Genetic Identification of AML Patients Older than 60 years Achieving Long-term Survival with Intensive Chemotherapy.

To design a simple and reproducible classifier predicting the overall survival (OS) of AML patients ≥ 60 years old treated with 7+3, we sequenced 37 genes in 471 patients from the ALFA1200 study (NCT01966497, median age 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (N=13), intermediate (N=339) or unavailable (N=35) cytogenetic risk. TP53 (HR=2.49; P=0.0003) and KRAS (HR=3.60; P=0.001) mutations independently worsened OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR=0.57; P=0.0004), FLT3-ITDs with low (HR=1.85; P=0.0005) or high (HR=3.51; P<10-4) allelic ratio, DNMT3A (HR=1.86; P<10-4), NRAS (HR=1.54; P=0.019) and ASXL1 (HR=1.89; P=0.0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a 'go-go' tier with a 2-year OS of 66.1%, 7.6% to the 'no-go' group (2-year OS 2.8%) while the 53.3% 'slow-go' patients had a 2-year OS of 39.1% (P<10-5). Across three independent validation cohorts, 31.2-37.7% and 11.2-13.5% of patients were assigned to the 'go-go' and the 'no-go' tiers respectively, with significant differences in OS between tiers in all 3 cohorts (HDF, N=141, P=0.003, SAL N=466 and AMLSG N=223, both P<10-5). The ALFA decision tool is a simple, robust and discriminant prognostic model for AML patients older than 60 years treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7+3 standard of care with less intensive regimens.