Venetoclax Plus Hypomethylating Agents for Treatment-Naïve Myelodysplastic Syndromes with Increased Blasts: A Prospective Multicenter Cohort Study

Na Zhao,1,2,* Lijun Zhu,1,* Xing Hu,1,* Juan Tong,1 Hongfeng Ge,3 Li Ye,4 Xijun Zhu,5 Can Gai,6 Yuhu Feng,7 Lei Zhang,1 Li Wang,1 Guangyu Sun,1 Lei Xue,1 Xiaoyu Zhu,1 Changcheng Zheng1,8 1Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 2State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 3Department of Hematology, Bozhou People’s Hospital, Bozhou, Anhui, 233500, People’s Republic of China; 4Department of Hematology, Lu’an People’s Hospital, Lu’an, Anhui, 237000, People’s Republic of China; 5Department of Hematology, Xuancheng People’s Hospital, Xuancheng, Anhui, 242000, People’s Republic of China; 6Department of Hematology, Huaibei People’s Hospital, Huaibei, Anhui, 235000, People’s Republic of China; 7Department of Hematology, Fuyang People’s Hospital, Fuyang, Anhui, 236000, People’s Republic of China; 8Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changcheng Zheng, Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China, Email [email protected]: Evidence supporting venetoclax combined with hypomethylating agents (HMAs) in treatment-naïve myelodysplastic syndromes with increased blasts (MDS-IB), a biologically aggressive subset with high risk of leukemic transformation, remains lacking. We conducted a prospective, multicenter cohort study to evaluate the efficacy and safety of venetoclax plus HMAs in newly diagnosed MDS-IB.Patients and Methods: In this prospective, multicenter, single-arm trial conducted at six hospitals in China (August 2022–September 2024), 43 newly diagnosed adults with MDS-IB received venetoclax (ramp-up to 400 mg on days 1– 14) plus azacitidine or decitabine in 28-day cycles. Dose adjustments were made for cytopenias, infections, or drug interactions. Primary endpoints were overall response rate (ORR), duration of response (DoR), and safety. Secondary endpoints included overall survival (OS) and transformation to acute myeloid leukemia. The study was registered in the Chinese Clinical Trial Registry (registration number: [ChiCTR2200055204]).Results: The ORR was 74.4% (95% CI, 58.8-86.5%), comprising 34.4% complete remission (CR), 59.4% marrow CR (mCR), and 6.3% partial response (PR). Among the thirty-two patients who got ORR, the median DoR was 8.1 months (range, 0.9– 29.0). The 6-, 12-, and 24-month DoR rates were 68.8% (95% CI, 49.7– 81.8%), 53.2% (95% CI, 33.7– 69.4%), and 47.7% (95% CI, 27.8– 65.1%), respectively. Median OS was 12.8 months, with 12- and 24-month OS rates of 62.4% (95% CI, 46.1– 75.1%) and 49.3% (95% CI, 32.2– 64.3%), respectively. Grade 3/4 neutropenia/febrile neutropenia occurred in 60% (26/43), and pneumonia in 16% (7/43). The median interval between cycles was 59 days (range 33– 113), mainly due to hematologic toxicity.Conclusion: Venetoclax plus HMAs demonstrated promising clinical activity with manageable toxicity in newly diagnosed MDS-IB, supporting further prospective evaluation of this combination in treatment-naïve patients with increased-blast MDS.Trial Registration: Chinese Clinical Trial Registry, ChiCTR2200055204, https://www.chictr.org.cn/index.html.Keywords: venetoclax, hypomethylating agents, myelodysplastic syndromes