thioguanine-anhydrous and Infections

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Chlorambucil; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Granulomatosis with Polyangiitis; Hepatitis; Humans; Immune Complex Diseases; Immunosuppressive Agents; Infections; Liver Cirrhosis, Biliary; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Nephrotic Syndrome; Ophthalmia, Sympathetic; Psoriasis; Thioguanine; Uveitis

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

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

Treatment of children with acute lymphoblastic leukaemia (ALL) aims to cure all patients with as little toxicity as possible and, if possible, to restrict further intensification of chemotherapy to patients with an increased risk of relapse. However in Medical Research Council (MRC) trial UKALL X two short myeloablative blocks of intensification therapy given at weeks 5 and 20 were of benefit to children in all risk groups. The successor trials, MRC UKALL XI and MRC ALL97, tested whether further intensification would continue to benefit all patients by randomising them to receive, or not, an extended third intensification block at week 35. After a median follow-up of 4 years (range 5 months to 8 years), 5 year projected event-free survival was superior at 68% for the 894 patients allocated a third intensification compared with 60% for the 887 patients who did not receive one (odds ratio 0.75, 95% CI 0.63-0.90, 2P = 0.002). This difference was almost entirely due to a reduced incidence of bone marrow relapses in the third intensification arm (140 of 891 in the third intensification arm vs. 171 of 883 in the no third intensification, 2P = 0.02). Subgroup analysis suggests benefit of the third intensification for all risk categories. Overall survival to date is no different in the two arms, indicating that a greater proportion of those not receiving a third intensification arm and subsequently relapsing can be salvaged. These results indicate that there is benefit of additional intensification for all risk subgroups of childhood ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Humans; Infant; Infections; Male; Methotrexate; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Proportional Hazards Models; Remission Induction; Risk; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine

Forty-eight patients with acute myelogenous leukemia (AML) not eligible for anthracycline or mitoxantrone treatment, mostly due to cardiac contraindications, were given aggressive therapy using m-amsacrine (AMSA) in combination with conventional or high-dose cytarabine for remission induction. Twenty-nine patients (60.4%) responded to treatment, and complete remission was attained in 19 (39.6%), partial remission in 4 (8.3%) and death in bone marrow aplasia without detectable blasts in 6 patients (12.5%). Median time to granulocyte recovery was 32 days, median duration of relapse-free survival 199 days. One patient experienced a serious cardiac adverse event; nausea and vomiting were observed in 73%, diarrhea in 44%, and hepatoxicity in 29% of patients. All potentially AMSA-related side effects were fully reversible, and a lethal complication did not occur. It is concluded that combination chemotherapy with AMSA and Ara-C is also effective and tolerable in leukemic patients in whom cardiotoxic drugs are contraindicated.

Topics: Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Heart Diseases; Humans; Incidence; Infections; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Middle Aged; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome

One hundred thirty-nine consecutive unselected adults with acute nonlymphoblastic leukemia were treated with a high-dose chemotherapeutic remission-induction regimen consisting of daunomycin (70 mg/m2 IV on days 1, 2, 3), cytosine arabinoside (100 mg/m2 IV every 12 hours), 6-thioguanine (100 mg/m2 orally every 12 hours), prednisone (40 mg/m2 daily), all given on days 1 through 7, and vincristine (1 mg/m2 IV on days 1 and 7). Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and prophylactic platelet transfusions. The complete remission (CR) rate was 60%. The median number of days to CR was 30. Fifty-eight of 77 (75%) patients under age 50 and 26 of 62 (42%) patients over age 50 attained CR. Despite the use of a relatively large dose of daunomycin and monthly maintenance chemotherapy, the median remission duration was only 39 weeks and the medial survival 64 weeks. Most patients who failed to achieve CR died early-77% of deaths occurred within the first six weeks. Infections accounted for the increase mortality in patients over age 50. Thirty-seven percent of patients over age 50 died of infections whereas only 10% under age 50 did so (P less than 0.001). Seven percent of the patients died of fungal infection during attempted remission induction. The incidence of resistance of the leukemia to the remission-induction regimen was low (8%).

