Safety of Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis: Results of the Primary Analysis of the Pivotal Phase 2/3 Study

Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Current conventional therapy for HLH is based on the combined use of dexamethasone and etoposide, and, although effective in many patients, these drugs may promote the development of opportunistic infections and tissue toxicity, and are associated with high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study (Locatelli et al. NEJM 2020) and investigate the relationship of adverse events (AE) to dose and duration of treatment.

Methods: Due to the rare and life-threatening nature of the disease, the efficacy and safety of emapalumab was assessed in an open-label pivotal study (NCT01818492) which included patients aged ≤18 years with a diagnosis of primary HLH and active disease (Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 3, 6 and 10 mg/kg if required, based on predefined laboratory and clinical response parameters. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Analysis was performed on 34 patients at a database cut-off date of July 2017 (Locatelli et al NEJM 2020). The relationship of AE to emapalumab treatment was reported by the study investigator. The impact of treatment duration on AE or infection occurrence was measured by the number of events with onset in a predefined time interval from emapalumab initiation. The impact of the dosing scheme on AE and infection occurrence was assessed by the number of AEs or infections in a predefined dose range.

Results: Overall, 29% of patients had at least one AE deemed related to emapalumab use. Most (90%) of these events were infusion-related reactions, all of which were mild to moderate and resolved. No severe or serious hypersensitivity reactions were reported. Infections caused by pathogens potentially favored by IFNy neutralization occurred in 1 patient during emapalumab treatment (disseminated histoplasmosis) and resolved with appropriate treatment. There was no increase in AE frequency or the number of viral, bacterial, or fungal infections with increased dose or duration of emapalumab treatment.

Conclusion: Neutralization of IFNy with emapalumab in this very fragile population of patients with active primary HLH was associated with a favorable and manageable safety profile across all doses and treatment durations assessed, allowing for flexible and tailored use based on patient clinical response. In addition, 102 patients have been treated in the US following FDA approval, and post-marketing surveillance has not revealed any additional safety concerns with the use of emapalumab in primary HLH (cutoff date 19 May 2020). Taken together, these safety results suggest that emapalumab may offer an additional advantage over conventional HLH therapies.