX) plus intermediate-dose mercaptopurine (MP); B--cytosine arabinoside (AC) plus daunorubicin (DNR); C--AC plus teniposide (VM-26). Triple intrathecal chemotherapy (AC, MTX, and hydrocortisone) was given for central nervous system (CNS) prophylaxis. Continuation therapy consisted of weekly MTX and daily MP until 2.5 years of continuous complete remission had been achieved.. Seventy-four children (age range, 1-19 years) at high risk of relapse were treated. Of 55 with B-lineage (early pre-B, pre-B) ALL, 24 have failed (2 induction failures, 2 deaths from infection, and 20 relapses). The event-free survival (EFS) rate at 4 years was 55.5% (standard error [SE] +/- 7.7%). Of 19 patients with T-cell ALL, 12 have failed (2 induction failures and 10 relapses). The EFS rate at 4 years was 32.6% (SE +/- 26.8%). Toxicities were significantly more common after AC and DNR or AC and VM-26 than IDMTX and MP. There were no toxicity-related deaths during intensive treatments.. Early intensive rotating therapy is tolerable and warrants consideration for additional trials of patients with high-risk, B-lineage ALL.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Hydrocortisone; Infant; Injections, Intramuscular; Injections, Intravenous; Injections, Spinal; Leukemia-Lymphoma, Adult T-Cell; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide; Treatment Failure

From 1985 to 1991, 20 patients with adult acute lymphoblastic leukemia (ALL) were treated with the DCVP-l-asp protocol, which consists of daunorubicin, cytosine arabinoside, vincristine, prednisolone, and I-asparaginase. of these 17 patients (85%) achieved complete remission. A Kaplan-Meier analysis predicted that 30% of the patients in remission would remain disease-free at 5 years. Four patients relapsed between 1 and 2.5 years from the start of treatment. The median survival time for the four patients with an abnormal karyotype was 15 months. No meningeal relapses occurred in patients treated with regular CNS prophylaxis. Myelosuppression was severe, but was well tolerated with supportive therapy, and there were no treatment-related deaths. We conclude that DCVP-l-asp is a feasible and effective protocol for adult ALLs including elderly patients. However, new treatment modalities, such as bone marrow transplantation, should be explored in patients with unfavorable prognostic factors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Survival Rate; Vincristine

Eight children in the final 3 mo of chemotherapy for acute lymphoblastic leukemia were studied while on oral 6-mercaptopurine (6MP) maintenance therapy and then again 4-9 mo after chemotherapy had been completed. Six of the eight were also studied a second time while on 6MP in the 24-h period after receiving intravenous methotrexate (MTX). 6MP reduced protein oxidation after a test meal and reduced fasting urinary urea excretion by enhancing the reutilization of endogenous amino acids for protein synthesis. MTX had no detectable effects on protein metabolism but reduced overnight carbohydrate utilization by enhancing fat utilization. A similar enhancement of fat utilization was evident after a test meal. The two drugs in combination resulted in effects on protein and energy metabolism that were the sum of the individual effects plus an increase in the rate of whole-body protein turnover and synthesis.

Topics: Adolescent; Child; Energy Metabolism; Female; Humans; Male; Mercaptopurine; Methotrexate; Models, Theoretical; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteins; Remission Induction

Topics: Adolescent; Child; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides

Ecto-5'-nucleotidase (ecto-5'NT) catalyzes the extracellular dephosphorylation of nucleotides like IMP. Cytoplasmic 5'NT (cyto-5'NT) and non-specific (e.g. acid- and alkaline) phosphatases (AP) regulate the intracellular degradation of nucleotides. High NT and AP activities might cause a resistance to the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We studied the relation between these enzymes and immunophenotype, drug resistance and prognosis in 77 children with acute lymphoblastic leukemia (ALL). Enzyme activities were assessed radiochemically; in vitro drug resistance was measured with the MTT assay. AP activities were higher in T-ALL and B-ALL than in precursor B-ALL. Cyto-5'NT activity was very low in all phenotypes and accounted for a significant proportion of total IMPase activity only in the very immature CD10- c mu- precursor B-ALL. CD10+ ALL cases with high ecto-5'NT activities showed a trend (p = 0.065) for a lower probability of continuous complete remission than those with a low activity. Ecto-5'NT activity was not related to in vitro drug resistance to 6-TG. A weak correlation was found between in vitro 6-TG resistance and cyto-5'NT and AP activities. We conclude that high ecto-5'NT activities do not cause a resistance to 6-thiopurines in childhood ALL. Some patients have high cyto-5'NT and AP activities associated with 6-thiopurine resistance.

Topics: 5'-Nucleotidase; Acid Phosphatase; Adolescent; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Daunorubicin; Drug Resistance; Female; Humans; Immunophenotyping; Infant; Leukemia, B-Cell; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Vincristine

A method for the measurement of 6-mercaptopurine (6MP) in urine using high-performance liquid chromatography is described. Urinary excretion of 6MP was measured in 46 children with acute lymphoblastic leukemia. The proportion of unchanged drug excreted after oral dosage in the morning was greater than after an evening dose (5.6 +/- 3.3% vs. 3.3 +/- 2.4%). Possible reasons for the discrepancy are discussed. In all children receiving 6MP in the morning, the drug was detected in urine at 2 and 4 h after ingestion. At 6 h, 6MP was still detectable in 77% of patients, at 8 h in 54%, at 10 h in 12%, and at 12 h in 8%. The reliability of urinary 6MP determination as a measure of drug compliance was assessed in 39 children accustomed to receiving their medication in the evening. 6MP was detected in 81% of first morning urine samples, indicating compliance with medication the preceding evening. The absence of 6MP in first morning urine samples did not necessarily indicate poor compliance because of the variability in 6MP excretion and unpredictable pattern of night voiding in children. The method was therefore a reliable measure of good short-term compliance. It also directed attention toward possible noncompliance in children with negative samples.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Circadian Rhythm; Drug Administration Schedule; Humans; Mercaptopurine; Methotrexate; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We made a retrospective study of 44 patients with acute non-lymphocytic leukemia (ANLL) and 14 patients with acute lymphocytic leukemia (ALL) admitted to our hospital from September 1984 to May 1991. The complete remission (CR) rate of ANLL was 90.9%, against 85.7% for ALL. The 5-year survival of ANLL was 50.7%, and that of ANLL under age 60 years was 70.3%. The 2-year median survival of ALL was 35.1%. These results were obtained with response-oriented individualized therapy, and intensive chemotherapy with a view to eradication of residual leukemic cells. Eight elderly patients with ANLL were treated with cytosine arabinoside in low doses. Complete remission was achieved in 6 patients, but these cases relapsed. These treatments should be reconsidered for long CR duration. Our schedules of response-oriented individualized therapy were too flexible to apply at another institute so they should be arranged for general application.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Survival Rate; Treatment Outcome

