Emapalumab, a drug that targets interferon-γ, led to a high overall response rate in the majority of patients with primary hemophagocytic lymphohistiocytosis, a rare genetic disorder that presents in infancy and is invariably fatal if untreated.
An 8-week treatment course with emapalumab allowed the majority of patients to proceed to allogeneic hematopoietic stem-cell transplantation, the only curative therapy for this disease.
Emapalumab, a drug that targets interferon-γ, led to a high overall response rate in the majority of patients with primary hemophagocytic lymphohistiocytosis, a rare genetic disorder that presents in infancy and is invariably fatal if untreated, a phase II-III study found.
In a total of 34 patients, 63% of previously treated patients (95% CI, 42-81%) and 65% (95% CI, 46-80%) of all 34 patients who received emapalumab responded to treatment, Franco Locatelli, MD, University of Rome, Italy, and colleagues reported in the New England Journal of Medicine.
Out of the 34 patients, 27 patients had been previously treated prior to receiving emapalumab, while only seven patients were treatment naïve.
Although the authors separated out responses for previously treated patients, all 34 patients were included in the emapalumab group.
Treatment was safe and well tolerated, with low levels of toxicity observed in any patient.
"Mounting evidence provides support for the pivotal pathogenic role of interferon-γ in hemophagocytic lymphohistiocytosis," Locatelli and colleagues observed.
"In this study, neutralizing interferon-γ and controlling hyperinflammation with emapalumab were efficacious in previously treated children with primary hemophagocytic lymphohistiocytosis," researchers concluded.
Emapalumab is a fully human IgG1 anti-interferon-γ antibody that binds free and receptor-bound interferon-γ.
N1-0501-04 was an open-label, single-group study carried out in several European countries as well as the United States.
Previously treated patients were 18 years of age and younger on study enrollment.
After screening, patients were treated with emapalumab for 8 weeks, which was shortened to 4 weeks if a donor was available and the patient well enough to undergo allogeneic hematopoietic stem-cell transplantation, the only curative therapy for the disorder, as investigators pointed out.
In a sister study, the N1-050104 study, investigators collected follow-up data until 12 months after transplantation.
"All the patients had active disease at enrollment, and the patients who had received previous treatment had worsened or reactivated disease, had had an unsatisfactory response to conventional therapy, or were unable to continue to receive conventional therapy because of adverse effects," the authors explained.
Emapalumab was initiated at a starting dose of 1 mg/kg of body weight, every three days.
Dose modifications were initially guided by clinical and pharmacokinetic assessments, after which they were based on predefined clinical and laboratory criteria.
Subsequent doses of emapalumab could be increased to 3, 6, and up to 10 mg/kg, researchers explained.
Dexamethasone was also given at a median daily dose of 10 mg/m2 at baseline. However, this dose could be tapered by at least 50% at eight weeks in 44% of previously treated patients and 47% of all patients who had received emapalumab.
"The primary efficacy end point was the overall response in previously treated patients at the end of treatment in the N1-0501-04 study," Locatelli and colleagues pointed out.
Among the group of previously treated patients, 26% had a complete response (CR), 30% had a partial response (PR), and 7% showed an improvement in measures of hemophagocytic lymphohistiocytosis.
Among all 34 patients who received emapalumab, 21% achieved a CR, 32% achieved a PR, and 12% showed an improvement in measures of hemophagocytic lymphohistiocytosis, investigators added.
The median time to response was eight days (95% CI, 7-14 days) in both previously treated patients and in the full cohort (95% CI, 5-10 days).
"During emapalumab treatments, CXCL9 levels rapidly and markedly decreased (median, 30% of the baseline level on day 5)," the authors noted.
Given that low levels of CXCL9 — a chemokine exclusively induced by interferon-γ and thus a measure of interferon-γ neutralization — were associated with treatment response, "these findings provided support for neutralization of interferon-γ as a relevant therapeutic objective in patients with primary hemophagocytic lymphohistiocytosis," researchers asserted.
Most adverse events were mild and were the result of reactivation or worsening of the disorder itself, among other variables. Emapalumab was not associated with myelosuppression, which is typically observed with conventional therapy used for the treatment of this disorder — conventional treatment is usually etoposide plus glucocorticoids plus or minus cyclosporine — Nor did it lead to any organ toxicity, although 10 patients developed severe infections during emapalumab treatment.
As the authors pointed out, patients could be re-enrolled in a long-term follow-up study where they were followed for one year after undergoing allogeneic hematopoietic stem-cell transplantation or for one year after the last dose of emapalumab if they did not undergo transplantation.
Seventy percent of patients in the previously treated group did undergo allogeneic hematopoietic stem-cell transplantation, as did 65% of the emapalumab group overall.
The estimated probability of survival at 12 months was 73.4% (95% CI, 52.2-86.4%) for previously treated patients and 69.3% (95% CI, 66.2-97.5%) for the group overall.
The estimated probability of survival after transplantation at 12 months was 89.5% (95% CI, 64.1-97.3%) among previously treated patients and 90.2% (95% CI, 66.2-97.5%) for all 34 patients who received emapalumab.
Despite this, 10 patients who received emapalumab died, eight prior to transplantation and two after they had undergone the procedure.
Researchers stressed that there were too few patients in the previously untreated group to reach any reasonable conclusion about the use of emapalumab in this particular cohort of patients.
However, they did feel that findings "support… further investigation of emapalumab in patients with secondary forms of hemophagocytic lymphohistiocytosis in whom interferon-γ has been suggested to be pathogenic."
Supported by NovImmune and by a grant from the European Commission through the First Targeted Therapy to Fight Hemophagocytic Lymphohistiocytosis (FIGHT HLH) program.
Locatelli is an unpaid consultant to NovImmune.