mercaptopurine and Neutropenia

The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Topics: Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Nausea; Neoplasms; Neutropenia; Opportunistic Infections; Pancreatitis

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

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

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

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

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

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

Daily oral 6-mercaptopurine (6MP) is important in the treatment of childhood lymphoblastic leukaemia (ALL), but there is great inter-patient variability in the pattern of evident drug effect (myelosuppression) seen at a standard dose. In an attempt to reduce that variability the current practise in the United Kingdom for the last 4 years has been to escalate the amount prescribed in patients who do not experience cytopenias at 75 mg/m2. We undertook a study to see whether that strategy would increase the total dose of 6MP prescribed in such patients and whether it would alter the pattern of myelosuppression. Over a 6-month period we studied 44 children treated conventionally (without escalation) and compared them with another 44 (matched for sex) who were treated on the same protocol but where doses were increased in monthly 25% steps if 75 mg/m2 was tolerated without cytopenias. We then compared the two groups for the total dose of drug prescribed and the frequency and duration of neutropenia or thrombocytopenia. The median cumulative dose of 6MP received by the conventionally treated children (10,002 mg/m2) was not significantly different from that of the children treated with dose escalation (9,429 mg/m2). In a comparison of the 30 children who actually received inflated doses of 6MP with the 37 from the conventional cohort who would have been eligible to do so, it was again found that the cumulative median doses were similar (10,460 versus 10,916 mg/m2). There was a difference between the two groups in the pattern of myelosuppression -- the escalated group spent significantly more time off 6MP than did the non-escalated group (median 4.5 versus 3 weeks; P<0.005, 95% CI from -1 to -3). These findings imply that the method of dose escalation employed does not allow more 6MP to be prescribed in children tolerant of the standard dose. The chief effect seems to be to generate longer periods off therapy, and this could paradoxically decrease the anti-neoplastic activity of the drug. Alternative ways of prescribing should be explored.

Topics: Antimetabolites, Antineoplastic; Bone Marrow; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Tolerance; Female; Humans; Infant; Leukemia, Lymphoid; Male; Mercaptopurine; Neutropenia; Thrombocytopenia

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

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

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

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

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

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

Children from the UKALL V trial were studied to assess the clinical importance of myelosuppression during uninterrupted 'maintenance' treatment of 'standard risk' lymphoblastic leukaemia. Those receiving daily 6-mercaptopurine and weekly methotrexate who were in first remission 20 months from diagnosis were divided into two groups on the basis of whether or not they had ever had an absolute neutrophil count of less than 0.5 x 10(9)/l recorded during maintenance treatment up to that time. Of 105 evaluable children, 45 (43%) became neutropenic at least once, and 60 (57%) did not. Seven (16%) of the neutropenic group subsequently relapsed compared with 27 (45%) of the remainder. This difference was still significant if the analysis was stratified by total treatment time (two or three years), age, sex, or diagnostic white cell count. Seven (16%) neutropenic children died in remission, compared with one (2%) of the non-neutropenic children. Therapeutic myelosuppression during standard maintenance treatment of 'standard risk' lymphoblastic leukaemia is associated with increased toxicity but a reduced risk of relapse. The unexplained improvement in long term survival in the United Kingdom in recent years may in large part be due to this.

Topics: Adolescent; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Female; Humans; Infant; Leukemia, Lymphoid; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neutropenia; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; United Kingdom

L-Asparaginase, in the dose of greater than or equal to 6000 IU/sq m three times weekly, was demonstrated to be an effective agent in reinduction of remissions in childhood leukemia. Four hundred thirteen children with acute lymphocytic leukemia were treated with L-asparaginase. Doses i.m. ranged from 300 to 12,000 IU/sq m. None of the patients had received prior asparaginase therapy. 6-Mercaptopurine was given p.o. concurrently. All of the patients had experienced several previous relapses, and their disease was not responsive to 6-mercaptopurine. L-Asparaginase was found to be effective in reinducing remissions at the following rates: 9.5% for 300 IU/sq m; 35.1% for 3,000 IU/sq m; 53.5% for 6,000 IU/sq m; and 62.5% for 12,000 IU/sq m. The drug was given three times weekly for four weeks. Hypersensitivity reactions occurred in 6.5% of patients.

Topics: Asparaginase; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Mercaptopurine; Neutropenia; Remission, Spontaneous

The first and second Medical Research Council UKALL trials have shown that alteration in the timing of methotrexate and 6-mercaptopurine maintenance therapy for the treatment of acute lymphoblastic leukaemia can markedly change drug induced toxicity. Maintenance chemotherapy in both trials used a similar total dosage of these drugs but the timing of their administration was different in the two schedules.