The present study was designed to evaluate the chemotherapy-induced cellular immunosuppression in 20 children with acute lymphoblastic leukemia (ALL) in remission and receiving maintenance chemotherapy. Peripheral blood was serially obtained from leukemic children during vincristine/cyclophosphamide/6-mercaptopurine/prednisone combined consolidation chemotherapy. The mean absolute number of peripheral blood lymphocytes as well as the mean absolute numbers of lymphocyte subsets (T cells, T cell subsets, B cells, and natural killer cells) from leukemic children before consolidation chemotherapy were all significantly lower than in control subjects; however, the percentages of lymphocyte subsets were similar in both groups. After consolidation chemotherapy, the percentages of CD4+ T lymphocytes and natural killer (NK) cells were significantly decreased and the percentages of monocytes and CD8+ T lymphocytes were significantly increased. Phytohemagglutinin- and 12-O-tetradecanoylphorbol-13-acetate-induced production of interleukin-2 (IL-2) and NK-cell-mediated cytotoxic activity by peripheral blood mononuclear cells (PBMC) were also substantially decreased in the post-therapy groups. NK activity correlated with the percentage of NK cells in PBMC. In contrast, OK432-induced production of tumor necrosis factor alpha (TNF alpha) and killer activity against NK-resistant target cells were significantly increased after therapy as compared with the pre-therapy and control groups. TNF alpha production correlated with the percentage of monocytes in PBMC. These results demonstrate that substantial quantitative and qualitative chemotherapy-induced abnormalities of the cellular immune system are present in the majority of patients treated with ALL. It is also suggested that the increased TNF alpha production by monocytes and the appearance of potent killing activity against NK-resistant targets might compensate for the defects of IL-2 production and NK activity during intensive consolidation chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Cytotoxicity, Immunologic; Humans; Immune Tolerance; Immunity, Cellular; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukocytes, Mononuclear; Lymphocytes; Mercaptopurine; Mice; Mice, Inbred C57BL; Phenotype; Picibanil; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Tumor Necrosis Factor-alpha; Vincristine

The primary purpose of this study was to determine the therapeutic efficacy of a protocol of treatment for acute lymphoblastic leukemia (ALL) in children. A prospective approach was adopted with an inception cohort of patients. Outcome measures were assessed on December 31, 1990. The study was conducted at two tertiary care centres (pediatric oncology programs) in Ontario, Canada. All children with ALL were eligible for study and consecutive recruitment took place between May 1984 and July 1987. They were classified at diagnosis into one of three categories for risk of relapse according to standardized criteria. Thirty-nine children were designated as having standard risk (SR), 31 as having high risk (HR), and 12 as having very high risk (VHR) disease. All patients are included in the analysis. Treatment was administered according to risk category-specific chemotherapy protocols, the details of which have been published. A distinguishing feature of these strategies is the intensive use of intramuscular L-asparaginase. Patients remained on these regimens for 2 years or until relapse or toxic death (events) ensued. Total and event-free survival data were determined by life-table analysis (Kaplan-Meier plots). With a minimum interval from diagnosis of 186 weeks and a median interval exceeding 5 years, the cumulative proportion of the entire cohort (C) surviving is 85% [95% confidence interval (CI), 77-93%]. For the respective risk groups, the corresponding proportions are SR 94% (95% CI, 87-100%), HR 74% (95% CI, 59-89%), and VHR 81% (95% CI, 59-100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cohort Studies; Cranial Irradiation; Cytarabine; Daunorubicin; Doxorubicin; Humans; Infant; Life Tables; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Remission Induction; Risk; Survival Analysis; Survival Rate; Treatment Outcome; Vincristine

In this study we investigated T-cell subsets, HLA-DR and IL2 receptor (IL2R, CD25) expression on T-cells in peripheral blood lymphocytes from the patients with childhood acute leukemia undergoing maintenance chemotherapy with 6-MP and MTX, and compared them with those in the healthy controls. There were decrease of relative number of CD4 positive (CD4+) cells and the increase of relative number of CD8 positive (CD8+) cells in comparison with those in controls; thus the ratio of CD4+ cells to CD 8+ cells decreased. HLA-DR and IL2R expression on T-cells increased in the patients. Increased HLA-DR expression was detected on both CD4+ cells and CD8+ cells, but the increased IL2R expression was related only to CD4+ cells. IL2R expression in the patients with side effects was higher than in controls. Methotrexate (MTX)-induced increase of HLA-DR and IL2R expression was observed in 2 of every 3 patients undergoing intensive chemotherapy.

Topics: Antigens, Surface; Antineoplastic Combined Chemotherapy Protocols; CD4-CD8 Ratio; Child; HLA-DR Antigens; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Interleukin-2; Remission Induction; T-Lymphocyte Subsets

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Diagnosis, Differential; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Time Factors; Vincristine

We evaluated the behavior of 38 children with standard-risk and high-risk acute lymphoblastic leukemia who received corticosteroids as part of their antileukemia chemotherapy. Each patient was assessed on two occasions: 16 weeks following remission and 1 year thereafter. Parent reports on emotional lability, attention span/hyperactivity, sleep disturbance, listlessness, peer relations, and depressed mood were obtained for 4 consecutive weeks: week before, week during, and 2 weeks after treatment administration. At the 16 week evaluation, standard-risk (N = 17) and high-risk (N = 21) treatment differed by steroid dose and systemic chemotherapy, while at the 1 year testing, treatment differed only by steroid dose (prednisone 40 mg/m2 vs. 120 mg/m2). Statistically significant changes in all measures were observed during treatment as compared with before and after treatment for both risk groups and assessment times. High-risk patients exhibited greater behavioral effects than standard-risk patients only for emotional lability, listlessness, and depressed mood at the 16 week testing, when both steroid dose and chemotherapy differed. Girls had slightly greater behavioral effects than boys, while no influence of age was observed. At the doses tested, steroid dose per se does not appear to be the primary variable affecting behavioral changes.

Topics: Age Factors; Analysis of Variance; Attention; Child; Child Behavior; Child, Preschool; Cytarabine; Depression; Doxorubicin; Drug Interactions; Emotions; Female; Humans; Infant; Interpersonal Relations; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prospective Studies; Sex Factors; Sleep; Vincristine

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Female; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Maintenance chemotherapy with 6-mercaptopurine and methotrexate, widely believed an essential contribution to the high cure rates achieved in children with acute lymphoblastic leukaemia (ALL), is thought to work by killing the leukaemia cells that remain after intensive chemotherapy. We suggest instead that ALL commonly arises in precursor B cells normally programmed to die, and that maintenance chemotherapy does not kill these cells but controls growth of the leukaemia clone so that programmed death can occur. A similar approach may apply to other cancers in which programmed death is intrinsic to the normal counterparts of the neoplastic cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Bone Marrow; Child; Humans; Long-Term Care; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis

Topics: Biotransformation; Carbon Radioisotopes; Cell Division; Cell Line; Cell Survival; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We measured 6-mercaptopurine levels in the cerebrospinal fluid and plasma of 15 children undergoing treatment for acute leukemia. Plasma and cerebrospinal fluid samples obtained by lumbar puncture were collected before, during, and after cranial irradiation in order to evaluate a possible change in blood-brain barrier permeability to orally administered 6-mercaptopurine. Considerable interpatient variability has been observed in both plasma and cerebrospinal fluid 6-mercaptopurine levels. No statistical differences in the 6-mercaptopurine cerebrospinal fluid levels under the three different conditions could be detected. Our data suggest that cranial irradiation does not significantly influence the cerebrospinal fluid levels.

