levoleucovorin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue.. A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects.. Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue.. Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

Topics: Bone Neoplasms; Child; Humans; Leucovorin; Methotrexate; Neurotoxicity Syndromes; Osteosarcoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

This study aimed to determine the efficacy of different Leucovorin regimens to reduce oral mucositis in children with acute lymphoblastic leukemia after high-dose Methotrexate (HD-MTX).. Twelve articles were included in a systematic literature review. Articles were categorized into low/medium/high risk of bias.. As no randomized controlled trial assessing the effect of Leucovorin has been performed, the efficacy of Leucovorin to reduce oral mucositis remains unknown. Leucovorin was initiated at 24, 36 or 42 h after HD-MTX at a dose of 15 or 30 mg/m. Even though future studies are necessary, higher cumulative Leucovorin doses and early initiation of Leucovorin after start of MTX seem to reduce oral mucositis.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Humans; Infant; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stomatitis; Treatment Outcome; Young Adult

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42-48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m(2)) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30-36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m(2)) be started no later than 36 hours from the start of MTX (5-6 g/m(2)).

Topics: Antineoplastic Agents; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B Complex

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Combined Modality Therapy; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sigmoid Neoplasms

High-dose intravenous methotrexate is an important component of many effective chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL). Its use has a strong pharmacologic rationale: to overcome mechanisms of resistance of the malignant cells and to achieve cytotoxic concentrations in sanctuary sites for lymphoblasts. Although therapeutic progress in ALL during the past 4 decades has been closely associated with more widespread use of intravenous methotrexate and in progressively larger doses, little data exist to clearly support the use of high-dose intravenous methotrexate over a regimen of prolonged administration of low-dose methotrexate. The implied superiority of intravenous methotrexate mainly stems from studies that used identical leucovorin rescue with low-dose methotrexate or from studies of upfront window therapy in untreated children with ALL in which single standard doses of oral methotrexate were compared with high-dose intravenous methotrexate with leucovorin rescue. The evidence favoring administration of intravenous methotrexate for children with ALL is critically reviewed. Despite its extensive use, high-dose intravenous methotrexate has not been proved conclusively to be more effective than less toxic, less labor intensive, and less costly methods of methotrexate administration.

Topics: Animals; Antimetabolites, Antineoplastic; Child; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Folic Acid Antagonists; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Methotrexate (MTX) remains a mainstay in the treatment of children with hematological malignancies. The availability of an antidote/rescue agent, leucovorin (LV) has allowed escalation of MTX doses to achieve enormous plasma concentrations, compared with plasma folate. However, a recent review of more than 40 trials for children with ALL concluded that the addition of high dose MTX (HDMTX) in many different doses and schedules did not improve CNS therapy and made only minor improvements in systemic therapy for children with ALL [11]. Some assessment suggested that by HDMTX benefits only limited amount of children with ALL. Recent treatment schedules vary markedly in terms of timing, dosing and scheduling of MTX and/or leukovorin, which may leave us uncertain with ideas such as "how should we best use HDMTX and LV?" or "why are we still using such by industry recommended doses of MTX?" The answer of how best to incorporate HDMTX and/or LV into ALL treatment plans is still not known and further clinical and pharmacological studies dealing with still controversial systemic MTX issue are actual even now, after more than 5 decades of clinical experiences with the MTX in pediatric oncology.

Topics: Antimetabolites, Antineoplastic; Child; Dose-Response Relationship, Drug; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

Neurotoxicity after the administration of methotrexate continues to worry physicians. However, inadequate folinic acid rescue is often not considered as a cause of this complication. To clarify whether adequate folinic acid rescue prevents methotrexate-induced neurotoxicity without reducing the cure rate in childhood ALL, published evidence that supported or refuted this claim was investigated. A literature search was conducted and the authors of the relevant studies were contacted. The published data supported the contention that neurotoxicity can be prevented by adequate folinic acid rescue even after very high doses of methotrexate. The safe minimum dose of folinic acid can be defined in terms of the dose of methotrexate given; the time to start of rescue is probably less important. There was no evidence that higher doses of folinic acid, such as those used after methotrexate in the treatment of osteosarcoma, rescue leukemia cells. No change in cure rate was found in relation to changes in scheduling or clinically relevant doses of folinic acid rescue. The accumulation of folinic acid in the cerebrospinal fluid did not seem to be of clinical relevance. No studies indicate that doses of folinic acid after high-dose methotrexate administration interfere with the killing of leukemia cells, nor that delaying the start of rescue beyond a certain point increases the antileukemic effect; neurotoxicity will, however, be increased. Review of current protocols that use low-dose folinic acid rescue and are associated with neurotoxicity is highly recommended.

Topics: Central Nervous System Neoplasms; Child; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Cyclophosphamide; Daunorubicin; Humans; Internationality; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Survival Rate; Treatment Outcome; Vincristine

The addition of methotrexate to treatment protocols in children with acute lymphoblastic leukemia has been found beneficial in preventing central nervous system relapse. However, MTX itself may be associated with neurologic morbidities, the most significant of which is leukoencephalopathy. The present study describes the clinical spectrum of leukoencephalopathy, which ranges from a subclinical disease manifested only radiologically to a progressive, devastating encephalopathy. The interaction of MTX with other components of the treatment protocol is discussed, as is the effect of leucovorin. A summary is presented of the metabolic pathways that may be involved in the development of MTX toxicity. Researchers are still seeking a biochemical marker to aid in the determination of the amount of MTX that may be safely administered.

Topics: Antimetabolites, Antineoplastic; Child; Drug Interactions; Humans; Leucovorin; Methotrexate; Neurotoxicity Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetrahydrofolate Dehydrogenase

A 7-y-old boy with acute lymphoblastic leukaemia (ALL) received 600 mg of i.v. methotrexate (MTX) over 2 h, followed by triple intrathecal therapy (TIT) with cytosine arabinoside 30 mg, methylprednisolone 10 mg and MTX 300 mg (instead of the prescribed 12 mg). Ninety minutes later the patient developed headache, loss of consciousness and generalized hypertonia. He was transferred to the Intensive Care Unit, intubated and treated with phenobarbital. Three hours after the TIT, the levogyrus form of folinic acid (equivalent to double doses of the racemic product) was started i.v. at a dose of 100 mg every 3 h for 24 h, and every 6 h in the following 24 h. Cerebrospinal fluid was examined and was found normal. The patient subsequently remained in normal neurological status. The favourable outcome in our case suggests that folinic acid rescue may be adequate to prevent sequelae in patients who undergo intrathecal MTX overdoses up to 300 mg.

Topics: Antidotes; Antimetabolites, Antineoplastic; Child; Drug Overdose; Humans; Injections, Spinal; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

'Acute lymphoblastic leukemia is the most common childhood malignancy'. Adding methotrexate to treatment protocols increased survival rate in children with leukemia. Methotrexate efficacy is limited by its hepatotoxicity.. To assess the therapeutic value of Black seed oil in 'methotrexate induced hepatotoxicity in Egyptian children with acute lymphoblastic leukemia'.. This study was conducted on 40 children with acute lymphoblastic leukemia' including 20 patients under methotrexate therapy and Black seeds 80 mg/kg/day for one week after each methotrexate dose [Group II] and 20 patients under methotrexate therapy and placebo [Group III]. This study included also '20 healthy children of matched age and sex as a control group' [Group I]. All patients were subjected to complete blood picture, bone marrow aspiration and liver functions.. No significant differences in liver functions between group II and III before therapy were observed. There were nonsignificant increase in total, direct and indirect serum bilirubin, serum ALT, AST, and alkaline phosphatase levels and prothrombin time in group II after methotrexate and Black seed oil therapy but there was significant increase in group III after treatment with methotrexate and placebo with 'significant differences between group II and III ' after therapy. There were significant differences in prognosis regarding remission, relapse, death and 'disease free survival but no significant difference in overall survival between group II and III'.. Black cumin seeds decreased MTX hepatotoxicity and improved survival in children with ALL and can be recommended as adjuvant drug in patients with ALL under methotrexate therapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cuminum; Female; Humans; Infant; Leucovorin; Liver; Male; Methotrexate; Plant Oils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Seeds

Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children’s Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 x 10(-7)), girls (P = 2.7 x 10(-4)), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 x 10(-11)). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 x 10(-19) for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596.

Topics: Adolescent; Alleles; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Gene Frequency; Genome-Wide Association Study; Genotype; Humans; Infant; Infusions, Intravenous; Leucovorin; Linear Models; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Clearance Rate; Methotrexate; Multivariate Analysis; Organic Anion Transporters; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Lymphoblastic lymphoma (LBL) is a highly aggressive lymphoma, for which intensive chemotherapy is necessary. This study was designed to evaluate the efficacy and toxicity of a modified acute lymphoblastic leukemia (ALL)-Berlin-Frankfurt-Münster (BFM)-90-based protocol in Chinese children and adolescents with LBL.. From March 1998 to November 2006, 60 untreated patients with LBL (age <18 years) from a single institution were enrolled. All patients were treated with the modified ALL-BFM-90 protocol, and prophylactic cranial radiotherapy was omitted.. The median age of the patients was 10 years (range, 2.5-18 years). Forty-eight (80%) patients had T-cell LBL, and 59 (98.3%) of the patients were stage III/IV. At the end of induction remission Ia (day 33), 3 patients had died of treatment-related toxicity. In the remaining 57 patients, complete remission (CR) or CR undetermined (CRu) had occurred in 47 (82.45%), who were designated as the moderate-risk group and partial remission (PR) had occurred in 10 patients (17.54%), who were designated the high-risk group. All patients experienced grade 3-4 hematological toxicity. At a median follow-up of 35 months, event-free survival was 78.81%+/-0.05 for all patients; the figure was 88.34%+/-0.05 for the moderate-risk group (90.91%+/-0.08 for stage III, 87.68%+/-0.06 for stage IV, 100% for those with B-cell LBL, 84.78%+/-0.06 for those with T-cell LBL, and 82.94%+/-0.08 for stage IV patients with more than 25% blast cells in bone marrow [BM]). The event-free survival in the high-risk group was 60%+/-0.15.. This modified ALL-BFM-90 protocol is an effective regimen and it greatly improved the survival rate of Chinese children and adolescents with LBL compared with the ALL protocols used previously.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Humans; Injections, Spinal; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.. Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses.. Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase.. Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.

Topics: Adolescent; Aminopterin; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Diseases; Child; Child, Preschool; Drug Overdose; Erythrocytes; Female; Fever; Folic Acid Antagonists; Gastrointestinal Diseases; Humans; Leucovorin; Male; Methotrexate; Neurotoxicity Syndromes; Pilot Projects; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Treatment Outcome

To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate.. The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors.. The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model.. A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.

