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Immune checkpoint inhibitors emerged as a novel powerful group of anti-cancer therapies frequently changing the outcomes of previously hopeless cases in oncology. De novo development of autoimmune diseases unfortunately may occur with their use. Cases of autoimmune hepatitis, myocarditis, pancreatitis thyroiditis, myasthenia gravis, interstitial nephritis with nephrotic syndrome have been recognised. Few cases of microangiopathic hemolytic anemias and hemophagocytic lymphohistiocytosis (HLH) have been reported with clinical response to therapeutic plasma exchange (TPE) and corticosteroids. Herein we present the case of development of atypical hemolytic syndrome (aHUS) after exposure to pembrolizumab (programmed cell death 1 inhibitor) resulting in severe anuric acute kidney injury (AKI) and need for renal replacement therapy.
A 65-year-old African American female with a past medical history of invasive ductal carcinoma of the left breast, stage IIB (T2 N0 M0) ER-, PR-, HER-. She was initially treated with Carboplatin, Paclitaxel and Pembrolizumab for 4 cycles followed by Doxorubicin, Cyclophosphamide, and Pembrolizumab for 4 cycles. She presented to the hospital 3 weeks after her last cycle of chemoimmunotherapy with severe fatigue and fever. After one week of hospitalization, she was noted to have an abrupt decline in hemoglobin to as low as 5.3 g/dl, thrombocytopenia with platelet count as low as 39 K/uL, high LDH 3111 U/L , 1+ schistocytes, increase in creatinine from 1.85 mg/dl to 4.9 mg/dl, and undetectable haptoglobin. Ferritin was more than 7500 ng/ml, triglycerides 382 mg/dl. Coombs' test was negative. Respiratory panel, EBV, blood and urine cultures were negative. She had minimal proteinuria 0.1 g and no hematuria. No sources of infection or blood loss were identified.There was no splenomegaly on imaging. Emergent empiric TPE with fresh frozen plasma was initiated along with high dose corticosteroid therapy, and was done daily for 19 treatments with minimal effect on hemolytic parameters. Peripheral flow cytometry showed two atypical T cells with virtual absence of B cells population suggestive of immune mediated process. Bone marrow biopsy was sent to the tertiary center for second opinion and showed hypercellular marrow with erythroid hyperplasia, atypical T-cell population and increased iron with 9% ring sideroblast, not suggestive of HLH. Patient required transfusions of red blood cells and platelets and unfortunately developed severe anuric AKI and anasarca. Renal replacement therapy in the form of hemodialysis was initiated. ADAMTS 13 factor was in the normal range 68% and clinical diagnosis shifted from thrombotic thrombocytopenic purpura and HLH to the drug induced aHUS. Treatment with Eculizumab was initiated, steroids were tapered, and PLEX was discontinued.
Patient experienced stabilization of her hemoglobin within one week following initiation of Eculizumab, and 4 weeks after initiation of treatment she experienced progressive renal recovery and she was taken off hemodialysis. Hemolysis resolved completely and a plan for bilateral mastectomies was carried on.
Per our best knowledge this is a first case describing development of drug induced aHUS with severe dialysis dependent AKI related to the exposure to Pembrolizumab. Contrary to the prior reports of Pembrolizumab related MAHA and HLH, use of corticosteroids and PLEX was not effective presumably due to the different mechanisms of immune injury. Prompt response to Eculizumab with complete renal and hematologic recovery points to the novel pathway of how Pembrolizumab can affect the immune system on the level of complement regulatory proteins.