Topics: Administration, Oral; Adolescent; Blood-Brain Barrier; Brain; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors

CD16 or CD45RA is known to be a functional molecule, which provides activation signals in natural killer (NK) cells or T cells, respectively. To dissect the decreased NK activity in childhood acute lymphoblastic leukemia (ALL), the expression of CD16 (Leu 11) or CD45RA (2H4) and the production of natural killer cytotoxic factor (NKCF) were investigated. CD16+ cells or CD45RA+ cells in peripheral blood lymphocytes were not decreased as compared with controls, however, CD16+CD45RA+ cells in ALL (4%) were lower (p less than 0.05) than controls (17%). The production of NKCF in ALL patients (9.2%) was lower (p less than 0.05) than controls (16.5). These data suggest that the decreased NK activity in ALL patients can be attributable at least in part to the functional impairment of NK cells to produce NKCF.

Topics: Adult; Antigens, CD; Antigens, Differentiation; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; CD8 Antigens; Child; Cytotoxicity, Immunologic; Dexamethasone; Flow Cytometry; Histocompatibility Antigens; HLA-DR Antigens; Humans; Killer Cells, Natural; Killer Factors, Yeast; Leukocyte Common Antigens; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Protein Biosynthesis; Proteins; Receptors, Fc; Receptors, IgG; Vincristine

We studied the combined cytotoxic effects of methotrexate and 6-mercaptopurine (6-MP) on a human acute lymphoblastic cell line (MOLT-3) in vitro according to various schedules. The combined effects were analysed with improved isobologram using the concept of additivity. Simultaneous and continuous exposure (72 h) to these two agents had subadditive to protective effects (antagonism). Partial simultaneous exposure to methotrexate (5 h) and 6-MP (72 h) showed additive to protective effects. Sequential exposure to methotrexate (5 h) followed by 6-MP (72 h) had an additive effect at 0 h and a supra-additive effect (synergism) at 3 h and 19 h intervals. Therefore, it would seem to be better to avoid the simultaneous administration of methotrexate and 6-MP when these two drugs are used in combination. Sequential administration of methotrexate first, followed by 6-MP at short intervals, is recommended.

Topics: Cell Division; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

In the group of 75 ALL patients treated between 1980 and 1989, two women (ages 25 and 17, both FAB-L2 and CALLA +, after 56 and 34 months of continuous CR, respectively) were found to have a relapse manifested as a local infiltration of skin, with involvement of the adjacent lymph nodes in one patient. The leukaemic character of the skin infiltration was confirmed by skin needle aspiration and tissue biopsy expressing CD10 and CD24. Both patients were given intensified systemic chemotherapy and local X-ray irradiation. Complete remission was obtained with the disappearance of the skin infiltrations followed after 13 and 8 months, respectively, followed by a marrow relapse with symptoms of CNS involvement in one case. Both patients died because of treatment resistance (the overall survival time equalled 70 and 44 months, respectively).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Immunotherapy; Leukemic Infiltration; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiotherapy; Recurrence; Remission Induction; Skin; Vincristine

To determine whether the pharmacokinetics of 6-mercaptopurine (6-MP) would show dose dependency, we studied three different single oral doses in eight children (aged 3.6 to 15.1 years) with acute leukemia in remission. Marked interindividual differences in maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were observed when children received the 50 mg/m2 dose. This variability decreased when the doses were increased. Six of the eight children showed a disproportionate increase in the AUC with increasing doses; the other two had a proportionate relationship between the AUC and dose. Overall mean (+/- SD) Cmax and AUC values increased disproportionately (88 +/- 123, to 326 +/- 194, to 653 +/- 344 ng/ml for Cmax, and 147 +/- 180, to 451 +/- 177, to 1291 +/- 415 ng/ml per hour for AUC, respectively) when the dose increased from 50 to 87.5 mg/m2 and then to 175 mg/m2. The results suggest that a saturable first-pass metabolism of oral 6-MP occurs with increasing oral doses in some, but not all, children. Whether and to what extent this pharmacokinetic character of oral 6-MP affects the interindividual difference in systemic exposure to the drug in children with leukemia receiving maintenance therapy require further studies.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Time Factors

Intraindividual variation in 6-mercaptopurine (6-MP) kinetics has been little studied. It has now been examined in 18 children with acute lymphoblastic leukaemia (ALL). On 2 to 4 occasions in each patient drug concentrations in plasma and red cells were followed for 4 h after administration by means of HPLC. The mean individual coefficient of variation (C.V.) in AUC was 57.9% and it was not related to dose or concentration. The variation was the same in plasma and in red cells. It is concluded that regular monitoring of 6-mercaptopurine concentration would identify periods when a patient deviates strongly from the mean range. Both undertreatment and concentration-dependent toxicity could then be corrected.

Topics: Administration, Oral; Adolescent; Biological Availability; Blood Cell Count; Child; Child, Preschool; Chromatography, High Pressure Liquid; Erythrocytes; Female; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

A simple, selective, sensitive, and rapid high-performance liquid chromatography (HPLC) method is described for the quantitation of 6-mercaptopurine (6-MP) in plasma of patients with acute lymphoblastic leukemia (ALL). Pharmacokinetic data are presented for seven children with ALL receiving 6-MP therapy. A sensitivity of greater than or equal to 2 ng/ml in plasma was achieved on a reverse-phase octadecylsilane column using an HPLC system following a cleanup step with a solid-phase extraction cartridge. The chromatogram was monitored at 325 nm. Analytical recovery of 6-MP was 90%. The coefficients of variation for intra- and interday variabilities were 2.51 and 4.23%. This assay method is clinically useful for pharmacokinetic studies of 6-MP in ALL patients.

Topics: Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Male; Mercaptopurine; Methods; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reproducibility of Results

Thiopurine methyltransferase deficiency, inherited as an autosomal codominant trait, is associated with aberrant mercaptopurine metabolism leading to excessive cellular accumulation of 6-thioguanine nucleotides, the active metabolites of mercaptopurine. We describe a case of severe thiopurine methyltransferase deficiency (activity less than 1 U/8 x 10(8) erythrocytes) in a young girl with acute lymphocytic leukemia. The level of 6-thioguanine nucleotide in the patient's erythrocytes was seven times the population median value, and she had intolerable hematologic toxic effects during postremission therapy with a standard dosage of mercaptopurine (75 mg/m2 per day). Subsequent therapy with 6% of this dosage (10 mg/m2 three times weekly) yielded erythrocytic 6-thioguanine nucleotide concentrations consistently above the population median but not associated with prohibitively toxic effects. This case demonstrates that thiopurine methyltransferase deficiency does not absolutely contraindicate mercaptopurine therapy, and it also provides insight into the mechanism of excessive toxic effects of mercaptopurine sometimes observed in children with acute lymphocytic leukemia.

Topics: Child; Erythrocytes; Female; Humans; Mercaptopurine; Metabolism, Inborn Errors; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleotides; Thioguanine

To explore the possibility that higher total dosage of 'maintenance' treatment may have contributed to the recent improvement in outlook of children in the United Kingdom with lymphoblastic leukaemia, details of the amount of 6-mercaptopurine prescribed during the first two years of treatment were studied in an unselected cohort of children diagnosed between 1973 and 1987. Eighty five patients were studied, 30 diagnosed before and 55 after 1980. The group diagnosed after 1980 showed an 18% improvement in relapse free survival at five years. Their median total dose of 6-mercaptopurine had increased by 22%, whereas according to the protocol it should have risen by an average of only 9%. After 1980 boys were prescribed significantly more 6-mercaptopurine than girls, and had fewer dose reductions because of myelosuppression. These findings support the clinical impression that after 1980 an important therapeutic difference resulting from the new United Kingdom acute lymphoblastic leukaemia protocols was an increase in the amount of 6-mercaptopurine that children actually received as a result of changes in prescribing guidelines rather than dose. They also provide further evidence that boys tolerate 6-mercaptopurine better than girls, which may be related to the still unexplained difference in prognosis between the sexes.