Topics: Adolescent; Age Factors; Alanine Transaminase; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bayes Theorem; Body Weight; Child; Child, Preschool; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Metabolic Clearance Rate; Methotrexate; Models, Biological; Monte Carlo Method; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Vitamin B Complex

We conducted a phase II study to evaluate in 72 adult patients the efficacy of the intensive LMB chemotherapy regimen, previously reported by the Société Française d'Oncologie Pédiatrique for children with Burkitt lymphoma and L3 acute lymphoblastic leukemia.. Treatment began with a prephase (low-dose steroids, vincristine and cyclophosphamide), except in patients with low tumor burden. Group A (resected stage I and abdominal stage II disease) received three courses of vincristine, cyclophosphamide, doxorubicin and prednisone. Group B (not eligible for groups A or C) received five courses of chemotherapy comprising high-dose methotrexate, infusional cytarabine and intrathecal (IT) methotrexate. Group C (patients with central nervous system and/or bone marrow involvement with < 30% of blast cells) received eight courses containing intensified high-dose methotrexate, high-dose cytarabine, etoposide and triple IT injections.. The 2 year event-free survival and overall survival rates for the 72 patients were 65% and 70%, respectively. Age > or = 33 years and high lactate dehydrogenase value were associated with a shorter survival. No response to COP was also associated with a poor outcome in group B.. Patients with advanced-stage Burkitt lymphoma, including those with bone marrow and/or central nervous system involvement, can be cured with a short-term intensive chemotherapy regime tailored to the tumor burden.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Hydrocortisone; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Survival Rate; Vincristine

The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity.. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance.. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed.. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Chile; Creatine; Disease-Free Survival; Drug Monitoring; Female; Hematologic Diseases; Humans; Infant; Leucovorin; Male; Metabolic Clearance Rate; Methotrexate; Mouth Mucosa; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stomatitis

Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL.. Thirty pediatric patients with relapsed medullary (n = 18) and extra-medullary (n = 12) ALL were enrolled at three pediatric institutions. Following receipt of induction and the first Block A and Block B of intensification, each patient was evaluated for toxicity, efficacy in achieving remission, and long-term survival. Additionally, minimal residual disease (MRD) detection by multidimensional flow cytometry (MDF) was performed.. During induction, the major non-hematopoeitic toxicities were mucositis (30% of patients) and bacteremia (50% of patients). Two patients (7%) died of toxicity during induction. Toxicity during intensification Block 1A and 1B was markedly reduced. Eight-nine percent of patients with marrow disease achieved a remission following induction and intensification. The event-free survival (EFS) for all patients at 2 and 4 years were 60% (95% CI: 42-78%) and 49% (95% CI: 30-68%), respectively.. This regimen for patients with relapsed ALL was successful in achieving a second remission for the majority of patients with acceptable toxicity.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacteremia; Bone Marrow Neoplasms; Child; Child, Preschool; Cytarabine; Dexamethasone; Etoposide; Female; Flow Cytometry; Humans; Idarubicin; Ifosfamide; Infant; Infusions, Intravenous; Leucovorin; Male; Mesna; Methotrexate; Mouth Mucosa; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Stomatitis; Thioguanine; Treatment Outcome; Vincristine

Acute, subacute, and chronic neurologic complications have been reported in children treated with high-dose methotrexate for various malignant diseases. It was the aim of this study to monitor central nervous system treatment with high-dose methotrexate in children with acute lymphoblastic leukemia by serial electroencephalographic (EEG) examinations. Electroencephalographic examinations with quantitative computed analysis were performed in 21 children before and on the third day after each of four high-dose methotrexate infusions with leucovorin rescue according to protocol M of trial ALL-BFM 90 of the German Society for Pediatric Haematology and Oncology. Six patients with a medium risk of relapse also received L-asparaginase. In the cohort treated with methotrexate solely, no statistically significant changes of the quantitative EEG parameters could be demonstrated. Only two children with delayed serum methotrexate clearance showed reversible diffuse EEG slowing of a slight to moderate degree. In the group with additional L-asparaginase treatment, slight transient EEG slowing also occurred. Our findings indicate that in patients with a normal methotrexate clearance during central nervous system treatment with high-dose methotrexate according to trial BFM-ALL 90, usually no subacute or cumulative EEG changes have to be expected. If neurologic or psychiatric symptoms or EEG slowing occur, delayed methotrexate clearance must be suspected.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain; Central Nervous System Neoplasms; Child; Child, Preschool; Electroencephalography; Female; Humans; Infant; Injections, Intravenous; Injections, Spinal; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Prognosis for children treated according to the BFM-90m protocol (Berlin-Frankfurt-Munster Group) for acute lymphoblastic leukemia (ALL) improved significantly as compared with previous modalities. Methotrexate was used in the dose of 1,000 mg/m2, 36 h. The paper presents the 10-year results for this modification. Patients aged 0-15 years were treated at hematological hospitals of Moscow, other Russian towns and in Minsk, Belarus, (July 5, 1990-November 11, 2000). BFM-90m treatment was given to 682 children out of 1,326 with primary diagnosis of ALL; a comparative trial of the MB-91 protocol hed been carried out at the same clinics since 1991. During 10 years, recurrence-free survival was 72% while overall survival--77%. Toxicity of side-effects was tolerable. The BFM-90m treatment showed significantly better results in both countries.

Topics: Adolescent; Age Factors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Child; Child, Preschool; Data Interpretation, Statistical; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Republic of Belarus; Risk Factors; Russia; Sex Factors; Survival Analysis; Time Factors

This study was undertaken to show that a high survival rate can be obtained in B-cell (Burkitt and large B-cell) lymphoma and L3 leukemia with multiagent chemotherapy adapted to the tumor burden (stage, resection status, percentage of blasts in bone marrow, and central nervous system [CNS] involvement) and early response to chemotherapy, to investigate actual prognostic factors, and to see if large B-cell lymphoma can be treated with the same regimen as Burkitt lymphoma. Patients were classified into 3 risk groups. Group A (resected stage I and abdominal stage II) received 2 courses of vincristine, cyclophosphamide, doxorubicin, and prednisone. Group B (patients not eligible for groups A or C) received 5 courses of chemotherapy with, in addition, high-dose methotrexate, 3 g/m(2) over 3 hours; infusional cytarabine; and intrathecal (IT) methotrexate. Group C (patients with CNS involvement and acute lymphoblastic leukemia with at least 70% of blasts in bone marrow) received 8 courses with, in addition, high-dose methotrexate, 8 g/m(2); high-dose cytarabine; etoposide; and triple IT. Except in group A, treatment started with a prephase (COP, low-dose vincristine and cyclophosphamide). It was intensified for patients who did not respond to COP in group B and any patient with residual viable cells after the consolidation phase. A total of 561 patients were enrolled in the SFOP LMB89 protocol (July 1989-June 1996). Five-year survival is 92.5% (95% confidence interval [CI], 90%-94%) and event-free survival (EFS) 91% (95% CI, 89%-93%). EFS is 98% (95% CI, 90%-100%), 92% (95% CI, 89%-95%), and 84% (95% CI, 77%-90%) for group A, B, and C, respectively. In group B, multivariate analysis of prognostic factors showed that a lactate dehydrogenase level more than 2-fold the normal value, no response after COP, and age of at least 15 years were associated with a lower EFS. CNS involvement was the only prognostic factor in group C. (Blood. 2001;97:3370-3379)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Hydrocortisone; Infant; Leucovorin; Lymphoma, B-Cell; Male; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Recurrence; Remission Induction; Survival Rate; Vincristine

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

To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL).. Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population.. There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups.. Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Topics: Antidotes; Antimetabolites, Antineoplastic; Central Nervous System; Child; Child, Preschool; Combined Modality Therapy; Demyelinating Diseases; Drug Interactions; Humans; Infant; Leucovorin; Methionine; Methotrexate; Myelin Basic Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; S-Adenosylmethionine; Tetrahydrofolates

To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (i.v.) mercaptopurine (MP) and extended intrathecal triple therapy.. Thirteen hundred four patients were entered onto Pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m2 i.v. infused over 24 hours and MP 1,000 mg/m2 i.v. infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m2 orally every 6 hours for six doses and i.v. MP; or regimen C, i.v. MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed.. Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on POG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen B, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leukoencephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1 % of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated i.v. MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of i.v. MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P=.031) when compared with ITM.. Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

Topics: Acute Disease; Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Diseases; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intravenous; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Tomography, X-Ray Computed

Topics: Administration, Oral; Child; Drug Administration Schedule; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

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

Advanced Burkitt's lymphoma (BL) has an extremely poor prognosis in adults. With a previous protocol including CNS prophylaxis, 40% of our adult patients achieved CR and only 13% became long survivors. In 1988, following this poor experience, we adopted a very intensive pediatric-derived protocol.. Twenty-one consecutive patients, 8 adults (median age 35, stage III: 1; IV: 7; leukemias: 6) and 13 children (median age 10, state III: 8; IV: 5; leukemias: 4) were treated with the same protocol (POG 8617), based on alternate two-phase cycles with sequential high-dose CTX, VCR, ADM + CNS chemoprophylaxis (phase A) and HD MTX + HiDAC (phase B). Adults received 6 cycles, children 8; i.t. prophylaxis in phase B was omitted in adults.. Twenty of 21 (95%) patients achieved CR (adults 100%, children 92%). Two patients died early; 2 relapsed at 4 and 9 months. With a median follow-up of 28 months (4-96), 17 patients (81%) are event free (adults 75%, children 85%). Severe infections affected 62% of adults and 15% of children.. (1) The prognosis of adult advanced BL definitely improved with this intensive protocol. (2) There were no differences in outcome between adults and children. (3) Outcome of lymphoma and leukemia was similar. (4) Severe infections occurred frequently in adults. This intensive pediatric protocol requires a careful supportive therapy.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome; Vincristine

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

Type and duration of treatment for highly aggressive non-Hodgkin's lymphoma has been a matter of debate over the past decade. To determine the therapeutic efficacy of an abbreviated treatment regimen, 26 patients with newly-diagnosed highly aggressive lymphomas, 17 of them belonging to the International Working Formulation (IWF) group I and 9 with Burkitt's lymphoma (IWF J), were entered in a study using short-term weekly chemotherapy followed by high-dose therapy and autologous bone marrow transplantation.. Besides histology, requirements for entry into to the study were age between 16 and 60 years, stage 1 bulky disease and elevated LDH or stage II to IV disease with or without bulk or elevated LDH, and an absence of HIV infection or CNS involvement at diagnosis. The treatment plan was 12 weeks of MACOP-B or VACOP-B chemotherapy followed by high dose therapy and autologous bone marrow transplantation in first complete remission.. Twenty patients (76%), 16 (62%) of those on MACOP-B or VACOP-B, 1 who had received 2 cycles of ProMACE-CytaBOM prior to MACOP-B and 3 after a first salvage regimen, achieved complete remissions. Seventeen patients (65%) were transplanted in first remission, and 15 (58%) after induction treatment with only MACOP-B or VACOP-B. Reasons for not being given high dose therapy and autologous bone marrow transplantation (ABMT) were failure to achieve complete remission in 6 patients, early relapse in 2 and severe pulmonary toxicity associated with chemotherapy in 1. The median time of follow-up was 45 months. At 3 years, the estimated event-free survival was 31% (CI 14%-50%) and the overall survival 48% (CI 25%-67%). There were no deaths from toxic effects of treatment. Pretreatment factors associated with relapse were stage III or IV disease, age over 30 years and bone marrow involvement. Logrank analysis showed that age was the only factor significantly associated with poor event-free survival.. Short-term weekly chemotherapy followed by high-dose therapy with the CBV regimen in first remission is not a higly effective treatment for advanced lymphoblastic and Burkitt's lymphomas. The 30% rate of failure to achieve partial remission after 6 weeks and/or complete response after 12 weeks of MACOP-B or VACOP-B treatment, as well as the 42% failure rate to undergo ABMT in first remission, suggest that more aggressive chemotherapy should be used in the beginning.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Burkitt Lymphoma; Carmustine; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Survival Rate; Transplantation, Autologous; 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

Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity.. Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL).. High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074).. This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.