Topics: Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Leukemia, Lymphoid; Leukocyte Count; Lymphocytes; Lymphopenia; Mercaptopurine; Methotrexate; Neutropenia; Neutrophils; Remission, Spontaneous; Time Factors

The degree of drug-induced neutropenia resulting from a controlled trial (UKALL I) of treatment in acute lymphoblastic leukaemia was analysed. The main agent associated with severe neutropenia was methotrexate, and methotrexate-induced neutropenia was significantly greater in patients who had received craniospinal irradiation. The synergistic toxic effect of irradiation followed by methotrexate treatment seems to have contributed to three of the five deaths which occurred in complete remission in this trial; all deaths in remission occurred in patients who had received central nervous system prophylaxis. Analysis of patients who subsequently relapsed compared with those still in remission after 18 months of treatment indicated that the former, on average, had slightly lower neutrophil counts. This suggests that the children who relapsed did not receive any less aggressive treatment than those who remained in remission.

Topics: Agranulocytosis; Central Nervous System; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Injections, Spinal; Leukemia, Lymphoid; Lymphocytes; Mercaptopurine; Methotrexate; Neutropenia; Prednisolone; Radiation Effects; Radiotherapy Dosage; Remission, Spontaneous; Time Factors; Vincristine

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

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

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

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

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Asian People; Azathioprine; Female; Genetic Variation; Humans; Inflammatory Bowel Diseases; Introns; Leukopenia; Male; Mercaptopurine; Middle Aged; Neutropenia; Retrospective Studies; Young Adult

NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure.. Whole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on well-known NUDT15 and TPMT were evaluated by multigene prediction models.. Among the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913).. The CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Topics: Bone Morphogenetic Protein Receptors; Child; Homozygote; Humans; Mercaptopurine; Methyltransferases; Neutropenia; Pyrophosphatases

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

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

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

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

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

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

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

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

Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine/6-mercaptopurine (6-MP). Mutations in the enzyme lead to generation of excess thioguanine, which causes suppression of various cell lineages, especially neutrophils. Data on the prevalence of TPMT polymorphism are available from Western and some Asian countries; such data from India are sparse.. The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodulator therapy and its relation to the development of neutropenia on azathioprine therapy.. In this retrospective study, data of all patients who underwent TPMT genotyping by PCR-RFLP and allele-specific PCR prior to immunomodulator therapy were analyzed. The frequency of on-treatment development of neutropenia (total neutrophil count <1,500 per cubic millimeters) was noted.. Data were available on 126 patients (mean age, 42 [SD 13.6] years; 73 men and 53 women). The disease indications included ulcerative colitis (61), Crohn's disease (43), indeterminate colitis (1), autoimmune hepatitis (16), and others (5). TPMT genotype was wild in 120 patients (95.23 %) and heterozygous in 6 patients (4.77 %); no patient had homozygous mutation. Seven of 87 patients (6.8 %) who received azathioprine developed neutropenia; blood counts normalized on cessation of the drug in all. The incidence of neutropenia in patients with wild type was 6/84 (7.14 %) and with heterozygous type 1/3 (33 %) (p = 0.5764).. Nearly 5 % of this population of patients requiring immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation.

Topics: Adult; Azathioprine; Female; Gastrointestinal Diseases; Heterozygote; Humans; Immunosuppressive Agents; India; Male; Mercaptopurine; Methyltransferases; Middle Aged; Neutropenia; Polymorphism, Genetic; Prevalence; Retrospective Studies

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

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

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

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

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

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

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

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

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

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

Thiopurine methyltransferase (TPMT) is the main enzyme responsible for inactivating toxic products of azathioprine (AZA) metabolism. Patients with homozygous deficiency of this enzyme have no enzyme activity and ideally should not be given AZA. Patients with heterozygous deficiency have 50% of enzyme activity and have been shown to respond well and tolerate half a standard dose. We describe a patient with homozygous deficiency of TPMT who developed life threatening neutropenic sepsis, and advocate that all patients should be tested for TPMT activity prior to starting AZA therapy.

