Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the PRF1A91V gene polymorphism

Abstract

BackgroundImmune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems.ObjectiveDescription of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence.Methods and resultsWe describe a patient with aggressive metastatic breast cancer who developed HLH while undergoing experimental treatment with pembrolizumab, resulting in critical illness and multiorgan system failure. Pembrolizumab discontinuation and high-dose corticosteroids were effective in managing HLH. Subsequent next-generation sequencing of 15 genes associated with HLH revealed a germline polymorphism in perforin-1 (PRF1), PRFA91V, that may have predisposed the patient to develop HLH. The patient has had no evidence of malignancy for 2 years following recovery despite receiving no further cancer-directed treatment.ConclusionsHLH is a rare but serious complication of immune checkpoint blockade. Patients with underlying hypomorphic alleles in PRF1 may be predisposed to develop this toxicity. Further studies are necessary to confirm a possible link between perforin gene mutations and immune checkpoint blockade-associated HLH.

Pembrolizumab-induced Hemophagocytic Lymphohistiocytosis: an immunotherapeutic challenge

“…On literature review, the case reports discussing immunotherapy-induced HLH have described a wide range of underlying malignancies including Squamous Cell Carcinoma of the Lung, Urothelial Carcinoma, Thymic Carcinoma, Merkel Cell Carcinoma, Breast Cancer, and Melanoma however to our knowledge this is the first report of immunotherapy-induced HLH in a HNSCC patient [3][4][5][6][7][8][9][10][11]. The time to HLH onset after starting immunotherapy has been shown to be highly variable, ranging from less than a month after receiving either pembrolizumab, nivolumab, or combination ipilimumab/nivolumab to over a year in a patient treated with pembrolizumab [3,4,7].…”

“…When compared to other hematologic irAEs HLH occurred earlier and was characterized by increased mortality [5]. HLH has also been described in patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, further highlighting the association between modulation of T-cell activity and development of HLH [6]. Whereas the infectious, malignant, and autoimmune causes of secondary-HLH are due to an underlying disease process, immunotherapy-induced HLH creates a different type of clinical challenge; the patient was started on immunotherapy in an effort to increase T-cell activity against the tumor however an unwanted side effect of this intervention was creation of the pathologic hyperinflammatory state that characterizes HLH.…”

“…Interestingly, some case reports discuss patients who became critically ill requiring ICU management due to complications of HLH who not only recovered with steroids but also demonstrated tumor regression, with some suggesting that the degree of antitumor efficacy with checkpoint inhibitors may correlate with the severity of side effects patient's experience [4,9]. Specific risk factors for development of HLH related to immunotherapy are currently unknown, however one case report describes a patient with breast cancer who developed HLH from pembrolizumab, recovered following a course of steroids, and underwent molecular genetic testing with subsequent discovery of a PRFA91V polymorphism [6]. Such polymorphisms are implicated in primary HLH and are known to exist in up to 3% of the North American population suggesting a potential component of genetic predisposition to develop HLH in adults receiving immunotherapy [6].…”

“…Specific risk factors for development of HLH related to immunotherapy are currently unknown, however one case report describes a patient with breast cancer who developed HLH from pembrolizumab, recovered following a course of steroids, and underwent molecular genetic testing with subsequent discovery of a PRFA91V polymorphism [6]. Such polymorphisms are implicated in primary HLH and are known to exist in up to 3% of the North American population suggesting a potential component of genetic predisposition to develop HLH in adults receiving immunotherapy [6].…”

“…The optimal management of irAEs continues to evolve with organizations like the Society for Immunotherapy of Cancer (SITC), National Comprehensive Cancer Network (NCCN), and American Society for Clinical Oncology (ASCO) recently publishing management guidelines [12,13]. Generally, discontinuing the presumed inciting agent and initiation of corticosteroids are first line treatments [6,12,13]. For more severe hyperinflammatory manifestations of immune therapy such as HLH corticosteroid monotherapy may be insufficient.…”