Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multicenter Cohort Study.

PURPOSE: We investigated whether homoharringtonine (HHT) added to venetoclax plus azacitidine (VA) could improve outcomes and counteract the negative effects of genetic patterns in patients with relapsed/refractory acute myeloid leukemia (RR-AML).

EXPERIMENTAL DESIGN: A multicenter retrospective cohort study of the response and genetic patterns of response to the VA plus HHT (VAH) versus the VA regimens as salvage treatment in patients with RR-AML was performed. The endpoints were the rates of composite complete remission, measurable residual disease, event-free survival, overall survival, and relapse between VAH and VA groups.

RESULTS: A total of 321 patients (VAH, n = 172; VA, n = 149) were analyzed. Compared with VA, VAH significantly improved the rates of composite complete remission (44.3% vs. 66.3%; P < 0.001), measurable residual disease negativity (34.8% vs. 59.3%; P = 0.002), prolonged overall survival (median: 15.1 months vs. not reached; P < 0.001), and event-free survival (median: 3.8 vs. 13.0 months; P < 0.001). VAH significantly mitigated the negative impact on VA efficacy of mutated FLT3-ITD/TKD, N/KRAS, and t(8;21)/AML1-ETO, as well as the relatively unfavorable effects of the TET2 and DNMT3A mutations. VAH significantly enhanced the response of patients with nonadverse European LeukemiaNet risk, with a trend toward improved response in those with adverse European LeukemiaNet risk, complex karyotype, and DNMT3A+FLT3+NPM1+. The incidence of grade 3 or higher adverse events was comparable between the two groups.

CONCLUSIONS: Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.