Abstract
BackgroundDecitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.ResultsTwenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A = epigenetic priming induction, 14 in Arm B = standard induction). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-induction marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, 1 week prior to the patient’s marrow aspirate confirming non-response. Decitabine-induced effects on end-induction (day 35–43 following initiation of treatment) marrows in Arm A were reflected by changes in DNA methylation in matched paired marrow diagnostic aspirates.ConclusionsThis first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML.Trial registrationNCT01177540
Highlights
Decitabine is a deoxycytidine nucleoside derivative inhibitor of Deoxyribonucleic acid (DNA)-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children
Patients with acute promyelocytic leukemia (FAB M3 subtype), symptomatic Central nervous system (CNS) involvement, white blood cell count over 100,000/μl, significant renal or hepatic disease, any prior chemotherapy or radiation therapy for acute myelogenous leukemia (AML), known Human immunodeficiency virus (HIV) infection, history of Chronic myelogenous leukemia (CML), and congenital syndromes known to predispose to AML were excluded
The toxicity and PK results observed in the patients in this study suggest that decitabine can be safely combined with standard doses and schedules of anticancer agents in children with newly diagnosed AML
Summary
Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. We conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints. Attaining complete response/remission (CR) is currently considered the essential first step in the effective treatment of acute myelogenous leukemia (AML). The most widely used induction therapy included 7 days of cytarabine plus 3 days of anthracycline (known as “7 + 3”). With this approach, 75–80% of children with AML achieve CR [1,2,3]. Of patients who do not attain remission, approximately one-half have resistant leukemia and a substantial proportion will die from complications of the disease or treatment. There is a need to develop new treatment strategies to improve outcomes for these patients
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