mercaptopurine and Hematologic-Diseases

Topics: Abnormalities, Multiple; Abortion, Spontaneous; Collagen Diseases; Cyclophosphamide; Female; Gastrointestinal Diseases; Hematologic Diseases; Immune System Diseases; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Leukopenia; Liver Function Tests; Lymphoma; Mercaptopurine; Methotrexate; Nervous System Diseases; Pregnancy

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

The ENCORE registry aimed at comparing the long-term safety of Crohn's disease [CD] treatment with infliximab [Remicade®] and with conventional therapies in real-world clinical practice.. The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories.. Patients who received infliximab [N = 1541], conventional therapies [N = 1121], or switched to infliximab [N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure-adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]).. Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade®] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azathioprine; Crohn Disease; Demyelinating Diseases; Drug Substitution; Drug Therapy, Combination; Female; Gastrointestinal Agents; Hematologic Diseases; Humans; Immunosuppressive Agents; Infections; Infliximab; Infusions, Intravenous; Lymphoproliferative Disorders; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Mortality; Narcotics; Prednisone; Prospective Studies; Registries; Risk Factors; Sulfasalazine; Time Factors; Young Adult

Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype.. Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0.5%), while the heterozygous TPMT genotype was identified in 8 patients (4.3%). In patients with IBD, leukopenia was observed in ten patients: one had the homozygous TPMT genotype, one the heterozygous genotype, and the remaining eight the wild type genotype.. The frequency of TPMT mutation in a Mediterranean area was low. TPMT genotyping is not a sensitive tool for predicting thiopurine-induced leukopenia.

Topics: Adult; Autoimmune Diseases; Azathioprine; Female; Hematologic Diseases; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Italy; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Mutation; Phenotype; Polymorphism, Genetic

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

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

Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role of the Mrp4, an ATP transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage-dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP.

Topics: Alleles; Animals; Cell Membrane; Cells, Cultured; Cytoprotection; Drug Resistance, Neoplasm; Hematologic Diseases; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Membrane Transport Proteins; Mercaptopurine; Mice; Mice, Knockout; Models, Biological; Multidrug Resistance-Associated Proteins; Polymorphism, Single Nucleotide; Purines; Sulfhydryl Compounds; Survival Analysis; Tissue Distribution

The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome.. Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment.. At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9).. These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.

Topics: Acute Disease; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cytarabine; Daunorubicin; Developing Countries; Disease-Free Survival; Drug Evaluation; Etoposide; Female; Gastrointestinal Diseases; Heart Diseases; Hematologic Diseases; Humans; Infant; Infections; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Prednisone; Remission Induction; Retrospective Studies; Singapore; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine

Burkitt's lymphoma is a rare aggressive lymphoma, which responds poorly to standard chemotherapy regimens used to treat high-grade non-Hodgkin's lymphoma (NHL). The use of intensive chemotherapy protocols using alkylating agents and intensive CNS prophylaxis has dramatically altered prognosis. We have treated eight patients with Burkitt's lymphoma with a modified BFM protocol. The dose of methotrexate was reduced from 5 g/m2 to 1.5 g/m2 with the aim of reducing toxicity. Seven patients received a total of six cycles of chemotherapy each and one patient received five cycles of chemotherapy. Each cycle included high-dose methotrexate, an alkylating agent (ifosphamide or cyclophosphamide) and two triple intrathecal injections of chemotherapy. Two patients with bulky abdominal disease in addition received an autologous stem cell transplant. The regimen was well tolerated with minimal toxicity. At a median follow-up of 16 months (range 10-28), six of the eight patients (75%) were alive and in complete remission. Two patients relapsed, one 24 months post-BFM chemotherapy and the other 1-month post-autologous stem cell transplantation and 2 months post-BFM chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphoma, AIDS-Related; Male; Mercaptopurine; Methotrexate; Prednisone; Recurrence; Remission Induction; Treatment Outcome; Vincristine

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

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

In 40 children suffering from a form of chronic juvenile arthritis (CJA), the authors found encouraging results after immuno-suppressive treatment. Indeed, major corticotherapy, often necessary in these forms, could be stopped in nearly half the cases. The immediate improvement in the clinical signs of the disease was very clear and the signs of corticoid intoxication regressed, and in particular growth was normally resumed in many of the children. While the immediate infectious and hematologic consequences are generally benign, the occurrence of malignant hemopathies at a distance, seen in 3 cases, mean that use of this type of therapy should be totally reconsidered during CJA. The authors feel that because of this grave oncogenic risk, the immunosuppressive treatments should not be reserved merely for forms that involves the vital prognosis in the more or less short run.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Arthritis, Juvenile; Child; Child, Preschool; Chlorambucil; Female; Follow-Up Studies; Genital Diseases, Male; Hematologic Diseases; Humans; Immunosuppressive Agents; Infections; Male; Mercaptopurine; Risk; Time Factors

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: 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: Aminopterin; Child; Child, Preschool; Diagnosis, Differential; Haptoglobins; Hematologic Diseases; Humans; Infant; Infections; Leukemia; Lymphoma; Mercaptopurine; Neuroblastoma; Prednisone

Topics: Animals; Busulfan; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug-Related Side Effects and Adverse Reactions; Folic Acid Antagonists; Haplorhini; Hematologic Diseases; Hematopoiesis; Infections; Leukocyte Count; Leukopenia; Mechlorethamine; Mercaptopurine; Models, Biological; Pyrimidines; Thiotepa; Triethylenemelamine; Vinblastine; Vincristine

Topics: Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Bone Marrow Examination; Busulfan; Chlorambucil; Cortisone; Daunorubicin; Etiocholanolone; Female; Hematologic Diseases; Hodgkin Disease; Humans; Leukemia; Leukocyte Count; Male; Mercaptopurine; Radiation Effects; Vinblastine

Topics: Antineoplastic Agents; Hematologic Diseases; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Multiple Myeloma; Polycythemia Vera; Prednisone; Vincristine; Waldenstrom Macroglobulinemia