Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP)

Abstract

BackgroundCTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis.Case presentationWe describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial.ConclusionThe range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients.

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].…”

Renal Toxicity From Pemetrexed and Pembrolizumab in the Era of Combination Therapy in Patients With Metastatic Nonsquamous Cell NSCLC

“…3 In addition, one case report described TMA as a result of checkpoint inhibition. 30 However, TMA is also associated with malignancies in general, which makes it uncertain if TMA can be caused by checkpoint inhibition. 31 TMA is characterized by hemolytic anemia owing to red blood cell fragmentation, thrombocytopenia owing to platelet consumption, and end-organ damage owing to microvascular thrombi.…”

An Update in Drug-Induced Thrombotic Microangiopathy

“…It is important to exclude any other diagnosis before attributing TMA to a drug. For example, in some cases such as these of ipilimumab, pazopanib, ustekinumab, and golimumab severe ADAMTS13 deficiency was found, plasma exchange was effective and no drug-dependent antibody inhibition of ADAMTS13 activity was reported, making drug-indused causal relationship unlikely (7,(16)(17)(18).…”