thioguanine-anhydrous and Down-Syndrome

There have been several reports of the association between Down's Syndrome and acute megakaryoblastic (M7) leukemia (AMKL). The diagnosis of this rare form of leukemia has been better delineated by the use of the platelet peroxidase reaction and the antifactor VIII antibody immunoperoxidase test. In the past, the prognosis of patients with a combination of Down's Syndrome and AMKL has been extremely poor, with a median survival of 6.9 months for 11 reported cases in the literature. The present report reviews the previously reported cases and describes a unique patient with mosaic Down's syndrome and AMKL with favorable response to therapy.

Topics: Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 17; Clone Cells; Cyclophosphamide; Cytarabine; Down Syndrome; Doxorubicin; Etoposide; Female; Humans; Hydrocortisone; Infant; Leukemia, Megakaryoblastic, Acute; Methotrexate; Mosaicism; Prednisone; Thioguanine; Trisomy

Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891).. COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).. The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/μL (range, 900-164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001).. The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Down Syndrome; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Thioguanine; Treatment Outcome

We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m2 body surface area twice daily for 4 days. Etoposide, 100 mg/m2/24 h, and cytarabine, 200 mg/m2/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 micromol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Down Syndrome; Doxorubicin; Drug Administration Schedule; Drug Monitoring; Erythrocytes; Etoposide; Female; Guanine Nucleotides; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Registries; Scandinavian and Nordic Countries; Thioguanine; Thionucleotides; Treatment Outcome

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

Topics: Adolescent; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Cytogenetic Analysis; Daunorubicin; Down Syndrome; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Leukemia, Myeloid; Leukocyte Count; Male; Mitoxantrone; Thioguanine; Treatment Outcome; United Kingdom

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cross-Sectional Studies; Cytarabine; Down Syndrome; Doxorubicin; Humans; Iceland; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Multicenter Studies as Topic; Preleukemia; Remission Induction; Scandinavian and Nordic Countries; Survival Rate; Thioguanine

Infections still remain a major cause of therapy-associated morbidity and mortality in children with acute myeloid leukemia (AML). To improve supportive care measurements, detailed information on frequency and characteristic features of infectious complications is needed. We retrospectively analyzed the medical charts of 304 children, treated in 30 hospitals according to the multi-institutional clinical trial AML-BFM 93. Overall, 855 infectious complications occurred in 304 patients (fever without identifiable source (n=523; 61.2%), clinically (n=57; 6.7%) and microbiologically documented infections (n=275; 32.1%)). Neutropenia was present in 74.1% of the infectious episodes. In all, 20 patients died of infection-associated complications (15/276 (5.4%) patients without and 5/28 (17.9%) with Down syndrome), most of them during early induction therapy (n=11). Blood stream infections occurred in 228 episodes (Gram-positive (n=202) and Gram-negative (n=42) pathogens). Invasive fungal infection was probable or proven in 15 patients. In 113 out of the 855 infectious episodes (13.3%), pneumonia was radiologically diagnosed. Better strategies of supportive care might help to improve overall survival in children undergoing chemotherapy for AML. Therefore, children with AML should be treated in specialized pediatric centers, and there should be a very low threshold to readmit patients, in particular patients with pulmonary symptoms.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Bacteria; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Down Syndrome; Etoposide; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Male; Mitoxantrone; Neutropenia; Prospective Studies; Retrospective Studies; Thioguanine

The incidence of acute leukemia in children with Down syndrome (DS) is high as compared to general population. Recent findings have demonstrated that DS children with acute myeloid leukemia (AML) have the highest event free survival rates with high dose cytosine arabinoside (Ara-C). We present 3 year-old DS female child with AML-M5, whose chromosomal analysis revealed constitutional t(21;21) alongwith del(5)(q31q33) and a unique translocation t(16;20)(q13;q12). After chemotherapy, child achieved complete clinical remission. Karyotype analysis of remission marrow showed disappearance of abnormal clone of der(20) t(16;20)(q13;q12), del(5q) indicating cytogenetic remission too. This case alongwith supportive literature indicate that pediatric DS-AML is a distinct biologic sub-group differs from that of non-DS-AML with respect to chemosensitivity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Cytarabine; Daunorubicin; Down Syndrome; Female; Humans; Leukemia, Monocytic, Acute; Thioguanine; Translocation, Genetic

