Safety and efficacy of the combination of azacitidine with venetoclax after hypomethylating agent failure in higher-risk myelodysplastic syndrome

IF 2.1 4区医学 Q3 HEMATOLOGY

Leukemia research Pub Date : 2025-04-08 DOI:10.1016/j.leukres.2025.107692

Julie S. Braish , Guillermo Montalban-Bravo , Farhad Ravandi , Nicholas Short , Tapan Kadia , Maro Ohanian , Kelly Chien , Lucia Masarova , Koji Sasaki , Musa Yilmaz , Sanam Logahvi , Naval Daver , Gautam Borthakur , Elias Jabbour , Heather Schneider , Lizabeth T. Romero , Hagop Kantarjian , Guillermo Garcia-Manero

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引用次数: 0

Abstract

Objective

Therapies for patients with higher-risk myelodysplastic syndromes (HR-MDS) who have failed hypomethylating agents (HMAs) are needed. This Phase I/II study evaluates the safety, tolerability, and efficacy of venetoclax, an orally bioavailable BCL-2 inhibitor, in combination with azacitidine in this population.

Methods

We conducted a single-center, dose-escalation, Phase I/II trial (NCT04550442) involving 33 patients with HR-MDS or CMML (IPSS ≥ 1.5) who had progressed after prior HMA therapy. Patients received intravenous or subcutaneous azacitidine (SC) (75 mg/m² for 5 days) and venetoclax (100–400 mg for 7–14 days in a 28-day cycle). The primary endpoints were safety/tolerability (Phase 1) and overall response rate (ORR) (Phase 2).

Results

Patients received a median of 3 cycles (range, 1–22). The maximum tolerated dose of venetoclax was 400 mg. Common grade 3–4 adverse events included neutropenia (19 %) and thrombocytopenia (10 %). The 4-week early mortality rate was 9 %. The ORR was 49 %, and the median overall survival (OS) was 7 months (95 % CI, 3.5–10.5). The median progression-free survival (PFS) was 6 months (95 % CI, 3.0–9.0). Four patients (12 %) underwent stem cell transplantation, with 3 of 4 alive at last follow-up (75 %).

Conclusion

Combining venetoclax with azacitidine is feasible for HR-MDS and CMML patients who failed prior HMA therapy. However, this combination did not significantly improve clinical outcomes in this patient population.

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阿扎胞苷联合venetoclax治疗高危骨髓增生异常综合征低甲基化药物失效后的安全性和有效性

低甲基化药物（HMAs）治疗失败的高危骨髓增生异常综合征（HR-MDS）患者需要治疗。这项I/II期研究评估了venetoclax（一种口服生物可利用的BCL-2抑制剂）与阿扎胞苷联合在该人群中的安全性、耐受性和有效性。方法：我们进行了一项单中心、剂量递增的I/II期临床试验（NCT04550442），涉及33例既往HMA治疗后进展的HR-MDS或CMML患者（IPSS≥1.5）。患者接受静脉注射或皮下注射阿扎胞苷（75 mg/m²，持续5天）和venetoclax（100-400 mg，持续7-14天，28天周期）。主要终点是安全性/耐受性（1期）和总缓解率（ORR）（2期）。结果患者接受了中位3个周期（范围，1 - 22）。venetoclax的最大耐受剂量为400 mg。常见的3-4级不良事件包括中性粒细胞减少（19% %）和血小板减少（10% %）。4周早期死亡率为9 %。ORR为49 %，中位总生存期（OS）为7个月（95 % CI, 3.5-10.5）。中位无进展生存期（PFS）为6个月（95 % CI, 3.0-9.0）。4例患者（12 %）接受了干细胞移植，最后随访时4例中有3例存活（75 %）。结论维妥乐联合阿扎胞苷治疗既往HMA治疗失败的HR-MDS和CMML患者是可行的。然而，这种组合并没有显著改善该患者群体的临床结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Leukemia research 医学-血液学

CiteScore

4.00

自引率

3.70%

发文量

259

审稿时长

1 months

期刊介绍： Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.