Influence of Pre-Treatment Features and Therapy Choice By Physicians on Overall Survival in Older Adults with Acute Myeloid Leukemia: A Report from the Beat AML Master Trial

Background: Acute myeloid leukemia (AML) therapy in older patients (age ≥ 60) has undergone a transformation with the introduction of multiple targeted therapies, which has allowed more patients to receive therapy than before. The most successful has been the combination of venetoclax + azacitidine (VA) which generated higher overall complete response rates in phase 2 studies than would be expected with azacitidine alone, leading to accelerated FDA approval on 21Nov2018. The VIALE-A phase 3 study confirmed the improved overall survival (OS, median 14.7 versus 9.6 months) of VA, leading to full FDA approval for marketing. This retrospective analysis provides real world data on the impact of baseline clinical and genomic markers of individuals receiving intensive chemotherapy versus VA. Methods: The precision medicine Beat AML Master Trial (NCT03013998) assigns patients to biomarker specific sub-study treatments based on targeted DNA sequencing and cytogenetics. However, a large subset of patients did not enroll on a sub-study, but were followed for off-study treatment and OS. From this subset, patients enrolled onward from 21Nov2018, when VA received accelerated approval, were examined for differences in clinical/genetic characteristics and OS in those receiving venetoclax + hypomethylating agent (V/HMA), any form of intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. The genetic mutations identified in this study are characterized by a variant allele frequency of 20%+, as defined in the trial for determining the dominant clone. The method of Kaplan-Meier was used to estimate OS, and the Cox model was fit to associate patient characteristics with OS. Results: From 21Nov2018, a total of 468 AML patients consented to the Beat AML trial and did not enroll to a sub-study. Treatment was chosen by the investigator based upon available clinical and genomic data. Of these 468 patients, 62 did not receive treatment, 2 had treatment data missing, 226 were treated with V/HMA, 112 with IC, and 66 with NIT. Demographics for all patients include median age 71 (60-90), 40% female, performance status (PS) (0-20%; 1-55%; 2-22%; 3-3%), median white blood cell (WBC) 4.1 (range 0.3-298.6), complex karyotype (CK) 20.6%, core binding factor (CBF) 7.8%, KMT2A-rearranged 3.6%, NPM1-mutated (m) 15.6%, IDH2m 14.6%, TP53m 13.2%, FLT3-ITD/TKD 12.9%, and NRASm/ PTPN11m/ KRASm/ NF1m/ CBLm 23.6%. Demographics that were significantly different (p