Re-induction with venetoclax in combination with hypomethylating agents (HMAs) versus FLAG-IDA in relapsed or refractory AML.

Abstract

e19030 Background: The optimal selection and sequence of salvage regimens during treatment of acute myeloid leukemia (AML) remains unclear. While venetoclax augmentation of a hypomethylating agent backbone is now routinely used as salvage following impressive performance in the front-line setting, little is known about outcomes in relapsed or refractory AML, especially when compared to re-inductions with anthracycline-based regimens. Thus, the aim of this study was to compare outcomes of venetoclax-based regimens versus FLAG-IDA in patients under 70 years. Methods: We retrospectively analyzed 47 patients with AML that were younger than 70 years in the relapsed and refractory setting treated with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine or azacitidine from July 2017 to December 2020. Two cohorts were created: a FLAG-IDA cohort and a matched venetoclax cohort for age, ECOG score, and comorbidities. Cytogenetic risk and molecular profiling (through next-generation sequencing [NGS]) at diagnosis and throughout treatment, dates and doses of induction, toxicity, responses, and measurable residual disease (MRD) analysis were recorded and analyzed. Results: In the venetoclax cohort of 32 patients, the median age was 60 years, the median ECOG score was 1, and the median Charlson Comorbidity Index (CCI) score was 4. Six out of 22 evaluable patients achieved either a CR or CRi for a composite response rate (CRR) of 27.3%. Out of three evaluable patients that responded, none were MRD-negative by NGS. The overall survival (OS) of the venetoclax cohort was 8.2 months. In the FLAG-IDA cohort of 15 patients, there were no statistical differences between age (p = .114), ECOG score (p = .249), or CCI score (p = .137) compared to the venetoclax cohort. The CRR of the FLAG-IDA cohort was 85.7%, a significant difference from the venetoclax cohort (p = .011), and 50% were negative for MRD by either NGS or PCR. The overall survival was not reached at a median follow-up time of 15.5 months, significantly different compared to the venetoclax cohort by the log-rank test (p = .001). A Cox proportional hazards model was used to investigate the effects of commonly mutated genes ( NPM1, ASXL1, FLT3, IDH1/2, RAS, TP53, TET2) on OS in venetoclax-based re-induction, and identified IDH1/2 mutations as having a favorable impact in the relapsed/refractory setting (HR 0.01, 95% CI 0.0001-0.7214). Conclusions: Our results highlight the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to CRR and survival, significantly favoring FLAG-IDA at the time of relapsed or refractory disease. Although limited by sample size, IDH1/2 mutations may convey a better prognosis in the relapsed/refractory setting when treated with venetoclax + HMAs. Larger studies are needed to confirm these findings.