Venetoclax with Hypomethylating Agents Versus Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with Myelodysplasia Related Changes: A Propensity Score Matched Analysis Based on International Consensus Classification
Authors: Wan Chao-Ling , Liu Yu-Qing , Liu Fang-Tong , Huang Yuan-Hong , Cao Han-Yu , Huang Si-Man , Tan Kai-Wen , Wang Zihao , Ge Shuai-Shuai , Wang Miao , Dai Haiping , Xue Sheng-Li 
Published: December 2024

Background
Acute myeloid leukemia with myelodysplasia-related changes (AML-MR) encompasses AML with myelodysplasia-related gene mutations and cytogenetic abnormalities in the International Consensus Classification (ICC). Patients with some MR mutations have been shown to benefit from venetoclax plus hypomethylating agents (VEN+HMA) regimen. VEN+HMA and intensive chemotherapy have been compared in AML patients overall, but has not been compared in the AML-MR subtype. Here, we retrospectively compared the efficacy of VEN+HMA and intensive chemotherapy in newly diagnosed (ND) AML-MR patients.
Methods
The clinical data of 188 AML-MR patients aged 18-64 years, who were treated with VEN+HMA or 7+3 induction regimen between January 2017 and June 2023 at the First Affiliated Hospital of Soochow University were retrospectively collected and analyzed after informed consent. AML-MR was diagnosed according to the ICC. Age and history of previous hematological malignancy were selected for propensity score matching in a 1:2 ratio in the VEN+HMA versus 7+3 cohort. Treatment responses were assessed according to the ELN 2022. Composite complete response (CRc) was defined as complete response (CR) + CR with incomplete count recovery (CRi). Overall response rate (ORR) was defined as CRc + morphology-free leukemia status (MLFS). Overall survival (OS) and event-free survival (EFS) were compared between groups by log-rank test.
Results
After matching, 164 AML-MR patients were paired, including 61 of 70 patients in the VEN+HMA cohort and 103 of 118 patients in the 7+3 cohort. Ninety-four patients had only myelodysplasia-associated gene mutations, 34 patients had only dysplasia-associated cytogenetic abnormalities and 36 patients had both gene mutations and cytogenetic abnormalities. The baseline clincial characteristics of the two cohorts were well matched.
After the first course of induction therapy, the ORR and CRc rate of the VEN+HMA cohort were significantly higher than that of the 7+3 cohort (75% vs 46%, P &lt; 0.001 for ORR, and 61% vs 32%, P &lt; 0.001 for CRc). Correspondingly, the measurable residual disease (MRD)-negative CR rate was also higher in VEN+HMA cohort than 7+3 cohort (46% vs 19%, P &lt; 0.001). Analyses based on genetic alterations showed that the ORR was higher for the VEN+HMA regimen than for the 7+3 regimen in the patients with one mutation of myelodysplasia genes (86% vs 43%, P = 0.001), with mutations of transcription factor genes (RUNX1) (82% vs 45%, P = 0.003) and chromatin-cohesin genes (ASXL1, EZH2, BCOR, STAG2) (77% vs 47%, P = 0.005).
Fifteen patients (15/61, 25%) failed the first cycle of induction with VEN+HMA and 56 (56/103, 54%) patients failed the first induction with 7+3 regimen. When analyzing the remission rate of the first two courses, both the CRc rate (69% vs 52%, P = 0.039) and MRD-negative CR rate (56% vs 36%, P = 0.013) for VEN+HMA were much higher than that for the 7+3 regimen. Univariate analysis (UVA) and multivariate analysis (MVA) both revealed that VEN+HMA regimen was the only predictor of a high ORR (OR = 3.654, P &lt; 0.001 for UVA and OR = 3.789, P = 0.001 for MVA) .
With a median follow-up of 16.3 (range, 13.6-19.0) months, the median OS were both not reached (NR) (P = 0.583). The median EFS in the VEN+HMA cohort was longer than that in the 7+3 cohort (NR vs 1.2 months, P &lt; 0.001). Thirty-four (56%) patients in the VEN+HMA cohort and 61 (59%) patients in the 7+3 cohort underwent allogeneic stem cell transplantation (ASCT). In the overall patients, those received ASCT had longer OS (NR vs 18.0 months, P &lt; 0.001) and EFS (15.5 months vs 4.3 months, P = 0.028) than those who were not transplanted. For patients who did not undergo ASCT, patients treated with VEN+HMA had a superior EFS (NR vs 3.6 months, P = 0.049) but a similar OS (NR vs 15.3 months, P = 0.351) compared with those who were treated with chemotherapy alone. VEN+HMA was shown to be a protective factor for prolonged EFS by both of UVA (HR= 0.362, P &lt; 0.001) and MVA (HR= 0.349, P &lt; 0.001). In addition, ASCT was also a protective factor for OS and EFS in the overall patients by UVA and MVA.
Conclusion
The VEN+HMA regimen showed higher overall and MRD negative response rates and better EFS compared to the 7+3 regimen in ND young 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 the 7+3 regimen. A prospective, multi-center and randomized study is needed to validate these findings.