Background: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, life-threatening syndrome which may develop on the background of several clinical conditions (e.g., autoimmune disease, infection or malignancy) and is characterized by uncontrolled hyperinflammation. Preclinical data have shown the central role of interferon-gamma (IFNγ) in the pathogenesis of this disease (Strippoli et al. 2012; Prencipe et al. 2018), and observational studies confirm the presence of an IFNγ signature in sHLH (data on file, Buatois et al. 2017, Bracaglia et al. 2017, Akashi et al. 1994, Henter et al. 1991; Ohga et al. 1993; Maruoka et al. 2014).

Emapalumab is a monoclonal antibody neutralizing IFNγ, approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.

Study design: This open-label, single arm, multicenter, phase 2/3 interventional study (NI-0501-10; NCT03985423) enrolls adult patients diagnosed with any non-primary HLH. The study includes an initial phase enrolling 10 patients, with subsequent broadened enrollment if no untoward significant safety signal attributable to emapalumab treatment (as judged by an independent Data Monitoring Committee) is identified. Emapalumab is administered intravenously at an initial dose of 6 mg/kg (on a background of glucocorticoids), and continued at a dose of 3 mg/kg every 3 days until Study Day 15, and twice-a-week afterwards. If the treating physician deems appropriate, the dose of emapalumab may be increased, guided by clinical and laboratory response. Treatment shall continue until a clinically satisfactory response is achieved. After treatment discontinuation (for any reason), patients will continue in the study for long-term follow-up until 1 year after the last emapalumab administration (or after hematopoietic stem cell transplantation, if performed).

Eligible patients include male and female patients 18 years and older at the time of HLH diagnosis, with fulfilment of at least 5 of the 8 HLH-2004 clinical criteria. Patients diagnosed with malignancy-associated HLH (M-HLH) must be treatment-naïve; patients diagnosed with HLH driven by any other etiology or idiopathic HLH can be either treatment-naïve or treatment-experienced. Patients who have already received conventional therapy for HLH must have failed prior treatment as per the treating physician's judgement. Excluded are patients with primary HLH, as well as patients receiving or scheduled to receive therapies known to trigger cytokine release syndrome, patients with a life-expectancy associated with the underlying disease (triggering HLH) <3 months, patients with active mycobacteria, Histoplasma capsulatum or Leishmania infections or with evidence of latent tuberculosis, patients who received bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to screening, or a live or attenuated live (other than BCG) vaccine within 6 weeks prior to screening.

The primary outcome measure of the study is Overall Response at Week 4. Secondary efficacy measures include survival, best response on treatment, Overall Response at end of treatment, time to Complete or Partial Response, duration of response, HLH relapse; safety endpoints include incidence, severity, causality and outcomes of adverse events; other endpoints include serum concentrations of emapalumab and biomarkers (IFNγ, CXCL9, sCD25, IL-6), and incidence of anti-drug antibodies. The primary analysis will evaluate the Overall Response Rate at Week 4. In this adaptive design, the data are reviewed periodically in order to assess each of the 2 etiologies (i.e., M-HLH and any other sHLH) for futility and efficacy. The first analysis will occur after 10 patients with one etiology reached the primary endpoint time point. Descriptive statistics and graphical methods will be used for the evaluation of the secondary efficacy endpoints. Safety data will be listed and summarized using descriptive statistics.

Study status: The study is expected to open enrollment in the US in Q3 2019. Study results will be presented after completion of the study.


Asnaghi:EmaCo SA: Employment. Ballabio:EmaCo SA: Consultancy. Jacqmin:EmaCo SA: Consultancy. de Graaf:EmaCo SA: Consultancy. De Min:EmaCo SA: Employment.

OffLabel Disclosure:

Emapalumab is FDA-approved for primary HLH. This study will investigate the use of emapalumab in secondary HLH.

Author notes


Asterisk with author names denotes non-ASH members.

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