mercaptopurine and Thrombocytopenia

Different hematologic abnormalities are often encountered in patients with inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs. Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. We present two cases with combination of these entities along with a literature review and treatment options. Immune thrombocytopenic purpura in these patients presented as an extraintestinal manifestation of inflammatory bowel disease mediated by a disturbance of the immune system.

Topics: Adolescent; Adult; Anemia; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytosis; Leukopenia; Male; Mercaptopurine; Prednisone; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombocytosis

Topics: Aged; Agglutination Tests; Alkaloids; Alkylating Agents; Anti-Bacterial Agents; Anticonvulsants; Antigen-Antibody Reactions; Azathioprine; Blood Cell Count; Blood Platelet Disorders; Blood Platelets; Bone Marrow; Bone Marrow Examination; Clot Retraction; Complement Fixation Tests; Cytarabine; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Humans; Hypoglycemic Agents; Infant, Newborn; Kidney Function Tests; Liver Function Tests; Male; Mercaptopurine; Middle Aged; Prothrombin Time; Thrombocytopenia; Tranquilizing Agents; Vinblastine; Vincristine

Topics: Adolescent; Adult; Antineoplastic Agents; Central Nervous System Diseases; Child; Cyclophosphamide; Cytarabine; Female; Guanidines; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Nitroso Compounds; Prednisone; Thrombocytopenia; Urea; Uric Acid; Vincristine

More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD.. In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]).. Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85).. Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Dosage Calculations; Female; Gastrointestinal Agents; Genetic Testing; Genetic Variation; Heterozygote; Homozygote; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Netherlands; Pharmacogenetics; Phenotype; Predictive Value of Tests; Prospective Studies; Risk Factors; Thrombocytopenia; Treatment Outcome; Young Adult

A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA.. After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).. After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity.. Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Crohn Disease; Dose-Response Relationship, Drug; Erythrocyte Indices; Female; Genotype; Guanine Nucleotides; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Remission Induction; Thionucleotides; Thrombocytopenia

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

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

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

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

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

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

Topics: Adolescent; Adult; Age Factors; Aged; Asparaginase; Blood Platelets; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocytes; Male; Mercaptopurine; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Thrombocytopenia

Topics: Adenocarcinoma; Anemia; Bone Marrow Diseases; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Colonic Neoplasms; Humans; Leukopenia; Lung Neoplasms; Mercaptopurine; Nausea; Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Thrombocytopenia; Vomiting

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

Topics: Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Agents; Genetic Variation; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Thrombocytopenia

Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.

Topics: Adult; Chemical and Drug Induced Liver Injury; Crohn Disease; Disease Progression; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine; Thrombocytopenia

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 development of xanthogranulomas has been linked to hematologic malignancies in children and adults, based on a number of reports in the literature. In children, a specific association between juvenile xanthogranuloma, neurofibromatosis 1, and juvenile myelomonocytic leukemia has been described. We report a case of a 9-month-old child, without a known diagnosis of neurofibromatosis 1, who presented with hepatosplenomegaly, anemia, thrombocytopenia, and multiple cutaneous nodules, which were confirmed to be juvenile xanthogranulomas upon biopsy. A concurrent work-up showed that the child had juvenile myelomonocytic leukemia. Although cutaneous juvenile xanthogranulomas are benign lesions, in several reported cases they have been shown to herald leukemia. This association between xanthogranulomas and hematologic malignancy is poorly understood. Juvenile xanthogranulomas have a number of morphologic variants and clinical presentations that can be confused with the cutaneous lesions of Langerhans cell histiocytosis and dermatofibroma. Recognition of the broad clinicopathologic spectrum of juvenile xanthogranulomas is critical for proper diagnosis.

