Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, TN 37232 USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 USA.
J Immunother Cancer. 2017 Feb 21;5:8. doi: 10.1186/s40425-017-0210-0. eCollection 2017.
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.
免疫检查点抑制剂，包括针对程序性死亡 1（PD-1）和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的抗体，在癌症治疗中的应用越来越频繁。免疫相关不良反应（irAEs）包括结肠炎、皮炎和肺炎等已得到充分描述，但随着接受治疗的患者数量增加，现在出现了较少见的事件。在此，我们描述了免疫检查点抑制剂治疗后血小板减少症的发生率和谱，并报告了两例特发性血小板减少性紫癜（ITP）的严重病例。
一名 47 岁女性，患有复发性 BRAF 突变阳性黑色素瘤，接受了抗 PD-1 和抗 CTLA-4 联合治疗。两周后，她出现黏膜出血、瘀点和血小板减少症，并接受了类固醇和静脉注射免疫球蛋白（IVIG）治疗 ITP 的标准治疗。骨髓活检证实了她的诊断，由于缺乏治疗反应，她接受了利妥昔单抗治疗。她开始恢复并稳定血小板计数，最终能够再次接受 PD-1 抑制治疗，且未再次出现血小板减少症。另一名患者为 45 岁女性，患有 BRAF 野生型黑色素瘤，接受了抗 PD-1 单药治疗，43 天后出现血小板减少症。3 周的类固醇治疗改善了她的血小板计数，但血小板减少症再次复发，需要额外的类固醇治疗。她后来接受了抗 CTLA-4 单药治疗，并出现严重的 ITP 和颅内出血。她的 ITP 在停用皮质类固醇、IVIG 和利妥昔单抗并停止检查点抑制后得到缓解。在对 2360 名接受检查点抑制剂治疗的黑色素瘤患者的回顾性图表审查中，<1%的患者在接受免疫检查点抑制后出现血小板减少症，其中大多数患者自发缓解，无需治疗。
免疫检查点抑制剂引起的血小板减少症，特别是 ITP，似乎是一种罕见的免疫相关不良反应，轻度病例可通过观察和/或标准 ITP 治疗方案进行管理。在我们的系列中，大多数患者的血小板减少症较轻，可自发缓解或对标准皮质类固醇方案有反应。然而，在两例严重病例中，除了类固醇外，还需要使用 IVIG 和利妥昔单抗。第一例患者成功恢复了检查点抑制，但第二例患者无法耐受再挑战。
