阿扎胞苷、维奈克拉和玛格罗利单抗用于新诊断及复发难治性急性髓系白血病：1b/2期研究及相关分析

Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis.

作者信息

Daver Naval, Senapati Jayastu, Kantarjian Hagop M, Wang Bofei, Reville Patrick K, Loghavi Sanam, Yilmaz Musa, DiNardo Courtney D, Kadia Tapan M, Yassouf Mhd Yousuf, Maiti Abhishek, Arora Sankalp, Montalban Bravo Guillermo, Tang Guilin, Borthakur Gautam, Sasaki Koji, Pemmaraju Naveen, Alvarez Joie, Nogueras Gonzalez Graciela M, Ning Jing, Issa Ghayas C, Konopleva Marina, Andreeff Michael, Ravandi Farhad, Garcia-Manero Guillermo, Abbas Hussein A

机构信息

The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

出版信息

Clin Cancer Res. 2025 Apr 8. doi: 10.1158/1078-0432.CCR-25-0229.

DOI:10.1158/1078-0432.CCR-25-0229

PMID:40198272

Abstract

PURPOSE

Magrolimab is a monoclonal antibody directed against macrophage checkpoint CD47 on myeloid leukemia cells that was pre-clinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation.

PATIENTS AND METHODS

In this phase 1b/2 study the triplet combination of azacitidine, venetoclax and magrolimab was evaluated in adult patients with frontline (ineligible for intensive chemotherapy) and relapsed/refractory AML. Azacitidine was dosed at 75mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase 2 dose [RP2D]) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, 15 and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2, then 30 mg/kg every 2 weeks cycle 3 and beyond. The primary endpoint was RP2D for phase 1b and rates of composite complete response (CRc) in phase 2.

RESULTS

The frontline cohort included 54 patients (median age 70.1 years); 35 (64.8%) were TP53 mutated (TP53mut). CRc was attained in 34 patients (63%); 49% in TP53mut and 90% in the TP53 wild-type patients. At a median follow-up of 27.9 months, the median event free survival (EFS) and overall survival (OS) was 6.6 months and 9.8 months respectively; for TP53mut patients the median EFS and OS was 5.9 and 7.6 months, while for TP53 wild type it was 9.6 months and 13 months respectively. CRc in the relapsed/refractory cohort (n=52) was 29% and median OS was 3.9 months. The regimen was well tolerated; infections were the most common ≥ grade 3 adverse event (75.4%) with no immune toxicities or deaths related to therapy. scRNAseq was performed on 27 longitudinal samples from 11 TP53mut patients (8 responders). Gene set enrichment analysis revealed enrichment of IFNγ and TNFα signaling in non-responders at baseline, while erythroid differentiation was associated with resistance. Patients at relapse also showed up-regulated CD47 expression and elevated leukemia regeneration score.

CONCLUSIONS

The triplet regimen was safe but did not lead to promising survival outcomes.

摘要

目的

玛格罗利单抗是一种针对髓系白血病细胞上巨噬细胞检查点CD47的单克隆抗体，在临床前研究中与阿扎胞苷-维奈克拉具有协同作用，值得进一步进行临床评估。

患者与方法

在这项1b/2期研究中，对阿扎胞苷、维奈克拉和玛格罗利单抗的三联组合在一线（不适合强化化疗）及复发/难治性急性髓系白血病（AML）成年患者中进行了评估。阿扎胞苷剂量为75mg/m²，连用7天；维奈克拉剂量为400mg/天，连用28天；玛格罗利单抗（推荐的2期剂量[RP2D]）如下：第1天和第4天剂量为1mg/kg，第8天为15mg/kg，第11天、第15天和第22天（第1周期）为30mg/kg，随后第2周期每周1次30mg/kg，第3周期及以后每2周1次30mg/kg。主要终点在1b期为RP2D，在2期为复合完全缓解（CRc）率。

结果

一线队列包括54例患者（中位年龄70.1岁）；35例（64.8%）为TP53突变（TP53mut）。34例患者（63%）达到CRc；TP53mut患者中为49%，TP53野生型患者中为90%。中位随访27.9个月时，中位无事件生存期（EFS）和总生存期（OS）分别为6.6个月和9.8个月；TP53mut患者的中位EFS和OS分别为5.9个月和7.6个月，而TP53野生型患者分别为9.6个月和13个月。复发/难治性队列（n = 52）中的CRc为29%，中位OS为3.9个月。该方案耐受性良好；感染是最常见的≥3级不良事件（75.4%），无免疫毒性或与治疗相关的死亡。对11例TP53mut患者（8例缓解者）的27个纵向样本进行了单细胞RNA测序（scRNAseq）。基因集富集分析显示，基线时无反应者中IFNγ和TNFα信号通路富集，而红系分化与耐药相关。复发患者还表现出CD47表达上调和白血病再生评分升高。