Topics: Anemia; Antimetabolites; Hepatomegaly; Humans; Infant; Leukemia, Myelomonocytic, Juvenile; Male; Mercaptopurine; Splenomegaly; Stem Cell Transplantation; Thrombocytopenia; Treatment Outcome; Xanthogranuloma, Juvenile

Thiopurines (azathioprine and 6-mercaptopurine) can induce life-threatening myelosuppression. This study determined the frequency, timing, and outcomes of mild and severe myelosuppression after initiation of thiopurine therapy.. This retrospective cohort study included patients with inflammatory bowel disease who were new users of thiopurines; those tested for thiopurine methyltransferase levels before therapy were excluded. Patients were followed from their first thiopurine prescription until the earliest of severe leukopenia (white blood cell count, <1.0 x 10(9)/L), severe thrombocytopenia (platelet level, <20 x 10(9)/L), the end of therapy, the first gap in therapy, disenrollment, or December 31, 2006.. Among 1997 new users, the incidence of severe leukopenia per 100 person-months was 0.16 (95% confidence interval [CI], 0.03-0.29; n = 6) in weeks 0 to 8, 0.00 in weeks 9 to 24, and 0.01 (95% CI, 0-0.03; n = 3) after week 26 of therapy. The incidence of severe neutropenia and severe thrombocytopenia per 100 person-months during the first 8 weeks of therapy was 0.51 (95% CI, 0.31-0.80; n = 19) and 0.08 (95% CI, 0.02-0.23; n = 3), respectively. During the first 8 weeks, the median duration from a normal white blood cell count to severe leukopenia was 13 days (range, 8-26 d) and to severe neutropenia was 14 days (range, 7-23 d).. The high incidence of severe myelosuppression justifies frequent monitoring during the first 8 weeks of therapy. Subsequently, the rate of severe myelosuppression and the proportion of patients who progress from mild to severe myelosuppression decrease, justifying less-frequent monitoring.

Topics: Adult; Aged; Antimetabolites; Azathioprine; Bone Marrow; Cohort Studies; Drug Monitoring; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thrombocytopenia; Time Factors; Treatment Outcome

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

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

Measurement of thiopurine metabolite levels may be useful as a clinical tool to optimize thiopurine treatment of paediatric inflammatory bowel disease (IBD).. The authors evaluated correlations between 6-thioguanine nucleotide (6-TGN) and therapeutic response, metabolite levels and drug toxicity.. Fifty-six paediatric IBD patients treated with thiopurines had 326 metabolite level measurements and were retrospectively reviewed. Clinical status and laboratory parameters were compared with metabolite levels.. There was significant correlation between 6-TGN levels and therapeutic response, with higher median 6-TGN levels among patients with therapeutic response than those with non-therapeutic response (194 vs. 146 pmol/8 x 10(8) RBC; P = 0.0004). Patients with 6-TGN levels >235 pmol/8 x 10(8) RBC were more likely to achieve therapeutic response than those below the cut-off (odds ratio, 2.5; 95% CI, 1.5-4.1). Patients who developed leukopenia tended to have higher median 6-TGN levels than those without leukopenia (261 vs. 160 pmol/8 x 10(8) RBC) but the difference was not statistically significant. There was no correlation between 6-methylmercaptopurine levels and hepatotoxicity. Two patients developed acute pancreatitis. Metabolite level measurements were helpful in identifying non-compliance in nine patients.. Monitoring of thiopurine metabolite levels is useful to guide and optimize dosing, as an adjunct to clinical judgement, blood count and liver biochemistry measurements to minimize the risk of drug toxicity and to confirm non-compliance.

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine; Thrombocytopenia; Treatment Refusal

Hepatic dysfunction is a rare presentation of leukemia in children. Because most chemotherapy agents are metabolized by the liver, this complication may have major adverse consequences and effective treatment could be compromised.. The MEDLINE database and current management guidelines from the United States Pediatric Cooperative Cancer Groups were reviewed and analyzed. Data from two institutional cases are described.. Although previous literature is not informative, our experience suggests that children with leukemia and moderate hepatic dysfunction may tolerate aggressive chemotherapy.. Current protocol guidelines for dose modification for liver disease may be overly stringent and modification may be beneficial.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Child, Preschool; Cholestasis, Intrahepatic; Chromosome Deletion; Daunorubicin; Hepatomegaly; Humans; Liver; Liver Function Tests; Male; Mercaptopurine; Methotrexate; Practice Guidelines as Topic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Thrombocytopenia; Ultrasonography; Vincristine

