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

Background Immune 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. Objective Description of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence. Methods and results We 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. Conclusions HLH 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.