Children with Down syndrome (DS) have an increased risk for leukemia. The prognosis for DS acute myeloid leukemia (AML) is better than for non-DS AML, but the clinical outcome of DS acute lymphoblastic leukemia (ALL) is equal to that of non-DS ALL. Differences in prognosis may reflect differences in cellular drug resistance. In vitro drug resistance profiles were successfully investigated on leukemic cells from 13 patients with DS AML and 9 patients with DS ALL and were compared with reference data from 151 non-DS AML and 430 non-DS B-cell precursor (BCP) ALL. DS AML cells were significantly more sensitive to cytarabine (median, 12-fold), the anthracyclines (2-7-fold), mitoxantrone (9-fold), amsacrine (16-fold), etoposide (20-fold), 6-thioguanine (3-fold), busulfan (5-fold), vincristine (23-fold), and prednisolone (more than 1.1-fold), than non-DS AML cells. Compared with DS ALL, DS AML cells were significantly more sensitive to cytarabine only (21-fold). After short-term exposure to methotrexate, DS AML cells were 21-fold more resistant than non-DS AML cells, but no difference was observed after continuous exposure. DS ALL cells and non-DS BCP-ALL cells were equally sensitive to all drugs, including methotrexate. Normal peripheral blood mononuclear cells from DS and non-DS children without leukemia showed highly resistant drug profiles. It was concluded that the better prognosis of DS AML might, at least partially, be explained by a specific, relatively sensitive drug-resistance profile, reflecting the unique biology of this disease. (Blood. 2002;99:245-251)

Topics: Amsacrine; Anthracyclines; Antineoplastic Agents; Busulfan; Cell Survival; Child; Child, Preschool; Cytarabine; Down Syndrome; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Thioguanine; Vincristine

Topics: Antineoplastic Agents; Blast Crisis; Cell Survival; Child; Cytarabine; Dexamethasone; Down Syndrome; Doxorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

Patients with trisomy 21 have an increased incidence of haematological disorders, including neonatal 'leukaemoid reaction' (transient myeloproliferative disorder [TMD]), and acute leukaemias. In the past it has been felt that patients with trisomy 21 and acute leukaemia do not tolerate, and hence may not warrant, therapy as intensive as those without the syndrome. The present authors' experience and the current literature do not support this view. Two cases are reported of acute myeloid leukaemia in children with trisomy 21, successfully treated with intensive chemotherapy and bone marrow transplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cytosine; Daunorubicin; Down Syndrome; Female; Follow-Up Studies; Health Care Rationing; Humans; Infant; Leukemia, Myeloid, Acute; Male; Thioguanine; Treatment Outcome

The treatment of acute myeloid leukemia (AML) in children with Down's syndrome (DS) has engendered considerable controversy. Because of the concerns for toxicity and increased rate of infections, treatment approaches varied considerably in the past with mixed results. However, experience on the recently completed Pediatric Oncology Group (POG) 8498 AML study suggests that DS children with AML constitute a distinct subgroup that responds well to therapy. Twelve of 285 children on POG 8498 (protocol for newly diagnosed AML) had DS. Children with DS and AML were predominantly male (9 of 12) and were quite younger at diagnosis (< 24 months in 10). The white blood cell count was less than 50 x 10(3)/microL in all 12 and French-American-British types M6 and M7 were frequent (5 of 12). An abnormal cytogenetic marker, in addition to constitutional trisomy 21, was present in 9 of 12 and involved chromosome 8 in 4 of 9. All cases studied (n = 5) were positive for myeloid cell surface markers (CD33, CD13, or CD11b) and, interestingly, were also positive for the CD7 antigen. Chemotherapy included daunorubicin, cytarabine (Ara-C), and 6-thioguanine for remission induction and featured high-dose Ara-C (3 g/m2 per dose) with or without L-asparaginase early in remission. Compared with children without DS, children with DS had a superior event-free survival (EFS at 4 years 100% v 28% +/- 6.2%; P = .003). The EFS remained superior even when compared with non-DS children less than 2 years of age with a white blood cell count less than 10 x 100,000/microL (100% v 48% +/- 17.3%; P = .01).

Topics: Acute Disease; Adolescent; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Azacitidine; Child; Chromosome Aberrations; Chromosome Disorders; Cytarabine; Daunorubicin; Down Syndrome; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Prednisone; Remission Induction; Thioguanine; Vincristine

Topics: Abnormalities, Multiple; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Down Syndrome; Humans; Infant; Leukemia, Myeloid, Acute; Male; Remission Induction; Tetralogy of Fallot; Thioguanine

Topics: Acute Disease; Adult; Aged; Autoradiography; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Nucleus; Culture Techniques; Cytarabine; Down Syndrome; Female; Floxuridine; Humans; Karyotyping; Leukemia; Leukocytes; Lymphocytes; Male; Mitosis; Prednisone; Thioguanine; Thymidine; Tritium; Vincristine