Topics: Child; Child, Preschool; Female; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Urine; Vomiting

Until now, folinic acid (FA) has been available the racemic mixture d1 FA, whose biological activity is supported by natural 1 FA. The purpose of this trial was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture dl FA with the pure 1 FA in the rescue of high-dose methotrexate (MTX) therapy. Eighteen children with acute lymphocytic leukemia (ALL) were entered in this trial planned with a cross-over design. Four cycles of MTX (5 g/m2, 24h CVI) were administered to each patient, with a 2-week interval between cycles. The rescue was achieved orally every 6h, starting 12h after the end of the MTX infusion, at a dose of 12 mg/m2 for dl FA and 6 mg/m2 for pure 1 FA. dl FA and 1 FA rescues were alternated from one cycle to the next. d FA, 1 FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific HPLC assay. After administration of dl FA, the accumulation of d FA in plasma was confirmed: mean residual concentrations were 420 and 652 nM after 2 and 6 intakes respectively. Total active folate concentrations (1 FA + 5-MTHF) were similar between the two types of rescue: 92 and 100 nM respectively for dl FA rescue and 1 FA rescue after two intakes, 186 and 184 nM respectively for dl FA rescue and 1 FA rescue after six intakes. Intra-individual statistical analysis of total active folates (1 FA + 5-MTHF) performed on 17 patients did not show any significant difference between dl FA rescue and 1 FA rescue. For both types of rescue, MTX terminal half-lives were identical (average value 13.9 h). Considering each type of toxicity (hematologic, hepatic, renal and digestive) there was no significant difference in the proportion of toxic cycles following l FA rescue or dl FA rescue. In conclusion, the administration of the pure l FA, as compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, and leads to equivalent treatment tolerance.

Topics: Adolescent; Antidotes; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stereoisomerism

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

We enrolled children with acute lymphoblastic leukemia (ALL) in a Pediatric Oncology Group (POG) pilot study to monitor erythrocyte (RBC) methotrexate (MTX) and folate (F) levels before and during treatment. The mean value for RBCF at diagnosis was 0.86 +/- 0.46 nmol/ml RBC in the 214 patients who achieved remission and 1.21 +/- 0.74 nmol/ml RBC in the 10 patients who did not (P = 0.020). Folate levels tended to increase during remission induction, but they dropped following an intensive consolidation with methotrexate to levels that were sustained throughout chemotherapy treatment. Methotrexate levels reached mean values of approximately 0.15 nmol/ml RBC at the end of an intensive methotrexate consolidation, then fell to levels that were sustained throughout maintenance therapy. There was a weak correlation between improved event-free survival and higher RBCMTX levels after consolidation, but no correlation was found between improved survival and the level of RBCMTX or RBCF during maintenance therapy. A larger study with more complete data is needed to determine whether RBCMTX or RBCF might be useful in predicting event-free survival in patients with ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Drug Monitoring; Erythrocytes; Folic Acid; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Time Factors

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

The effect of folinic acid rescue dose on the event-free survival of 71 children with acute lymphoblastic leukaemia was examined in a retrospective clinical study. All patients, diagnosed between 1 January 1980 and 1 January 1989, were treated according to the Norwegian Pilot protocol which included eight courses of high dose (6-8 g/m2/24 h intravenous infusion) methotrexate. Following the infusion, a uniform dose of 75 mg (at 36 h after the beginning of the drug infusion) and 15 mg (at 39-106 h) folinic acid rescue was administered to all patients, at predetermined intervals. The uniformity of the rescue dose resulted in distribution of dosages in the range of 38-140 mg/m2 and 7.5-28 mg/m2 for the different periods, respectively, when the dose was recalculated on the basis of the body surface area of the individual patients. The event-free survival of children receiving less or more than 15 mg/m2 (75 mg/m2) rescue dose was compared. Although no significant difference was found, a tendency was observed for a lower risk of relapse in patients receiving less folinic acid. No major methotrexate-related toxicity was observed in the group of patients receiving the lower dose of rescue. These observations suggest that the reduction of folinic acid rescue dose below the generally accepted 12-15 mg/m2 dose may increase the efficacy of high-dose methotrexate therapy while still remaining safe in preventing treatment-related toxicity. Prospective, randomised clinical trials are needed to examine the role of rescue as a determinant of effective exposure to methotrexate in patients receiving high-dose methotrexate treatment.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Infant; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence; Retrospective Studies; Risk Factors

Thirty-three patients with ALL/AUL in first relapse were treated with an induction of prednisone, vindesine, daunorubicin, Erwinia asparaginase, i.t. MTX (phase I), high-dose cytarabine, and etoposide (phase II). Twenty-one (64%) achieved a complete remission, one a partial remission. Side effects of induction-phase I were predominantly hematological with subsequent infections and gastrointestinal toxicity. In phase II some patients had additional cutaneous, ocular, and hepatic toxicity. The treatment efficiently induced remissions with tolerable toxicity in relapsed ALL. The disease-free survival, however, needs to be improved.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Brain Neoplasms; Combined Modality Therapy; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Germany, West; Humans; Ifosfamide; Leucovorin; Life Tables; Male; Methotrexate; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Spinal Cord Neoplasms; Teniposide; Testicular Neoplasms; Vindesine

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

Laboratory studies have demonstrated the ability of teniposide to markedly enhance the intracellular accumulation of methotrexate suggesting that combination therapy with these agents may produce clinical benefit. Studies of methotrexate and teniposide were conducted in 19 children with relapsed acute lymphocytic leukemia to evaluate the pharmacokinetics of this previously untested combination of agents given alone or in combination and to demonstrate the feasibility of a Bayesian dose optimization strategy. Patients were randomly assigned to receive intermediate dose methotrexate as a 24-h continuous infusion, administered either simultaneously with continuous infusion teniposide or sequentially with the teniposide infusion beginning 12 h after the end of the methotrexate infusion. Plasma samples were obtained during and after infusions at appropriate times for a comprehensive pharmacokinetic study of each drug. Two measured drug concentrations obtained during the infusion were used to adjust each patient's dose rate to achieve target values of 10 microM for methotrexate and 15 microM for teniposide. Pharmacokinetic parameters for teniposide were not different for patients given simultaneous methotrexate from parameters estimated for patients receiving teniposide 12 h after the end of the methotrexate infusion. Despite similar end of infusion methotrexate concentrations, 24-h postinfusion methotrexate concentrations were lower (0.137 versus 0.235 microM; P less than 0.05) in the patients receiving simultaneous infusions. The patient specific dose regimens yielded acceptably precise, minimally biased steady state drug concentrations. These pharmacokinetic results provide the basis for further clinical studies with this combination of antileukemic agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Drug Administration Schedule; Humans; Infusions, Intravenous; Leucovorin; Metabolic Clearance Rate; Methotrexate; Podophyllotoxin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide

Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cells, Cultured; Child; Cytarabine; DNA, Neoplasm; Drug Evaluation; Drug Synergism; Hematopoietic Stem Cells; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied.. This prospective observational study consecutively enrolled children < 12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded: age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels.. Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45.. Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible.

Topics: Child; Humans; Hypoalbuminemia; Kidney; Leucovorin; Malnutrition; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity.. Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given.. A pharmacokinetically guided FA rescue of one or two 15 mg/m

Topics: Acute Disease; Child; Cohort Studies; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Methotrexate-induced epidermal necrosis (MEN) is an uncommon but potentially fatal complication. We present two pediatric oncology patients, a 5-year-old girl and a 3-year-old boy, who developed MEN from high-dose methotrexate therapy for pre-B-cell acute lymphocytic leukemia. Following administration of systemic methotrexate, the patients developed erythematous lesions with subsequent skin erosions. Pre-medication with systemic corticosteroids and administration of folinic acid rescue following the methotrexate infusion allowed both patients to resume their chemotherapy regimen with methotrexate.

Topics: Child; Child, Preschool; Female; Humans; Leucovorin; Male; Methotrexate; Necrosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Skin Diseases

Methotrexate is a versatile antineoplastic and immunosuppressive agent. We report a case of a young adult on the Cancer and Leukaemia Group B 10403 treatment protocol for B-cell acute lymphoblastic leukaemia. She has previously completed the induction and consolidation phases with good tolerance then started on Capizzi methotrexate during the interim maintenance phase. Few days after receiving one intermediate dose of methotrexate, she developed severe multiorgan toxicities including pancytopaenia and several dermatologic toxicities. The patient underwent extensive diagnostic workup, with all results negative, pointing eventually towards severe methotrexate toxicity. This case highlights the broad spectrum of toxicities that can occur even with low doses of methotrexate. Capizzi methotrexate therapy implies no leucovorin therapy, hence putting patients at risk for multiorgan toxicity. Our experience reinforces the importance of close monitoring for patients receiving methotrexate, regardless of dose, and the prompt administration of high-dose leucovorin once toxicity suspected.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

We have recently established a protocol to grow wildtype human oral mucosa organoids. These three-dimensional structures can be maintained in culture long-term, do not require immortalization, and recapitulate the multilayered composition of the epithelial lining of the oral mucosa. Here, we validate the use of this model to study the effect of Leucovorin (LV) on Methotrexate (MTX)-induced toxicity. MTX is a chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia. Although effective, the use of MTX often results in severe side-effects, including oral mucositis, which is characterized by epithelial cell death. Here, we show that organoids are sensitive to MTX, and that the addition of LV reduces MTX toxicity, in both a concentration- and timing-dependent manner. Additionally, we show that a 24 hour 'pretreatment' with LV reduces MTX-induced cell death, suggesting that such a pretreatment could decrease mucositis in patients. Taken together, we provide the first in vitro model to study the effect of MTX on wildtype oral mucosa cells. Our findings underscore the relevance of the clinically applied LV regimen and highlight the potential of this model to further optimize modifications in dosing and timing of Leucovorin on oral mucosa cells.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Child; Humans; In Vitro Techniques; Leucovorin; Methotrexate; Mouth Mucosa; Organ Culture Techniques; Organoids; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stomatitis