Topics: Child; Child, Preschool; Clinical Protocols; Cohort Studies; Drug Administration Schedule; Drug Tolerance; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Sex Factors

Diminished growth rate during treatment for acute lymphoblastic leukemia (ALL) is of the multifactorial etiology. Effects on GH secretion have been shown after discontinuation of treatment including prophylactic CNS irradiation. Seventeen children treated for ALL with three different CNS preventive schedules were followed longitudinally with repeated estimations of the spontaneous GH secretion during a 24-month period. No difference was found in GH secretion during this time between patients who had received no radiotherapy and those who had received 18 or 24 Gy as CNS prophylaxis. During dexamethasone treatment the GH secretion was completely suppressed, which can be a mediator for the diminished growth rate during the first 2 years of ALL treatment. We conclude that there is no clinical reason to perform GH analysis within the first 24 months of treatment for ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Height; Body Weight; Child; Child, Preschool; Combined Modality Therapy; Dexamethasone; Female; Glucocorticoids; Growth; Growth Hormone; Humans; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Radiotherapy Dosage; Vincristine

To evaluate the reasons for the wide variability in bioavailability of orally administered 6-mercaptopurine in children with acute lymphoblastic leukemia, we studied several pharmacokinetic parameters of the drug in 18 affected children receiving remission maintenance therapy, and compared them with their anthropometric data and with the results of intestinal function tests. No correlation was found between estimates of small intestinal absorption (the oral lactose tolerance test and 1 h blood xylose test) and 6-mercaptopurine serum levels. Of the anthropometric measurements considered, only the weight/height percentile (an index of the fat body mass) strongly and linearly correlated with the area under the curve of 6-mercaptopurine. The dose of 75 mg of 6-mercaptopurine/m2 of body surface resulted in higher serum concentrations in children below the 75th percentile than in those with a weight/height ratio exceeding the 75th percentile. In conclusion, these data caution about the risk of underdosing 6-mercaptopurine in overweight children when administering it on the basis of body surface area.

Topics: Administration, Oral; Adolescent; Biological Availability; Body Weight; Child; Child, Preschool; Female; Humans; Intestinal Absorption; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

6-mercaptopurine (6-MP) can be inactivated by S-methylation, which is catalysed by thiopurine methyltransferase (TPMT). An alternative metabolic route leads to the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). To investigate whether these two pathways compete with each other to affect the therapeutic response to 6-MP, 6-TGN concentrations and TPMT enzymatic activity were measured in erythrocytes (RBC) from 95 children on long-term 6-MP therapy for lymphoblastic leukaemia (ALL). RBC TPMT activities were also measured in 130 control children and 104 long-term survivors of ALL no longer on treatment. The 95 children on 6-MP showed wide interindividual differences in RBC 6-TGN concentrations at the full protocol dose of 75 mg/m2, and RBC 6-TGN concentrations correlated negatively with RBC TPMT activity. Children with 6-TGN concentrations below the group median had higher TPMT activities and a higher subsequent relapse rate. 50 of the 104 long-term survivors had been treated with "gentle" low-dose protocols, and this subgroup contained an excess of children with lower TPMT activities compared with normal controls. These results indicate that genetically determined TPMT activity may be a substantial regulator of the cytotoxic effect of 6-MP, an effect which in turn could be important in influencing the outcome of therapy for childhood ALL.

Topics: Actuarial Analysis; Administration, Oral; Adolescent; Adult; Analysis of Variance; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Erythrocytes; Female; Follow-Up Studies; Guanine Nucleotides; Homozygote; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Thionucleotides; Time Factors

Topics: Child; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We describe a case of acute leukemia with t(4;11) (q21;q23) in a 3-month-old girl suffering from congenital hypothyroidism. The blast cells were cytochemically and immunologically classifiable as acute lymphoblastic leukemia of an early B-cell lineage (HLA-DR +, B4 +, CALLA-). but we treated this patient with a protocol designed mainly for acute nonlymphocytic leukemia, employing Adriamycin, vincristine, and cytosine arabinoside. Although the prognosis of this type of leukemia is known to be extremely poor, our patient is currently alive and in continuous complete remission lasting 35 months to date. This case may demonstrate a potential alternative therapeutic strategy for acute leukemia with t(4;11) as well as clinical evidence for the mixed-lineage characteristics of this condition. However, the pathogenetic role of congenital hypothyroidism in the development of acute leukemia is still uncertain.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Congenital Hypothyroidism; Cranial Irradiation; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Hypothyroidism; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Translocation, Genetic; Vincristine

The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay, which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay, up to now the most valid but laborious assay. In this study, in vitro drug sensitivity was assessed in cells from 82 children with leukemia, 79 of whom had ALL, with the MTT assay. Dose response curves were obtained for 6-mercaptopurine, 6-thioguanine (6-TG), prednisolone (Pred), daunorubicin (DNR), vincristine (VCR), cytosine arabinoside (Ara-C), L-asparaginase (L-Asp), mafosfamide, and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients, leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG, Pred, Ara-C, mafosfamide and mustine but not to DNR, VCR, and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested, addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.

Topics: Asparaginase; Cells, Cultured; Child; Coloring Agents; Culture Media; Cyclophosphamide; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Mechlorethamine; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Tetrazolium Salts; Thiazoles; Thioguanine; Vincristine

In a retrospective population-based study of 122 children with non-B-cell acute lymphoblastic leukemia (ALL), we analyzed the relation between risk of relapse and the degree of leukopenia achieved during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). After a median follow-up of 62 months for patients still in remission, 43 patients had relapsed (including 28 bone marrow relapses). Patients with a mean white blood cell count during MT (mWBCMT) of less than or equal to 3.5 x 10(9)/L had a significantly lower risk of hematological relapse (p = 0.007) as well as of any relapse (p = 0.02) compared to patients with higher mWBCMT. The clinical advantage of leukopenia could be demonstrated for all risk groups and was not explained by differences in year of diagnosis, gender, age, and white blood cell count at diagnosis, or the prescribed dose of MTX and 6MP. Although prospective studies are needed to establish the benefit of upward dose adjustments to achieve leukopenia, these results indicate a clinical advantage of keeping WBCs low during MT.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Retrospective Studies; Risk Factors

A total of 44 children with acute lymphoblastic leukemia were immunized against chickenpox with the Oka/Merck strain live attenuated varicella vaccine. Of these children, 24 continued oral chemotherapy with 6-mercaptopurine during the immunization period and 20 had suspension of all chemotherapy for 1 week before and 1 week after the vaccine. Seroconversion, as determined by the detection of fluorescent antibody to membrane antigens, occurred in 91% and did not differ between patients continuing 6-mercaptopurine from those in whom chemotherapy was suspended. Fever and/or rash occurred in less than one third of vaccinated children. Unexpected reactions occurred in two vaccinated children, one from each group, both of whom had low absolute lymphocyte counts (less than 750/microL) on the day of immunization. Vaccine-induced immunity appeared effective in preventing or modifying chickenpox after exposure to natural disease.

