Emapalumab induces rapid, durable responses and reliable bridging to curative HSCT in patients with primary HLH: Pooled analysis of prospective trials NI-0501-04, NI-0501-05 and NI-0501-09

Abstract Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening, genetically driven, interferon-γ (IFNγ)–mediated hyperinflammatory disorder. Allogeneic hematopoietic stem-cell transplantation (HSCT) still remains the only potentially curative therapy, but optimal conditioning and transplant success depend on achieving adequate disease control beforehand. Emapalumab, a fully human immunoglobulin-G1 anti-IFNγ monoclonal antibody that binds both free and receptor-bound IFNγ neutralizing its biological activity, has been FDA-approved since 2018 for adult and pediatric patients with pHLH with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. The pivotal NI-0501-04 study first showed, and the NI-0501-09 study later confirmed, that emapalumab rapidly controls hyperinflammation and enables successful HSCT in patients with pHLH (Locatelli et al., 2020, 2025). Objective: To conduct a post-hoc pooled analysis of 3 prospective trials, quantifying (i) investigator-assessed overall response (OR), (ii) bridging-success survival, defined as survival to HSCT or alive ≥3 months after end-of-treatment (EOT) without HSCT, and (iii) glucocorticoid (GC)-sparing effects of emapalumab. Methods: Individual patient data from NI-0501-04 conducted from 2013 to 2019 (n=45), its long-term follow-up study NI-0501-05 which completed in 2021 (n=37 of 45 in NI-0501-04), and NI-0501-09 conducted from 2019 to 2022 (n=35) were combined, for a total of 80 emapalumab-treated patients. Protocol-defined responses have been previously reported for each study (Locatelli 2020; Jordan 2023; Locatelli 2025). As the stringent per protocol response definitions may not fully capture the benefits of treatment with emapalumab, this post-hoc analysis instead used the treating investigator's global assessment, classified as complete response [CR] (complete response or non-active disease), partial response [PR] (partial response or HLH improvement) or no response [NR] (progressive disease, reactivation, worsening or death), to more closely reflect real-world clinical practice. Investigator-assessed OR was CR + PR. Patients who received ≥3 emapalumab doses with investigator assessments made up the response-evaluable set at week 8 or EOT (n=68) and the best-response set (n=74); those with ≥3-month follow-up formed the bridging-success survival set (n=70). Results: At baseline, the median age was 0.8 years (range 0.01–16.67); 54% (43/80) were males; 31% (25/80) had central nervous system involvement and 66% (53/80) had received prior HLH therapy. At Week 8/EOT, 57/68 evaluable patients achieved OR (84%), including CR in 19/68 (28%). Considering best response up to Week 8/EOT, 68/74 patients responded (92%) and 26/74 attained CR (35%). Median time to first OR was 16 days (95% CI 16–16) and 28 days (95% CI 19–29) to first CR among those who achieved a CR at any time. The response was durable among patients who responded: the best overall response was maintained for a median of 176 days (mean 240; range 14–583), while the Week 8/EOT response persisted for a median of 180 days (mean 218; range 3–536). Bridging-success survival was achieved by 57/70 patients (81%): 51 proceeded to HSCT and 6, without HSCT, were alive ≥3 months after EOT (median 273 days; [95% CI 111-422]). An assessment of CR or PR by Week 8 conferred an ≈5-fold greater probability of bridging success than NR (95% and 97%, respectively vs 18%). GC tapering by 25% and 50% from baseline occurred within 14 days for 42/80 patients (53%) and 31/80 patients (39%), respectively. By EOT, 68/80 (85%) and 63/80 (79%) achieved those same reductions. Although safety was not evaluated in this analysis, emapalumab's favorable safety profile compared to alternative treatment options has been documented in the individual trials and reported by Locatelli et al. (2020, 2025). Conclusions: This pooled post-hoc analysis from 3 different prospective clinical trials confirms that emapalumab, through IFNγ activity neutralization, delivers rapid and durable responses, enables substantial GC tapering and secures HSCT or ≥3 months survival in >80% of patients with pHLH. These findings reinforce and extend previously published evidence of emapalumab's efficacy and clinical utility as a well-tolerated bridge to curative HSCT in this difficult-to-treat population of children with a high mortality rate (Locatelli 2020, 2025; Jordan et al. 2023).