Venetoclax with Hypomethylating Agents Compared with Priming Regimens for Newly Diagnosed Patients with Acute Myeloid Leukemia with Myelodysplasia Related Changes: A Single Center Retrospective Study
Authors: Liu Fangtong , Wan Chao-Ling , Liu Yu-Qing , Huang Yuan-Hong , Cao Han-Yu , Huang Si-Man , Tan Kai-Wen , Ge Shuai-Shuai , Wang Miao , Liu Mei-Jing , Wang Zihao , Xue Sheng-Li , Dai Haiping 
Published: December 2024

Background
Acute myeloid leukemia with myelodysplasia related (AML-MR) represents a high-risk and heterogeneous subtype of AML, with a lower remission rates and median overall survival compared to non-MR AML. Given that AML-MR tends to occur in the older patient population, intensive chemotherapy may be intolerant at times. Venetoclax based regimens have been approved for newly-diagnosed (ND) AML patients with advanced age or those who are unfit for intensive chemotherapy. Some clinical studies also supported that the priming regimens of low doses might potentially provide an alternative therapeutic approach for high risk patients with encouraging efficacy. However, no study has compared these two treatments in patients with AML-MR. Here, we performed a single center retrospective study to compare the efficacy of VEN+HMA and priming regimen in ND AML-MR patients.
Methods
The clinical data of 146 patients admitted to the First Affiliated Hospital of Soochow University between January 2017 and June 2023 were collected after informed consent. AML-MR were diagnosed according to the 2022 International Consensus Classification. Seventy patients received venetoclax plus hypomethylating agents (VEN+HMA) and 76 patients received priming regimens based on cytarabine(A), G-CSF(G) and idarubicin(I), aclarubicin(A) or homoharringtonine(H) with or without hypomethylating agents (IAG±HMA, AAG±HMA, HAG±HMA). Morphology, R-banded karyotyping, multiplex PCR and target next generation sequencing (NGS) were performed following the routine protocol of our institute. Molecular mutation analyses included all MR genes which were categorized into RNA splicing factors (SRSF2, SF3B1, U2AF1, ZRSR2), chromatin-cohesin genes (ASXL1, EZH2, BCOR, STAG2) and transcription factor (RUNX1).
Results
The median age of the 146 patients was 48 years (range, 18-64), with 86 (58.9%) males and 60 (41.1%) females. The number of patients with mutations in RNA splicing factor genes, chromatin-cohesin genes and transcription factor was 50 (34.2%), 88 (60.3%) and 62 (42.5%), respectively. And no statistically significant difference existed in the distribution of gene mutations between the VEN+HMA and priming regimens group (P=0.479, P=0.784, P=0.446). Thirty-seven (48.7%) patients received subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in priming regimen group and 39 (55.7%) patients received in VEN+HMA group (P=0.396).
After the first course of induction therapy, VEN+HMA group reflected a superior overall remission rate (ORR) (75.7% vs. 53.9%, P=0.006) and a higher complete remission (CR) rate (45.7% vs. 18.4%, P&lt;0.001) compared with priming regimen. Correspondingly, non-remission (NR) rate of VEN+HMA group was significantly lower compared with priming regimen group (10.0% vs. 30.3%, P=0.002). And in priming regimen group, there was no significant statistical difference in ORR (P=0.886) and CR (P=0.806) among three different subgroups mentioned above (IAG±HMA, AAG±HMA, HAG±HMA).
The median follow-up time of the patients was 17.2 months (range, 14.4~19.9). Compared with priming regimen, VEN+HMA cohort demonstrated superior event-free survival (EFS) (not reached vs. 5.7 months, P=0.002), whereas there was no statistically significant difference in overall survival (OS) between the two groups (both not reached, P=0.108). Patients who received allo-HSCT had significantly better OS and EFS than those who did not receive (not reached vs. 17.4 months, P&lt;0.001; 34.8 months vs. 6.8 months, P=0.005). However, among the patients who have not received transplantation, VEN+HMA cohort has shown superior OS (not reached vs.13.3 months, P=0.04) and EFS (16.1 vs. 3.5 months, P=0.027) than priming regimen group. Multivariate analysis showed that induction with VEN+HMA regimen was an independent favorable prognostic factor for higher ORR (OR=3.036, P=0.008) and longer EFS (HR=0.551, P=0.022).
Conclusion
In conclusion, under the mode of low intensity treatment, VEN+HMA exhibited higher ORR and better EFS compared with the priming regimen in ND AML-MR patients in this study. Our data may help guide treatment decisions for ND AML-MR patients who are eligible candidates for both of VEN+HMA and priming regimens. Of course, a large prospective, multi-center, randomized study is needed to validate these findings.