Topics: Adolescent; Chickenpox; Chickenpox Vaccine; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Viral Vaccines

Topics: Antineoplastic Combined Chemotherapy Protocols; DNA, Neoplasm; Drug Synergism; Humans; Lymphocytes; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Thymidine; Tumor Cells, Cultured

In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT] during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT less than or equal to 40 IUl-1. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r greater than 0.70, P less than 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk). Patients with a mATMT greater than 40IUl-1 had a lower risk of relapse than patients with a mATMT less than or equal to 40IUl-1 (4.5 year CCR: 0.70 and 0.50, P = 0.06; and 4.5 year haematological remission: 0.83 and 0.63, P = 0.03). The favourable outcome for patients with hepatoxicity could be demonstrated for all risk groups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Liver Diseases; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Transaminases

Plasma levels and cumulative urine excretion of 6-mercaptopurine (6-MP) were measured using a specific and sensitive high-performance liquid chromatographic assay in seven children with acute lymphoblastic leukemia (ALL) as well as in one healthy volunteer. The dose of 6-MP varied in the range of 25-75 mg/m2 of body surface area and was administered with a standard breakfast. A 4- to 11-fold variation between individuals was found in the pharmacokinetic parameters: peak concentration, time to reach peak, area under the plasma concentration-time curve (AUC), and fraction of dose excreted in the urine. Three repeated determinations in one individual revealed that AUC also varied more than sixfold following an overnight fast. In three individuals, the reducing agents glutathione (10 mg/kg) and ascorbic acid (15 mg/kg) were coadministered with 6-MP to evaluate their possible role in the protection of 6-MP from oxidation and degradation in the intestinal lumen. No consistent effect was observed, however, on the AUCs of either of these agents. A clear relationship was found between AUCs and the 24-h urinary excretion of unchanged drug (r = 0.9381), indicating that determinations of 6-MP in the urine may replace the painful procedure of repeated blood sampling. Further studies are necessary to determine the factors contributing to the unpredictable plasma levels following oral doses of 6-MP and to determine the value of pharmacokinetic monitoring in ALL patients.

Topics: Administration, Oral; Adolescent; Adult; Ascorbic Acid; Biological Availability; Child; Chromatography, High Pressure Liquid; Female; Glutathione; Humans; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors

A reversed phase high performance liquid chromatographic procedure was developed to quantify 6-thioguanine, 6-mercaptopurine, methylthioguanine, and methylmercaptopurine in red blood cells. The free base of each thiopurine was liberated from the respective nucleoside and nucleotide moiety by acid hydrolysis, which allowed for a determination of the total thiopurine present. 6-Thioguanine and 6-mercaptopurine were analyzed on an octadecylsilane column using methanol + 20 mM sodium phosphate (15:85), pH 7.5, containing 0.07% tetrabutylammonium chloride. Detection was by potassium permanganate oxidation and fluorescence detection at 290 nm excitation and 400 nm emission. Methylmercaptopurine and methylthioguanine were analyzed on a cyanopropylsilane column using methanol + 40 mM sodium phosphate (18:82), pH 2.7, and then ultraviolet absorption at 314 nm and 290 nm, respectively. The method was used to quantify the four primary thiopurines present in red blood cells of an acute lymphoblastic leukemia patient. The procedure may be a therapeutic monitoring technique that quantifies the cytotoxic drug burden in patients receiving azathioprine or 6-mercaptopurine therapy.

Topics: Child; Chromatography, High Pressure Liquid; Erythrocytes; Humans; Male; Mercaptopurine; Microchemistry; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality Control; Thioguanine

Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse.. To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted.. There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005).. Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Recurrence; Remission Induction; Risk Factors; Survival Analysis; Xanthine Oxidase

In the present study of 12 boys and 19 girls 2-16 years of age (median, 7 years) on oral 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy (MT) for non-B-cell acute lymphoblastic leukemia (ALL), we found that (a) during MT, 6-thioguanine nucleotides (6TGN) (the major cytotoxic metabolite of 6MP) accumulate in the erythrocytes (E-6TGN); (b) for patients receiving an unchanged dose of 6MP, no significant correlation could be demonstrated between the mean E-6TGN (mE-6TGN) and the dose of 6MP (r = -0.11, P = 0.28) (31 patients); (c) among 21 patients receiving 50-75 mg/m2 6MP, a variation of up to 3 orders of magnitude in mE-6TGN could be demonstrated, with the interindividual coefficient of variation (CV) in mE-6TGN for these patients being 0.31; (d) the median intraindividual CV in E-6TGN at an unchanged dose of 6MP was 0.11 (range, 0.04-0.18); and (e) the degree of myelodepression as measured by the mean white cell count was related to mE-6TGN (r = -0.55, P = 0.0006). These results indicate that E-6TGN could be a useful parameter for monitoring 6MP maintenance chemotherapy, although this needs to be explored in prospective studies.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythrocytes; Female; Guanine Nucleotides; Humans; Leukopenia; Male; Mercaptopurine; Methotrexate; Monitoring, Physiologic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides

Multiple melanocytic nevi showing an unusual accumulation on the soles of the feet were observed in an 8-year-old boy after he had received chemotherapy for acute lymphatic leukemia. This observation confirms the occurrence of chemically induced melanocytic nevi as well as their affinity for the acral sites.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Foot Diseases; Humans; Male; Mercaptopurine; Methotrexate; Nevus, Pigmented; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors

During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 +/- 142 minutes vs 176 +/- 22 minutes, mean +/- SEM). The area under the concentration-time curve (AUC0-infinity) was significantly larger in the evening (24,713 +/- 3536 ng/mL per minute vs 17,120 +/- 1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 min-infinity, 7724 +/- 2955 ng/mL per minute in the evening vs 2597 +/- 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 x 10(9)/L to 2.2 x 10(9)/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78 x 10(9)/L to 1.05 x 10(9)/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Circadian Rhythm; Drug Administration Schedule; Female; Half-Life; Humans; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intracellular thioguanine nucleotides (6-TGN) are the major cytotoxic metabolites of mercaptopurine (6-MP). Red blood cell (RBC) 6-TGN concentrations were measured in a group of 120 consecutive children with lymphoblastic leukemia (ALL) to assess interpatient variability and its clinical importance. Assays were performed after at least 2 months 6-MP maintanance chemotherapy and a minimum 7 days unattenuated protocol dose of 75 mg/m2. Observed 6-TGN concentrations ranged from 126 to 832 pmol/8 x 10(8) RBCs (median, 275). There was a correlation between 6-TGN and neutropenia 14 days postassay (rs = .51; P less than .0005), and an inverse correlation between 6-TGN and the length of time uninterrupted full protocol dose was tolerated without neutropenia (rs = -.3; P less than .01). After a median follow-up of 49 months, 19 children had relapsed, of whom 17 (89%) had 6-TGN concentrations below the group median (log-rank chi 2 = 11.9; P less than .001). Multivariate analysis using Cox's proportional hazards regression showed the 6-TGN effect on disease control to be independent of diagnostic WBC count, sex, age, immunological cell type, French-American-British (FAB) type, variation in other antineoplastic therapy, and duration of remission at the time of 6-TGN assay. Children with ALL taking the same dose of 6-MP show great variability in its measurable cytotoxic effect, and this variability is apparently important in predicting treatment outcome.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Erythrocytes; Humans; Leukocyte Count; Mercaptopurine; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Analysis; Thioguanine

