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)
Authors: Jaekel Nadia , Hubert Karolin , Hänel Mathias , Maschmeyer Georg , Herbst Regina , Schulze Susann , Wang Song-Yau , Kahl Christoph , Wass Maxi , Sayer Herbert G. , Brosteanu Oana , Niederwieser Dietger , Al-Ali Haifa Kathrin 
Published: October 2019

Abstract
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.

Disclosures
Hänel: Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Sayer:RIEMSER Pharma GmbH: Honoraria. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Al-Ali:Gilead: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Alexion: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding.