Severe immune-related autoimmune hemolytic anemia induced by pembrolizumab: a case report with novel immunosuppressive strategy

Introduction: Immune checkpoint inhibitors (ICIs), including PD-1 inhibitors, have significantly improved survival outcomes in patients with melanoma; however, serious adverse events may occur as a consequence of immune dysregulation. Autoimmune hemolytic anemia (AIHA) is a rare but potentially life-threatening condition. While corticosteroids remain the cornerstone of AIHA management, some patients with severe anemia require additional immunosuppressive agents beyond steroids alone. Case report: A 52-year-old woman with anal canal malignant melanoma presented with severe generalized fatigue, lower back pain, and gross hematuria. She had received one cycle of pembrolizumab two weeks prior to presentation. She had severe anemia with reticulocytosis, elevated lactate dehydrogenase and bilirubin levels, and a positive direct Coombs test, and was diagnosed with severe AIHA secondary to pembrolizumab therapy. Despite initial treatment with corticosteroids and intravenous immunoglobulin (IVIG), hemolysis progressed. The condition was ultimately controlled with cyclophosphamide (CTX) and fluorouracil (5-FU) in addition to corticosteroids. Three months later, pembrolizumab was again administered and the resulting AIHA was managed with corticosteroids alone. The patient subsequently completed cycles 3-8 of pembrolizumab without further recurrence and achieved sustained tumor control. Conclusion: This case illustrates a novel immunosuppressive strategy for management of pembrolizumab-induced AIHA, a rare but serious hematologic adverse effect associated with immunotherapy. We describe the clinical presentation and report that the combination of CTX and 5-FU in addition to corticosteroids and IVIG was successful in treating severe AIHA. Further investigation in larger cohorts is warranted to validate this approach for intervention in AIHA. With appropriate and prompt management, safe rechallenge and continuation of ICIs may be feasible in selected patients.