High-dose methotrexate (HDMTX) is recommended to be administered with serial monitoring of methotrexate (MTX) levels, which may not be universally feasible in resource-limited settings. In this study, we evaluated the overall experience of administration of HDMTX at our center by monitoring a single drug level at 54 h from the start of MTX infusion.. This retrospective study was performed at a tertiary level hospital in north India, over a 5-year period (2011-2015). All patients <18 years of age with newly diagnosed acute lymphoblastic leukemia (ALL) and T-non-Hodgkin lymphoma (T-NHL) were enrolled in the study. Details of HDMTX and all significant toxicities requiring prolonged or repeat hospitalization were retrieved from the medical records. All eligible patients received HDMTX as per the recommendations followed by at least three doses of leucovorin rescue, before drug levels were sent at 54 h. Subsequent leucovorin doses were adjusted accordingly.. The records of 598 cycles of HDMTX in 184 patients were reviewed. A total of 531 of 598 cycles (88.7%) were managed with monitoring only a single plasma drug level at 54 h from the beginning of infusion. Delayed MTX clearance was seen in 260 of 598 cycles (43.5%). Only three episodes (0.5%) were associated with significant toxicity. There were no deaths.. The strategy of monitoring MTX concentration at 54 h was safe in our cohort. Although recommended, dynamic monitoring of plasma drug levels may not always predict toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Monitoring; Female; Follow-Up Studies; Humans; India; Infant; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies; Survival Rate

Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.. We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.. Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.. Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Topics: Adolescent; Antidotes; Child; Child, Preschool; Erythrocytes; Female; Folic Acid; Folic Acid Antagonists; Homocysteine; Humans; Infant; Leucovorin; Male; Metabolic Networks and Pathways; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Vitamin B 12

Acute lymphoblastic leukaemia (ALL) is a common paediatric cancer with a tendency to relapse, usually within 3 years of remission. Most patients present with hepatomegaly, splenomegaly, pallor, fever and bruising. Localised muskuloskeletal presentation is extremely rare. Here, we present a case of leukaemia relapse in the bone marrow of a 28-year-old man 9 years after achieving remission, presenting only with ankle pain and normal routine labs besides mild hypercalcemia, and no signs of disease in common bone marrow biopsy sites. This highly localised presentation is unusual and would hopefully inform clinicians to have a high index of suspicion for relapse in an adult patient who has had childhood ALL.

Topics: Adult; Ankle; Diagnosis, Differential; Humans; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Pain; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tomography, X-Ray Computed; Vincristine

We aimed to investigate the association between dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms and the risk of pediatric acute lymphoblastic leukemia (ALL) and its prognosis after chemotherapy. A total of 147 pediatric ALL patients diagnosed by our hospital between January 2011 and December 2014 were included in the case group, and 102 healthy people who received a physical examination during the same time frame in our hospital were included in the control group. DNA sequencing was applied for site determination and genotyping of the DPYD 85T > C, 2194G > A, 1156G > T, and IVS14 + 1G > A polymorphisms. The genotype and allele frequencies of the two groups were compared. A significant difference was found in the comparison of the mutant gene and allele frequencies of the 85T > C polymorphism between the case and control groups (P < 0.05). The CT and CC genotypes in the 85T > C polymorphism were associated with the risk of the disease (OR = 1.592, 95 % CI = 1.010-2.509), suggesting that the recessive gene (85C) was more likely to lead to the occurrence of ALL compared with the dominant gene (85T) (P < 0.05). Patients carrying the C allele of the 85T > C polymorphism presented higher damage of their liver functions and higher infection rates compared with patients carrying the non-C allele (P < 0.05). A higher proportion of liver function damage and a higher infection rate were found in patients with the GA genotype in the IVS14 + 1G > A polymorphism compared with the GG genotype (P < 0.05). The complete remission (CR) rate in patients with the GG genotype in the IVS14 + 1G > A polymorphism was higher than in patients with the GA genotype (P = 0.020). After 5-fluorouracil/calcium folinate (5-FU/CF)-based chemotherapy, the event-free survival (EFS) rate of patients with the TT genotype was higher than patients with the CT and CC genotypes (P < 0.05). Our results revealed that the C allele of the 85T > C polymorphism might be associated with susceptibility to pediatric ALL. Patients carrying the C allele may have an increased risk of ALL. Thus, the 85T > C polymorphism may be a predictor of CR for pediatric ALL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dihydrouracil Dehydrogenase (NADP); Disease-Free Survival; Female; Fluorouracil; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Risk Factors

To explore the clinical and prognostic features as well as treatment response of childhood B-cell non-Hodgkin's lymphoma/acute lymphoblastic leukemia (B-NHL/B-ALL), so as to better modify the treatment for further improving the prognosis.. The clinical data of 43 patients with newly-diagnosed childhood B-NHL/B-ALL from July 2005 to December 2013 in West China Second Hospital of Sichuan University were retrospectively analyzed with particular focus on clinical presentations, laboratory findings and histology. Among them 26 patients received B-NHL-2010 protocol and 17 patients received LMB-89 protocol treatment. Kaplan-Meier method was used to compare the survival rates between groups, while multiple factor logistic regression was used to identify the prognostic factors.. (1) The median age at diagnosis was 7.58 (2.42-13.67) years. The male-to-female ratio was 2.9 : 1. No significant difference was found in the median age at diagnosis between male and female children with B-NHL/B-ALL (P = 0.837). (2) Burkitt's lymphoma was the most common (34/43, 79.07%), followed by diffuse large B cell lymphoma (4/43, 9.3%), ALL-L3 (3/43, 6.98%) and others (2/43, 4.65%) in decreasing frequency. (3) According to St. Jude staging classification, 4 patients (9.30%) were divided into stage I, 9 patients (20.93%) into stage II, 23 patients (53.49%) into stage III and 7 patients (16.28%) into stage IV; (4) Clinically, the common predilection sites were as following: ileocecus (11/43, 25.58%), nasopharynx (10/43, 23.26%), faciomaxillary (9/43, 20.93%), superficial lymphadenopathy (8/43, 18.60%), other sites such as mediastinum and bone marrow (5/43, 11.63%). (5) With a median follow up of 24 months (0.7-105 months), the 2-year overall survival (OS) rate and event-free survival (EFS) rate were 79.8% ± 6.5%% and 71.0% ± 7.2%, respectively. The 2-year OS and EFS rates in patients treated with B-NHL-2010 protocol were 79.1% ± 8.4% and 74.1% ± 8.4%, while those in patients treated with LMB-89 protocol were 87.5% ± 8.3% and 66.7% ± 12.4%, respectively, but there was no significant difference between them (P > 0.05). The 2-year EFS rate in patients with LDH > 2N and bone marrow infiltration were significantly lower than that of other groups (P < 0.05). (6) 8 patients (18.6%) relapsed. The median relapsed time was 6 months (2-9 months). 1 patient suffered progressive disease. Male, systemic symptom, elevated LDH, bone marrow and CNS infiltration and advanced stage (stage III and stage IV) were associated with relapse /progressive disease. Logistic regression analysis showed that LDH > 2N was an independent unfavorable prognostic factors (OR = 31.129, P = 0.02).. Outcome of B-NHL/B-ALL is greatly improved by current intensive and short-time chemotherapy regimen. The 2-year event-free survival (EFS) rate is 71.0% ± 7.2%. There is no significant difference in EFS rate between patients treated with B-NHL-2010 protocol and LMB89 protocol. The long-term survival rate in patient with advanced disease need to be further improved.

Topics: Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Hydrocortisone; Leucovorin; Logistic Models; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Multivariate Analysis; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Retrospective Studies; Survival Rate; Vincristine

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

Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.. Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.. Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.. MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Germ-Line Mutation; Humans; Leucovorin; Leukoencephalopathies; Logistic Models; Magnetic Resonance Imaging; Male; Methotrexate; Neurotoxicity Syndromes; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors

Recent studies suggest that SLCO1B1 c.521T > C variant decreases the clearance of methotrexate (MTX) and elevates its plasma concentration, hence leucovorin doses may need to be adjusted. However, high leucovorin doses may affect the cure rate in childhood acute lymphoblastic leukemia (ALL). Hitherto neither the appropriate dose of leucovorin in carriers of SLCO1B1 c.521T > C variant nor the impact of SLCO1B1 polymorphism on the risk of ALL relapse has been clarified.. A double-blind and controlled study was conducted in 136 children with ALL. They were genotyped for rs4149056 single nucleotide polymorphism into wild-type group and variant group, and received MTX at 3-5 g/m(2) . Plasma concentration MTX and its metabolite were determined by HPLC. The toxicity of MTX, dose of leucovorin and 5-year relapse rate of ALL were recorded.. Compared with wild-type group, area under the concentration time curve of MTX increased by 4.2-fold and peripheral clearance rate decreased significantly in variant group. Patients carrying rs4149056 C allele endured a remarkable longer time above the MTX safety threshold and suffered from a higher frequency of toxicity, so 2.2-fold leucovorin was given. However, no association was found between SLCO1B1 c.521T > C variant and the relapse risk in five years.. The SLCO1B1 c.521T > C variant was an important determinant of MTX disposition and their carriers were exposed to increased intensity and time of MTX. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity. The c.521T > C variant wasn't associated with the risk of ALL relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Genotype; Humans; Leucovorin; Liver-Specific Organic Anion Transporter 1; Male; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Organic Anion Transporters; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Risk Factors

To provide guidance for the high-dose methotrexate (HD-MTX) treatment of pediatric acute lymphoblastic leukemia (ALL), and to understand the impact of SLCO1B1c.521T>C (rs4149056) variant on methotrexate (MTX) pharmacokinetics and clinical outcome in children with ALL.. Eighty-two children with ALL in Division of Hematology of Wuhan Children's Hospital from January 2008 to February 2013 were enrolled. All patients were genotyped for rs4149056 single nucleotide polymorphism (SNP) into wild-type group (TT genotype) and variant group (TC/CC genotype). According to the ALL-BFM 2000 protocol, all patients received intravenous infusion of MTX every ten days at 3 to 5 g/m(2). Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours. The concentrations of MTX and its metabolite at 24, 48 and 72 h were determined by high performance liquid chromatography with solid phase extraction. Population pharmacokinetic parameters were estimated by the NLME software. The pharmacokinetics, toxicity and leucovorin rescue was compared. The relapse rate within 5 years and event-free survival were followed up.. Eighty-two pediatric patients were classified into two groups: variant group including 20 TC genotype carriers and one CC genotype carrier, wild-type group included 61 patients with TT genotype. Compared with wild-type group, plasma concentration of MTX at 48 and 72 h increased significantly [48 h: (1.00±1.41) vs.(0.34±0.17) µmol/L, t=2.131, P=0.046; 72 h: (0.31±0.26) vs.(0.08±0.04) µmol/L; t=3.995, P=0.001]. Area under the concentration time curve (AUC48-∝) of MTX significantly increased in variant group [(23.18±19.91) vs.(5.66±2.01) h·µmol/L] (t=4.025, P=0.001). Time above the MTX safety threshold (TC>0.1 µmol/L) increased significantly in variant group [(95.3±22.0) vs.(67.1±7.5) h, t=5.880, P<0.001]. Rescue dosage of leucovorin in variant group was higher than that in wild-type group [(312.7±287.8) vs.(140.6±27.5) mg/m2, t=2.614, P=0.017]. The children carrying rs4149056 C allele suffered from a higher frequency of serious adverse effect [gastrointestinal toxicity: 33% (7/21) vs. 5% (3/61);hepatic toxicity: 24% (5/21) vs. 2% (1/61)]. The difference was statistically significant (χ2=9.275, 8.289, all P<0.05). Hospital stay of variant group was significantly longer than that of wild-type [(4.95±1.43) vs. (4.05±0.22) d, t=2.881, P=0.009]. The relapse rate within 5 years of variant group and wild-type group were 9% (2/21) and 13% (8/61), respectively. There were no significant differences in the event-free survival between the two groups (χ2=0.001, P=0.971).. The SLCO1B1 c.521T>C variant was an important determinant of MTX pharmacokinetics. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity and did not affect the long-term clinical outcome.

