Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.
Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.
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分化抗体的耐受性和疗效47抗体Magrolimab与阿扎西替丁在先前未经治疗的AML：IB期结果的患者中结合使用。
DOI：
10.1200/jco.22.02604
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发表时间：
2023-11-01
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Magrolimab是针对分化簇47的首个人源化单克隆抗体，分化簇47是癌细胞用于逃避吞噬作用的抗吞噬信号。阿扎胞苷上调AML细胞上的原噬细胞信号，当与magrolimab组合时进一步增加吞噬作用。我们报告了magroliumab联合阿扎胞苷治疗不适合强化化疗的未经治疗的AML患者的最终Ib期数据（ClinicalTrials.gov标识符：NCT 03248479）。既往未接受过治疗的AML患者（包括TP 53突变型AML）接受magrolimab静脉给药作为初始剂量（1 mg/kg，第1天和第4天），随后在第8天接受15 mg/kg给药一次，并每周或每2周一次接受30 mg/kg给药作为维持剂量。阿扎胞苷75 mg/m2静脉/皮下给药，每日一次，每28天为一周期，第1-7天给药。主要终点是安全性/耐受性和完全缓解（CR）的比例。87例患者入组并接受治疗; 72例（82.8%）有TP 53突变，中位变异等位基因频率为61%（范围，9.8-98.7）。57例（79.2%）TP 53突变患者具有欧洲白血病网2017不良风险细胞遗传学。患者接受了中位4个（范围，1-39）周期的治疗。最常见的治疗后出现的不良事件包括便秘（49.4%）、恶心（49.4%）和腹泻（48.3%）。30例（34.5%）患者发生贫血，血红蛋白自基线至首次给药后评估的中位变化为-0.9 g/dL（范围：-3.6至2.5 g/dL）。28例（32.2%）患者达到CR，包括23例（31.9%）TP 53突变患者。TP 53突变型和野生型患者的中位总生存期分别为9.8个月和18.9个月。在不适合接受强化诱导化疗的AML患者（包括TP 53突变患者）中，Magroliumab联合阿扎胞苷的耐受性相对良好，疗效令人鼓舞，因此需要进一步评估Magroliumab联合阿扎胞苷治疗AML的疗效。III期随机ENHANCE-2（ClinicalTrials.gov标识符：NCT 04778397）和ENHANCE-3（ClinicalTrials.gov标识符：NCT 05079230）研究正在招募一线AML患者。
Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was –0.9 g/dL (range, –3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.