Bone Marrow Findings of Immune-Mediated Pure Red Cell Aplasia Following Anti-Programmed Cell Death Receptor-1 Therapy: A Report of Two Cases and Review of Literature.

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.