Background
Phase 3, randomized, open-label trial. 233 patients (median age 70 years, range 60–90) with IPSS Intermediate-2 or High-risk MDS, age ≥60 and ineligible for intensive chemotherapy. 53% had poor-risk cytogenetics. Median MDS duration at randomization was 3 months. Sponsored by the EORTC Leukemia Group and the German MDS Study Group.
Interventions and follow up
Arm A: Decitabine 15 mg/m² IV over 4 hours three times daily for 3 days, every 6 weeks (n=119)
Arm B: Best supportive care (BSC) only (n=114)
Primary endpoint: Overall survival (OS)
mFollow up: Not specified (final results report)
Arm B: Best supportive care (BSC) only (n=114)
Primary endpoint: Overall survival (OS)
mFollow up: Not specified (final results report)
Results
OS: Median 10.1 vs 8.5 months, HR 0.88 (95% CI 0.66–1.17), P=.38 (not significant)
PFS: Median 6.6 vs 3.0 months, HR 0.68 (95% CI 0.52–0.88), P=.004
AML-free survival: 8.8 vs 6.1 months, HR 0.85, P=.24 (not significant)
AML transformation at 1 year: 22% vs 33%, P=.036
CR: 13% (decitabine) vs 0% (BSC)
ORR (CR+PR+HI): 34% vs 2%
PFS: Median 6.6 vs 3.0 months, HR 0.68 (95% CI 0.52–0.88), P=.004
AML-free survival: 8.8 vs 6.1 months, HR 0.85, P=.24 (not significant)
AML transformation at 1 year: 22% vs 33%, P=.036
CR: 13% (decitabine) vs 0% (BSC)
ORR (CR+PR+HI): 34% vs 2%
Adverse events
Hematologic: Grade 3–4 febrile neutropenia 25% (decitabine) vs 7% (BSC)
Infections: Grade 3–4 infections 57% vs 52%
Other: Patient-reported QOL scores improved with decitabine treatment
Infections: Grade 3–4 infections 57% vs 52%
Other: Patient-reported QOL scores improved with decitabine treatment
Conclusions
Decitabine administered in 6-week cycles did not achieve a statistically significant OS improvement over BSC in older, chemotherapy-ineligible HR-MDS patients, though it significantly prolonged PFS and reduced 1-year AML transformation. The OS HR of 0.88 suggests a trend toward benefit not powered to detect. Short MDS duration at enrollment was an independent adverse prognosticator.
Key Limitations
The primary OS endpoint was not met and the trial was likely underpowered for the modest difference observed. The 6-week cycle schedule is non-standard (most decitabine use is 5-day cycles every 28 days), limiting comparison with AZA-001. Crossover was not systematically tracked. The BSC arm performed better than expected (median OS 8.5 months), possibly reflecting patient selection. The high infection rate in the decitabine arm (57%) mirrors HMA experience.
Clinical Context
DACO-016 is the pivotal phase 3 trial for decitabine in HR-MDS in Europe. Despite not meeting the primary OS endpoint, decitabine received EMA approval for HR-MDS based on the totality of evidence. It remains a widely used HMA alongside azacitidine, though azacitidine (AZA-001, OS benefit shown) is generally preferred per ELN/ESMO guidance for HR-MDS. Oral decitabine + cedazuridine (ASTX727) is now available, and venetoclax combinations are under investigation.
References