We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6-mercaptopurine (6MP) in the same children. There was an eightfold variability in area-under-concentration time-curve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0----infinity (r = 0.95, P less than 0.001). Elimination T1/2 was between 1.34 and 5 hours (mean 2.16 +/- 0.23 hr, mean +/- SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P less than 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (greater than 15 mo) vs. short therapy (less than 12 mo) (462 +/- 75 and 246 +/- 58 ng.ml-1.min.mg-1.m2, P less than 0.025). No statistical differences in AUC of MTX were found between short and long therapy. The large interpatient variability in MTX pharmacokinetics supports the possibility that differences in absorption and/or clearance of the drug may affect the clinical response. Because of the excellent correlation between peak and AUC of MTX, and because 3 measurements, at 30, 60, and 90 minutes will almost invariably identify the peak, this measurement can be used to estimate AUC for purpose of correlation with clinical outcome.

Topics: Administration, Oral; Adolescent; Age Factors; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Metabolic Clearance Rate; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To explore the clinical significance of the concentration of methotrexate (MTX) in erythrocytes (E-MTX), 42 boys and 31 girls were studied during maintenance chemotherapy for childhood acute lymphoblastic leukemia for periods of 3-22 months (median, 8 months) at an unchanged dose of MTX. For each study period, a weighted mean of white cell counts (mWBC), absolute neutrophil counts (mANC), and serum aminotransferases (mAT) were calculated, using as weights the intervals from sampling until the next WBC, ANC, or AT determinations were done. In 17 patients who underwent at least six measurements of E-MTX during a period in which the MTX dose remained unchanged for up to 22-months, the median intraindividual coefficient of variation for E-MTX was 10% (range, 5%-22%). For each patient, a mean of all E-MTX values (mE-MTX) during a study period (range, 1-15 measurements; median, 3) was used as an index of the RBC accumulation of MTX at the prescribed dose of MTX. Among 42 patients receiving full-dose MTX (greater than 17.5 mg/m2), the mE-MTX ranged between 3.4 and 9.6 nmol hemoglobin (Hb) (interindividual coefficient of variation, 33%). The mE-MTX was significantly related to the MTX dose (r = 0.45, P = 0.00003). The mWBC and mANC were both significantly related to the mE-MTX (mWBC: r = -0.31, P = 0.004; mANC: r = -0.35, P = 0.02), but not to the dose of MTX (mWBC: r = -0.08, P = 0.25; mANC: r = -0.22, P = 0.08). Each of four patients with a persistent rise in AT above the upper normal limit (40 IU/l) and an mAT of greater than 80 IU/l had an mE-MTX of greater than 6.5 nmol/mmol Hb. Due to its low intraindividual variation, E-MTX may be useful for detecting persistent or intermittent failure of patient compliance. Its prognostic significance and its clinical value in MTX dose adjustment should be explored in prospective studies.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Leukocyte Count; Liver; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Time Factors; Transaminases; Vincristine

Plasma levels of 6-mercaptopurine were determined in 22 consecutive children with acute lymphoblastic leukemia on oral remission maintenance therapy during the time period of August 1984 to January 1988. Each child received the drug once daily for up to 3 years and was studied repeatedly (1-12 times). An HPLC method was used for drug analysis. We found large interpatient variations in the mean peak plasma concentration (range of 50-424 ng/ml) and in the mean area under the concentration vs. time from 0-4 h curve (range of 82-637 ng ml-1 h). There were also pronounced variations between different sampling occasions in the same patient. Nine of the 22 patients had complications during the maintenance therapy. Five children with a mean peak plasma level below 135 ng/ml and a mean area under the curve (AUC) value below 251 ng ml-1 h relapsed (three in the central nervous system and two in the bone marrow). Both children with a bone marrow relapse died. Relapse risk was related to the AUC (p less than 0.05). Four children with a mean peak plasma level above 166 ng/ml and a mean AUC value above 363 ng/ml/h developed severe myelotoxicity, which necessitated a temporary cessation of the maintenance therapy. In addition, two patient relapsed 6 and 11 months after termination of maintenance therapy. Their mean peak and AUC values were not low but the concentrations decreased markedly towards the end of the maintenance period. The results indicate that the plasma levels of 6-mercaptopurine, when determined repeatedly, might be of significance for the outcome of the remission maintenance treatment.

Topics: Adolescent; Bone Marrow Diseases; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Risk Factors

Since April, 1978 to October, 1988, 66 acute lymphocytic leukemia (ALL) patients aged 15 to 79 (21 L1, 43 L2, 2 L3/6 Ph1+) were treated with 3 different therapeutic protocols. The drugs used for induction were VCR (VDS) + Pred, followed by DNR + VCR (VDS) + 6MP + Pred and VCR (VDS) + L-asp + Pred in protocol I, Ad + VCR + Pred in protocol II and DNR + VCR + Pred in protocol III. Complete remission (CR) was attained in 72.7% of 66 patients. The CR rate of each group as followings; 71.4% in protocol I and 75.0% in protocol II and III, respectively. The median duration of remission was 10.2 months + and the probability of being in continuous CR at 3 years was 21.9%. For the 48 patients in remission the median survival was 17.8 months and the probability of being alive at 3 years was 24.3%. The intensified induction and consolidation therapy is expected in the cure oriented treatment of adult ALL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Daunorubicin; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Mercaptopurine; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Survival Rate; Vincristine

The pharmacokinetics of oral 6-mercaptopurine (6-MP) was assessed in ten children with acute lymphoblastic leukemia during maintenance chemotherapy. The doses were 175 mg/m2, 87.5 mg/m2, and 50 mg/m2. The relation between doses and the means of AUC (area under the curve) and Cmax (maximum concentration) suggested a non-linear pharmacokinetics. Our results demonstrated wide interindividual variability as reported by others. We demonstrated individual variation between clinically stable patients. The relationships between predicted and observed concentrations were variable among four patients studied. Some of the patients showed discrepancy between the both concentrations, whereas others did not. The results indicate that serum concentration after oral administration is predictable by further analysis of therapeutic drug monitoring.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The effects of some environmental and genetic factors on the inter- and intraindividual variations of 6-mercaptopurine (6-MP) pharmacokinetics were studied in children on oral remission maintenance therapy for acute lymphoblastic leukemia or non-Hodgkin's lymphoma. Blood samples were obtained 0-4 h after drug intake. 6-MP concentrations were determined in plasma and in erythrocyte concentrates. The influence of food on the pharmacokinetics was examined in a prospective study of 15 children. Each child was examined four times, twice in the fasted state and twice after intake of a standardized, milky, breakfast. There were pronounced inter- and intraindividual variations. Food intake seemed to reduce these variations but there were no significant changes in peak concentrations and area under the plasma concentration vs time curves (AUC) between the fasted and fed states. Food intake reduced the time to peak concentration both in plasma, from 1.8 h to 1.1 h (P less than 0.01) and in red blood cells, from 1.8 h to 1.3 h (P less than 0.01). Retrospective subdivision of the patients indicated a tendency for different pharmacokinetic patterns according to dose; five out of seven patients receiving greater than 70 mg m-2 had a higher AUC in the fasting state, while five out of eight patients receiving less than 70 mg m-2 had a higher AUC in the fed state. The cytochrome P-450-dependent hydroxylation capacity was evaluated with debrisoquine but no correlation was found to the pharmacokinetics of 6-MP.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Debrisoquin; Erythrocytes; Fasting; Female; Humans; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Child; Coloring Agents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Thioguanine