Topics: Alleles; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Daunorubicin; Disease-Free Survival; Genotype; Humans; Leucovorin; Liver-Specific Organic Anion Transporter 1; Methotrexate; Organic Anion Transporters; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome; Vincristine

Ataxia-telangiectasia (AT) is a hereditary disorder characterized by progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. Pediatric patients may develop acute lymphoblastic leukemia (ALL). However development of ALL in an adult patient with AT is a rare occurrence. Here we report such a patient who presented with hyperleukocytosis and were treated with leukapheresis. A 25years old male patient, who were diagnosed with AT and mental retardation, was admitted to the emergency department due to fatigue, nausea and headache. On admission he had a moderate general condition and was fully cooperated. His white blood cell (WBC) count were 466×10(9)/l. Blastic cells were observed in peripheral blood smear. Flow cytometry (FC) of peripheral blood showed T-ALL. Two sessions of large volume leukapheresis was performed. Symptoms due to hyperleukocytosis markedly improved after leukapheresis. Patients with AT should be closely monitored due to risk of malignancy. Leukapheresis may improve the prognosis of high risk ALL patients presenting with hyperleukocytosis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Ataxia Telangiectasia; Doxorubicin; Flow Cytometry; Humans; Leucovorin; Leukapheresis; Leukocytosis; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Steroids; Vincristine

It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments.. In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively.. Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003).. Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.

Topics: Algorithms; Antidotes; Antimetabolites; Dose-Response Relationship, Drug; Drug Delivery Systems; Fluorescence Polarization Immunoassay; Gastrointestinal Diseases; Humans; Injections, Spinal; Leucovorin; Methotrexate; Models, Biological; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intensification of systemic chemotherapy with inclusion of high dose methotrexate (HDMTX) has helped omit cranial irradiation from standard risk acute lymphoblastic leukemia (ALL) protocols, thereby eliminating the adverse side effects associated with its use. Administration of HDMTX needs meticulous monitoring. Limitations in the availability of trained staff and adequate infrastructure often pose problems in the developing world. The aim of this study was (1) to treat childhood ALL with a protocol that would have reduced use of cranial irradiation and containing infusions of high-dose methotrexate HDMTX (5 g/m(2)) without compromising on survival, and (2) evaluate the experience with HDMTX in a tertiary care cancer centre in a developing country.. A retrospective chart review was done of 41 consecutive children with a confirmed diagnosis of ALL who had received at least one cycle of HDMTX as part of their consolidation treatment with regard to the patient demographic profile, details of HDMTX infusion and leucovorin rescue, toxicity, additional hospitalization, delay in next cycle of chemotherapy and survival.. The clinically most significant toxicities observed were mucositis 39% (58/149) and fever 28% (42/149) together leading to additional hospital stay in 7% (11/149) cycles and neutropenia grade 3 or more in 24.8% (34/137) contributing to delay in next cycle of chemotherapy in 15% (23/149) cycles.. With this strategy, it was possible to omit or reduce the dose of cranial irradiation while maintaining survival outcomes. The administration of HDMTX therapy was found to be feasible and safe with the precautions described.

Topics: Antimetabolites, Antineoplastic; Cancer Care Facilities; Child; Child, Preschool; Female; Humans; Infant; Injections, Spinal; Leucovorin; Male; Methotrexate; Mucositis; Neutropenia; Patient Readmission; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.

Topics: Adiposity; Animals; Antimetabolites, Antineoplastic; Apoptosis; Bone Marrow; Bone Resorption; Child; Chondrocytes; Cytokines; Femur; Gene Expression; Humans; Leucovorin; Male; Methotrexate; Osteoblasts; Osteoclasts; Osteogenesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RANK Ligand; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Vitamin B Complex; X-Ray Microtomography

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.

Topics: Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Child; Dexamethasone; Female; Humans; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Methotrexate; Neurotoxicity Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Time Factors; Vitamin B Complex

Acute renal failure (ARF) is one of rare and severe methotrexate (MT)-induced complications in patients with acute lymphoblastic leukemia. A case of MT-induced renal dysfunction with an extremely high serum MT concentration is reported. This toxicity required conduction of hemodiafiltration for extracorporeal MT elimination. The presence of homozygous mutation of methylene-tetrahydrofolate reductase reflects an individual metabolism of MT and its renal clearance.

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Humans; Kidney Function Tests; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

Topics: Adolescent; Drug Hypersensitivity; Exanthema; Fever; Humans; Leucovorin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B(12) concentrations in children treated with high-dose methotrexate with leucovorin rescue.. We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate.. Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t(42), when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P 10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate.. Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a "folate overrescue" concept.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Folic Acid; Homocysteine; Humans; Infant; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B 12; Vitamin B Complex

We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m2 (non-high risk) or 8 g/m2 (high risk) over 24 h, 2-9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1-49%, P = 0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

Topics: Antimetabolites, Antineoplastic; Case-Control Studies; Child; Child, Preschool; Disease-Free Survival; Drug Interactions; Female; Humans; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Registries; Risk Factors; Secondary Prevention; Vitamin B Complex

Topics: Central Nervous System; Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Humans; Leucovorin; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Recurrence; Risk

The purpose of this study was to examine cognitive functioning and neuroimaging in children with leukemia treated with the Pediatric Oncology Group 9605 protocol at the Children's Hospital of Eastern Ontario. Mean age at diagnosis was 4.88 +/- 2.54 years. The mean (n = 24) Wechsler Verbal and Performance IQ fell in the low-average range (87.33 +/- 15.69 and 84.83 +/- 19.11, respectively). Mean (n = 20) Verbal and Visual Memory Indexes of 82.95 +/- 15.46 and 88.30+/- 10.80, respectively, were obtained. The proportion of scores on measures of intelligence and memory falling > 1 SD below the normative mean was substantially higher than expected. Paired t-test suggested that Wechsler Verbal IQ and memory remained stable, whereas Wechsler Performance IQ declined significantly. The results of growth curve analyses replicated these findings and suggested a significant adverse effect of cumulative dosage of intrathecal methotrexate on estimated Wechsler Performance IQ. Although only two children experienced seizures, 78% of the group showed leukoencephalopathy on at least one magnetic resonance image. Reliance on seizures as a predictor of leukoencephalopathy might underestimate the incidence of neurotoxicity.

Topics: Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain; Child; Child, Preschool; Cognition Disorders; Cohort Studies; Cytarabine; Female; Hematinics; Humans; Hydrocortisone; Leucovorin; Male; Methotrexate; Neuropsychological Tests; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Wechsler Scales

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Infusions, Intravenous; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adult; Aminophylline; Brain Diseases; Female; Humans; Leucovorin; Magnetic Resonance Imaging; Methotrexate; Neurotoxicity Syndromes; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

Topics: Antineoplastic Agents; Asparaginase; Child; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Toxicity from intermediate-dose methotrexate (MTX) is unusual. A severely obese adolescent with acute lymphoblastic leukemia experienced significant, delayed nephrotoxicity from intermediate-dose MTX. Altered MTX disposition may occur as a consequence of other ingestions or conditions such as obesity. The use of radioisotope renography established the diagnosis and followed the resolution of the patient's MTX-induced nephrotoxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radioisotope Renography

To evaluate the frequency of metabolic complications and dialysis due to tumor lysis syndrome in patients with B-cell advanced-stage non-Hodgkin's lymphoma (NHL) and L3 leukemia at initiation of chemotherapy including the use of urate-oxidase.. Retrospective review of the clinical records of 410 patients with stage III and IV B-cell NHL and L3 leukemia treated in France and prospectively registered in the LMB89 protocol.. During the first week of chemotherapy, only 34 of 410 patients recorded metabolic problems that included hypocalcemia (< 70 mg/dl) in 24 patients, hyperphosphatemia (> 6.5 mg/dl) in 28 and elevation of creatinine > or = 2 SD in 16. Six patients underwent dialysis for life-threatening problems and a seventh as a preventive measure. In the other 27 cases, metabolic problems were successfully resolved using urate-oxidase in combination with alkaline hyperhydration. Among the 410 patients, one case of hemolysis was reported and there was no severe allergic reaction to urate-oxidase.. Only 1.7% of patients in our study receiving urate-oxidase during their induction chemotherapy needed renal dialysis. Urate-oxidase was well tolerated, and used as prophylaxis and/or treatment of hyperuricemia and tumor lysis syndrome consistently gave a lower rate of renal and metabolic complications than in other series of similar patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; France; Humans; Hydrocortisone; Leucovorin; Lymphoma, B-Cell; Male; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Risk Assessment; Sensitivity and Specificity; Survival Rate; Treatment Outcome; Tumor Lysis Syndrome; Urate Oxidase; Vincristine

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Central Nervous System; Central Nervous System Diseases; Child; Child, Preschool; Electroencephalography; Female; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tomography, Emission-Computed, Single-Photon

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 resistance to folate-based antifolates is associated with impaired function of the reduced folate carrier (RFC), one of the major routes of folate transport into cancer cells. To clarify the importance of RFC functions in the antifolate resistance, we have examined the expression of RFC1 and its phenotype as a folate transporter in human leukemia cell lines resistant to various antifolates. MOLT-3 cells resistant to ZD9331 (a thymidylate synthase (TS) inhibitor that utilizes the RFC for cell entry) (MOLT-3/ZD9331) showed decreased expression of RFC1 concomitant with diminished cellular uptake of [3H]methotrexate (MTX). K562 cells resistant to raltitrexed (ZD1694, another TS inhibitor that utilizes the RFC for cell entry) (K562/ ZD1694 x C) scarcely expressed RFC1, which is in accordance with the impaired uptake of folate analogs and the high degree of resistance to ZD1694 and MTX. On the other hand, no apparent decrease of RFCI1 expression was found in transport-deficient MTX-resistant MOLT-3 cells (MOLT-3/MTX10000) though its phenotype showed defective transport of MTX or ZD1694. In these cell lines with impaired RFC function, [3H]leucovorin (LV) uptake was only moderately decreased as compared to [3H]MTX or [3H]ZD1694 uptake. These cells grew with a minimal retardation in folate-free medium supplemented with 10 nM LV, suggesting that these cell lines with impaired RFC function had enough folate transporters to transport LV. In contrast to downregulation of RFC, the much greater uptake of [3H]MTX was observed in the MOLT-3/trimetrexate (TMQ)800-MTX10000 in parallel with increased RFC1 expression. These cell lines with the altered expression of RFC1 may serve as models useful for investigating the regulation of RFC1 expression and for understanding the molecular mechanism(s) behind the transport-mediated antifolate resistance.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Carrier Proteins; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Proteins; Membrane Transport Proteins; Methotrexate; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quinazolines; Tetrahydrofolate Dehydrogenase; Thiophenes; Tumor Cells, Cultured

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Transplantation Conditioning; Vincristine

Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypetidase-G2 (CPDG2) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG2 in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG2 rescue administered with thymidine and leucovorin in 20 patients is presented here.. Patients with high-dose methotrexate-induced renal dysfunction received one to three doses of CPDG2, 50 U/kg body weight intravenously (i.v.), thymidine 8 g/m2/d by continuous i.v. infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) were measured before and after CPDG2 using high-pressure liquid chromatography (HPLC). Tolerance of CPDG2 and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored.. Twenty patients who received high-dose methotrexate for osteosarcoma (n = 11), lymphoid cancers (n = 8), and gastric cancer (n = 1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mumol/L at hour 46). CPDG2 and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days.. CPDG2, thymidine, and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion.

