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Emapalumab shows efficacy, safety in hemophagocytic lymphohistiocytosis
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SAN DIEGO — The anti-interferon-gamma therapy emapalumab conferred an overall response rate of more than 60% in a cohort of young children with primary hemophagocytic lymphohistiocytosis, according to results of an international, multicenter, open-label, single-arm, phase 2/phase 3 study presented during the late-breaking abstract session at ASH Annual Meeting and Exposition.
Hemophagocytic lymphohistiocytosis (HLH) — which is characterized by hyperinflammation due to high production of interferon-gamma — has lacked effective and curative therapies, according to study author Franco Locatelli, MD, of Bambino Gesù Children’s Hospital IRCCS. Allogeneic hematopoietic stem cell transplantation is, in fact, curative, but carries risk and complications.
“This is an unmet medical need, namely for patients with primary HLH,” Locatelli said during a press conference. “It is characterized by severe clinical signs and symptoms that, if not promptly recognized and timely treated, can even lead to the death of patients.”
These symptoms include prolonged fever, splenomegaly/hepatomegaly, cytopenias, hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, hemophagocytosis and hypercytokinemia, according to Locatelli.
Emapalumab (Gamifant; Sobi, Novimmune) is a monoclonal antibody developed specifically for the purpose of treating HLH by binding to and neutralizing interferon-gamma. The FDA approved emapalumab as the first treatment for primary HLH in November based, in part, on the results of this study.
“It is a fully human IgG1 able to fully recognize both the interferon-gamma and interferon-gamma bound to its receptor,” Locatelli said. “Use of this monoclonal antibody impairs the dimerization of the interferon-gamma receptors, blocking the cascade that is activated by hyper-production of interferon-gamma.”
The analysis included 34 patients (median age, 0.85 years; 52.9% female), 27 of whom had failed previous therapies. Thirty patients had symptoms of central nervous system disease.
Clinicians administered the study drug intravenously at an initial dose of 1 mg/kg every 3 to 4 days, with the study protocol allowing for increases to 3 mg/kg, 6 mg/kg and 10 mg/kg if deemed necessary. Patients also received concomitant 5 mg/m2 to 10 mg/m2 dexamethasone, which could be tapered over the study.
Duration of treatment was 8 weeks, although it could be shortened to a minimum of 4 week or extended up to allogeneic HSCT.
Overall response rate — defined as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen or D-Dimer levels and CNS abnormalities, with no sustained worsening of sCD25 serum levels — served as the study’s primary endpoint. To meet significance, the treatment had to show improvement upon a prespecified null hypothesis of 40% at a one-sided 0.025 significance level, according to Locatelli.
Results showed a 63% (95% CI, 42-81) ORR rate in the subgroup of patients who had previously failed therapy and a 64.7% (95% CI, 46-80) ORR rate for the overall cohort. Thus, the primary efficacy endpoint was met, with a significantly higher ORR than the prespecified null hypothesis of 40% (overall, P = .0031; treatment failure, P = .0134).
The analysis also included an investigator-assessed ORR, which included the sum of complete response, partial response and nonactive disease. For this outcome, 70.4% of treatment-experienced patients and 70.6% of the overall cohort showed a response.
Median time to overall response was 8 days in both groups.
“The median time to overall response was indeed fast,” Locatelli said. “After the second dose of monoclonal antibody, these patients reached their response.”
He added that responses were durable, with a median cumulative duration of response until HSCT conditioning of 33 days in the treatment-experienced group and 33.5 days for the overall cohort. Moreover, patients remained in response for a median of 75% of treatment days.
Adverse events occurred in 96% of patients in the treatment-experienced group and in 94% overall.
“These children are very fragile, so it’s not surprising that several adverse events were reported,” Locatelli said.
Although serious events occurred in about half of patients in each group, only 3.7% of those in the treatment-experienced group and 2.9% overall discontinued due to adverse events.
Commonly reported adverse events that occurred among all treated patients included infections (56%), hypertension (35%), infusion-related reactions, (27%) and pyrexia (24%).
“In view of this result, on Nov. 20, the FDA approved emapalumab as the first agent for adults and newborns with primary HLH,” Locatelli said. – by Rob Volansky
Reference:
Locatelli, et al. Abstract LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Locatelli reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
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Mark Crowther, MD, MSc, FRCPC
This just became the first FDA-approved medicine for HLH, a rare and devastating pediatric blood disorder. HLH has been a condition associated with a very high risk for death. Dr. Locatelli and his group’s work represents one of the first major advancements in this field and, instantaneously, I suspect, establish a treatment standard for this very rare condition.
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