Novel Immunotherapy for Primary Hemophagocytic Lymphohistiocytosis

Results of a study evaluating the safety and efficacy of a promising new agent were presented at ASH 2018.

Emapalumab could be a promising new therapeutic option for patients with primary hemophagocytic lymphohistiocytosis (pHLH). Results of the study (late-breaking abstract 6) were presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 1–4 in San Diego.

A rare condition, pHLH is a syndrome of hyperinflammation, which is usually linked to defects in cytotoxic function. Clinical characteristics of this disease include prolonged fever, hepatomegaly, splenomegaly, hemophagocytosis, hypercytokinemia, cytopenias, hyperferritenemia, hypofibrinogenemia, and hypertriglyceridemia. Although dexamethasone and etoposide are usually used to treat this disease, this regimen isn’t US Food and Drug Administration–approved. Moreover, the addition of cyclosporine A to dexamethasone and etoposide has not been shown to improve survival outcomes. Notably, available treatments for pHLH yield various degrees of broad immunosuppression, with etoposide leading to myelosuppression.

Emapalumab, an anti-interferon gamma monoclonal antibody under development, counteracts interferon gamma, levels of which are increased in pHLH. Lead author of the current study, Franco Locatelli, of the Department of Pediatric Hematology and Oncology at Babino Gesu Pediatric Hospital in Rome, stressed the vital need for research on emapalumab.

“This trial was conducted both in the Europe and the United States to address an unmet clinical need, namely the treatment of patients with pHLH,” Locatelli said. “Recent attempts to improve the dexamethasone and etoposide-based regimen did not show a significant improvement in overall probability of survival. There is no standardized therapy for patients who fail front-line treatment, although alemtuzumab has been reported to be effective in retrospective analysis.”

A total of 34 pHLH patients aged 18 years or younger were included in the open-label, pivotal study. Of those included, 27 failed conventional HLH treatment and 7 were treatment-naïve. The overall median age was about 1 year, and 18 of the 34 were female. Researchers administered participants up to 10 mg/kg of emapalumab for between 4 to 8 weeks in addition to concomitant dexamethasone. This regimen was extended to the time of allogeneic hematopoietic stem cell transplantation as needed. After the study ended, patients began with the extension phase.

The primary outcome of the study was the overall response rate (ORR) at the conclusion of treatment, which was determined by either normalization or ≥ 50% improvement from baseline in clinical characteristics of the disease. Investigators found that the ORR was much higher than the pre-specified null-hypothesis of 40%. Specifically, the ORR was 63% in patients who failed prior HLH therapy (P = .0134; 95% CI, 42%–81%), and 64.7% in all-treatment patients, including those who were treatment-naïve (P = .0031; 95% CI, 46%–80%).

Another result of the study included a short median time to overall response of 8 days. Furthermore, patients were in response for a median of 75% of treatment days.

“In terms of safety and tolerability, in this population of fragile children, it’s not surprising that several adverse events were recorded,” said Locatelli. “Serious adverse events were recorded in half of the patients but only 1 of 34 patients [required] discontinuation. In [light] of these results, on November 20, 2018, the FDA approved emapalumab as the first agent for newborns, children, and adults with pHLH refractory to treatment, relapsed [pHLH], [pHLH] not fully responsive to other agents, or patients intolerant to therapy.”   

Mark Crowther, MD, MSc, chair and professor of pathology and molecular medicine at McMaster University in Hamilton, Ontario, Canada, put the study’s findings into perspective. “This [study] illustrates how advances in molecular genetics and drug design, which have been made predominantly in the malignant disease, have now been translated to traditionally non-malignant diseases.”