Topics: Adolescent; Adult; Antidotes; Antimetabolites, Antineoplastic; Carboxypeptidases; Child; Child, Preschool; Female; Humans; Infant; Kidney; Kidney Diseases; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sarcoma; Thymidine

We report on a case of methotrexate (MTX) intoxication occurring in a 19-year-old man treated for a leukemia. Exchange-transfusion (ET) was performed in attempt to remove the MTX from the body. This exchange-transfusion was unable to decrease the MTX plasma concentration. This inefficacy of ET in MTX intoxication is in contradiction with previously reported recommendations. However, this result is easily explained by MTX pharmacokinetics parameters.

Topics: Acute Kidney Injury; Adult; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Diuretics; Drug Overdose; Exchange Transfusion, Whole Blood; Furosemide; Humans; Leucovorin; Male; Methotrexate; Pancytopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Failure

Risk-directed chemotherapeutic regimens in recent use have improved the prognosis of children with acute lymphocytic leukemia (ALL). However, many patients relapse during or shortly after cessation of the initial continuation chemotherapy. Since achievement of a second complete remission (CR) is the initial step in successful retreatment effort, it is important to develop salvage protocols for children with relapsed or refractory ALL. In the present study, we developed a new salvage protocol (MLL-93) and applied the concept of dual chemical modulation of cytarabine, hydroxyurea, and etoposide with the alternative administration of high doses of myeloid- and lymphoid-directed agents. We also planned to perform allogeneic bone marrow transplantation (BMT) following a CR if patients had HLA-identical donor(s). The six patients treated with the MLL-93 protocol achieved a second CR. One patients in CR died of interstitial pneumonia after an unrelated allogeneic BMT. The other five patients have been in CR for 12-41 months. We suggest that the concepts of alternative administration of lymphoid- and myeloid-directed drugs and biochemical modulation are useful in the treatment of children with relapsed or refractory ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Drug Administration Schedule; Drug Evaluation; Etoposide; Female; Fever; Gastrointestinal Diseases; Humans; Hydrocortisone; Hydroxyurea; Leucovorin; Male; Methotrexate; Mitoxantrone; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Salvage Therapy; Treatment Outcome

Intrathecal methotrexate is a standard and important therapy in acute leukemia. Unfortunately, overdose is a well reported complication of this therapy. We report a fatal event secondary to intrathecal leucovorin.. An 11-year-old boy with a 6-month history of treatment of acute lymphocytic leukemia received an "overdose" of 20 mg of intrathecal methotrexate. He was treated with intrathecal leucovorin and subsequently experienced severe neurotoxicity and died. This was attributed to the use of intrathecal leucovorin, the first such case reported in the medical literature.. A review of the literature indicates that a careful definition of overdose needs to be applied in cases of intrathecal methotrexate: those <100 mg need less intervention, >500 mg will not respond to any intervention, and the middle group, 100-500 mg, can be treated with a variety of approaches, which are outlined. The standard treatment includes the use of ventriculolumbar washout, CSF exchange, or intravenous pharmacotherapy with leucovorin. Recently, the use of carboxypeptidase has been under investigation. All clinicians who administer intrathecal medications should be aware of these complications and the appropriate treatments of them (including rescue). Leucovorin should not be given intrathecally.

Topics: Catheterization, Central Venous; Child; Cytarabine; Drug Overdose; Humans; Hydrocortisone; Injections, Spinal; Leucovorin; Male; Medication Errors; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Variation of the bridge linking the heterocyclic ring and p-aminobenzoyl-L-glutamate portions of our previously described classical 2,4-diaminofuro[2,3-d]pyrimidines 1 and 2 are reported as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and as antitumor agents. Specifically -CH2CH2- and -CH2NHCH2- bridged analogues, N-[4-[2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid (3) and N-[4-[[N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl) methyl]amino]methyl]benzoyl]-L-glutamic acid (4), respectively, were synthesized. Compound 3 was obtained via a Wittig reaction of the tributylphosphonium salt of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine (5) and methyl 4-formylbenzoate (6) followed by reduction and coupling with the diethyl ester of L-glutamic acid. Compound 4 was synthesized by the nucleophilic displacement of 5 with diethyl N-[4-(aminomethyl)benzoyl]-L-glutamate (15) and saponification. Both analogues were evaluated in vitro as inhibitors of DHFRs from (recombinant) human, human CCRF-CEM cells, and Lactobacillus casei. Compound 3 showed moderate activity (IC50 10(-6)-10(-7) M). Compound 4 was essentially inactive (IC50 10(-5) M, CCRF-CEM). The compounds were also evaluated against TS from (recombinant) human and L. casei and were of low activity (IC50 10(-5) M). The three-atom-bridged analogue 4 was somewhat more inhibitory to human TS than methotrexate (MTX). Compound 3 inhibited the growth of tumor cells in culture (IC50 10(-7) M) while 4 showed a low level of growth inhibitory activity. The inhibition of the growth of leukemia CCRF-CEM cells by both compounds parallels their inhibition of CCRF-CEM DHFR. Analogue 3 was a good substrate for human folylpolyglutamate synthetase (FPGS) derived from CCRF-CEM cells (Km 8.5 microM). Further evaluation of the growth inhibitory activity of 3 against the MTX-resistant subline of CCRF-CEM cells (R30dm) with decreased FPGS indicated that poly-gamma-glutamylation was important for its action. Protection studies with 3 in the FaDu squamous cell carcinoma cell line indicated that inhibition was completely reversed by leucovorin [(6R,S-5-formyltetrahydrofolate] or by a combination of thymidine and hypoxanthine, suggesting an antifolate effect directed at DHFR.

Topics: Antineoplastic Agents; Cell Division; Folic Acid; Folic Acid Antagonists; Humans; Hypoxanthine; Hypoxanthines; Kinetics; Lacticaseibacillus casei; Leucovorin; Methotrexate; Molecular Structure; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Recombinant Proteins; Structure-Activity Relationship; Thymidine; Thymidylate Synthase; Tumor Cells, Cultured

Impaired transport of methotrexate (MTX) is a common resistance mechanism of tumor cells to this drug. Trimetrexate (TMTX), a second-generation folate antagonist, is still active against MTX-transport-resistant cells because it enters cells by passive diffusion and does not use the reduced folate transport system for cell entry. Therefore, although leucovorin (LV) protects MTX-sensitive cells from TMTX toxicity, MTX-transport defective cells are poorly rescued by LV. Severe combined immunodeficiency mice bearing MTX-transport-resistant CCRF-CEM acute lymphoblastic leukemia tumors were treated with TMTX alone or with the combination of TMTX and LV, with tumor regressions in both groups (P < .001) and without significant toxicity. These results indicate that TMTX with LV protection may be a useful therapeutic regimen for patients with MTX-transport-defective acute lymphoblastic leukemia. Furthermore, resistance to TMTX plus LV may result in reversion to MTX sensitivity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Transport; Drug Resistance; Humans; Leucovorin; Methotrexate; Mice; Mice, SCID; Neoplasm Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Heterologous; Trimetrexate

Urinary N-acetyl-beta-D-glucosaminidase (NAG-ase) activity is a very sensitive parameter of kidney proximal tubular damage. Using urinary NAG-ase activity/urinary creatinine as the NAG index, the serum methotrexate (MTX) level and urinary pH were investigated simultaneously. These parameters were measured in 17 leukaemic children. During MTX treatment, NAG indices were normal in 5 children and only slightly elevated occasionally in 9 patients. Among them, transiently high serum MTX levels (Patient A) or low urinary pH (Patient B) were accompanied by high NAG indices. MTX toxicity has been diagnosed in 3 cases, when permanently high NAG indices were in accordance with other clinical signs.

Topics: Acetylglucosaminidase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Burkitt Lymphoma; Child; Creatinine; Diuresis; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Kidney Tubules, Proximal; Leucovorin; Leukemia; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Proteins; 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

A method for the simultaneous determination of the antifolates methotrexate and 7-hydroxymethotrexate as well as the folates 5-methyltetrahydrofolic acid and folinic acid (5-formyltetrahydrofolic acid) in serum and cerebrospinal fluid (CSF) is described. High-performance liquid chromatography with gradient elution and dual detection (ultraviolet absorption and fluorescence) was used to separate and quantitate the analytes. Serum samples containing high levels of the substances of interest and CSF samples were injected directly onto the HPLC column. For determination of low concentrations, serum samples were subjected to a solid-phase extraction method for clean-up and concentration purposes. The determination limits were 10 ng/ml for both antifolates, 100 ng/ml for folinic acid, and 0.1 ng/ml for the physiologically occurring methylated folate which is about 1/100 the serum concentration in healthy children. The suitability of the method for pharmacokinetic monitoring of high-dose methotrexate therapy combined with leucovorin rescue administered to children with acute lymphoblastic leukemia was demonstrated. Minimum values of the serum folate during treatment ranged from 0.2 to 3.1 ng/ml. Even those very low concentrations could be reliably measured.

