Conventional 7+3 Consolidation Is Equal in Long-Term Outcome to High Dose ARA-C in Case of the High Total Doses of Different Anthracyclines/Anthracenedione in Induction/Consolidation - the Interim Results of Russian Randomized Multicenter AML-10 Trial

Introduction. The vast majority of AML clinical trials incorporate high-dose ARA-C (HDARA-C) as a basic approach. Though it was recently proved by a controlled prospective comparison that different treatment strategies in patients with AML did not show clinically relevant outcome differences (Th.Buchner, JCO, 2012), the RALSG initiated a randomized multicenter AML-10 trial (ClinicalTrials.gov Identifier: NCT01587430) aiming to evaluate the necessity of HDARA-C in consolidation in the context of high total dose of different anthracyclines/anthracenedione (660-720 mg/m 2 ). Materials and methods . The patients aged 16-60 yy with de novo AML (except APL) were randomized before treatment start to different types of consolidation after two induction 7+3 with daunorubicin 60 mg/m 2 x3 and ARA-C 100 mg/m 2 bid iv (1-7d) in the 1 st course and 200 mg/m 2 /d (1-7d) continuous infusion in the 2 nd course: (1 st arm) two courses of 7+3 with Idarubicin (Ida) 12 mg/m 2 x3 and with Mitoxantrone (Mito) 10 mg/m 2 x3, in both ARA-C 100 mg/m2 bid iv (1-7d); (2 nd arm) two courses of HDARA-C 1g/m 2 bid iv 1-3 days with Ida 8 mg/m 2 3-5 days and Mito10 mg/m 2 3-5 days. After consolidation all pts proceeded to the maintenance 5+5 courses (ARA-C 100 mg/m 2 bid iv 1-5 days with 6-mercaptopurine 50 mg/m 2 1-5 days). Allogeneic HSCT was indicated to patients from intermediate and poor cytogenetic risk groups, late CR, WBC > 100*10 9 /l. Results. From Jan 2010 till Jan 2014, 250 AML patients from 20 centers were randomized: (1 st arm) 125 pts (m.age 45 y, 17-59 yy; 73f / 52m; LDH=674 IU (128-6653); cytogenetics favorable - 17,3%, intermediate - 66,7%, poor - 16%) and (2 nd arm) 125 pts (m.age 43y, 16-60yy; 69f/56m; LDH=704 IU (123-8159); cytogenetics favorable - 20%, intermediate - 58,6%, poor - 21,4%). No molecular testing in cytogenetically normal pts was done. The analysis was performed in May 2014. The follow-up data were available in 199 pts. CR was achieved in 72,9% (n=145), early death was registered in 12,7% (n=25) and refractory disease - in 12,4% (n=24). Death in CR did not differed in a randomized groups (1 st ) 13,9% and (2 nd ) 13,7%. 17% of CR pts (n=20) were withdrawn from the protocol due to refusals (3,5%), infectious complications (13,5%). No relevant cardiotoxicity was registered on both arms. 12% (8 pts on the 1 st arm, 9 - on the 2 nd ) were transplanted in 1 st CR from HLA-identical donors. 3-years OS and DFS by intent-to-treat analysis were identical on both arms: (1 st arm) 43% and 62%, (2 nd arm) - 38% and 51%, respectively. For those patients in whom consolidation was fulfilled the comparison of DFS in different cytogenetic groups demonstrated equal efficacy of each consolidation arm: favorable - 85% (1 st ) and 85% (2 nd ), intermediate -65% (1 st ) and 57% (2 nd ), poor - 20% (1 st ) and 22% (2 nd ). In a multivariate analysis only cytogenetic group (HR=3,01, p=0,005) and CR achievement after the 2 nd induction course (HR=2,83, p=0,0007) adversely influenced DFS. As the land-mark (5 mo of CR) analysis have shown, the bad prognosis of late CR could be modified by allo-HSCT in 1 st CR: DFS of transplanted patients = 86%, non-transplanted=27% (p=0,03). Conclusion. Our interim analysis has demonstrated that conventional 7+3 consolidation is equal in long-term outcome to high dose ARA-C in case of the high total doses of different anthracyclines/ anthracenedione in induction/consolidation. CR after the 2 nd induction became independent adverse prognostic factor (even inside cytogenetic risk groups) defining patients who should be transplanted in 1 st CR. Disclosures No relevant conflicts of interest to declare.