Pembrolizumab-induced thrombotic thrombocytopenic purpura

Abstract

<jats:sec><jats:title>Introduction</jats:title><jats:p> Pembrolizumab is a humanised monoclonal antibody targeting the receptor programmed cell death protein-1 (PD-1), with anti-tumour activity demonstrated for many malignancies. Such immune checkpoint inhibitors are associated with many immune-related adverse events including rash, colitis, hepatitis, pneumonitis, endocrinopathy and, rarely, haematological adverse events, including immune-related thrombocytopenia. </jats:p></jats:sec><jats:sec><jats:title>Case report</jats:title><jats:p> We report a 60-year-old female with metastatic non-small cell lung cancer treated with pembrolizumab every three weeks. Following her fifth cycle, she presented to our hospital with community-acquired pneumonia. Thrombocytopenia developed the next day and, after detailed investigations, thrombotic thrombocytopenic purpura was diagnosed. </jats:p></jats:sec><jats:sec><jats:title>Management and outcome</jats:title><jats:p> Pembrolizumab was immediately ceased and plasma exchange commenced along with IV methylprednisolone 250 mg daily for three days followed by oral prednisolone. After five days of plasma exchange, platelet counts normalised and haemolytic anaemia resolved. </jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p> Acquired thrombotic thrombocytopenic purpura is an autoimmune disorder caused by an inhibitory autoantibody against ADAMTS-13. While most cases of acquired thrombotic thrombocytopenic purpura are idiopathic, certain conditions (e.g. bacterial infection, autoimmune disorders, malignancies) and medications are associated with thrombotic thrombocytopenic purpura. Other potential causes were eliminated in our patient. As acquired thrombotic thrombocytopenic purpura is an autoimmune disorder, pembrolizumab, given its unique mechanism of action and association with immune-related adverse events, is believed to be implicated in the development of thrombotic thrombocytopenic purpura. This case is one of only two linking anti-PD-1 therapy to thrombotic thrombocytopenic purpura development (the other occurring in a patient on nivolumab plus ipilimumab). Thrombotic thrombocytopenic purpura is life-threatening and clinicians are advised to be aware of its possible occurrence in immune checkpoint inhibitor-treated patients. </jats:p></jats:sec>

Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitors in Solid Cancer: Case Report and Literature Review

“…Although ICIs have been approved for treating various types of human malignancies, immune-related thrombocytopenia is most likely to be reported in NSCLC ( 5 – 11 , 24 , 25 ), melanoma ( 12 – 20 ), lymphoma ( 21 ), pancreatic cancer ( 22 ), and renal cell carcinoma ( 23 ), which is consistent with retrospective data from multiple institutions ( 26 ). Previous case and retrospective studies show that immune thrombocytopenia occurred in cancer patients treated with PD-1 inhibitor monotherapy, such as nivolumab or pembrolizumab, or a CTLA-4 inhibitor, or a combination with PD-1 and a CTLA-4 inhibitor ( Table 1 ).…”

“…An increased number of cases of hematologic disorders have been reported since 2017, which may be attributed to increased application of ICIs and improved recognition of adverse effects ( 4 ). In particular, immune thrombocytopenia induced by ICIs has been reported in a few NSCLC, melanoma, and other malignancies ( 5 – 25 ). We herein describe one case of immune thrombocytopenia induced by the PD-L1 inhibitor durvalumab and its clinical management.…”

Nivolumab-Induced Thrombotic Thrombocytopenic Purpura in a Patient with Anal Squamous Cell Carcinoma: A Lesson on Hematologic Toxicity from Immunotherapy

“…As in our patient's case, ADAMTS 13 inactivation is frequently caused by the presence of an inhibitor, which in most cases is related to autoimmunity and associated autoantibodies [14]. TTP as an irAE from ICIs is a rare clinical complication that has not been discussed in comprehensive reviews of hematologic irAEs [6–10], with only three prior cases reported to date [11–13] (Table 2). Given the high fatality rate if plasma exchange is delayed, TTP must be included in the differential diagnosis for thrombocytopenia and hemolytic anemia of patients with cancer receiving immunotherapy, as early detection and treatment are critical to prevent morbidity and mortality.…”

“…It has been reported that anti–CTLA‐4 agents are more toxic than anti–PD‐1 therapy [4], and retrospective reviews showed higher incidence of immune‐related fatalities with the former [5]. In addition, single‐agent pembrolizumab was also recently reported to be associated with TTP in a patient with metastatic non‐small cell lung cancer [13]. Nivolumab is associated with a wide variety of hematologic irAEs, but to our knowledge, this is the first report of immunotherapy‐induced TTP from single‐agent nivolumab.…”

“…Other reviews show that treatment with ICIs can be complicated by rare but life-threatening clinical entities including red cell aplasia, neutropenia, immune thrombocytopenia, acquired hemophilia A, cryoglobulinemia, and hemophagocytic lymphohistiocytosis [6][7][8][9][10]. Thrombotic thrombocytopenic purpura (TTP), a potentially fatal syndrome, has been excluded from previous reviews, and only three cases of immunotherapy-associated TTP have been previously reported [11][12][13].…”