Topics: Aged; Arthritis, Rheumatoid; Azathioprine; Bone Marrow Diseases; Diagnostic Tests, Routine; Female; Homozygote; Humans; Immunosuppressive Agents; Inactivation, Metabolic; Mercaptopurine; Methylation; Methyltransferases; Neutropenia; Prodrugs; Sepsis; United Kingdom

There is limited information on the optimal use of thiopurinic immunomodulators in inflammatory bowel disease (IBD) and the dosage, efficacy and toxicity of these drugs has not been clearly established.. To evaluate clinical outcomes and the toxicity of thiopurinic immunomodulators in clinical practice (effectiveness), as well as possible associated variables.. Data were obtained from a database of patients with ulcerative colitis and Crohn's disease who started treatment with azathioprine or 6-mercaptopurine with an identical predetermined schedule and follow-up. Remission, relapse and toxicity were defined and analyzed and their relationship with clinical, biologic and demographic variables was evaluated with multivariate analysis.. We evaluated 150 courses of treatment in 126 patients. Treatment was given to induce clinical remission in 118 courses and 62% of the patients reached this outcome, which was maintained for a mean of 52 months. The only variable associated with poor response was perianal disease. Adverse events were detected in 34% of the courses and were the main cause of treatment withdrawal. Factors significantly associated with withdrawal due to adverse events were starting with full doses of thiopurinic drugs (OR, 4.26; 95% CI, 1.12-16.32) and cotreatment with infliximab (OR, 5.6; 95% CI, 1.17-27.1).. Some clinical variables such as disease phenotype, the use of full doses of thiopurinic drugs from the start of treatment, and co-treatments can have a notable influence on adverse effects and thus on the effectiveness of this therapy in IBD.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Digestive System Diseases; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Middle Aged; Neutropenia; Patient Acceptance of Health Care; Remission Induction; Reoperation; Retrospective Studies

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.

Topics: Abscess; Adult; Anus Diseases; Bone Marrow; Crohn Disease; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Ileitis; Immunosuppressive Agents; Leukocyte Count; Male; Mercaptopurine; Mesalamine; Neutropenia

Topics: Antimetabolites, Antineoplastic; Apoptosis; Child, Preschool; Humans; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Child; Female; History, 20th Century; Humans; Male; Mercaptopurine; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Azathioprine, a cytostatic and immunosuppressive drug in use for some 30 years, can give rise to life-threatening neutropenia and thrombocytopenia. This may be caused by unexpectedly high concentrations of cytotoxic metabolites due to abnormally slow inactivation of 6-mercaptopurine (6-MP) by thiopurine S-methyltransferase (TPMT) and/or xanthine oxidase. Low TPMT activity may be due to genetic polymorphism or interaction with drugs such as salicylic acid derivatives, while xanthine oxidase may be inhibited by allopurinol. High TPMT activity, on the other hand, may hamper cytostatic treatment. Safer and more effective treatment with azathioprine and its metabolite 6-MP becomes possible with new laboratory methods for pharmacotherapy monitoring.

Topics: Aged; Antimetabolites, Antineoplastic; Azathioprine; Bone Marrow Cells; Female; Genotype; Hematologic Diseases; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Neutropenia; Pancytopenia; Risk Factors

As a prelude to a nationwide randomized trial of thioguanine (TG) versus mercaptopurine (MP) for childhood lymphoblastic leukaemia we compared a pilot group of 23 children taking TG with a matched group taking MP. We assessed drug tolerance based on haematological toxicity and measured erythrocyte (RBC) concentrations of thioguanine nucleotides (TGN). The median tolerated dose of TG was 30 mg/m2 compared to 55 mg/m2 for MP. There was no difference in the pattern of anaemia or neutropenia between the two groups, but dose-limiting thrombocytopenia was more evident in the TG children (P< 0.001), four of whom had a decrease in platelet count to <20 x 10(9)/l compared to only one on MP. The median RBC TGN concentration for those on 40 mg/m2 TG was 1726 pmol/8 x 10(8) RBCs compared with 308 pmol/8 x 10(8) RBCs for those on 75 mg/m2 MP (P< 0.0001). There was an inverse correlation between RBC TGNs and neutrophil count in the MP group but not in those on TG. No correlation between metabolite concentration and thrombocytopenia was found in either group. These results provide further evidence that TG has a selective effect on platelets. They also showed that RBC TGN were, on average, 5-fold higher in those taking TG but did not obviously relate to myelotoxicity as found in children on MP. The higher concentrations seen may partly reflect the erythrocyte's ability to metabolize TG directly to TGN by pathways not open to MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; Infant; Lymphocyte Count; Male; Mercaptopurine; Neutropenia; Neutrophils; Nucleotides; Platelet Count; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Thrombocytopenia

