DiNardo Courtney D, Jen Wei-Ying, Montalban-Bravo Guillermo, Wang Xuemei, Loghavi Sanam, Lavu Sravanthi, Short Nicholas J, Chien Kelly, Issa Ghayas C, Pemmaraju Naveen, Yilmaz Musa, Andreeff Michael, Borthakur Gautam, Kadia Tapan M, Daver Naval G, Garcia-Manero Guillermo, Mill Christopher P, Su Xiaoping, Fiskus Warren, Bhalla Kapil N
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Blood Neoplasia. 2025 Jul 25;2(4):100145. doi: 10.1016/j.bneo.2025.100145. eCollection 2025 Nov.
Mutations in ( ) occur in 10% to 20% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and are associated with poor outcomes to standard therapy. Omacetaxine mepesuccinate (OM), a semisynthetic analog of homoharringtonine, has been shown to be lethal to AML cells in vitro through reduction of MCL1 and BCL-XL, and synergizes with venetoclax (VEN) in AML models. We investigated the safety and efficacy of OM + VEN in relapsed/refractory MDS/AML in a Bayesian Optimal Interval design. VEN 400 mg daily from days 1 to 14 and OM 1.25 mg/m twice daily from days 2 to 4 was selected as the recommended phase 2 dose. Twenty-four patients were treated, 22 with AML and 2 with MDS with excess blasts. There were no dose-limiting toxicities or episodes of tumor lysis syndrome. The most common grade ≥3 toxicity was infection. There were no responses in our heavily pretreated cohort of patients with AML. Both patients with MDS achieved composite complete remission and transitioned to allogeneic stem cell transplant. Treatment-induced downregulation in gene expression in the β-catenin and hedgehog signaling pathway genes were identified in peripheral blood mononuclear cells from patients who responded. As compared to nonresponders, samples from responders also exhibited reduced antiapoptotic and increased proapoptotic protein expression. OM can synergize with VEN to promote loss of viability of myeloid cells. Clinical responses were seen exclusively in patients with MDS, which suggests that dose optimization or combination with cytoreductive agents may be necessary for eliciting clinical activity in AML. This trial was registered at www.ClinicalTrials.gov as #NCT04874194.
（某基因）突变发生在10%至20%的骨髓增生异常综合征（MDS）或急性髓系白血病（AML）患者中，并且与标准治疗的不良预后相关。奥马西他辛甲磺酸盐（OM）是高三尖杉酯碱的半合成类似物，已显示在体外通过降低MCL1和BCL-XL对AML细胞具有致死性，并且在AML模型中与维奈克拉（VEN）协同作用。我们采用贝叶斯最优区间设计研究了OM + VEN在复发/难治性MDS/AML中的安全性和疗效。选择第1至14天每天400 mg的VEN和第2至4天每天两次1.25 mg/m²的OM作为推荐的2期剂量。24例患者接受了治疗，其中22例为AML，2例为有过多原始细胞的MDS。没有剂量限制性毒性或肿瘤溶解综合征事件。最常见的≥3级毒性是感染。在我们经过大量预处理的AML患者队列中没有缓解。两名MDS患者均实现了完全缓解并过渡到异基因干细胞移植。在有反应的患者外周血单个核细胞中鉴定出治疗诱导的β-连环蛋白和刺猬信号通路基因的基因表达下调。与无反应者相比，有反应者的样本还表现出抗凋亡蛋白表达降低和促凋亡蛋白表达增加。OM可以与VEN协同作用以促进髓系细胞活力丧失。仅在MDS患者中观察到临床反应，这表明对于在AML中引发临床活性可能需要优化剂量或与细胞减灭剂联合使用。该试验在www.ClinicalTrials.gov上注册为#NCT04874194。
