Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis

Abstract

BACKGROUND Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis.

Epstein-Barr Virus Versus Novel Coronavirus-Induced Hemophagocytic Lymphohistocytosis: The Uncharted Waters

“…5 In cases of HLH refractory to standard therapy, literature is limited, but there is evidence of possible response to anakinra, alemtuzumab, and antithymocyte globulin. 5,6 In May 2020, emalapumab, a monoclonal antibody against interferon-γ, was found to achieve response in nearly two thirds of 27 patients with refractory HLH opening new horizons in treatment of this challenging entity. 6 With regard to EBV-induced HLH in particular, the addition of rituximab to standard HLH-therapy is recommended to assist with destruction of EBV-harboring B-lymphocytes and improving overall outcome.…”

Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome

“…Primary HLH is perhaps the paradigm for this model, in that the interferon-γ/chemokine ligand(CXCL)-9 axis is central to the pathophysiology of the disease, [28] and blocking this axis with emapalumab produces deep and sustained remissions. [29] Likewise, IL-1 has been shown to play a similar role in autoinflammatory syndromes and secondary HLH, and blockade with anakinra or canakinumab results in clinical benefit. [30,31] Evidence that IL-6 drives immune dysregulation and respiratory failure in COVID-CSS is rapidly accumulating.…”

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“…ropean Union. Emapalumab is approved for treatment of primary HLH that is refractory, recurrent, progressing or intolerant to current HLH treatments in both adult and pediatric patients [40]. Ruxolitinib, a Janus kinase 1/2 inhibitor, can be option as a front-line therapy in children with secondary HLH.…”