A 59-year-old man was referred to our hospital because of pancytopenia. Peripheral blood examination showed a WBC of 1,500/microliters with 2% blasts, Hb 8.1 g/dl and a platelet count of 4.1 x 10(4)/microliters. A bone marrow aspiration revealed hyperplasia with proliferation of blasts (15.7%) and myelodysplasia. Chromosome analysis revealed multiple aberrations, including -5, -7, +8. The patient was given a diagnosis of refractory anemia with excess of blasts (RAEB) and treated with combination chemotherapy. Agranulocytosis and high fever remained after chemotherapy, and abdominal pain and diarrhea developed. An abdominal X-ray film and computed tomography scan demonstrated dilated small bowel, thickness of the bowel wall, and ascites. A diagnosis of neutropenic enterocolitis was given. During the WBC recovery period from nadir, massive hematochezia developed in the patient. Angiography detected the leakage of contrast medium from a peripheral region of the first jejunal artery into the jejunal lumen. A partial resection of the jejunum was thus performed, and a histological examination revealed the presence of irregularly dilated blood vessels in the submucosal layer. These findings were consistent with the features of angiodysplasia, and indicate that angiodysplasia should be considered one cause of intestinal hemorrhage in elderly patients during intensive chemotherapy.

Topics: Anemia, Refractory, with Excess of Blasts; Angiodysplasia; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Therapy, Combination; Emergencies; Enterocolitis; Gastrointestinal Hemorrhage; Humans; Idarubicin; Jejunal Diseases; Male; Mercaptopurine; Middle Aged; Neutropenia; Prednisolone; Vincristine

Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m2 6MP produced TGNs of 2348 pmol/8 x 10(8) red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m2 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m2 daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity.

Topics: Antimetabolites, Antineoplastic; Child; Drug Administration Schedule; Erythrocytes; Female; Guanine Nucleotides; Humans; Mercaptopurine; Methyltransferases; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Thrombocytopenia

Mucormycosis is a rare fungal infection that has been described mainly in oncologic and diabetic patients. We here report the cases of two leukaemic patients in whom pulmonary mucormycosis was diagnosed. Prompt diagnosis, therapy with amphotericin B and surgery when possible, are the cornerstones in the treatment of this fungal infection. Although infrequent, this infection must be suspected in oncohaematological patients with lung infiltrates.

Topics: Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Itraconazole; Leukemia, Promyelocytic, Acute; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Mucormycosis; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We describe an unusual case of disseminated subcutaneous abscesses caused by Nocardia asteroides in a 17-year-old female with AML undergoing allogeneic BMT. She was receiving immunosuppressive therapy with CYA and a corticosteroid for acute GVHD, and maintenance therapy with ganciclovir for interstitial pneumonia (IP) caused by CMV, but was not neutropenic. The subcutaneous abscesses spread from the primary infection on her right anterior leg to both thighs, the left buttock, both upper arms, the left forearm and right shoulder, indicating hematogenous dissemination. Nocardia asteroides was identified from biopsy material in culture. The patient was successfully treated with a combination of trimethoprim/sulfamethoxazole (TMP/SMX) and minocycline, given for 3 months. The possibility of nocardiosis should be considered in the differential diagnosis of such patients.

Topics: Abscess; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Immunocompromised Host; Incidence; Leukemia, Myeloid, Acute; Mercaptopurine; Neutropenia; Nocardia asteroides; Nocardia Infections; Opportunistic Infections; Prednisolone; Remission Induction; Skin Diseases, Infectious

During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 +/- 142 minutes vs 176 +/- 22 minutes, mean +/- SEM). The area under the concentration-time curve (AUC0-infinity) was significantly larger in the evening (24,713 +/- 3536 ng/mL per minute vs 17,120 +/- 1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 min-infinity, 7724 +/- 2955 ng/mL per minute in the evening vs 2597 +/- 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 x 10(9)/L to 2.2 x 10(9)/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78 x 10(9)/L to 1.05 x 10(9)/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Circadian Rhythm; Drug Administration Schedule; Female; Half-Life; Humans; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Neutropenic enterocolitis, also known as typhlitis or ileocecal syndrome, in leukemic patients undergoing chemotherapy has a high reported mortality. A recent increase in the incidence of neutropenic enterocolitis is associated with aggressive chemotherapy for acute leukemia. In this report, we report the incidence, diagnosis, and treatment of neutropenic enterocolitis during low-dose DCMP and high-dose DCMP regimen for 95 adults with acute nonlymphocytic leukemia, and review the literature pertaining appropriate medical and surgical management, and method of prevention. Finally we propose the favorable results of gut sterilization for the treatment and prevention of the disease.