The medical records of 58 patients who were surviving after completing treatment for acute lymphoblastic leukemia were reviewed to determine the incidence of skin rash occurring after their treatment had ended. Twenty-eight (48%) developed a rash within 3 months of completing treatment. In the majority this was erythematous, affected the face, and in all patients was transient. There was an increased incidence of rash in those patients who had eczema or asthma or who had a family history of eczema or asthma. It would seem prudent to warn parents of this phenomenon and reassure them of it's benign nature.

Topics: Erythema; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Methotrexate (MTX) and mercaptopurine (MP) are the mainstays of continuation therapy for acute lymphocytic leukemia (ALL). These drugs are stored in tissues as active metabolites. Relapse in ALL might reflect failure to achieve adequate intracellular drug levels. Assured (parenteral) delivery of higher doses of MTX and MP should maximize tissue levels of these drugs by overcoming individual variations in absorption, metabolism, clearance, and compliance. Fifty-nine children with ALL at lower risk of relapse received 12 intensive MTX/MP courses immediately after 4 weeks of standard vincristine, prednisone, and asparaginase induction. Each 2-week intensive course included: MTX, 200 mg/m2 intravenous (IV) push then 800 mg/m2 IV over 24 hours on day 1; MP, 200 mg/m2 IV push then 800 mg/m2 IV over 8 hours on day 2; MTX, 20 mg/m2 intramuscularly on day 8; and MP, 50 mg/m2 orally daily on days 8 to 14. After the 6 months of intensive therapy, continuation therapy was weekly MTX/MP (as on days 8 to 14) for 1 or 2 years. Age-based MTX was given intrathecally (IT) for CNS prophylaxis. All patients entered remission. Three patients relapsed: bone marrow (at 24 and 37 months), and bone marrow and CNS (at 34 months). There were no isolated CNS relapses or deaths in remission. Event-free survival at 4 years is 94% (SE, 7%) by Kaplan-Meier analysis. Toxicities (infection, mucositis) occurred in less than 10% of intensive MTX/MP courses. However, a child with Down's syndrome withdrew after three courses because of recurrent severe mucositis. Further studies of this regimen are in progress.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Seizures

The chronopharmacokinetics of the orally administered antileukemic drugs, 6-mercaptopurine and methotrexate, were examined in 13 children with acute lymphoblastic leukemia (ALL) to establish if there is a pharmacokinetic basis for the lower relapse rate associated with administration of these agents in the evening. Children with ALL in complete remission had plasma drug concentrations monitored for 8 h following an oral dose of either methotrexate or 6-mercaptopurine administered in the morning (8 a.m.) and the evening (8 p.m.). Total drug exposure to oral methotrexate, as measured by the mean area under the plasma concentration-time curve (AUC), was 2.75 microM.h following the morning dose and 2.77 microM.h in the evening. For 6-mercaptopurine, the mean morning AUC (198 ng.h/ml) was higher than that following the evening dose (167 ng.h/ml) (p greater than 0.05); but compared to the wide interpatient variability observed with this drug, this 20% difference is not likely to be clinically significant. These results indicate that the suggested benefit of evening drug administration is not likely to be a result of diurnal variation in drug disposition.

Topics: Administration, Oral; Child; Circadian Rhythm; Drug Administration Schedule; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

There is ample evidence of the value of intensive therapeutic strategies in the management of acute lymphoblastic leukemia (ALL), the commonest form of malignant disease in children. Such a program, devised at the Dana-Farber Cancer Institute (DFCI), Boston, and incorporating high-dose L-asparaginase, was adopted in 1984 by the Children's Hospital at Chedoke-McMaster, Hamilton, Ont., and the Children's Hospital of Western Ontario, London. We describe the experience of these institutions in the treatment of 82 children with ALL, 19 of whom were switched to the DFCI protocols while in continuing first remission with other treatment programs to complete a minimum of 2 years of maintenance therapy; the remaining 63 children, who had recently diagnosed disease, were consecutively enrolled in the DFCI protocols. Each child was assigned at diagnosis to a category of risk for relapse and treated accordingly. There were no remission induction failures or deaths due to induction therapy among the patients with newly diagnosed disease. There were no differences in total or event-free survival rates between the patients in Hamilton and those in London or between those whose protocols were switched and those who were treated from the beginning with the DFCI protocols. With a median follow-up interval of 144 weeks the total survival rate was 95% and the event-free survival rate 88%. For patients at standard risk of relapse the event-free survival rate was 100%, for those at high risk the rate was 82%, and for those at very high risk the rate was 67%. If infants (all of whom suffered a relapse) are excluded from the last category the rate was 89%. These results were achieved with moderate toxic effects (except for two deaths, one of which was due to a therapeutic misadventure) and suggest that the prospect for cure in children with ALL. may now approximate 80%, a degree of success that demands that consideration be given to reducing total therapy, at least for children with standard-risk disease. Further follow-up will determine whether these high event-free survival rates will stabilize and meet the criteria for cure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Boston; Child; Clinical Protocols; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Ontario; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk Factors; Survival Rate; Vincristine

Purine nucleotides become available for a cell by two routes, namely purine de novo synthesis and the purine salvage pathway. 5'Nucleotidase is a purine pathway enzyme and is present in two forms. Cytoplasmic 5'nucleotidase (cyto 5'NT) catalyzes the intracellular degradation of purine nucleotides into their corresponding nucleosides. The plasma membrane bound form (ecto 5'NT) has its active site facing the external medium. Its function is the extracellular dephosphorylation of nucleotides, to which cells are generally impermeable, into nucleosides and the transport of these nucleosides through the cell membrane. Lymphoblastic 5'NT activity varies between different children with common-ALL. 5'NT positive cases have a higher relapse rate and thus a poorer prognosis than 5'NT negative cases. This can be explained by two hypotheses which are not mutually exclusive: 1. Rescue hypothesis. When purine de novo synthesis is blocked by methotrexate (MTX) and/or 6-mercaptopurine (6-MP), the malignant cell has to rely on the purine salvage pathway. This pathway depends on the ecto-5'NT activity. So, leukemic cells might be resistant to MTX and/or 6-MP because of ecto-5'NT activity. 2. Breakdown hypothesis. Leukemic cells are resistant to 6-MP because of the breakdown of the toxic nucleotide form of 6-MP into the nucleoside form by cyto-5'NT.

