Updated results of the ECOG-ACRIN E2906 randomized study

At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, James Foran, Mayo Clinic Florida, Jacksonville, FL, US, presented the updated results of the ECOG-ACRIN E2906 trial that investigated patient outcomes after decitabine (DAC) maintenance therapy vs observation (OBS) in intensively-treated older patients (≥60 years) with acute myeloid leukemia (AML)¹. Feasibility of DAC maintenance was previously confirmed in a large phase II study.²

Primary results for E2906 were first reported at ASH 2015:³

• Inferior overall survival (OS) of the single-agent clofarabine (CLO) in comparison to standard daunorubicin and cytarabine (7&3) induction and consolidation therapy
• Superior OS after achieving CR/CRi (complete remission with incomplete complete blood count recovery) following induction therapy
• Superior outcome for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in CR
• Superior outcome for patients who were MRD negative in CR1, particularly after CLO consolidation

Design of the E2906 study¹

• Step 1 induction: 1:1 randomization to either 7&3 or CLO
• Step 2 consolidation: All patients in CR/CRi after induction received 2 cycles of consolidation therapy with either cytarabine or CLO
• Step 3 maintenance:
  • Patients had to be in CR after consolidation therapy
  • 1:1 randomization to either DAC 20mg/m² three times daily, every four weeks for one year or OBS
  • Stratification by age, cytogenetic risk group, and induction therapy
  • No DAC dose reductions were allowed and the maximum number of DAC cycles was 13 over one year

The target accrual of Step 3 was N= 172, but the accrual was suspended after recruitment of 120 patients in February 2015 by the data monitoring committee due to superior OS observed with standard chemotherapy vs CLO

• Of these patients, 69 were assigned to the OBS arm and 59 to the DAC arm
• The median age was 69 years (range, 60-85), 74% of patients had intermediate risk cytogenetics, and 96% had an ECOG performance status of 0-1

Results¹

• The median follow-up was 49.8 months
• The median number of DAC cycles received was 6 (range, 0-13)
• The disease-free survival (DFS) was better in the DAC arm (15.3 months) than the OBS arm (8.2 month; hazard ratio [HR]= 0.77; 95% CI, 0.50-1.19; p= 0.12)
• The OS was superior in the DAC arm (25.8 months) vs the OBS arm (19.5 months) (HR= 0.69; 95% CI, 0.43-1.09; p= 0.06)
• 87.5% (84/96) of tested patients were FLT3-ITD-negative. These patients had superior OS when treated with DAC maintenance vs OBS:
  • Median OS of DAC vs OBS was 38.3 months vs 25.2 months (p= 0.039), respectively
• DAC was tolerable apart from a few grade 3 febrile neutropenia events (9%), with reversible grade 4 cytopenias and no grade 5 events

Conclusions¹

• DAC maintenance for one year was associated with improved OS and a trend for a longer DFS
• A significantly improved outcome was observed for the FLT3-ITD-negative subgroup
• Limitations are based on incomplete accrual due to early termination of the parent E2906 study but results suggest an important impact of DAC maintenance on OS
• These data support a phase III randomized study of DAC maintenance particularly in the FLT3-ITD-negative subgroup