Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission: A Phase II Cancer and Leukemia Group B Study (CALGB 10503, Alliance)
Authors: Blum William , Sanford Ben , Klisovic Rebecca B , DeAngelo Daniel J. , Uy Geoffrey , Powell Bayard L. , Stock Wendy , Baer Maria R. , Kolitz Jonathan E. , Wetzler Meir , Hoke Eva , Bloomfield Clara D. , Geyer Susan , Marcucci Guido , Stone Richard M. , Larson Richard A. 
Published: October 2019

Abstract
Abstract 44
CALGB (now part of the Alliance for Clinical Trials in Oncology) performed a non-randomized phase II study testing one year (yr) of investigational maintenance therapy with decitabine for newly diagnosed adult AML patients (pts) <60 yrs of age (CALGB 10503, Alliance). The study included induction followed by molecular and cytogenetic risk-adapted consolidation identical to that given in the prior CALGB study for younger AML pts (19808). Induction used daunorubicin 90 mg/m2 for 3 days, etoposide 100 mg/m2 for 3 days, and cytarabine 100 mg/m2 for 7 days (3+3+7). Reinduction (2+2+5) was given for residual disease on day 14. Favorable risk pts [defined here as t(8;21), inv(16), or t(16;16)] in complete remission (CR) received 3 cycles of high dose cytarabine (HiDAC); all other pts received two-step consolidation with chemo-mobilization and autologous transplantation (autoHCT) if eligible, or HiDAC-based consolidation if not. However, removal from study for alloHCT in 1st CR, instead of the two-step autoHCT, was permitted for non-favorable risk pts. Maintenance decitabine began as soon as possible after recovery from consolidation; pts had to have CR with neutrophils >1 × 109/L, platelets >75 × 109/L, and be within 90 days after day 1 of the final consolidation. Decitabine 20mg/m2 was given IV over 1 hour for 4–5 days, every 6 weeks, for 8 cycles. 546 pts enrolled with a median age of 48 yrs (range, 17–60) and median presenting white blood count (WBC) of 12.6 × 109/L (range, 0.3–380 × 109/L). 75% achieved CR (412/546). Reasons for CR pts not receiving maintenance were mainly early relapse, alloHCT in 1st CR, inadequate count recovery, and patient refusal (Blum et al. ASH 2011). 33% of CR pts (134/412) received investigational maintenance. Of these, 46 (34%) were favorable risk; among the remaining 88 pts, 73 were consolidated with autoHCT, and 15 received HiDAC-based consolidation. The median time from initial study registration to initiation of maintenance therapy was 6.3 months. Pts receiving decitabine had a median age of 45 yrs (range, 18–60) and presenting WBC of 13.5 × 109/L (range, 0.4–221 × 109/L). Treatment with decitabine maintenance was feasible and reasonably well tolerated; the primary toxicity was myelosuppression. Preplanned dose reduction criteria for neutropenia were met after the first 20 pts had been treated. After this early timepoint, all subsequent pts who had been consolidated with autoHCT received only 4 days of decitabine per cycle (HiDAC consolidated pts continued to receive 5 days per cycle). The median number of cycles of decitabine received was 7 (range, 1–8); 46% of pts (62/134) received all 8 cycles, and 75% completed at least 4 cycles. Reasons for discontinuation of decitabine before completing 8 cycles included relapse (28%, 38/134), pt refusal (13%), adverse events (4%), and others. In this selected cohort of pts who received post-CR maintenance with decitabine, 1-yr and 3-yr overall survival (OS) were 96% and 66%; 1-yr and 3-yr disease-free survival (DFS) were 80% and 53%. 1-yr “failure-free survival” calculated from the time of registration to decitabine was 68% (70% for favorable risk, 68% for others). These results are similar to the outcomes for comparable pts enrolled on our prior CALGB study 19808 who received identical chemotherapy for induction and consolidation and then were randomized to observation or maintenance with interleukin-2 (3-yr OS 61% and 68%, 3-yr DFS 45% and 56%, for observation and IL-2 respectively). Post-consolidation maintenance with decitabine appears to provide only modest, if any, benefit overall. Correlative studies for CALGB 10503 are ongoing, including investigations into the impact of decitabine in unique molecular and cytogenetic subsets of disease, the prognostic/predictive value of aberrant methylation and other molecular markers, and assessment of minimal residual disease. Supported by CA33601 and CA128377.

Disclosures:
No relevant conflicts of interest to declare.