Topics: 5'-Nucleotidase; Child, Preschool; Drug Resistance; Humans; Infant; Mercaptopurine; Methotrexate; Nucleotidases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Purine Nucleotides

In a retrospective study of 84 children with standard-risk acute lymphoblastic leukemia diagnosed in 1981-1986, mean white cell count (mWBC) during maintenance chemotherapy (MT) was found to be significantly related to risk of hematological relapse, giving patients with the higher mWBC the poorer outcome. The only other significant relapse-related risk factor was white-cell count at diagnosis. mWBC was not significantly related to white cell count at diagnosis, sex, age, or dose of methotrexate or mercaptopurine. Patients with low mWBC also had relatively low white-cell counts after cessation of therapy when compared with patients with high mWBC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Humans; Leukocyte Count; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence; Remission Induction; Retrospective Studies; Risk Factors

Sixteen children with refractory hematological malignancies were treated with a combination of BH.AC, aclacinomycin-A, 6-MP and predonisolone (BH-AC.AMP protocol). They were ALL(6), ANLL(8), CML(1) and NHL(1). The CR ratio was 17% in ALL, 50% in ANLL, and blast crisis of CML was treated successfully but NHL failed in the induction remission. Major complications were vomiting, nausea, gastrointestinal bleeding, hematuria and hemorrhagic cystitis. More than 10 days or 120 mg/m2 administration of aclacinomycin-A was thought to induce more severe side effects.

Topics: Aclarubicin; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Female; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction

48 patients with ALL (3%) treated according to two different protocols survived 5 years or longer. The mean survival time was 13.0 +/- 5.0 years, but 29 patients lived 16.5 +/- 3.0 years. Only 18 patients (38%) were 16.9 +/- 3.0 years in them 1. CCR, the longest remission time amounted to more than 25 years. Of the patients relapsed 9 are 8.4 +/- 2.8 years in 2. CR. Late relapses after 5 years were observed in seven cases the last in the 9th year of disease. After 5 years the survival rate in both protocols was not different. As a late sequelae, there was one patient with intrahepatic block and portal hypertension and one with encephalopathy and imbecility. All patients were able to leave their professional examination, 5 patients married and 6 healthy children were born.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

20 consecutive adult patients with acute lymphoblastic leukemia were treated with an intense induction regimen including vincristine, doxorubicin, prednisolone, L-asparaginase and cyclophosphamide. 16 patients (80%) achieved complete remission and were then given CNS prophylaxis and 3 years of maintenance therapy. With minimum follow-up of 24 months, the median duration of first remission is 37+ months. Out of 10 patients who have completed maintenance therapy, 2 have relapsed after 14 and 22 months, respectively, and 7 are in continuous complete remission 1+-55+ months off therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Transfusion; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Clinical Protocols; Cytarabine; Daunorubicin; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Vincristine

A convenient HPLC assay, which allows for the simultaneous measurement in extracellular fluids of 6-mercaptopurine and four of its metabolites, 6-thioguanine, 6-mercaptopurine riboside, 6-thioxanthine and 6-thiouric acid is described. Solid phase extraction allows for the clean isolation of analytes from plasma, urine or cerebrospinal fluid. The simultaneous determination of 6-mercaptopurine and some of its major metabolites in extracellular fluids may contribute to the monitoring of patient compliance, bioavailability, and individual variation in metabolism and absorption.

Topics: Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Infant; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Pubertal growth was studied in 10 girls previously treated for acute lymphoblastic leukemia. The average age at menarche was 12.2 years, which is significantly lower (p less than 0.01) than the expected 13.1 years. Compared with normal girls, these girls showed a subnormal (p less than 0.05) peak height velocity during the second year before menarche. The remaining growth before menarche as well as the total postmenarchal growth was close to the normal average. The average final standing height was 1 SD less than what would be expected from their height 1 year after the cessation of therapy. A relative growth hormone deficiency in combination with early onset of puberty could account for this loss in final height.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Body Height; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Female; Growth Disorders; Growth Hormone; Humans; Menarche; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Puberty; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Epilepsy, Tonic-Clonic; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers, Tumor; Blood Proteins; Brain Neoplasms; Doxorubicin; Humans; Mercaptopurine; Methotrexate; Orosomucoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

Plasma and erythrocyte concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Eleven children (9 with acute lymphatic leukemia) were studied after oral intake of 6-MP doses ranging between 31 and 128 mg/m2 body surface area. The concentrations of 6-MP in plasma were found to vary considerably between patients even after dose normalization to 75 mg/m2. After dose normalization the mean peak plasma concentration was 0.68 microM (range 0.12-1.38) and the area under the plasma concentration-time curve (AUC) was 1.37 microM.h (range 0.12-3.04). The mean time taken to reach the peak concentration was 1.3 h (range 1-2), and the half-life of elimination was 1.8 h (range 0.6-2.5). No patient had detectable 6-MP concentrations 12 h after dose intake. The concentrations of 6-MP tended to be higher in erythrocytes than in plasma. The mean peak concentration in erythrocytes was 131% and the AUC 145% of that found in plasma. The mean half-life of elimination from erythrocytes was 2.0 h (range 0.7-2.8). These data indicate that 6-MP can pass through all membranes rapidly to reach intracellular concentrations equal to or even higher than in plasma. In summary, marked interindividual differences in pharmacokinetics were found, probably due to highly variable bioavailability of oral 6-MP. Further studies are needed to determine whether measurements of plasma concentrations of 6-MP can be used to optimize maintenance treatment of childhood leukemia.

Topics: Administration, Oral; Adolescent; Autoimmune Diseases; Child; Child, Preschool; Drug Evaluation; Erythrocytes; Female; Humans; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Contraindications; Drug Interactions; Drug Tolerance; Folic Acid; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Regression Analysis

Plasma levels of 6-mercaptopurine (6-MP) were measured after oral administration in 17 children with acute lymphoblastic leukemia (ALL). In the fasting state or after a breakfast consisting of 250 ml milk and 50 g biscuits, 6-MP was administered at a dose of 75 mg/m2. In patients studied in a fasting state, the mean time to plasma peak (tmax) level was 1.2 h, whereas in patient studied after breakfast the mean tmax was 2.3 h. This difference is statistically significant (p less than 0.001). Moreover, the 6-MP peak plasma concentration (cmax) and the areas under the plasma concentration time curves (AUC) were significantly reduced when the drug was administered after breakfast. The mean Cmax +/- SD were 0.98 +/- 0.54 microM and 0.63 +/- 0.48 microM, respectively (p less than 0.05). The mean 6-MP AUC +/- SD in patients studied in a fasting state and after breakfast were 143 +/- 69 microM min and 105 +/- 68 microM, respectively (p less than 0.01). These results indicated that 6-MP should be taken in a fasting state to optimize drug absorption in children undergoing chemotherapy for ALL.

Topics: Administration, Oral; Adolescent; Biological Availability; Child; Child, Preschool; Eating; Fasting; Female; Food; Humans; Infant; Intestinal Absorption; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adolescent; Adrenal Cortex Hormones; Deafness; Drug Therapy; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adolescent; Antineoplastic Agents; Blood; Child; Complement System Proteins; Cyclophosphamide; Humans; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Serologic Tests; Spectrophotometry; Thioguanine

Topics: Adolescent; Child; Hematoma; Hematoma, Epidural, Cranial; Hematoma, Subdural; Humans; Hydrocephalus; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Meninges; Mercaptopurine; Methotrexate; Pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiography; Subarachnoid Hemorrhage; Vinblastine

Topics: Humans; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines

Topics: Acute Disease; Humans; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines