Introduction: To provide additional insights into treatment with emapalumab in primary hemophagocytic lymphohistiocytosis (pHLH), we present an expanded pooled dataset to allow for further assessment of treatment responses in previously untreated patients and in those with central nervous system (CNS) involvement. Emapalumab, a fully human IgG1 anti- interferon-γ (IFNγ) monoclonal antibody that binds both free and receptor-bound IFNγ, neutralizing its biological activity, is FDA-approved for adult and children with pHLH with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.

Objective: To compare, by baseline CNS status and prior-treatment (previously untreated vs previously treated): (i) investigator-assessed overall response (OR = complete response [CR] + partial response [PR]) at Week 8/end-of treatment (EOT) and best OR up to Week 8/EOT, (ii) time to first investigator-assessed response, and (iii) bridging-success survival, defined as survival to allogeneic hematopoietic stem-cell transplantation (HSCT) or alive ≥3 months post-EOT without HSCT.

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 pooled for a total of 80 emapalumab-treated patients. Patients who received ≥3 emapalumab doses and had a recorded investigator assessment comprised the response-evaluable set at week 8/EOT (n=68) and the best response-evaluable set (n = 74); those with ≥3-month follow-up formed the bridging-success survival set (n = 70). Baseline CNS status was available for 77 patients and prior treatment for all 80. Responses were evaluated using the treating investigator global assessments, classified as CR (complete response or non-active disease), PR (partial response or HLH improvement) or no response (NR; progressive disease, reactivation, worsening or death), in place of protocol definition, to reflect real-world clinical practice more closely. Absolute risk differences (RD) in bridging-success survival were accompanied by two-sided 95% confidence intervals (CI) calculated with the Newcombe method (Wilson score for each proportion) and χ² p values (α = 0.05).

Results: Median patient age was 0.8 years (0.01–16.67); 54% were male. CNS involvement was present in 25/77 patients (32%); 27/80 (34%) were previously untreated.

CNS subgroup: At Week 8/EOT, 15/20 evaluable CNS-positive patients (75%) achieved OR (CR 20%, PR 55%), whereas 42/48 evaluable CNS-negative patients (88%) achieved OR (CR 31%, PR 56%). Best OR up to Week 8/EOT were 91% and 92% in the CNS-positive and CNS-negative groups, respectively. Median time to first OR was 16 days in both groups; median time to first CR was longer with CNS disease—43 days (95% CI 16–61) versus 28 days (16–29) without CNS involvement. Bridging-success survival occurred in 15/22 CNS-positive patients (68%) and 42/48 CNS-negative patients (88%), RD –19% (95% CI –47% to +8%; p = 0.08).

Prior-treatment subgroup: Previously untreated patients had an OR of 20/24 (83%) at Week 8/EOT (CR 29%, PR 54%) and 96% best OR up to Week 8/EOT (CR 33%, PR 63%); previously treated patients had an OR of 37/44 (84%; CR 27%, PR 57%) at week 8/EOT and 90% best OR (CR 36%, PR 54%). Median time to first OR was 15 days (14–16) in the previously untreated cohort and 16 days (16-16) in the previously treated cohort; median time (95% CI) to first CR was 28 days (16-62) versus 28 days (16-29), respectively. Bridging-success survival was 83% vs 80%, respectively, RD +3% (95% CI –25% to +27%; p = 0.77).

Safety was not re-analyzed; however, emapalumab's favorable safety profile compared to alternative treatment options has been previously reported (Locatelli et al. 2020 & 2025).

Conclusions: Emapalumab provides substantial efficacy across pHLH subgroups. Despite slower CR kinetics, a high proportion of CNS-positive patients responded and reached HSCT or maintained durable response. Outcomes were equally robust in previously untreated and previously treated cohorts, supporting emapalumab's efficacy both as a first-line or second-line therapy. These pooled data reinforce IFNγ neutralization with emapalumab as a versatile strategy that achieves high response rates, swift onset of action and meaningful survival irrespective of CNS status or prior therapy.

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2025
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