To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.. TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.. Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.. There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Female; Genotype; Hospitalization; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Neoplasms; Phenotype; Platelet Transfusion; Polymorphism, Restriction Fragment Length; Risk Factors; Thrombocytopenia

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

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

A feared complication of therapy with 6-mercaptopurine (6-MP) is myelosuppression. To evaluate whether rigorous blood count monitoring is necessary, we prospectively followed the hematologic profiles of 57 patients with inflammatory bowel disease who were treated with low-dose 6-MP. Most patients (97%) were treated initially with a single dose of 50 mg/day and 79% never used more than 50 mg/day. Blood counts were obtained at weekly intervals over the first month, every two weeks for the second month, and monthly thereafter in the first year. Sixteen (28%) developed mild leukopenia (white blood count < 4.5 x 10(3)/mm3). No patient had a white blood cell count < 2.8 x 10(3)/mm3 and no patient developed leukopenia prior to three months of treatment. In only five patients did the leukopenia prompt a change in 6-mercaptopurine dose. Very mild thrombocytopenia (platelet count of < 145 x 10(3)/mm3) developed in three (5%) and macrocytosis (mean cell volume > 101 fl) was seen in nine (16%). In conclusion, leukopenia was not uncommon in patients treated with low-dose 6-MP, but was not clinically significant. Leukopenia occurred no earlier than three months and as late as 42 months into therapy. Thrombocytopenia was uncommon, mild, and was not associated with apparent bleeding. Macrocytosis may occur in the absence of vitamin B12 and folate deficiencies. Patients can be spared from weekly blood count monitoring when using low-dose 6-mercaptopurine treatment.

Topics: Anemia, Macrocytic; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Monitoring, Physiologic; Prospective Studies; Thrombocytopenia

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

Topics: Adolescent; Adult; Agranulocytosis; Child; Child, Preschool; Drug Evaluation; Humans; Infant; Infusions, Intravenous; Liver; Mercaptopurine; Neoplasms; Thrombocytopenia

Topics: Allopurinol; Anaphylaxis; Anemia; Antibiotics, Antineoplastic; Bicarbonates; Blood Transfusion; Child; Child, Preschool; Cystitis; Disseminated Intravascular Coagulation; Erythrocytes; Female; Furosemide; Heart Arrest; Heparin; Humans; Hydrogen-Ion Concentration; Kidney; Leukemia; Lung Diseases; Male; Mercaptopurine; Mutation; Neoplasms; Phospholipids; Renal Dialysis; Thrombocytopenia; Uric Acid

A 3 months old girl presented with significant enlargement of liver, spleen and lymphnodes, with moderate anemia, thrombopenia and leucocytosis. In the differential count there was a shift to the left and an increase of monocyte-like cells (35%). Differential diagnosis included leucemoid reaction, infectious mononucleosis, myelo-proliferative disorder with a missing C chromosome and chronic myeloid leucemia. Clinical symptoms, cytochemistry and caryotype of bone marrow cells suggested infantile chronic myeloic leucemia and normal ALP index and possibly normal HbF. Treatment with 6-mercaptopurine was followed by partial remission. The therapeutic consequences of exact differential diagnosis are discussed.

Topics: Anemia; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Humans; In Vitro Techniques; Infant; Infectious Mononucleosis; Leukemia, Myeloid; Leukocytosis; Liver Diseases; Lymphatic Diseases; Mercaptopurine; Myeloproliferative Disorders; Splenic Diseases; Thrombocytopenia

Topics: Animals; Antineoplastic Agents; Blood Platelets; Bone Marrow; Bone Marrow Cells; Deoxyribonucleosides; Diarrhea; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Erythrocyte Count; Feeding and Eating Disorders; Female; Haplorhini; Hematocrit; Humans; Injections, Intravenous; Leukocyte Count; Leukopenia; Lymphocytes; Macaca; Male; Mercaptopurine; Neutrophils; Thrombocytopenia; Time Factors; Vomiting

Topics: Anemia, Pernicious; Blood Cell Count; Bone Marrow Cells; Cytarabine; Cytoplasm; Follow-Up Studies; Hematologic Diseases; Humans; In Vitro Techniques; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Megakaryocytes; Mercaptopurine; Plasmacytoma; Polycythemia; Thioguanine; Thrombocytopenia

