Sallman David A, Komrokji Rami S, Dezern Amy E, Sebert Marie, Garcia-Manero Guillermo, Rahmé Ramy, Winer Eric S, Lehmann-Che Jacqueline, Roboz Gail J, Madelaine Isabelle, Sekeres Mikkael A, Peterlin Pierre, Chan Onyee, Beyne-Rauzy Odile, Kuykendall Andrew, Recher Christian, McLemore Amy, Stamatoullas Aspasia, Zhang Ling, Willems Lise, Mo Qianxing, Raffoux Emmanuel, Nardelli Lisa, Berthon Céline, Al Ali Najla H, Quesnel Bruno, Padron Eric, Kantarjian Hagop M, List Alan F, Ades Lionel, Lancet Jeffrey E, Fenaux Pierre, Cluzeau Thomas
Malignant Hematology Department H. Lee Moffitt Cancer Center and Research Institute Tampa Florida USA.
Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Baltimore Maryland USA.
Hemasphere. 2025 Jul 13;9(7):e70164. doi: 10.1002/hem3.70164. eCollection 2025 Jul.
gene mutations (m) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR-246) is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in m cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents-naïve m higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1-4) + azacitidine 75 mg/m sc/iv × 7 days in 28-day cycles. The primary objective was the complete remission (CR) rate by International Working Group (IWG) 2006 criteria. In total, 100 patients were enrolled with a median age of 68 years (34-87; 47% male). Febrile neutropenia occurred in 37% of patients. Thirty- and 60-day mortality was 1% and 7%, respectively. By intention-to-treat, overall response rate by IWG was 69% with 41% CR. The median duration of CR was 10.2 months (95% CI 8.7-11.8). With a median follow-up of 52 months, median overall survival (OS) was 11.8 months (95% CI 9.4-14.3). Although allogeneic hematopoietic cell transplantation (allo-HCT) was borderline predictive of OS in the overall cohort by landmark analysis (14.7 vs. 14.4 months; P = 0.046), OS was significantly improved in allo-HCT patients based on CR/ next-generation sequencing (NGS) negativity (P = 0.00085; 2-year OS of 54%). In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well-tolerated with synergistic response rates in m MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HCT, validating NGS clearance as a critical biomarker of allo-HCT outcomes in m patients.
基因突变（m）代表了一组预后较差的独特分子群体。依普萘妥（APR-246）是一种新型的、同类首创的小分子药物，可重新激活p53并靶向细胞氧化还原平衡，最终在m癌细胞中诱导凋亡和铁死亡。这是一项多中心、国际合作研究，涉及美国骨髓增生异常综合征/肿瘤（MDS）临床研究研讨会以及法国骨髓增生异常研究小组（GFM），针对未接受过低甲基化药物治疗的m高危MDS和原始细胞过少的急性髓系白血病（AML；原始细胞≤30%；NCT03072043/NCT03588078）。患者接受依普萘妥4500mg静脉注射（第1 - 4天）+阿扎胞苷75mg/m²皮下注射/静脉注射×7天，每28天为一个周期。主要目标是根据国际工作组（IWG）2006标准的完全缓解（CR）率。总共入组了100例患者，中位年龄为68岁（34 - 87岁；47%为男性）。37%的患者发生发热性中性粒细胞减少。30天和60天死亡率分别为1%和7%。按意向性分析，IWG评估的总缓解率为69%，CR率为41%。CR的中位持续时间为10.2个月（95%置信区间8.7 - 11.8）。中位随访52个月，中位总生存期（OS）为11.8个月（95%置信区间9.4 - 14.3）。尽管通过标志性分析，异基因造血细胞移植（allo-HCT）对整个队列的OS有临界预测价值（14.7个月对14.4个月；P = 0.046），但基于CR/下一代测序（NGS）阴性的allo-HCT患者的OS显著改善（P = 0.00085；2年OS为54%）。在这项对依普萘妥+阿扎胞苷治疗的2期患者的国际联合分析中，该联合方案耐受性良好，在m MDS/AML中具有协同缓解率。缓解质量和NGS阴性强烈预测OS，特别是在allo-HCT的情况下，验证了NGS清除作为m患者allo-HCT结局的关键生物标志物。
