A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML

• DOI: 10.1186/s13148-017-0411-x
• Publication Date: 2017-10-05T11:40:06Z
• Authors: Lia Gore; Timothy J. Triche; Jason E. Farrar; Daniel Wai; Christophe Legendre; Gerald C. Gooden; Winnie S. Liang; John Carpten; David Lee; Frank Alvaro; Margaret E. Macy; Carola Arndt; Philip Barnette; Todd Cooper; Laura Martin; Aru Narendran; Jessica Pollard; Soheil Meshinchi; Jessica Boklan; Robert J. Arceci; Bodour Salhia
• Keywords: Male; 0301 basic medicine; Adolescent; QH426-470; Decitabine; Pediatrics; Epigenesis, Genetic; 03 medical and health sciences; 0302 clinical medicine; AML; Genetics; Humans; Pharmacokinetics; Child; Promoter Regions, Genetic; Etoposide; DNA methylation; Research; Daunorubicin; R; Cytarabine; Infant; Induction Chemotherapy; DNA Methylation; 3. Good health; Leukemia, Myeloid, Acute; Treatment Outcome; Pharmacodynamics; Child, Preschool; Azacitidine; Medicine; Epigenetics; Female

ABSTRACTBackgroundDecitabine 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, 14 in Arm B). 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-point marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, one week prior to the patient’s marrow aspirate confirming non-response. Decitabine-induced effects of end-induction marrows in Arm A were reflected by changes in DNA methylation and gene expression comparison with 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. This trial was registered atwww.clinicaltrials.govasNCT01177540.