Poor Response of Venetoclax/Azacitidine in Monocytic-like Acute Myeloid Leukemia Might be Associated with Genetic Patterns and Could be Improved By Addition of Homoharringtonine
Authors: Yu Guopan , Chen Yishan , Yin Zhao , Zhang Yu , Zhao Weihua , Weng Guangyang , Du Xin , Nie Danian , Guo Ziwen , Sun Zhiqiang , Zhang Hongyu , Lin Dongjun , Liang Xinquan , Shi Pengcheng , Jiang Xuejie , Xu Dan , Xuan Li , Ping Baohong , Liu Qifa 
Published: December 2024

Purpose Recent studies reveal that monocytic-like acute myeloid leukemia (AML) responds poorly to venetoclax/azacitidine (VA) regimen. Our previous study showed homoharringtonine (HHT) enhanced the anti-leukemia effect of VA. In this study we aimed to explore the impact of genetic patterns on the response of VA in monocytic-like AML and whether addition of homoharringtonine (HHT) could enhance the response. Methods 321 patients with relapsed/refractory (RR) AML from the South China Hematology Alliance database, being salvagedly treated with VA or VA combined with HHT (VAH) for at least one cycle, were included and retrospectively analyzed their response and the impact of genetic patterns on the response. Results According to French-American-British classification, there were 139 patients with monocytic-like AML (included M4/M5) and 182 non-monocytic AML (excluded M3), of whom 149 patients were treated with VA and 172 with VAH regimen. In the cohort with VA treatment, the patients with monocytic-like AML had a lower response than those with non-monocytic AML (overall response rate (ORR), 27/57(47.4%) vs. 60/92(65.2%), P=0.032; composite complete remission (CRc) rate, 21/57(36.8%) vs.45/92(48.9%), P=0.149). However, in the cohort with VAH treatment, monocytic-like AML patients had similar response to those with non-monocytic AML (ORR, 61/82(74.4%) vs. 66/90(73.3%) , P=0.956; CRc rate, 52/82(63.4%) vs. 62/90(68.9%), P=0.832). In addition, in the patients with monocytic-like AML, VAH significantly improved the response compared to VA (ORR, 74.4% vs. 47.4%, P=0.001; CRc rate, 63.4% vs. 36.8%, P=0.002). Also, the patients with monocytic-like AML had better survival with VAH treatment than those with VA (median overall survival (mOS), not reach vs. 12.4 months, P=0.087; median event-free survival (mEFS), 14.0 vs. 2.0 months, P&lt;0.001), especially significantly in those without being bridged to allogenetic hematopoietic stem cell transplantation. Analysis of genetic pattern of response showed that FLT3, NPM1 mutations and MLL rearrangement were enriched in monocytic-like AML, while ASXL1, SRSF2 and AML1-ETO-positive had higher incidence in non-monocytic AML. FLT3, DNMT3A mutation and MLL rearrangement were the adverse factors for the response of VA. In the patients with monocytic-like AML, VAH significantly improved the response of the patients with FLT3, RAS, DNMT3A and NPM1 mutations, compared to VA. Conclusions Poor response of VA in monocytic-like AML might be associated with genetic patterns. Addition of HHT to VA could improve the response and overcome the negative impact of certain genetic patterns.

Key words Acute myeloid leukemia, monocytic-like, venetoclax/azacitidine, homoharringtonine, genetic pattern