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Infections; Leukemia; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Abnormalities, Drug-Induced; Adult; Aged; Azathioprine; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Cost-Benefit Analysis; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Hypersensitivity; Drug Interactions; Female; Genetic Testing; Humans; Immunosuppressive Agents; Infections; Kidney Diseases; Lactation; Male; Methyltransferases; Nausea; Neoplasms; Off-Label Use; Patient Education as Topic; Pregnancy; Risk Factors; Skin Diseases; Thioguanine; Virus Diseases

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

Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years (range 20-70 years). According to the development of infectious complications the patients were assigned retrospectively to group 1 (no or only mild infections, n = 29) or to group 2 (severe infection or death due to infection, n = 15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7+/-13.7 (SEM) vs 170.0+/-19.2, mean channel fluorescence; p =0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in group 2 (24.8+/-6.1 vs 14.5+/-3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters could help to estimate the individual risk of infection for a patient with ANLL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Fever; Humans; Idarubicin; Immunocompromised Host; Infections; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Mitoxantrone; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils; Phagocytosis; Respiratory Burst; Retrospective Studies; Risk Factors; Thioguanine; Vidarabine

Eighty two children with acute lymphoblastic leukaemia presenting at this hospital received one or two modules of intensive chemotherapy to consolidate remission. Modules were given after four and roughly 19 weeks on treatment. Each included two doses of daunorubicin (45 mg/m2/day), cytosine arabinoside (100 mg/m2 twice daily X 5), etoposide (100 mg/m2/day X 5), and 6-thioguanine (80 mg/m2/day X 5). A total of 132 courses were given. This study included all new patients except girls aged 1-14 years with presenting leucocyte count less than 20 X 10(9)/l. Twenty patients with recurrent disease were also included. The first 32 patients were given cytosine as a 24 hour infusion, but combined with the other agents this was associated with severe intestinal toxicity, which necessitated a change to a less toxic 12 hourly bolus regimen. The complications of the module are reviewed in terms of myelosuppression, enterotoxicity, infection, and other clinical problems encountered. All patients became profoundly neutropenic and thrombocytopenic. The latter was significantly more severe after cytosine infusion. Overall, 64% received platelet transfusions and 85% were re-admitted with fevers requiring intravenous antibiotics for between four and 56 days. Gastrointestinal toxicity with the modified module occurred in 38% of patients and was severe in 13%. This intensification module has been adopted by the Medical Research Council Working Party on Childhood Leukaemia for use in a multicentre study (UKALL X) and the details of the problems encountered in the pilot study may be of value to other centres now using this protocol.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Infections; Leukemia, Lymphoid; Male; Neutropenia; Pilot Projects; Thioguanine; Thrombocytopenia

Twenty-seven patients over 60 years of age with acute nonlymphocytic leukemia (ANLL) were prospectively treated with one of three intensive chemotherapeutic regimens. Complete remissions were achieved in eight patients (30%). Remissions were obtained in seven of 14 patients (50%) age 61 to 70 years, but in only one of 13 patients (8%) 71 years and older. The most effective regimen in patients 61 to 70 years consisted of a combination of daunorubicin and cytosine arabinoside. The median duration of remission for all eight responders is 9+ months and their median survival is 14+ months. Intensive therapy is indicated in the elderly patient 61 to 70 years of age with ANLL.

Topics: Acute Disease; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infections; Length of Stay; Leukemia; Male; Middle Aged; Prednisone; Prospective Studies; Remission, Spontaneous; Thioguanine; Time Factors

Topics: Administration, Oral; Adolescent; Age Factors; Antineoplastic Agents; Asparaginase; Carmustine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Hydroxyurea; Infant; Infections; Injections, Intravenous; Leukemia, Lymphoid; Male; Meningitis; Methotrexate; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine