PracticeUpdate Conference Series ASH 2018

Emapalumab Safe and Effective in Pediatric PatientsWith Primary HLH Results suggest this monoclonal antibody should have a substantial impact on disease prognosis.

I n pediatric patients with primary hemo- phagocytic lymphohistiocytosis (HLH), the monoclonal antibody emapalumab offers substantial symptom improvement with an acceptable safety profile, accord- ing to results of an open-label, phase II/III study presented at ASH 2018. Emapalumab is the first monoclonal antibody developed specifically to treat primary HLH, working by neutralizing interferon-gamma, a cytokine implicated in the disease. To assess theperformanceof emapalumab in the management of primary hemo- phagocytic lymphohistiocytosis, study investigators enrolled 34 patients with the condition at 14 medical centers across Europe and the United States. Of the chil- dren enrolled, the majority were less than 1 year old, and 27 had previously failed to respond to chemoimmunotherapy. Researchers administered emapalumab intravenously twice weekly at a starting dose of 1 mg/kg (increased to up to 10 mg/ kg) for 8 weeks alongside 5 to 10 mg/m 2 / day of dexamethasone. After 8 weeks, the researchers assessed patients for the study’s primary endpoint, which was over- all response to treatment. The study was sponsored by Novimmune, manufacturers of emapalumab. The researchers defined response as normalization or a 50% improvement from baseline in several indicators of disease severity, including enlarged spleen, fever, central nervous system abnormalities, low platelet and neutrophil counts, and the presence of biomarkers including ferritin, fibrinogen, and CD25 in the blood. The study met its primary endpoint, in that 70% of enrolled patients experienced a response. This response was substantially better than the prespecified null hypothe- sis, which called for a 40% response rate (one-sided P < .025). The median time to overall response was 8 days. The median cumulative duration of response was 33.0 days in patients who had failed prior therapy and 35.5 days in all treated patients. Specific signs and symptoms, such as fever, dissipated after a few days of treat- ment with emapalumab for some patients

who responded, and other improvements were observed before the end of the trial. Study presenter Franco Locatelli, MD, of Bambino Gesu Hospital in Rome, Italy, con- cluded during a press conference that now “hematologists and pediatricians have a new effective option for controlling” pri- mary hemophagocytic lymphohistiocytosis. Because children born with primary hemophagocytic lymphohistiocytosis have few current treatment options, and because many children included in the trial had failed best available treatment, Dr. Locatelli suggested that the adoption of emapalumab therapy as a standard practice could significantly improve the prognosis for babies born with this condition. Dr. Locatelli added that he hoped emapalumab therapy would bridge “a child to allogeneic hematopoietic stem cell transplantation, while sparing toxicities associated with conventional therapies.” Most of the patients who received emapalumab during the course of the trial were subsequently able to proceed to allogeneic hematopoietic stem cell transplantation therapy and achieve pos- itive clinical outcomes. Adverse events encountered during the trial were generally mild, and emapalumab was well-tolerated. However, mild to moderate infusion-related reactions did occur in 27% of patients, and an infection possibly linked to suppression of inter- feron-gamma signaling occurred during the trial (disseminated histoplasmosis), but this infection resolved with appropriate treatment. Overall, 56% of patients receiv- ing emapalumab experienced infections. There were no observed off-target effects. The United States FDA approved emapalumab for the treatment of both pediatric and adult patients with primary hemophagocytic lymphohistiocytosis in November 2018. The drug is currently approved for use in patients with treat- ment-resistant, recurrent, or progressive disease, or in patients for whom conven- tional therapy is contraindicated.

Patients who received daratumumab were more than 3 times more likely to experience major residual disease neg- ativity (24.2% vs 7.3%, P < .0001). “These results support adding dara- tumumab to [lenalidomide and dexamethasone] as the new standard of care for patients with transplant-ineligi- ble newly diagnosed multiple myeloma,” study presenter Thierry Facon, MD, of Claude Huriez Hospital in Lille, France, said during a press briefing. Certain adverse events were at least 5% more likely to occur among patients receiving daratumumab; in particular, elevated rates of grade 3 and grade 4 pneumonia, neutropenia, and leukopenia were observed this arm. Treatment-emergent adverse events with the outcome of death occurred at a rate of 7% in the daratumumab-containing arm and a rate of 6% in the other arm. Dr. Facon suggested during a press briefing that this safety profile was not unexpected and that it is consistent with previously reported studies involving daratumumab. “No new safety signals were observed using [daratumumab] in newly diagnosed multiple myeloma patients,” he said. “This regimen is very manageable. This regimen is a very gentle regimen, which is important when you’re talking about patients over the age of 75.”

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES 19