Outcome at Two Years after a Response-Adapted Approach with Azacitidine and Intensive Chemotherapy in Patients > 60 Years with Newly Diagnosed AML Treated within the DRKS00004519 Trial of the East German Study Group (OSHO)

The heterogeneity of AML requires a personalized treatment strategy to achieve a high initial response and translate this response into long-term survival. Based on a possible synergistic effect of azacitidine (AZA) and cytarabine (ARA-C) when AZA is given first through the induction of deoxycytidine kinase by AZA which phosphorylates ARA-C to its active compound, ara-CTP, priming with AZA was integrated with intensive chemotherapy (IC) in a response-based sequential approach in the multicenter RAS-AZIC (DRKS00004519) study for patients (pts) >60 years (y). The safety, the remission rate of 64%, and a low TRM of 10% up to day (d) 90 were previously reported (Jaekel et al, ASH 2017). The final results of outcome at two years are presented.

Patients and methods: Pts >60 y with newly diagnosed AML (de novo, secondary, and therapy related) were included (n=109). All received priming with AZA (75 mg/m²/day s.c) for 7 days. Irrespective of baseline bone marrow (BM) blasts, pts with d15 blasts ≥45% received IC (Mitoxantrone 10 mg/m²/day d1-3 and ARA-C 1g/m²/BID d1,3,5,7). If the count was <45%, AZA was continued at d28. The second treatment adaptation was based on d56 response. If CR/CRi were documented, AZA maintenance or allogeneic HCT were given. Otherwise, IC was applied followed by AZA maintenance or allogeneic HCT if a remission was achieved on d90. Response (CR, CRi, PR) on d90 was the primary endpoint. The two-year OS, event-free survival (EFS), and relapse-free survival (RFS) were secondary endpoints. Recruitment was closed on 23.05.2016 and LPLV (last patient last visit) was performed on 25.05.2018. Statistical analysis was planned on an intention-to-treat base. The trial was supervised by an independent Data Monitoring Committee. All pts gave written informed consent.

Results: Patient characteristics are shown in table 1. Median age was 70y. Treatment sequels were AZA1+AZA2, n=24 (22%); AZA1+AZA2+IC1, n=30 (27.5%); AZA1+ IC1, n=35 (32.1%); AZA1+ IC1+IC2, n=9 (8.3%)]. The median of days alive and out of hospital till d90 was 41 days. The centrally reviewed response rate was 64.2% [CR/CRi 57.8%; PR 6.4%]. Remissions were achieved with AZA therapy± only one cycle of IC in 91% of responders. Maintenance with AZA was started in 53/70 (76%) responders and 12 (17%) pts received allogeneic HCT. Response translated into an improved survival at two years with a median survival time of 22 months (m) vs 7m only in non-responders (p<0.001). For the entire cohort, the two-year OS was 35.1% with a median survival time of 16m (95% CI, 12.9 to 18.8) (figure 1). Baseline BM blasts, WBC, FLT3 status, and the type of AML had no impact on response or OS. Older age was not associated with an inferior OS [median survival time of 16m in pts ≥75y vs 15m in pts ≤ 64y]. Although statistically not significant, the presence of an NPM1 mutation tended to be associated with a superior response [81% vs 61%; (p=0.08)] and OS [median survival time of 20 vs 16m; (p=0.22)]. Response in favorable, intermediate (int)-I; int-II, and adverse genetics was 73%, 80%, 52%, and 53% respectively (p=0.098). Genetics had a strong impact on OS [median survival times were not reached in favorable and int-I; 15.3 and 11.4m in int-II and adverse risk respectively (p=0.001)]. The two-year EFS was 23% with a median EFS time of 10m (95% CI, 7.7 to 12). Again, genetics had a strong impact on EFS [median EFS times were 20 in favorable, 14 in int-I; 9 in int-II, and 7m in adverse risk (p=0.002)]. EFS correlated with response [median EFS time was 13 m in responders vs 4m only in non-responders (p<0.001)]. Relapse incidence and RFS at two years were 60% and 26% respectively with a median RFS time of 11m (95% CI, 6 to 15.6) (figure 1). Median RFS times were not reached in favorable, 15.5 in int-I; 12.7 in int-II, and only 4m in adverse risk genetics (p=0.003)].

Conclusion: Integrating an epigenetic therapy with IC in elderly pts with AML in an individualized response-based approach is feasible with low TRM and yields responses at least comparable to those achieved with repeated cycles of IC across all cytogenetic risk groups even in pts >70y. Most importantly, response could be translated into an improved survival particularly in pts with favorable and int-I risk genetics. Relapse remains high in adverse genetics. The results might further be improved through mutational profiling which allows the integration of emerging targeted therapies.

View largeDownload slide

View largeDownload slide

Close modal