Topics: Adult; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Daunorubicin; Enterocolitis, Pseudomembranous; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Neutropenia; Prednisolone

Methotrexate (MTX) and 6-mercaptopurine (6-MP) are used for maintenance therapy of acute lymphoblastic leukemia (ALL) of childhood, and both are myelotoxic. Clinically the individual tolerance to the two drugs is variable. In order to study to what extent the MTX accumulation in circulating neutrophils is related to the absolute neutrophil count (ANC), neutrophils were isolated on a discontinuous two-step Percoll gradient in 16 children with ALL in maintenance therapy. The MTX concentration in the neutrophils was determined with a sensitive radioligand binding assay. In all children except one who admitted noncompliance, MTX was found in the neutrophils in concentrations (56-460 pmol/10(9) cells) positively correlated with the weekly dose of MTX (r = 0.51, p less than 0.01). The interindividual variation was large. Children with relatively low neutrophil MTX exhibited the widest intraindividual variation of neutrophil MTX upon reexamination during continued MTX administration with the same dosage schedule. Increases in the weekly dose of MTX resulted in proportional increases in the neutrophil MTX. In half the cases the ANC was less than 1.5 X 10(9)/l. The ANC was not related to the weekly MTX dose or the daily 6-MP dose. In children with ANC greater than 1.5 X 10(9)/l there was a significant inverse correlation between the ANC and the neutrophil MTX (r = -0.71, P less than 0.01), which was not found in the group of children with ANC less than 1.5 X 10(9)/l. These findings may be explained by differences in the kinetics of the granulopoiesis between children with high and children with low neutrophil counts.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Separation; Child; Drug Administration Schedule; Humans; Leukemia, Lymphoid; Leukocyte Count; Mercaptopurine; Methotrexate; Neutropenia; Neutrophils; Statistics as Topic

The effect of folic acid supplements on 6-mercaptopurine remission maintenance therapy in lymphoblastic leukaemia (ALL) was investigated in a retrospective longitudinal study of 10 children. Red cell concentrations of 6-thioguanine nucleotide, a cytotoxic metabolite of 6-mercaptopurine, were measured and the peripheral neutrophil count was used as an index of myelosuppression. During the control period of the study there were significant correlations between 6-mercaptopurine dose and 6-thioguanine nucleotide concentration (rs = 0.59, P less than 0.0005) and between 6-thioguanine nucleotide concentration and the peripheral neutrophil count at 14 days (rs = 0.58, P less than 0.0005). These relationships were absent when the same children were subsequently taking folate supplements. Also when taking folate supplements the children tolerated significantly more 6-mercaptopurine (P less than 0.005) for a significantly longer time (P less than 0.005) before neutropenia developed. There was no significant difference in red cell 6-thioguanine nucleotide concentration in the absence and presence of folate supplements. These findings suggest that folate supplements may interfere with remission maintenance therapy in ALL.

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Folic Acid; Humans; Leukemia, Lymphoid; Leukocyte Count; Male; Mercaptopurine; Neutropenia; Neutrophils; Thioguanine

The pharmacokinetics of oral 6-mercaptopurine (6MP) was assessed in 20 children with acute lymphoblastic leukemia during maintenance therapy. The AUC was between 0 and 6 X 10 ng X min/ml, and AUC normalized to 1 mg/m2 of 6MP was between 0 and 815 ng X min/ml. Good correlation existed between peak concentrations and AUC (r = 0.866; P less than 0.001). In more than half of the cases there was evidence of prolonged elimination t1/2 or rebound of a serum concentration during the elimination phase corresponding to either an additional compartment or enterohepatic circulation of 6MP. One child did not achieve detectable concentrations on 2 different study days and was switched to a different protocol. The two children who had severe myelotoxicity achieved the largest AUC values per milligram per square meter of 6MP. Our results indicate that pharmacokinetic variability may contribute to either severe myelotoxicity or therapeutic failures. This suggests that monitoring of this drug in children with acute lymphoblastic leukemia may be helpful.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Kinetics; Leukemia, Lymphoid; Male; Mercaptopurine; Neutropenia

6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P less than 0.01; n = 90 and r = -0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 X 10(8) RBCs. The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Topics: Adolescent; Agranulocytosis; Bone Marrow Diseases; Child; Child, Preschool; Erythrocytes; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Neutropenia; Thioguanine

Topics: Acute Disease; Age Factors; Animals; Antineoplastic Agents; Asparaginase; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Mitosis; Neutropenia; Prednisone; Remission, Spontaneous; Vincristine

Topics: Acute Disease; BCG Vaccine; Central Nervous System Diseases; Humans; Immunosuppression Therapy; Immunotherapy; Leukemia, Lymphoid; Leukocyte Count; Lymphocytes; Lymphopenia; Mercaptopurine; Methotrexate; Neutropenia