Down syndrome and leukemia: unusual clinical aspects and unexpected methotrexate sensitivity

Abstract

Twenty-four patients with Down syndrome and leukemia were studied. A strong male predominance (79%) was found. Age ranged between 18 months and 15 years (mean: 5 6/12); 54% of the patients were less than 4 years of age at the time of diagnosis. A preleukemic phase was noted in 6/24 patients. This phase, characterized essentially by thrombocytopenia, lasted from 2-8 months. Patients with preleukemia had unusual blast cell morphology and involvement of more than one cell line (dyserythropoiesis, hypolobulated megakaryocytes) and were probably M7 leukemias. All patients demonstrated severe methotrexate toxicity at standard methotrexate doses. Toxicity, manifesting as mouth ulcerations and bone marrow depression was seen regardless of the route of administration (oral, intrathecal or intravenous). A 30%-50% reduction of the standard dose was tolerated. Methotrexate absorption and clearance were studied in two patients and were found to be normal. We postulate that the observed toxicity of methotrexate may be due to a gene dosage effect for enzymes known to be on chromosome 21 and intervening in purine metabolism. Increased purine synthesis implies greater tetrahydrofolic acid demands and therefore greater sensitivity to an antifolate agent.

Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia

“…2,16,24 In our study, a significantly higher proportion of children with DS experienced methotrexate-induced gastrointestinal toxicity compared with the non-DS controls, which is consistent with other reports. 2,16,24,25 Dose reductions were applied both in anticipation of possible toxicity, and because of apparent excessive toxicity, and were restricted to DS patients only. However, due to excessive toxicity both DS-ALL patients (n=3) and one non-DS-ALL patient, each received one course less than required per protocol.…”

Down’s syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials

“…3 As in the present study, the majority of other investigators reported an unusual increased MTX toxicity in DS patients. [3][4][5]6,8,9,11,12 One pharmacokinetic study in patients with DS showed a slower than expected intracellular clearance of methotexate (1 g/m 2 ) and significant increased toxicity in comparison to other children with ALL. 12 In the present study, total duration of therapy with 18 vs 24 months in trials ALL-BFM 81 and 83 had no significant influence for outcome in DS patients.…”

“…In contrast, survival rates for DS patients were inferior in most studies but ranged between 23 and 71%. [4][5][6][7][8][9][10][11][12] The inferior outcome was mainly attributed to excessive therapy-related toxicities caused either by altered drug metabolism and/or poor tolerance of infection and therefore, less treatment intensity. Authors from the Pediatric Oncology Group found the event-free survival (EFS) for children with DS and ALL with 50% similar to other children with ALL, once they received intensive chemotherapy.…”

Acute megakaryoblastic leukemia in Down syndrome, following thrombocytopenia with antiplatelet antibody.

“…A number of such reported cases exhibited a preleukemic phase, characterized by thrombocytopenia (Beven and Rose 1982;Hayashi et al 1986;Peeters and Poon 1987), but the etiology of thrombocytopenia has been unknown. We describe a case of AMKL in a boy with Down syndrome, following thrombocytopenia with antiplatelet antibody.…”

“…Though he received chemotherapy, he expired 4 months after admission. A number of reported cases of AMKL with Down syndrome exhibit a preleukemic phase, characterized by thrombocytopenia (Beven and Rose 1982 ;Hayashi et al 1986;Peeters and Poon 1987). The patients in this phase were diagnosed as having ITP, preleukemia or refractory anemia with excess of blasts.…”