Details

Autor(en) / Beteiligte

• Gore, Lia
• Triche, Jr, Timothy J
• Farrar, Jason E
• Wai, Daniel
• Legendre, Christophe
• Gooden, Gerald C
• Liang, Winnie S
• Carpten, John
• Lee, David
• Alvaro, Frank
• Macy, Margaret E
• Arndt, Carola
• Barnette, Philip
• Cooper, Todd
• Martin, Laura
• Narendran, Aru
• Pollard, Jessica
• Meshinchi, Soheil
• Boklan, Jessica
• Arceci, Robert J
• Salhia, Bodour

Titel

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

Ist Teil von

• Clinical epigenetics, 2017-10, Vol.9 (1), p.108-108, Article 108

Ort / Verlag

Germany: BioMed Central Ltd

Erscheinungsjahr

2017

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. 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. Twenty-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. This 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. NCT01177540.