title: Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy.
abstract: Immune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP).
  
  
  
  A 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment.
  
  
  
  Thrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.
authors.affiliation: Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, TN 37232 USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Shiuan
authors.affiliation: Division of Hematology/Oncology, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, Nashville, TN USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Beckermann
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Ozgun
authors.affiliation: Sarcoma Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065 USA.
authors.forename: Ciara
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: McKean
authors.affiliation: Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McQuade
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232 USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY 14263 USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Division of Hematology/Oncology, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, Nashville, TN USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Greer
authors.affiliation: Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057 USA.
authors.forename: Suthee
authors.initials: S
authors.lastname: Rapisuwon
authors.affiliation: Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065 USA.|Weill Cornell Medical College, Cornell University, New York, NY 10065 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Postow
authors.affiliation: Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Eroglu
authors.affiliation: Division of Hematology/Oncology, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, Nashville, TN USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Johnson
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000074324:Ipilimumab / Q000009:adverse effects* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D000069283:Rituximab / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000188:drug therapy
chemical_list: D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; D000069283:Rituximab
keywords: CTLA-4; Checkpoint inhibitor; Immune thrombocytopenic purpura; Melanoma; PD-1; Thrombocytopenia