Moffitt Cancer Center, Tampa, FL.
City of Hope National Medical Center, Duarte, CA.
J Clin Oncol. 2023 May 20;41(15):2815-2826. doi: 10.1200/JCO.22.01794. Epub 2023 Mar 8.
Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479).
Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate.
Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In -mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS.
Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).
马格利单抗是一种单克隆抗体，可阻断细胞分化抗原 47（CD47），这是一种在癌细胞上过表达的“不要吃我”信号。马格利单抗阻断 CD47 可促进巨噬细胞吞噬肿瘤细胞，并与阿扎胞苷协同作用，后者增加“吃我”信号的表达。我们报告了未接受治疗的高危骨髓增生异常综合征（MDS）患者接受马格利单抗和阿扎胞苷治疗的最终 Ib 期数据（ClinicalTrials.gov 标识符：NCT03248479）。
未接受过治疗的修订后的国际预后评分系统（IPSS）中危/高危/极高危 MDS 患者接受马格利单抗静脉注射作为起始剂量（1mg/kg），然后逐步增加至 30mg/kg，每周一次或每两周一次维持剂量。阿扎胞苷 75mg/m2 每日静脉注射/皮下注射，在每个 28 天周期的第 1-7 天。主要终点是安全性/耐受性和完全缓解（CR）率。
95 名患者接受了治疗。IPSS 风险分别为 27%、52%和 21%的中危/高危/极高危。59 例（62%）有不良预后的细胞遗传学异常，25 例（26%）有 突变。最常见的治疗相关不良反应包括便秘（68%）、血小板减少（55%）和贫血（52%）。从基线到首次给药后评估的中位血红蛋白变化为-0.7g/dL（范围，-3.1 至+2.4）。CR 率和总反应率分别为 33%和 75%。中位反应时间、CR 持续时间、总反应持续时间和无进展生存期分别为 1.9 个月、11.1 个月、9.8 个月和 11.6 个月。中位总生存期（OS）尚未达到，随访 17.1 个月。在 突变患者中，40%达到 CR，中位 OS 为 16.3 个月。34 例（36%）患者接受了异基因造血干细胞移植，2 年 OS 率为 77%。
马格利单抗+阿扎胞苷在未经治疗的高危 MDS 患者中具有良好的耐受性和有前景的疗效，包括那些有 突变的患者。一项马格利单抗/安慰剂+阿扎胞苷的 III 期试验正在进行中（ClinicalTrials.gov 标识符：NCT04313881 [ENHANCE]）。
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