Topics: Agranulocytosis; Anemia, Aplastic; Anti-Bacterial Agents; Antineoplastic Agents; Asparaginase; Blood Platelets; Blood Transfusion; Cytarabine; Daunorubicin; Drug Therapy, Combination; Hemorrhage; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Mercaptopurine; Methotrexate; Prednisone; Thrombocytopenia; Vincristine

Topics: Adolescent; Appendicitis; Child; Child, Preschool; Gastrointestinal Diseases; Humans; Hypersplenism; Infant; Intestinal Obstruction; Intussusception; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Pancreatitis; Postoperative Complications; Prednisone; Thrombocytopenia; Time Factors

Topics: Adolescent; Adult; Age Factors; Aged; Blood Platelets; Blood Transfusion; Cytarabine; Daunorubicin; Female; Humans; Hydrazines; Hyperplasia; Leukemia, Myeloid; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission, Spontaneous; Thrombocytopenia; Time Factors

Topics: Adolescent; Agranulocytosis; Anemia; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Synergism; Female; Hemorrhage; Humans; Infant; Injections, Intravenous; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Mercaptopurine; Neutrophils; Prednisolone; Thrombocytopenia; Vincristine

Topics: Anemia, Hemolytic, Autoimmune; Azathioprine; Humans; Immunosuppressive Agents; Mercaptopurine; Thrombocytopenia

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Thrombelastography; Thrombocytopenia; Vinblastine

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Humans; Male; Mercaptopurine; Middle Aged; Splenectomy; Thrombocytopenia

Topics: Adolescent; Adult; Aged; Alopecia; Ampicillin; Anemia, Aplastic; Antibiotics, Antineoplastic; Blood Platelets; Blood Transfusion; Cardiomyopathies; Cephaloridine; Electrocardiography; Female; Heart; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Paresthesia; Remission, Spontaneous; Sulfamethoxazole; Thrombocytopenia; Trimethoprim

Topics: Anemia, Hemolytic, Autoimmune; Anti-Bacterial Agents; Antimetabolites; Blood Specimen Collection; Bone Marrow Diseases; Busulfan; Chromosome Aberrations; Diuretics; Hodgkin Disease; Humans; Karyotyping; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemoid Reaction; Mercaptopurine; Prednisone; Specimen Handling; Thrombocytopenia; Time Factors

Topics: Adolescent; Adult; Aged; Agranulocytosis; Allopurinol; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Blood Transfusion; Cytarabine; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Muramidase; Nausea; Prednisolone; Thrombocytopenia; Vincristine

Topics: Anemia, Hemolytic; Antineoplastic Agents; Autoimmune Diseases; Azathioprine; Collagen Diseases; Humans; Lupus Erythematosus, Systemic; Mercaptopurine; Sjogren's Syndrome; Thrombocytopenia

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Agranulocytosis; Anemia, Hemolytic, Autoimmune; Azathioprine; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Mercaptopurine; Middle Aged; Prednisone; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Adolescent; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Agranulocytosis; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Azathioprine; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Middle Aged; Prednisone; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia

Topics: Animals; Antineoplastic Agents; Asparaginase; Blood Platelets; Bone Marrow Cells; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Models, Animal; Drug Synergism; Hemorrhage; Humans; Infections; Leukemia L1210; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Mice; Prednisone; Prognosis; Thrombocytopenia; Vincristine

Topics: Adolescent; Adult; Aged; Anemia, Hemolytic, Autoimmune; Autoimmune Diseases; Dactinomycin; Female; Granuloma, Lethal Midline; Humans; Male; Mercaptopurine; Middle Aged; Prednisone; Purpura, Thrombocytopenic; Thrombocytopenia

Topics: Adolescent; Adult; Aged; Anemia; Blood Platelets; Blood Transfusion; Blood Urea Nitrogen; Bone Marrow Cells; Bone Marrow Examination; Chromosome Aberrations; Cytomegalovirus; Female; Fever; Hemorrhage; Humans; Jaundice; Leukemia, Myeloid; Leukocyte Count; Leukocytes; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Nocardia Infections; Pneumonia; Prednisone; Proteus Infections; Pseudomonas Infections; Sepsis; Thrombocytopenia; Vincristine

