Association of Genetic Characteristics with Response to Venetoclax Plus Hypomethylating Agents in Relapsed and Refractory Acute Myeloid Leukemia

The heterogeneity of relapsed or refractory AML (R/R AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are strongly associated with response of treatment in adults AML. Currently, the association of genetic characteristics with outcomes receiving VEN-based therapy in R/R AML has been reported in some studies with small sample size, in which controversial conclusions still exist. In this study, we aimed to evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potentially predictive factors for response in R/R AML. The total 136 R/R AML patients were enrolled in this multi-center retrospective study. The overall response rate (ORR) was 58.8%, including 23.5% complete remission (CR), 21.3% CR with incomplete hematologic recovery,1.5% morphologic leukemia-free state and 11.8% partial remission (PR), in which 20 patients achieved MRD-negative response. With median follow-up of 11.8 (95% CI, 7.4 to 14.3) months, 56 (41.2%) patients died, including 9 patients due to relapse, 8 transplant-related complications, 30 primary disease progression, and 9 others. 1- and 2-years overall survival was 49.6% (95% CI; 39.9%-61.8%) and 39.0% (95% CI; 27.2%-55.9%), respectively. Sequential allo-HSCT could improve survival of patients receiving VEN-based therapy (p<0.001). Adverse cytogenetics and ELN risk predicted inferior response to VEN-based therapy (CRc: 28.2% and 35.6%). Mutations in IDH1/2, NPM1 and ASXL1 predicted superior response to VEN-based therapy (CRc: 78.3%, 70.8% and 65.0%, respectively), while mutations in active signaling, such as FLT3-ITD, K/NRAS predicted inferior response (CRc: 29.0% and 28.6%). Mutations in chromatin-cohesin suggested higher response rates (CRc: 63.6%). In summary, based on a large sample size, we demonstrated that VEN combined with HMA were effective to R/R AML patients, and the response of treatment was associated with genetic characteristics.

No relevant conflicts of interest to declare.