背景:复发/难治性(R/R)急性髓性白血病(AML)患者的治疗选择有限。在AML的临床前模型中,抑制PD-1/PD-L1轴显示抗白血病活性.Avelumab是一种抗PD-L1免疫检查点抑制剂(ICI),已在多种实体瘤中获得批准。作者进行了1b/2期临床试验,以评估阿扎胞苷联合阿维鲁单抗治疗R/RAML患者的安全性和有效性。
方法:年龄≥18岁的R/RAML患者在第1天至第7天接受阿扎胞苷75mg/m2治疗,在第1天和第14天接受阿维鲁单抗治疗。
结果:19例患者接受治疗。中位年龄为66岁(范围,22-83岁),100%患有2017年欧洲白血病不良风险疾病,63%的人曾接触过低甲基化剂。前7名患者的Avelumab剂量为3mg/kg,随后的12名患者剂量为10mg/kg。最常见的≥3级治疗相关的不良事件是中性粒细胞减少和贫血各2例。2例患者出现免疫相关不良事件2级和3级肺炎,分别。总体完全缓解率为10.5%,两者均完全缓解,并伴有残余血小板减少症。中位总生存期为4.8个月。通过质量细胞计数分析骨髓母细胞的免疫相关标志物,显示出PD-L2的表达明显高于PD-L1,无论是在治疗前还是在治疗期间的所有时间点,随着治疗中PD-L2表达的增加。
结论:尽管阿扎胞苷和阿维鲁单抗的联合用药耐受性良好,临床活动有限。PD-L2在骨髓母细胞中的高表达可能是AML中抗PD-L1治疗耐药的重要机制。
■本报告描述了阿扎胞苷与抗PD-L1免疫检查点抑制剂avelumab治疗复发性/难治性急性髓性白血病(AML)患者的1b/2期研究结果。联合疗法的临床活性适中,总体反应率为10.5%。然而,质谱分析显示,在所有时间点进行分析的所有患者的AML母细胞中,PD-L2的表达显著高于PD-L1.这些数据表明PD-L2作为AML免疫逃逸手段的新的潜在作用。
BACKGROUND: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical
trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML.
METHODS: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m2 on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles.
RESULTS: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy.
CONCLUSIONS: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML.
UNASSIGNED: This report describes the results of a phase 1b/2
study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape.