General AML

Updated results of the ECOG-ACRIN E2906 randomized study

At the 61st 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
References
  1. Foran J.M. 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. Oral Abstracts S615. 2019 Dec 7. 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, FL, US
  2. Lübbert M. et al., A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 2012 Mar; 97(3):393-401. DOI: 10.3324/haematol.2011.048231
  3. Foran J.M. et al., North American Leukemia‚ Intergroup Phase III Randomized Trial of Single Agent Clofarabine As Induction and Post-Remission Therapy‚ and Decitabine As Maintenance Therapy in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age ≥60 Years): A Trial of the ECOG-ACRIN Cancer Research Group (E2906). Oral abstract S615. 2015 Dec 6. 57th American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, FL, US
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