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Maintenance Decitabine Impacts DFS and OS After Intensive Therapy in Older Adults With AML
Relapse is the most common cause of treatment failure following intensive induction and consolidation (CONS) therapy in older adults with acute myeloid leukemia (AML).
James M Foran, MD, and colleagues conducted a prospective randomized phase 2 study to determine the safety and impact on disease-free survival (DFS) (relapse or death) and overall survival (OS) of decitabine (DAC) maintenance using an abbreviated 3-day schedule administered every 4 weeks for 1 year (per Lubbert et al,Haematologica. 2012;97:393) vs observation (OBS) after intensive AML therapy, conducted in the large multicenter E-A E2906 phase 3 trial in patients age ≥60 years.
The design and primary clinical results for E2906 (n=727) were previously reported (Foran et al, ASH #217a, 2015), demonstrating superior OS following “Standard” 7&3 (daunorubicin 60mg/m2) induction and intermediate dose Ara-C consolidation (CONS) vs single-agent clofarabine (CLO, provided by SANOFI), despite similar CR/CRi (CR with incomplete CBC recovery) and induction mortality rates. All CR/CRi patients after induction (n=311) were assigned to 2 cycles CONS with either Ara-C (1.5g/m2 x 12 doses; 6 doses if age >/=70 years), or single-agent CLO, based on induction randomization.
Ongoing CR/CRi after recovery from CONS was confirmed with restaging BM biopsy. Eligible patients were invited to participate in the “Step 3” maintenance study, a 1:1 randomization (stratified by induction therapy, cytogenetic risk group, age <70 years) to either OBS vs DAC (20mg/m2IV days 1-3, q4 weeks) for 1 year. DAC could be held for up to 4 weeks for delayed hematologic recovery, but dose reductions were not permitted per protocol, and DAC was not continued beyond 12 months. Patients in both arms were evaluated with CBC q4 weeks for 1 year, and surveillance BM biopsy every 3 months (or at the time of suspected clinical relapse) for 2 years.
“Step 3” was designed as a phase 2 pilot randomized study, with target accrual n=172, allowing 90% power to detect 36% reduction in DFS hazard ratio (HR) with DAC maintenance for 1 year, assuming 140 events and 2 years of follow-up from randomization. However, further accrual to E2906 was suspended in 2/2015 by independent DSMC due to superior OS observed with standard Arm, so that “Step 3” completed only 70% of target accrual. (P values reported are two-sided by convention unless specified otherwise.)
“Step 3” total accrual was N=120 (of 172 planned) (DAC 61, OBS 59), with median age 69 years (range 60-85). Groups were very well balanced for baseline clinical characteristics; most patients had intermediate risk cytogenetics (74.2%) and ECOG performance status (PS)=0/1 (96%). The median number of DAC cycles received was 6 (range 0-13), and analysis was “intention-to-treat.” The median follow-up is 49.8 months. There were 90 DFS events (47 OBS, 43 DAC), with 82 deaths (46 OBS, 36 DAC).
FLT3-ITD status is available for n=96 patients, and 84 were FLT3-ITD-negative (46 OBS, 38 DAC). Importantly, researchers observed a significant association of DAC maintenance with superior OS in the large FLT3-ITD-neg subgroup (P=.039).
DAC was generally well tolerated apart from grade 3 febrile neutropenia (9%) and reversible grade 4 cytopenias, with no grade 5 events.
In summary, researchers found that DAC maintenance for 1 year after intensive AML therapy was associated with improved HR for OS and a trend for DFS, using protocol-specified statistical design. They also found there was a significant impact on OS for the FLT3-ITD-negative population.
The team acknowledged limitations based on incomplete accrual due to early termination of the parent E2906 study, and inherent to the phase 2 design of this E2906 endpoint, but results suggest an important impact of DAC maintenance on survival.—Amanda Del Signore
Foran J, Sun Z, Claxton DF, et al. Maintenance Decitabine (DAC) Improves Disease-Free (DFS) and Overall Survival (OS) after Intensive Therapy for Acute Myeloid Leukemia (AML) in Older Adults, Particularly in FLT3-ITD-Negative Patients: ECOG-ACRIN (E-A) E2906 Randomized Study. Presented at: the 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 115.
