Thrombotic Thrombocytopenic Purpura due to Checkpoint Inhibitors

Abstract

Ipilimumab is a monoclonal antibody that enhances the efficacy of the immune system by targeting a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is a protein receptor that downregulates the immune system. Nivolumab is also a humanized monoclonal antibody that targets another protein receptor that prevents activated T cells from attacking the cancer; this receptor is called programmed cell death 1 (PD-1). The FDA approved ipilimumab combined with nivolumab as a frontline therapy for patients with metastatic melanoma or renal cell carcinoma and as a second-line therapy for patients with microsatellite instability-high (MSI-H) metastatic colon cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during or weeks to months after therapy. We report a case of thrombotic thrombocytopenic purpura (TTP) in a patient with metastatic renal cell carcinoma following one cycle of ipilimumab and nivolumab. Only one case report of ipilimumab-induced TTP exists in the medical literature. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event.

Thrombotic thrombocytopenic purpura associated to dual checkpoint inhibitor therapy for metastatic melanoma

“…Retrospectively, we postulate a secondary TTP as an immune-related adverse event (irAE) followed by administration of dual checkpoint inhibitor. However, we acknowledge that advanced malignancies can trigger TTP itself [4], strikingly, the temporal parallel of initiation of dual checkpoint inhibition and onset of TTP within weeks is the common characteristic of our and the other reported cases [1][2][3]. An up-regulation of T-cell immune function may result in TTP as checkpoint inhibitors are associated with exacerbation of underlying autoimmune conditions in up to 50% of patients [5].…”

“…Common immune-related adverse events of this regimen comprise organ directed autoimmune phenomena as hypophysitis, pneumonitis, hepatitis, colitis, and nephritis. To our knowledge, development of an immunemediated thrombotic thrombocytopenic purpura (TTP) following ipilimumab alone or in combination with nivolumab was reported only in three cases up to date [1][2][3].…”

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

“…A combination of ipilimab with the PD1‐blocking monoclonal antibody (nivolumab) causes adverse effects such as autoimmune inflammation–mediated colitis, encephalitis, hepatitis, nephritis, pneumonitis, thyroiditis, thrombotic thrombocytopenic purpura and the aforementioned hypophysitis. These side effects emerge during therapy or, within weeks to months after therapy …”

“…These side effects emerge during therapy or, within weeks to months after therapy. 220,221 Among these organ-specific or systemic inflammatory disorders, two are perilously life-threatening: fulminant myocarditis and the so-called cytokine release syndrome with signs of microvascular endothelial injury manifested by ARDS and disseminated intravascular coagulation. 222,223 The term "cytokine release syndrome" is a misnomer since the cause of this complication, that is monoclonal antibody treatment, is known and cytokines are induced together with other mediators of inflammation rather than being "released" since they are usually not stored in secretory granules or vesicles.…”

Hematological toxicities in immune checkpoint inhibitors: A pharmacovigilance study from 2014 to 2019

“…Besides durable and impressive clinical effects, ICIs could also induce multiple severe or even fatal organ system toxicities, including those of the hematological system. Frequently reported clinical hematological complications include neutropenia, 8 immune thrombocytopenia, 9 autoimmune hemolytic anemia, 10 and immune thrombocytopenic purpura 11,12 . ICI‐induced hematological AEs are rare but potentially life‐threatening events 10‐12 .…”