10-day decitabine versus conventional chemotherapy (“3+7”) followed by allografting in AML patients ≥ 60 years: Long-term follow-up results of the randomized phase III trial AML21 of the EORTC leukemia group, GIMEMA and german MDS Study group

Abstract Background In older AML patients (pts), cure by allografting (HSCT) is often not achieved after standard, intensive chemotherapy (IC), because of intercurrent infections or other sequelae of IC. Extended, i.e. 10-day decitabine (DEC) treatment is effective and well-tolerated in elderly AML pts (Blum et al., Proc. Natl. Acad. Sci. USA 2010, Ritchie et al., Leuk. Lymph. 2013), providing a rational alternative to IC as bridging to HSCT, particularly in pts with adverse genetics. Embarking on this de-escalation approach, we conducted a randomized trial (DEC vs. standard „3+7“ induction) in older AML pts fit for IC, with the goal of effectively leading them to HSCT. After a median follow-up of 4 years, similar overall survival (OS) was attained, the rates of non-hematologic adverse events were lower in the DEC group (Lübbert, Wijermans et al., Lancet Haematol. 2023), as was attrition of health-related quality of life (Efficace, Kicinski et al., Blood 2024). Here, we present the long-term follow-up of this trial, providing critical insights into the durability of responses and post-HSCT outcomes in this population. Patients and Methods This open-label, randomized, controlled, phase III trial was conducted at 54 hospitals in 9 European countries. Pts were aged >=60 years, newly diagnosed with AML, had an ECOG performance status of 0-2 and were eligible for IC. Pts were randomized (1:1) to receive DEC or 3+7 IC. DEC (20 mg/m²) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles of 5 or 10 days of DEC. Pts in the 3+7 group received daunorubicin (60 mg/m² days 1-3) and cytarabine (200 mg/m² days 1-7), followed by 1–3 additional chemotherapy cycles. For both groups, HSCT was strongly encouraged. OS in the intention-to-treat (ITT) population was the primary endpoint, secondary endpoints included progresssion- and disease-free survival (PFS, DFS), HSCT rates and outcome. Safety was assessed in all pts who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872. Results Between Dec 1, 2014, and Aug 20, 2019, 606 pts were randomized to the DEC (n=303) or 3+7 (n=303) group. The cutoff date for this analysis was June 30, 2023, median follow-up was 5.8 years. Median pt age was 68 years, 57% were males, 13% had secondary AML, 15% had leukocyte counts >=30 × 10⁹/L, 15% had a monosomal karyotype and >60% had adverse risk by ELN 2022 criteria. By the clinical cut-off date, 452 deaths had occurred. In the ITT analysis, 23.7% (95% CI: 18.9-28.7%) of pts were alive in the DEC and 25.5% (95% CI: 20.5-30.8%) in the 3+7 group at six years from randomization. The estimated hazard ratio (HR) was 1.02 (95% CI: 0.84-1.22) in the main analysis, with similar results in the sensitivity analyses. The estimated HR was 1.29 (99% CI: 0.77-2.15) for pts aged 60-64, 1.12 (99% CI: 0.77-1.65) for pts aged 65-69, and 0.82 (99% CI: 0.55-1.21) for pts aged 70 years or older (p-value for trend: 0.056). PFS was also comparable between the treatment groups (HR=1.06, 95% CI: 0.89-1.27, p-value=0.52). DFS from CR/CRi at 6 years was 23.2% (95% CI: 16.4-30.8%) in the DEC and 27.5% (95% CI: 20.8-34.6%) in the 3+7 group. Rates of on-protocol allogeneic HSCT were similar between groups: 122 (40%) of 303 pts for DEC, 118 (39%) of 303 pts for 3+7. At time of HSCT, 23% and 9% of pts were not in CR/CRi after DEC and 3+7, respectively. However, OS at 6 years from HSCT was nearly identical in both groups: 41.6% (95% CI: 32.6-50.4) in the DEC group, 41.2% (95% CI: 32.0-50.2) in the 3+7 group. Specifically, in the DEC group, among those in CR/CRi at time of transplant (n=92), 41.9% of pts (95% CI: 31.3-52.1) were alive 6 years from HSCT, among those not in CR/CRi at time of transplant (n=28), 42.9% (95% CI: 24.6-60.0). Conclusions The AML21 trial constitutes the first prospective, randomized phase III trial for fit AML pts comparing an HMA-based de-escalation therapy approach to standard intensive induction. With longer follow-up, the results of the primary analysis of the AML21 trial were confirmed and extended: 10-day DEC resulted in comparable survival as 3+7, with a more favorable safety profile and health-related quality of life. HSCT rate and survival were both very encouraging; pts in the DEC group who were not in CR/CRi at time of HSCT had the same long-term survival as CR/CRi pts, confirming that attainment of CR/CRi is not an absolute prerequisite for successful HSCT.