Michael Jordan, MD, a physician-scientist in the division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children’s Hospital Medical Center HLH Center of Excellence, discusses primary hemophagocytic lymphohistiocytosis (HLH) and the phase 2/3 clinical trial presented at the American Society of Hematology (ASH) Annual Meeting in San Diego. Dr. Jordan was a primary investigator in the emapalumab (Gamifant) clinical trial.

Emapalumab is a new treatment option for primary HLH patients. HLH is an often-fatal syndrome of hyperinflammation in which massive hyperproduction of interferon gamma (IFNy) is thought to drive immune system hyperactivation, ultimately leading to organ failures. It is estimated that fewer than 100 cases of primary HLH are diagnosed each year in the US, but this is believed to represent under diagnosis. Diagnosis is challenging due to the variability in signs and symptoms, which may include fevers, swelling of the liver and spleen, severe low red and white blood cell counts, bleeding disorders, infections, neurological symptoms, organ dysfunction and organ failure. Primary HLH can rapidly become fatal if left untreated, with median survival of less than two months. The immediate goal of treatment is to quickly control the hyperinflammation and to prepare for haematopoietic stem-cell transplant. The current conventional treatment prior to transplant includes steroids and chemotherapy and are not specifically approved to treat primary HLH.

The FDA approval of emapalumab was based on results from a global, multicenter, open-label, single-arm pivotal Phase 2/3 clinical study (NCT01818492), which enrolled 34 primary HLH patients. The efficacy of emapalumab was evaluated in the cohort of 27 patients with refractory, recurrent or progressive disease during conventional HLH therapy or who were intolerant to conventional HLH therapy, meaning that they had not responded, not achieved a satisfactory response, not maintained a satisfactory response, or not been able to tolerate conventional therapy. Emapalumab was administered concomitantly with dexamethasone, which could be tapered during the study. The primary endpoint was achieved, with 63% of patients (p=0.013) demonstrating an overall response at the end of treatment, defined as achievement of either a complete or partial response, or HLH improvement. In addition, 70% of patients proceeded to hematopoietic stem cell transplant (HSCT). Of the 27 refractory patients treated in the study, 82% had a genetically confirmed primary HLH diagnosis. The most common adverse reactions reported during the study were infections (56%), hypertension (41%), infusion-related reactions (27%), and fever (24%).


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