Le Aye Le, Harris James B, Siddiqi Imran, Hagiya Ashley
Department of Hematopathology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
Department of Pathology, Good Samaritan Hospital, Los Angeles, CA, USA.
J Hematol. 2019 Jun;8(2):71-78. doi: 10.14740/jh507. Epub 2019 Jun 30.
Immune checkpoint inhibitors have recently emerged as important and effective advanced cancer treatment options. Programmed cell death receptor-1 (PD-1) antagonists such as pembrolizumab and nivolumab have been approved by the US Food and Drug Administration for treatment of many advanced cancers. As anti-PD-1 checkpoint inhibitor use has been increasing, previously unreported rare side effects emerge. These checkpoint inhibitors upregulate humoral and cellular immune responses to tumor antigens. Consequently, they can be associated with immune-related adverse events including hematological-related reactions such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia and pancytopenia. However, pure red cell aplasia (PRCA) induced by anti-PD-1 checkpoint inhibitors is rarely reported in the literature. We herein report cases of two patients who developed PRCA during treatment with anti-PD-1 checkpoint inhibitors. In both cases, a peripheral blood smear examination demonstrated reticulocytopenia. Bone marrow biopsies revealed severe erythroid hypoplasia with maturation arrest at the proerythroblast stage, relative granulocytic hyperplasia and lymphocytosis. Flow cytometry and immunohistochemistry revealed that the lymphocytes were predominantly CD8 T cells. T lymphocytosis, especially in one of the two patients, mimicked a T-cell lymphoproliferative disorder; lack of clonality indicated a reactive process. Our findings, in addition to data presented in the literature, suggest that T cells play a critical role in the pathogenesis of immune-related PRCA. PRCA is an under-recognized immune-mediated adverse event that does not manifest during the clinical trial phase. It is a potentially life-threatening complication, which should be considered in the differential diagnosis of anemia in patients treated with anti-PD-1 checkpoint inhibitors.
免疫检查点抑制剂最近已成为重要且有效的晚期癌症治疗选择。程序性细胞死亡受体-1（PD-1）拮抗剂，如派姆单抗和纳武单抗，已获美国食品药品监督管理局批准用于治疗多种晚期癌症。随着抗PD-1检查点抑制剂的使用不断增加，出现了先前未报告的罕见副作用。这些检查点抑制剂上调对肿瘤抗原的体液和细胞免疫反应。因此，它们可能与免疫相关不良事件有关，包括血液学相关反应，如自身免疫性溶血性贫血、免疫性血小板减少症、中性粒细胞减少症和全血细胞减少症。然而，抗PD-1检查点抑制剂诱导的纯红细胞再生障碍性贫血（PRCA）在文献中鲜有报道。我们在此报告两例在抗PD-1检查点抑制剂治疗期间发生PRCA的患者病例。在这两例病例中，外周血涂片检查均显示网织红细胞减少。骨髓活检显示严重的红系造血低下，原红细胞阶段成熟停滞，相对粒细胞增生和淋巴细胞增多。流式细胞术和免疫组化显示淋巴细胞主要为CD8 T细胞。T淋巴细胞增多，尤其是在两名患者中的一名，类似于T细胞淋巴增殖性疾病；缺乏克隆性表明是一个反应性过程。我们的研究结果以及文献中的数据表明，T细胞在免疫相关PRCA的发病机制中起关键作用。PRCA是一种在临床试验阶段未表现出来的未被充分认识的免疫介导不良事件。它是一种潜在的危及生命的并发症，在抗PD-1检查点抑制剂治疗的贫血患者鉴别诊断中应予以考虑。
