MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS)
MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS)
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MDS-482 Magrolimab 联合阿扎胞苷对高危骨髓增生异常综合征 (HR MDS) 患者红细胞 (RBC) 的影响
DOI：
10.1016/s2152-2650(22)01421-5
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发表时间：
2022
影响因子：
2.7
通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Chen J
背景：Magrolimab是一种阻断CD 47的抗体，CD 47是癌细胞上表达的“不要吃我”信号，以逃避免疫监视和巨噬细胞介导的清除。临床前研究发现，CD 47对RBC稳态至关重要，CD 47缺乏会降低RBC半衰期。Fc介导的调理作用也会消耗RBC，引起人们对使用抗CD 47药物可能导致潜在靶向贫血的担忧。几项临床试验证明，magroliumab可以安全地作为单药治疗给药，初始较低的“启动”剂量产生一过性贫血伴代偿性网织红细胞增多症，在较高的维持剂量下未观察到贫血。然而，潜在的机制尚未完全defined.Objective：描述可管理的贫血在magrolimab治疗的患者，并进一步调查的潜在机制在preclinical models.Design：前瞻性分析从ph 1试验magrolimab+阿扎胞苷（NCT 03248479）。在预先规定的时间点采集患者的全血细胞计数（CBC）、外周血和骨髓（BM）。测量CBC，并通过流式细胞术分析血液和BM样品中RBC和白色血细胞（WBC）上的CD 47表达。在鼠模型中，包括C57 BL/6 J B-hSIRPA/hCD 47小鼠，使用完整和Fc缺陷型抗小鼠CD 47（MIAP 410）和抗人CD 47（magrolimab）抗体进行临床前建模研究。患者：57名HR MDS患者。干预：Magrolimab IV 1 mg/kg（引发），然后30 mg/kg QW，然后Q2 W（维持）。阿扎胞苷75 mg/m2第1-7天（每个28天周期）。结果：用magrolimab+阿扎胞苷治疗导致可耐受的贫血，这与RBC中而不是WBC中的CD 47的快速、几乎完全丧失相关。初始1 mg/kg引发剂量足以导致CD 47损失，随后30 mg/kg维持剂量持续存在。这两个结果与实体瘤患者接受magroliumab单药治疗和淋巴瘤患者接受magroliumab+利妥昔单抗治疗的既往临床观察结果一致。我们对小鼠模型的临床前研究表明，CD 47的清除机制与先前描述的RBC抗原调节机制和细胞区室无关。相反，这种CD 47损失需要抗-CD 47红细胞和非-RBCs.Conclusions之间的交联：这些结果支持的想法，在目标magrolimab介导的贫血是减轻了RBC CD 47的接近完全的损失。接受magrolimab+阿扎胞苷治疗的HR MDS患者在预激和维持剂量下可耐受贫血。
Context:Magrolimab is an antibody blocking CD47, a “don't eat me” signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Preclinical studies found that CD47 is critical to RBC homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD47 agents. Several clinical trials demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower “priming” dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at higher maintenance doses. However, the underlying mechanism has not been fully defined.Objective:To describe manageable anemia in magrolimab-treated patients and further investigate the underlying mechanisms in preclinical models.Design:Prospective analysis from a ph1 trial of magrolimab+azacitidine (NCT03248479). Complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected from patients at prespecified time points. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for CD47 expression on RBCs and white blood cells (WBCs). Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice.Patients:57 patients with HR MDS.Interventions:Magrolimab IV 1 mg/kg (priming) then 30 mg/kg QW, then Q2W (maintenance). Azacitidine 75 mg/m2days 1-7 (each 28-day cycle).Results:Treatment with magrolimab+azacitidine resulted in tolerable anemia that correlated with rapid, near-complete loss of CD47 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for CD47 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab+rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 cross-linking between RBCs and non-RBCs.Conclusions:These results support the idea that on-target magrolimab-mediated anemia is mitigated by a near-complete loss of RBC CD47. Patients with HR MDS treated with magrolimab+azacitidine had tolerable anemia with priming and maintenance doses.