Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome
Acute Myeloid Leukemia in children with Down syndrome (DS) is a distinct form of myeloid leukemia (DS AML) that is characterized by a young age of onset (< 4 years of age), a frequently megakaryoblastic blast morphology and immunophenotype, a common prodrome of myelodysplastic syndrome, and a high probability of event-free survival (EFS) for the majority of children compared to AML in children without DS. DS AML blasts typically contain somatic mutations of the gene encoding the hematopoietic transcription factor GATA1 and are hypersensitive to selected chemotherapeutic agents such as cytarabine, which has historically been used at high doses for the treatment of AML. Recent studies, therefore, have pursued reduced treatment intensity for children with DS AML to reduce the morbidity associated with its treatment.
COG study A2971 used therapy based on CCG 2891 but eliminated dexamethasone as well as etoposide and, despite this reduction in treatment, maintained favorable survival outcomes (5-year EFS 79%). AAML0431, building on A2971, focused on the reduction of the cumulative dose of daunorubicin (by 25%) and of intrathecal chemotherapy (from 7 to 2 doses) and achieved a 3-year EFS of 90%. These results demonstrate that the 85-90% of children with DS AML have a highly favorable prognosis and may therefore benefit from further reduction of treatment intensity. Therefore, given the hypersensitivity of DS AML blasts to cytarabine and the profound neutropenia and infections associated with its use, the elimination of high-dose cytarabine therapy (HD Ara-C) is the next logical step in reducing treatment intensity for the majority of children with DS and AML. As described below, children with DS AML will be stratified based on the level of MRD at the end of induction to receive reduced intensity therapy versus standard therapy. Using this approach, we aim to maintain the overall excellent outcome for children with DS AML, yet reduce morbidity in the 85-90% with a favorable prognosis. AAML0431, the level of minimal residual disease (MRD) measured by multi-parameter flow cytometry in the bone marrow at the end of this first cycle of induction therapy, predicted outcome. Therefore, as described below, MRD will be used to stratify patients with DS AML to reduced intensity versus standard therapy.
All patients will first receive a common cycle of induction therapy that includes a continuous infusion of standard-dose cytarabine, bolus infusion of daunorubicin and oral 6-thioguanine (TAD). Patients in the standard risk group (MRD 0.05% at the end of Induction I) will receive reduced intensity therapy consisting of two additional induction cycles of TAD and two cycles of intensification therapy with standard-dose cytarabine and etoposide. HD Ara-C will be eliminated from the treatment of standard risk DS AML. Furthermore, due to the extremely low risk for central nervous system leukemia in DS AML, only a single dose of intrathecal cytarabine will be administered to patients without CNS disease. In contrast, patients in the high risk group (MRD 0.05% at the end of Induction I) will be treated with intensified therapy consisting of cycles of mitoxantrone and cytarabine (MA), etoposide and cytarabine (AE) and Capizzi II (HD Ara-C and asparaginase) as used for high risk AML in children without DS.