Topics: Calibration; Child; Chromatography, High Pressure Liquid; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Specimen Handling; Tetrahydrofolates

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

The efficacy and toxicity of the MA-COP-B regimen were assessed after outstanding results were reported in diffuse large cell lymphoma (DLCL) by the Vancouver group. The results are reported according to several proposed prognostic indices, including the recent International Prognostic Factors (IPF) Project.. Forty-seven patients with untreated DLCL received MACOP-B chemotherapy. Thirty patients, most of whom had bulky disease, also received consolidative radiation therapy (RT). Patient characteristics include median age of 42 years, Stage III/IV (57%), bulky or symptomatic Stage II disease (43%), elevated lactic dehydrogenase (81%) and at least one extranodal site (72%).. At a median follow-up of 3.3 years, overall survival was 57% and freedom from progression (FFP) was 52%. The 3-year FFP data were related to tumor extent: 74% for limited stage versus 38% for extensive disease. These data correlated well with four prognostic indices reported in the literature. The IPF index accurately identified low-, intermediate-, and high-risk subgroups.. Patients with limited or low-risk DLCL have an excellent prognosis with MACOP-B +/- RT. These results do not support the use of consolidative high-dose therapy and bone marrow transplantation in patients with limited disease, even if bulky or accompanied by an elevated lactic dehydrogenase. Compared to historical CHOP data, MACOP-B +/- RT does not appear to improve outcome for those patients with poor prognostic features, most of whom will fail. The IPF index is a simple, accurate method of distinguishing high-risk patients who require new therapeutic initiatives.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Risk Factors; Survival Rate; Vincristine

Between 1982 and 1990, we treated patients with poor prognosis non-Hodgkin's lymphoma (NHL) with inpatient, dose-intensive multidrug chemotherapy. Dose intensity was approximately 2.6 times that of the standard CHOP regimen. All patients had intermediate or high grade NHL, as well as one or more clinical features predictive of poor prognosis. Initial results were previously reported in a group of 56 patients, and in a subgroup of 20 patients with small noncleaved cell lymphoma. In this report, we present long-term followup of the patients previously reported. Median follow up is now 75 months (range 48-122 months). Since our initial reports, the survival curves have remained essentially unchanged, with an actuarial 5 year survival of 48% for the entire group and 60% for the patients with small noncleaved cell lymphoma. Disease-free survival is 42% for patients in Shipp's category 3. Three late relapses occurred, all > 36 months after treatment. No late toxicities or second malignancies have been observed. Intensive, short duration therapy is feasible and effective, and may provide particular advantage to patients with small noncleaved cell histology or other poor prognostic features. Exploration of the importance of dose intensity in lymphoma treatment should continue; comparison of this regimen with standard CHOP is indicated.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Prognosis; Survival Analysis; Vincristine

CCRF-CEM human leukemia sublines resistant to short-term methotrexate (MTX) exposure as a result of decreased folylpolyglutamate synthetase (FPGS) activity were examined for their response to other cytotoxic agents. The R3/7 and R30dm sublines display 25 and 1%, respectively, of the FPGS activity of CCRF-CEM cells as measured with MTX in vitro. Response to agents in outgrowth experiments was examined under both continuous exposure (120 h, where MTX resistance is not observed) and short-term (6-14.5 h) exposure. During continuous exposure to various classes of agents, cross-resistance of R3/7 and R30dm that correlated with FPGS level was not observed, although some minor (< or = 3-fold) stochastic variations in sensitivity were noted. These agents included actinomycin D, Adriamycin, etoposide, vincristine, cisplatin, cytosine arabinoside, 5-fluorouracil, and some other antifolates. Cross-resistance during continuous exposure that did correlate with FPGS level was noted, however, to glutamate-containing thymidylate synthase inhibitors (including ICI D1694) and, to a minor extent, to 6-mercaptopurine and 5-fluorodeoxyuridine. Slight collateral sensitivity during continuous exposure that apparently correlated with FPGS level was noted to the lipid-soluble antifolate trimetrexate and to 5,8-dideazapteroyl-L-ornithine, an FPGS-specific inhibitor. In short-term exposures (where MTX resistance of the sublines is observed), the resistant sublines displayed sensitivity or cross-resistance to each agent that was qualitatively similar to that observed for the same agent in continuous exposure. Because of the requirement for reduced folates in the anti-DNA mechanism of action of fluoropyrimidines and the current clinical use of leucovorin (LV) to enhance their effects, the interaction of LV and fluoropyrimidines was examined. The results suggest that even highly FPGS-deficient cells are as sensitive to the effects of LV modulation as are wild-type cells even at fluoropyrimidine exposure times as short as 4 h.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Division; Drug Resistance; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Quinazolines; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured

The active isomer of leucovorin (LV), LV-6S was compared with the racemic form, LV-6R,S and the inactive form, LV-6R.. Pharmacokinetic studies of LV-6S and 6R,S were performed on normal volunteers and patients. Growth of Pediococcus Cerevisiae (PC), a LV-dependent strain, was measured with the 3 forms of LV. CCRF-CEM, a leukemic human cell line, was used to compare the effect of LV-6S, 6R,S and 6R on the rescue of methotrexate (MTX) and on the cytotoxicity of 5-fluorouracil (5-FU).. LV-6S exhibits pharmacokinetic patterns similar to those obtained with LV-6R,S whatever the route used, oral or intravenous. The growth of PC was similar with the active isomer and the racemic form while the unnatural isomer, LV-6R did not promote any growth. Cells exposed to MTX (10(-7) to 10(-5) M) were rescued from MTX cytotoxicity with LV-6S and LV-6R,S at concentrations 100 and 200 fold higher, whereas LV-6R did not reverse toxic effects of MTX. An enhancement of the cytotoxicity induced by 5-FU (10(-4) M) was obtained after preexposure of cells to LV-6S or LV-6R,S while LV-6R did not exhibit any synergistic effect.. LV-6S has similar effects to LV-6R,S in vitro and in vivo but at half doses; its clinical use prevents the possible interference of the inactive isomer, especially in patients receiving high doses of LV.

Topics: Drug Synergism; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Pediococcus; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stereoisomerism; Tumor Cells, Cultured

Folinic acid (FA) has been reported to expand the pool of peripheral blood stem cells (PBSC) after chemotherapy. We evaluated the efficacy of FA for harvesting PBSC following cytotoxic chemotherapy in 4 patients with acute leukemia. After achieving a complete remission (CR), 3 courses of chemotherapy for a consolidation of the CR were administered to the patients. Two successive cycles of leukapheresis were performed during the recovery phase from consolidation chemotherapy, which consisted of an intermediate dose of cytosine arabinoside. For the second cycle of leukapheresis, FA was administered intravenously at a dose of 50 mg/day following consolidation. The yields of either mononuclear cells or burst-forming units-erythroid (BFU-E) were not affected by FA administration. In contrast, the yields of colony-forming units-granulocyte/macrophage (CFU-GM) were significantly decreased in all patients compared to the CFU-GM yields after the first cycle of leukapheresis (P = 0.032). Thus FA is considered not to be effective in expanding the peripheral blood progenitor pool when given in a fashion different from the original report.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Combined Modality Therapy; Drug Administration Schedule; Female; Hematopoietic Stem Cells; Humans; Leucovorin; Leukapheresis; Leukemia, Myeloid; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Treatment of elderly patients with hematological malignancies is difficult and a matter of controversy. Low responsiveness to therapy and high risk of mortality have been reported. The risk of chemotherapeutic death increases after age 60, and an age-adjusted chemotherapy schedule is needed. In stage III and IV Hodgkin's disease, for example, an age-adjusted COPP regimen may be adopted. Many non-Hodgkin lymphomas (NHL) of elderly patients have a slow course. However, for intermediate to high grade aggressive NHL, dose-reduced CHOP regimen, or non- or low-dose methotrexate-containing programs like BECALM, CNOP, and low dose-ACOP-B are acceptable. MACOP-B regimen with G-CSF may be used for patients under age 65. For the treatment of elderly patients with AML, it is reported that a reduced-dose DAT regimen is better than the standard dose for inducing CR in patients older than 60. In elderly AML patients over 60, the dose-adjustment reported by Mori, or low-dose cytarabine with G-CSF, is recommended. Information about elderly patients with acute lymphoblastic leukemia is scarce. Aggressive treatments like L-17 M regimen are not tolerable by elderly patients, and a combination chemotherapy consisting of vincristine and prednisolone is recommended.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Hodgkin Disease; Humans; Leucovorin; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Methotrexate; Mitoxantrone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Vincristine

Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolidation and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL.. This report describes these toxic effects and outlines our successful approach to the problem.. The standard four-drug induction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/m2 every 6 hours four times daily in four weekly courses concomitant with weekly triple intrathecal therapy--MTX, ARA-C, and hydrocortisone--plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercaptopurine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy.. Twenty-five of the 138 patients evaluated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite discontinuation of intrathecal ARA-C, which eliminated simultaneous intravenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amendment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study.. These findings suggest that folate replacement due to administration of leucovorin modulated MTX toxicity and/or modified an interaction among VP-16, ARA-C, intrathecal therapy, and the central nervous system.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Etoposide; Female; Humans; Infant; Leucovorin; Male; Methotrexate; Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We established a novel human acute lymphoblastic leukemia cell line made resistant to two folate analogues, trimetrexate (TMQ) and N10-propargyl-5,8-dideazafolic acid (CB3717), by sequential exposure of the 200-fold TMQ-resistant cells (MOLT-3/TMQ200) to CB3717. A 30-fold-resistant subline to CB3717 was selected from the TMQ-resistant cells and designated as MOLT-3/TMQ200-CB371730. This double-folate-resistant cell line was 15-fold more resistant to methotrexate (MTX) than MOLT-3/TMQ200; however, TMQ resistance was decreased to 10-fold as compared to MOLT-3/TMQ200. The doubly resistant cells also showed 2-fold cross-resistance to 5-fluorouracil (5-FU). Equimolar concentrations of leucovorin almost completely reversed the inhibitory effect of MTX on the doubly resistant cells and partially that of CB3717 and TMQ; on the other hand, leucovorin enhanced the inhibitory effect of 5-FU. Thymidylate synthase activities demonstrated little or no difference among these three cell lines, being consistent with no overexpression of mRNA for this enzyme in the doubly resistant cells. MOLT-3/TMQ200 cells displayed classical multidrug resistance; sequential development of CB3717 resistance in the TMQ-resistant cells resulted in an enhancement of the multidrug-resistance phenotype and a concomitant increase of MDR1 mRNA. The development of a complex resistance pattern seen in this double-folate-resistant subline indicates intricacy in the study of drug resistance after multidrug chemotherapy.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Division; Cell Line; Cisplatin; Cross Reactions; Dactinomycin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Etoposide; Fluorouracil; Folic Acid; Humans; Leucovorin; Membrane Glycoproteins; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quinazolines; RNA, Messenger; Thymidylate Synthase; Trimetrexate; Vincristine

A total of 20 adults patients presenting with previously untreated lymphoblastic lymphoma underwent an intensive chemotherapy protocol. Either the BACOP or the m-BACOD regimen was used for induction. If the patients achieved a complete clinical remission (CR) after three courses, they were given intensive consolidation and maintenance chemotherapy based on a protocol that was modified from the L10/L17M regimen of the Memorial Sloan-Kettering group for acute lymphoblastic leukaemia and lymphoblastic lymphoma. Patients exhibiting localised areas of bulky disease were given additional involved-field radiotherapy. In all, 15 (75%) men and 5 (25%) women were entered in this study. Their median age was 28 years (mean, 30 years; range, 12-64 years). Overall, 3 (15%) had stage II disease, 3 (15%) had stage III disease and 14 (70%) had stage IV disease; 7 (35%) patients exhibited B symptoms and 4 (20%) had bulky disease. The overall (CR) rate was 10/20 (20%), and that following BACOP and m-BACOD therapy was 4/8 (50%) and 6/12 (50%), respectively. In all, 7 of the 10 complete responders (70%) relapsed. The disease-free survival of the ten who achieved a CR was 23% at 3 years. The overall survival of all 20 patients at 3 years was only 37%, and there were very few long-term survivors. More effective treatment for adult lymphoblastic lymphoma is required.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Fluorouracil; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

We have tested folinic acid (FA) for ability to increase peripheral blood stem cells (PBSC) after chemotherapeutic aplasia in acute leukaemia. Five adult patients (four AML, one ALL) entered the study, each patient underwent two series of three leukapheresis, the first following induction chemotherapy and the second following the first course of consolidation. The first leukapheresis of each series was done when the white blood cell count reached 10(9)/l with subsequent leukapheresis every other day. Folinic acid (Lederle Laboratories, France) was administered at a dose of 50 mg (i.v.) per day, 15 days from initiation of chemotherapy and continuing through the third leukapheresis of the series (days 25-30). PBSC were collected on a Haemonetics V50 cell separator. In these five cases we observed an increased yield of both colony-forming units, granulocyte macrophage (CFU-GM) and burst forming units-erythroid (BFU-E) expressed per ml of cytapheresis product: CFU-GM x 18, BFU-E x 3 and if expressed per 10(4)/kg of body weight: CFU-GM x 30, BFU-E x 3 (CFU-GM P less than 0.05, BFU-E less than 0.01). Long-term blood culture (LTSC) from FA stimulated leukapheresis, in an attempt to quantitate the most primitive stem cells, demonstrated that this expansion of the PBSC was sustained in time. We found by means of LTSC that FA did not stimulate CFU-L from patients with AML (two cases tested). Finally two AML patients were grafted with FA-PBSC after Cytotoxan and total body irradiation (TBI). Haematopoietic reconstitution was rapid complete and sustained in time in both patients. This indication for folinic acid should be further studied with or as an alternative to haematopoietic growth factors.

