Primary HLH is a rare, genetic immune-mediated disorder, usually diagnosed during infancy or early childhood. It is characterized by severe and often life-threatening immune activation, hyperinflammation and immune-mediated organ damage. Like some other rare diseases, the epidemiology of primary HLH is not well defined. Published data suggest the annual incidence of primary HLH is 1.8 per 100,000 live births in Sweden (Meeths et al. Pediatr Blood Cancer 2015). Current conventional treatment for primary HLH includes chemoimmunotherapy to suppress the immune hyperactivation and then offering patients the only potentially curative treatment, namely allogenic hematopoietic stem cell transplantation (HSCT). Chemoimmunotherapy (as recommended in the HLH-94 and HLH-2004 treatment protocols) is based on the combined use of dexamethasone, etoposide and cyclosporine. The side effects associated with these drugs are expected to increase the burden of the illness. Emapalumab, a fully human monoclonal antibody that neutralizes IFN-gamma, is approved in the USA for use in adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. Patients with primary HLH are likely to be hospitalized for extended periods during diagnosis and chemoimmunotherapy (8-week induction course followed by continuation phase until HSCT). Most published data for primary HLH focus on the treatment and management of HLH in treatment-naïve patients; data from the largest prospective study on HLH reported that the median time to HSCT was 148 days (range, 25-2105) (Bergsten et al. Blood 2017). We performed a post-hoc analysis of the NI-0501-04/05 study, which followed patients treated with emapalumab for up to 1-year post-HSCT, to assess the patterns of hospitalization.
Emapalumab was evaluated in an open-label, single-arm, multicenter phase 2/3 trial in patients aged ≤18 years with suspected or confirmed primary HLH (NCT01818492; Locatelli et al. N Engl J Med 2020). Patients were treatment-naïve or -experienced, with active disease at enrollment; treatment-experienced patients had shown worsened/reactivated disease, poor response to conventional therapy, or were unable to continue treatment due to adverse events. Emapalumab was administered as an intravenous infusion at an initial dose of 1 mg/kg every 3 days and subsequent doses could be increased to 3, 6 and 10 mg/kg if required. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Patients were required to stay in hospital initially for 2 weeks, and then could return home whilst awaiting HSCT at the discretion of the treating physician. Patients were invited to participate in a long-term follow-up study for up to 1 year after the last dose of emapalumab or after HSCT. They could continue treatment with emapalumab beyond week 8 if HSCT was delayed and the benefit-risk ratio was considered favorable (NCT02069899). Post-hoc analyses were conducted using data from all patients who received of ≥1 dose of emapalumab. Descriptive analyses were performed for the hospitalization data collected.
The study population comprised treatment-naïve (n=7) and treatment-experienced patients (n=27). All patients were hospitalized for at least 2 weeks as per the trial protocol. The mean (standard deviation [SD]) duration of hospitalization until HSCT, death or end of study (EOS) was 83 (47) and 64 (35) days in treatment-naïve and treatment-experienced patients, respectively (Table 1). Twenty (59%) patients were discharged while waiting for HSCT. The mean (SD) period of time spent at home until HSCT, death or EOS was 164 (212) and 61 (106) days in treatment-naïve and treatment-experienced patients, respectively.
Over 50% of treatment-naïve and -experienced patients with HLH who received emapalumab were permitted to be at home for an average of 12 weeks. Reduced length of hospitalization is expected to lead to improved patient health-related quality of life, reduced burden on patients and caregivers, and reduced healthcare utilization and costs. These factors are intended to be explored within future research studies.
Wilson:Sobi: Current Employment, Current equity holder in publicly-traded company. Pochopien:Sobi: Consultancy. Nazir:Sobi: Current Employment. Rao:Sobi: Consultancy, Other: Advisory Board. Locatelli:Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau.
Asterisk with author names denotes non-ASH members.