Article Text

Short report
Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the PRF1A91V gene polymorphism
  1. Hanny Al-Samkari1,2,
  2. Gregory D Snyder3,
  3. Sarah Nikiforow2,
  4. Sara M Tolaney2,
  5. Rachel A Freedman2,
  6. Julie-Aurore Losman2,4
  1. 1 Center for Hematology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
  3. 3 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4 Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Julie-Aurore Losman, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Julieaurore_Losman{at}


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.

  • haemophagocytic lymphohistiocytosis
  • cancer immunotherapy
  • HLH
  • PRF1
  • pembrolizumab

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  • Contributors HAlS designed the case report, collected data, analysed data, and wrote and revised the manuscript. GDS collected data, analysed data and wrote the manuscript. SN provided expertise in haemophagocytic lymphohistiocytosis and critically revised the manuscript. SMT and RAF provided expertise in breast cancer and revised the manuscript. JAL designed the case report, oversaw writing of the manuscript and critically revised the manuscript.

  • Disclaimer No funding, writing support or other assistance was obtained from Eisai or Merck & Company by the authors. Neither Eisai nor Merck & Company had influence on the contents of the manuscript.

  • Competing interests HA: consultancy, Agios Pharmaceuticals. SN: advisory board member, Kite Pharmaceuticals. SMT: institutional funding from Genentech, Eli Lilly, Novartis, Pfizer, Exelixis, Bristol Myers Squibb, Eisai, AstraZeneca, Merck, Nektar; served on advisory boards for Genentech, Eli Lilly, Novartis, Pfizer, Exelixis, Merck, Bristol Meyers Squibb, Eisai, AstraZeneca, Nektar, Puma, Nanostring. RAF: institutional funding only from Eisai and Puma Biotechnology. JAL: institutional funding from Eli Lilly, Bayer. GDS has nothing to disclose.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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