Topics: Adult; Colony-Forming Units Assay; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leucovorin; Leukapheresis; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g.m-2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL). The median steady-state concentration of MTX was 66 mumol.l-1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg.m-2.min-1. The 7-OHMTX level increased during each infusion and a Cmax of 19 mumol.l-1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8. The MTX metabolite APA was detected in concentrations less than 0.06 mumol.l-1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mumol.l-1 and 18 h following the last dose of LCV it was 0.44 mumol.l-1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mumol.l-1 with a median ratio of 5-MTHF to MTX of 2. Twenty infusions with 48 h MTX levels of less than 0.5 mumol.l-1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mumol.l-1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.

Topics: Child; Child, Preschool; Chromatography, High Pressure Liquid; Half-Life; Humans; Leucovorin; Metabolic Clearance Rate; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Experimental data show that Leucovorin (LCV) can remarkably modify the cytotoxicity of 5-fluorouracil (5-FU). The combined use of both substances results in a more prolonged and pronounced inhibition of DNA-metabolism by inhibiting thymidylate-synthase (TS) activity. This effect is caused by stabilisation of the ternary complex of 5-fluoro-deoxyuridine monophosphate (5-FdUMP), TS and N5,N10-methylenetetrahydrofolate (CH2FH4). The influence of the combined treatment with 5-FU and LCV has been studied on permanently growing human lymphoblastoid cells. Two different methods were used: a) Tritium-release-assay for measurement of TS activity; b) incorporation of 3H-deoxyuridine (3H-dUR) and 3H-thymidine (3H-dTR) into the DNA for determination of the intrinsic nucleoside pools. The results with both methods were similar. Neither with sequential nor with simultaneous application of both substances was it possible to demonstrate a significantly increased substances was it possible to demonstrate a significantly increased inhibition of TS as compared with 5-FU alone. The methods demonstrated are easy to perform and permit the biochemical characterisation of cell populations in which the combination of LCV + 5-FU is not more effective than 5-FU alone. It is suggested that lymphoid cells and normal bone marrow are such populations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cell Survival; DNA Replication; Drug Synergism; Fluorouracil; Humans; Leucovorin; Nucleosides; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thymidylate Synthase; Tumor Cells, Cultured

Tolerability and efficacy of high-dose methotrexate was studied in 70 pediatric patients with lymphoblastic tumors (acute lymphoblastic leukemia and non-Hodgkin's lymphoma). Methotrexate was given by 24-hour infusion of 500-1000 mg/m2 (total dose-700-3000 mg) after remission had been achieved. An antidote--calcium folinate--was administered 24 hours postinfusion. Major adverse side-effects involved were stomatitis, hepatotoxicity and fever. Survival in the study group was higher than in controls.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Evaluation; Drug Tolerance; Female; Humans; Infant; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Time Factors

An intensive 6-month schedule of drugs was devised with both systemic and central nervous system activity, known by the acronym 'MACHO', to treat 24 newly and consecutively diagnosed children, 13 with stage IV B-cell non-Hodgkin's lymphoma (B-NHL) and 11 with B-cell acute lymphoblastic leukaemia (B-ALL). There were three deaths from complications of chemotherapy (two infective, one biochemical). Five children with central nervous system disease at diagnosis (CNS+) received planned additional megatherapy/bone marrow transplants. Event-free survival (EFS) at 1 year for the 11 cases of B-ALL is 64% (95% confidence intervals [CI] 31-89%) and of 13 stage IV B-NHL cases is 50% (95% CI 19-75%). Patients with bulky abdominal disease had a 32% EFS at 1 year (CI 13-68%) compared with 76% (CI 39-94%) for those without bulky abdominal disease. Overall EFS for eight CNS+ patients is 73% at 1 year (95% CI 34-97%) compared with 48% (95% 24-74%) for those without CNS disease (CNS-). However, only two of the CNS+ cases had bulky abdominal disease (patients 10 and 12) and the difference is not significant (P less than 0.5). A score of 1 was given for each of the following potential prognostic features: bulky abdominal disease, pleural effusion and severe renal dysfunction within 48 h of presentation. Patients who scored 0 or 1 fared significantly better than those who scored 2 or 3 (EFS at 1 year 78% [CI 49-95%] versus 24% [6-65%], P less than 0.04). Two patients with a score of 2 survived past 6 months and another is currently well, but has not regenerated his marrow following autologous transplantation. This protocol is relatively effective for patients who have B-ALL, but those patients who have bulky abdominal disease, often associated with severe renal dysfunction, and those with CNS disease, do not fare so well and require new approaches to therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Leucovorin; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Vincristine

The biological activities of novel analogues of methotrexate (MTX) and aminopterin (AMT) in which the gamma-carboxyl was replaced by a 1H-tetrazol-5-yl ring, an isosteric group with acidic properties similar to a carboxyl group, were investigated. The tetrazolyl analogues of MTX and AMT were more potent inhibitors of the growth of CCRF-CEM and K562 human leukemia cell lines during continuous (120 h) and 24-h pulse exposure than were the respective parent drugs; only when the exposure time was reduced to 6 h were the parent drugs more potent. These inhibitory effects on growth correlated with the onset of and recovery from inhibition of de novo thymidylate biosynthesis. Growth inhibition by the analogues was protectable by leucovorin. MTX-resistant CCRF-CEM sublines with decreased transport or increased dihydrofolate reductase (DHFR) levels were cross-resistant to the analogues. The analogues were as potent as their parent drugs in inhibiting DHFR activity in vitro and at displacing [3H]MTX from intracellular DHFR. Each analogue was more effective than its parent drug at inhibiting uptake of [3H]MTX into CCRF-CEM cells. The tetrazole analogue of AMT was a linear competitive inhibitor (Kis = 50 microM) of CCRF-CEM folylpolyglutamate synthetase, while the tetrazole analogue of MTX, unlike all other inhibitors, was linear noncompetitive (Kis = 51 microM, Kii = 321 microM). The data suggest that, compared with MTX or AMT, the tetrazole substituent, in place of the gamma-carboxyl group, allows more efficient transport into cells via the reduced folate/MTX carrier and the resulting greater uptake of the analogues leads to inhibition of DNA synthesis and cell death at lower extracellular concentrations during long exposures. The mechanism of cell death could involve inhibition at folypolyglutamate synthetase, but DHFR is the primary target. The low potency of the analogues during short exposure is presumably related to the inability to form the poly-gamma-glutamyl metabolites required for intracellular retention.

Topics: Aminopterin; Animals; Biological Transport; Cell Division; Folic Acid Antagonists; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Humans; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Child, Preschool; Humans; Injections, Jet; Leucovorin; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Bone Marrow; Child; Cytological Techniques; Humans; Infusions, Intravenous; Interphase; Leucovorin; Methotrexate; Myelodysplastic Syndromes; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma

In the first part of this study the availability of folinic acid (FA) and its main active circulating metabolite, 5-methyltetrahydrofolate (5-MTHF), were studied in plasma and cerebrospinal fluid (CSF) from normal subjects after i.v. administration of 100 and 250 mg of FA. 5-MTHF rapidly appeared in plasma, the maximum value being reached at the first observation time point (1 h). FA was eliminated in plasma more slowly than 5-MTHF. Between the two doses, there was no evidence of modification in pharmacokinetic parameters (terminal half-life, clearance) for either FA or 5-MTHF in plasma and CSF; 5-MTHF was the only product detectable in CSF. Considering FA plus 5-MTHF together, the AUC (area under the curve) ratios between CSF and plasma were close to 1%. 5-MTHF was cleared very slowly from CSF (t 1/2 = 85 h). This finding suggested possible accumulation of 5-MTHF in CSF during repeated administration of FA combined with medium or high dose MTX. In the second part of the study, dealing with a group of eight children treated by such protocols, an increase in CSF 5-MTHF was detected from cycle to cycle in five (r = 0.91, P less than 0.01) with a maximum at 5 x 10(-8) M. This progressive accumulation of 5-MTHF in CSF may have a negative effect on the local action of MTX and should be taken into account for therapeutic strategies designed for the management of meningeal leukaemia.

Topics: Child; Child, Preschool; Female; Humans; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetrahydrofolates

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Half-Life; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Five children, ages 2.5 to 12 years (mean 6.2 years), with acute lymphoblastic leukemia or non-Hodgkin's lymphoma were given 22 courses of high-dose methotrexate (HD-MTX) therapy (6-8 g/m2/24 h). No serious clinical complications were encountered, but stomatitis occurred after three (14%) of the courses. First-phase elimination half-lives (t1/2(alpha)) of MTX and 7-hydroxy-methotrexate (7-OH-MTX) after 21 infusions were 2.7 +/- 0.4 h and 6.5 +/- 1.8 h (mean +/- SD). In one course (4.5%) there was delayed systemic MTX elimination, with first-phase elimination half-lives (t1/2(alpha] for MTX and 7-OH-MTX of 4.2 and 9.9 h, respectively, and second-phase elimination half-lives (t1/2(beta)) of 43 and 58 h. Significant decreases in white blood cell count, increases in serum creatinine, and increases in alanine aminotransferase and/or aspartate aminotransferase during the first 2-6 days were present in five (23%), three (14%), and six (27%) of the courses, respectively. The regimen was tolerated well by the children.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Evaluation; Half-Life; Humans; Infusions, Intravenous; Leucovorin; Lymphoma, Non-Hodgkin; Metabolic Clearance Rate; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Stomatitis; Vincristine

Three patients, in whom tumour overkill by cytotoxic treatment, including high dose methotrexate with folinic acid rescue, resulted in the 'phosphate shower syndrome' (hyper-uricaemia, hyperkalaemia and hyperphosphataemia with hypocalcaemia and tetany, with metabolic acidosis and acute renal impairment) are described. Severe methotrexate toxicity occurred in two of these patients. High dose methotrexate would appear contra-indicated in situations where massive tumour lysis is possible.

Topics: Adolescent; Adult; Calcium; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Phosphates; Precursor Cell Lymphoblastic Leukemia-Lymphoma

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