Nivolumab Associated Direct Antiglobulin-Negative Hemolytic Anemia with Pure Red Cell Aplasia – An Unforeseen Consequence


Eve Schodowski, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio Abdul Rahman Al Armashi MD, Case Western Reserve University, Cleveland, Ohio


Immune checkpoint inhibitors (ICIs) are commonly used in the treatment of advanced melanoma, as they have transformed survival rates, tumor regression, and long-term disease control. ICIs function by blocking inhibitory receptors on T-cells (such as PD-1 and CTLA-4), leading to a more robust T-cell-mediated immune response to cancer cells. Despite these advances, many immune-related adverse events (irAEs) associated with ICIs have been reported. Herein we illustrate, to our knowledge, the first described irAE of direct antiglobulin (DAT) negative hemolytic anemia with pure red cell aplasia (PRCA) associated with nivolumab, a PD-1 inhibitor.

Case Presentation

A 50-year-old woman with a past medical history of malignant melanoma with metastasis to the lungs presented with weakness, fatigue, and hematuria. Her melanoma treatments prior to admission included three cycles of ipilimumab complicated by dermatitis, followed by one cycle of nivolumab complicated by transaminitis the month prior to admission. Initial physical exam was untelling but labs revealed anemia with an initial hemoglobin of 6 g/dL, elevated LDH, decreased haptoglobin, indirect hyperbilirubinemia, and persistent transaminitis. Urinalysis showed 2+ blood but no RBCs. Further work-up demonstrated negative DAT, low reticulocyte count, elevated EPO, and a bone marrow biopsy revealing pure red cell aplasia. Right upper quadrant ultrasound was performed for transaminitis and showed hepatic steatosis. Autoimmune hepatitis work-up was largely negative but did show a positive ANA in a speckled pattern and positive anti-ssA. Throughout her 18-day hospital course, the patient required persistent blood transfusions and received 13 units of pRBC in total. She was treated with high-dose steroids, mycophenolate mofetil (MMF), and two doses of intravenous immune globulin (IVIG) due to a high degree of suspicion for ICI irAE in the setting of DAT negative, hemolytic, hypoproliferative anemia. With this treatment, the patient's hemolytic labs, frequency of transfusions, and transaminitis progressively improved. Once the patient did not require a blood transfusion for a minimum of 72 hours, she was deemed stable for discharge on prednisone and MMF, with arrangements for regular outpatient hemolytic labs, periodic blood transfusions, and close follow-up with hematology/oncology.


This case illustrates the first described case of ICI irAE DAT negative hemolytic anemia and pure red cell aplasia. Comparatively, there are two described cases of ICI-associated autoimmune (DAT positive) hemolytic anemia with PRCA in the literature. All cases described utilized blood transfusions, high-dose steroids, and IVIG for treatment of the irAE, ultimately with each patient normalizing their hemoglobin and reticulocyte counts after several weeks. Therefore, physicians should maintain a high degree of suspicion for autoimmune hemolytic anemia in patients treated with an ICI, even if the DAT is negative, to assure a favorable outcome.



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