Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy

Abstract

Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al.: BMC Med 2016;14: 20], metastatic non-small cell lung cancer [Guibert and Mazières: Expert Opin Biol Ther 2015;15: 1789–1797], metastatic renal cell cancer [Farolfi et al.: Expert Opin Drug Metab Toxicol 2016;12: 1089–1096], and relapsed or refractory classic Hodgkin’s lymphoma [Villasboas and Ansell: Expert Rev Anticancer Ther 2016;16: 5–12]. Given the current and increasing indications for these drugs, it is essential for all physicians to become well versed with their common adverse effects and to be observant for other less documented clinical conditions that could be unmasked with the use of such medications. A definite association between autoimmune hemolytic anemia and the immune checkpoint inhibitor nivolumab has not been clearly documented, although a few cases have been reported recently [Kong et al.: Melanoma Res 2016;26: 202–204; Schwab et al.: Case Rep Oncol 2016;9: 373–378; Tardy et al.: Hematol Oncol 2016, DOI: 10.1002/hon.2338]. We report a case of fatal autoimmune hemolytic anemia refractory to steroids in a patient treated with nivolumab for metastatic lung cancer, and reflect on the other reported cases of autoimmune hemolytic anemia after the use of nivolumab.

Hematologic Complications of Immune Checkpoint Inhibitors

“…A number of isolated case reports and case series have demonstrated that uncommon severe and even fatal hematologic toxicities may complicate immune checkpoint inhibitor therapy . However, no series has evaluated more than 10 cases; thus, the timing, spectrum, and clinical presentation of hematologic irAEs are poorly understood.…”

Nivolumab-induced cold agglutinin syndrome successfully treated with rituximab

“…12 In the reported AIHA cases secondary to nivolumab, in addition to cessation of therapy and packed red blood cell transfusion, there have been 2 approaches for the management: high-dose steroids and rituximab. 9,10 Although high-dose steroids seem to be effective and adequate therapy for AIHA secondary to nivolumab, 1 patient did not respond to steroid treatment and died, and another patient partially responded to steroids and was also treated with rituximab.…”

A case of autoimmune haemolytic anaemia after 39 cycles of nivolumab

“…Depletion of B lymphocytes leads to reduction in autoantibodies, inflammatory cytokines and T-cell activation 7. In most of the cases, the anaemia was responsive to steroids, except for Palla et al 8. Nevertheless, clinicians should have a low threshold for initiating steroids in patients with suspected nivolumab-related AIHA, and rituximab could be considered early on as an addition to steroids in first-line treatment or as a second-line agent in those who fail to respond to steroids.…”