Garcia Jacqueline S, Platzbecker Uwe, Odenike Olatoyosi, Fleming Shaun, Fong Chun Yew, Borate Uma, Jacoby Meagan A, Nowak Daniel, Baer Maria R, Peterlin Pierre, Chyla Brenda, Wang Huipei, Ku Grace, Hoffman David, Potluri Jalaja, Garcia-Manero Guillermo
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, Universitätsklinikum Leipzig, Leipzig, Germany.
Blood. 2025 Mar 13;145(11):1126-1135. doi: 10.1182/blood.2024025464.
Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). As of May 2023, 107 patients received venetoclax and azacitidine combination at the RP2D. Best response of CR or marrow CR was observed in 29.9% and 50.5% (mOR, 80.4%), respectively. Median OS was 26.0 months, with 1- and 2-year survival estimates of 71.2% and 51.3%, respectively. Among 59 patients with baseline red blood cell and/or platelet transfusion-dependence, 24 (40.7%) achieved transfusion independence on study, including 11 (18.6%) in CR. Fifty-one (49.0%) of 104 evaluable patients achieved HI. Median TTNT excluding transplantation was 13.4 months. Adverse events reflected known safety profiles for venetoclax and azacitidine, including constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%). Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to confirm survival benefit of this combination. This trial was registered at www.clinicaltrials.gov as #NCT02942290.
高危骨髓增生异常综合征（HR MDS）患者的预后较差，一线治疗选择有限。这项1b期研究调查了维奈克拉（一种选择性B细胞淋巴瘤2抑制剂）在推荐的2期剂量（RP2D；每28天周期14天，每天400毫克）下，与阿扎胞苷（每28天周期7天，75毫克/平方米）联合用于初治HR MDS的安全性和有效性。安全性是主要结局，完全缓解（CR）率是主要疗效结局。次要结局包括改良总缓解率（mOR）、血液学改善（HI）、总生存期（OS）和下次治疗时间（TTNT）。截至2023年5月，107例患者接受了RP2D剂量的维奈克拉与阿扎胞苷联合治疗。CR或骨髓CR的最佳缓解率分别为29.9%和50.5%（mOR，80.4%）。中位OS为26.0个月，1年和2年生存率估计分别为71.2%和51.3%。在59例基线时依赖红细胞和/或血小板输血的患者中，24例（40.7%）在研究期间实现了输血独立，其中11例（18.6%）达到CR。104例可评估患者中有51例（49.0%）实现了HI。排除移植后的中位TTNT为13.4个月。不良事件反映了维奈克拉和阿扎胞苷已知的安全性特征，包括便秘（53.3%）、恶心（49.5%）、中性粒细胞减少（48.6%）、血小板减少（44.9%）、发热性中性粒细胞减少（42.1%）和腹泻（41.1%）。总体而言，RP2D剂量的维奈克拉加阿扎胞苷耐受性良好，预后良好。一项3期研究（NCT04401748）正在进行，以确认这种联合治疗的生存获益。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT02942290。