Topics: Acetazolamide; Acute Kidney Injury; Adult; Allopurinol; Anuria; Bicarbonates; Blood Gas Analysis; Blood Urea Nitrogen; Carbon Dioxide; Cystoscopy; Electroencephalography; Eye Manifestations; Female; Humans; Leukemia, Lymphoid; Leukocytosis; Mannitol; Mercaptopurine; Methotrexate; Peritoneal Dialysis; Prednisone; Splenomegaly; Thrombocytopenia; Uric Acid; Urinary Catheterization; Vincristine; Water-Electrolyte Balance

Topics: Adolescent; Adult; Aged; Azathioprine; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Middle Aged; Nitrogen Mustard Compounds; Thrombocytopenia

Topics: Adolescent; Adult; Female; Hepatitis; Humans; Leukopenia; Liver Cirrhosis; Male; Mercaptopurine; Middle Aged; Prednisolone; Thrombocytopenia

Topics: Alkylating Agents; Carbamates; Chlorambucil; Fluorouracil; Humans; Leukocyte Count; Leukopenia; Mercaptopurine; Mitomycins; Neoplasms; Thrombocytopenia

Topics: Adolescent; Blood Platelets; Blood Transfusion; Chronic Disease; Female; Humans; Infant; Male; Mercaptopurine; Prednisone; Thrombocytopenia; Vincristine

Topics: Adrenal Cortex Hormones; Alkylating Agents; Child; Cyclophosphamide; Drug Therapy; Herpes Zoster; Hodgkin Disease; Leukemia; Lymphoma; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Prednisolone; Surgical Procedures, Operative; Thrombocytopenia

Topics: Adolescent; Adult; Anemia, Aplastic; Biopsy; Child; Female; Humans; Kidney; Leukopenia; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Microscopy, Electron; Nephrotic Syndrome; Proteinuria; Thrombocytopenia

Topics: Anemia; Anemia, Hemolytic; Betamethasone; Chlorambucil; Dexamethasone; Geriatrics; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Non-Hodgkin; Mechlorethamine; Mercaptopurine; Methylprednisolone; Pharmacology; Prednisone; Radiotherapy; Thrombocytopenia; Triamcinolone

Topics: Adolescent; Adrenal Cortex Hormones; Child; Humans; Infant; Infant, Newborn; Mercaptopurine; Physiology; Purpura; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Animals; Gastropoda; Humans; Mercaptopurine; Prednisone; Purpura; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Bone Marrow; Injections, Intravenous; Leukopenia; Mercaptopurine; Mice; Neoplasms; Nucleosides; Pharmacology; Purines; Pyrimidines; Research; Thioinosine; Thrombocytopenia; Toxicology

Topics: Adrenal Cortex Hormones; Humans; Mercaptopurine; Purpura; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Afibrinogenemia; Blood Cell Count; Bone Marrow Examination; Drug Therapy; Factor V Deficiency; Fibrinogen; Humans; Hypoprothrombinemias; Leukemia; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Mercaptopurine; Pathology; Statistics as Topic; Thrombocytopenia

Topics: Adrenal Cortex Hormones; Chromium Isotopes; Drug Therapy; Hemagglutination; Humans; Mercaptopurine; Prednisone; Purpura; Purpura, Thrombocytopenic; Splenectomy; Thrombocytopenia

Topics: Adrenal Cortex Hormones; Alkaline Phosphatase; Blood Cell Count; Bone Marrow Examination; Busulfan; Child; Chromosome Aberrations; Drug Therapy; Hemoglobins; Humans; Infant; Leukemia; Leukemia, Myeloid; Mercaptopurine; Splenomegaly; Thrombocytopenia

Topics: Blood Platelet Disorders; Busulfan; Child; Humans; Leukemia; Leukemia, Myeloid; Leukocytosis; Lymph Nodes; Mercaptopurine; Prednisone; Primary Myelofibrosis; Radiotherapy; Thrombocytopenia; Triamcinolone