thioguanine-anhydrous and Agranulocytosis

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; DNA Nucleotidylexotransferase; Female; Fever; Humans; Infant; Leukemia, Myeloid, Acute; Male; Multivariate Analysis; Random Allocation; Receptors, Glucocorticoid; Recurrence; Remission Induction; Retrospective Studies; Survival Rate; Thioguanine; Tumor Cells, Cultured; Vincristine

To investigate the value of maintenance chemotherapy after early consolidation treatment, an attempt was made to induce remission in 162 previously untreated patients, age-range 7-65 years (median 43). The 74 patients who were still in remission after early consolidation treatment (given for 3-5 months) were assigned to either maintenance chemotherapy every 8 weeks for 2 years or to observation only. After a median observation period of 44 months there was no difference between the groups in duration of remission or survival. Surprisingly, patients above 40 survived longer after early consolidation (median 4 years) than did patients aged 40 and below (median 1.6 years, p = 0.0002).

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Clinical Trials as Topic; Cytarabine; Evaluation Studies as Topic; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Prognosis; Random Allocation; Thioguanine; Thrombocytopenia; Vincristine

Topics: Adult; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Critical Care; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Humans; Leukemia, Myelomonocytic, Acute; Male; Multiple Organ Failure; Pneumonia; Shock, Septic; Thioguanine; Time Factors

Topics: Agranulocytosis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Depression, Chemical; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Mitoxantrone; Mycoses; Thioguanine; Thrombocytopenia

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

Implications and course of fever were evaluated during hospitalization of 24 patients with acute myelogenous leukemia. Forty-five febrile episodes were identified. Fever present at admission was usually associated with a diagnosable and treatable infection; fever shortly after induction was self-limited; and fever during granulocytopenia was more likely to be associated with bacteremia. Bacteremia and pneumonia were the most common types of infection. Only Gram-negative bacteria and Candida were identified as causes of infection during life, with Pseudomonas and Klebsiella the most frequently isolated pathogens. Invasive candidiasis was a major postmortem finding. A delay in initiation of empirical treatment beyond the third day of fever was associated with an increase in mortality as was continuation of treatment for longer than 14 days.

Topics: Agranulocytosis; Anti-Bacterial Agents; Candidiasis; Cytarabine; Daunorubicin; Fever; Humans; Klebsiella Infections; Leukemia, Myeloid, Acute; Pseudomonas Infections; Thioguanine