EMAPALUMAB IN PATIENTS WITH PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: EFFICACY AND SAFETY OUTCOMES FROM A MULTINATIONAL, OPEN-LABEL, SINGLE-ARM STUDY.
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All Authors
Locatelli, F.
Naqvi, A.
James, B.
Sevilla, J.
Cesaro, S.
Ehl, S.
Halimi, D.
Monnet, E.
Peace, B.
Asnaghi, V.
LTHT Author
James, Beki
Sevilla, Julian
Sevilla, Julian
LTHT Department
Leeds Children's Hospital
Contributor Profession (Non Medical)
Publication Date
2025
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Background Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening disorder characterized by immune dysregulation and hyperinflammation driven by excessive interferon-gamma (IFNgamma) levels. Allogeneic hematopoietic stem cell transplant (HSCT) is the only potentially curative treatment. Emapalumab, an anti-IFNgamma monoclonal antibody that binds free and receptor-bound IFNgamma, has demonstrated efficacy in controlling hyperinflammation in patients with pHLH before undergoing HSCT and is approved by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with pHLH with refractory, recurrent or progressive disease or intolerance with conventional therapy. Aims To further investigate the efficacy and safety of emapalumab for treating patients (pts) with pHLH in 1st-line and treatmentexperienced settings and evaluate a 3 mg/kg starting dose. Methods Pts with pHLH enrolled in this open-label, single-arm, multinational, phase 3 study were administered an initial intravenous infusion of emapalumab 3 mg/kg with subsequent infusions twice weekly (NCT03312751). Investigators could increase dosing to 6 or 10 mg/kg in case of unsatisfactory response. Endpoints included overall response at end of treatment (EOT) or Week 8, access to HSCT, time to response, >=50% reduction in glucocorticoid (GC) dose from baseline and safety. Biomarkers of IFNgamma activity (chemokine C-X-C motif ligands-9 and -10 [CXCL9/CXCL10]) and hyperinflammation (soluble CD25 [sCD25]) were also assessed. Results Most of the 35 pts were infants (age, 28 days-2 years; 21 males). Genetic confirmation of pHLH was available for 26 pts (74.3%); 16 pts (45.7%) were treatment-naive. Pts were administered a mean of 17.3 doses of emapalumab (range 1-51) over a median duration of 59.2 days (range 1-183 days). Emapalumab dosing was increased above 3 mg/kg for 31 (88.6%) pts. Overall response rate was 62.9% (95% confidence interval [CI], 44.9-78.5) with a median time to response of 4 days (95% CI, 4.0-13.0; Figure). 28 (80%) pts experienced >=1 response that was maintained for >=4 days at any time. GC dosing was reduced by >=50% in 15 (42.9%) pts. 25 (71.4%) pts either underwent HSCT or survived to study end. After accounting for 3 deaths within the first 6 days in pts who received <3 doses of emapalumab, 78.1% of pts had undergone HSCT or were alive at study end. In addition, 4 pts discontinued emapalumab treatment before Week 8 to undergo HSCT. Of the 23 pts who underwent HSCT, 17 (73.9%) were alive at study end. Mean serum CXCL10 and CXCL9 levels decreased by ~4- and ~7-fold, respectively, and sCD25 halved, between baseline and EOT or Week 8. The safety profile was consistent with the FDA-approved label for emapalumab. Most adverse events (AEs) were mild or moderate in severity, but a high proportion of pts reported severe AEs, consistent with the expected profile of pts with pHLH. 30 drug-related AEs were reported by 9 (25.7%) pts. 13 infusion-related reactions (2 serious; pyrexia [mild] and acute respiratory distress [severe, resulting in emapalumab discontinuation]) were reported in 7 (20.0%) pts. Summary/Conclusion When initiating emapalumab in pts with pHLH at 3 mg/kg, 80% of pts responded with a median time of 4 days. Pts who responded to treatment achieved the clinical stability necessary to undergo HSCT, while maintaining a favorable safety profile. These outcomes were consistent with those of pts with pHLH treated with emapalumab in a previous clinical trial and in real-world clinical practice. Results The median age at HSCT was 18 years (interquartile range [IQR], 13-35), and the median follow-up time 14 months (IQR 6-35). Indications for HSCT were transfusion-dependent BMF (n=12), pre-emptive therapy for progressive disease (increasing TP53 mutational load, dysplasia, or erythroid predominance; n=8), and high-risk hematologic malignancies (HM; n=25). All adult patients tested (96%) had 1-4 TP53 mutations. We did not record primary engraftment failures. The cumulative incidence (CIN) of TRM was 20.5% (95% CI 6.0-35.0) and 26.8% (95% CI 9.1-44.4) for relapses at 3 years. For all, the 3-year OS was 53.7% (95% CI 34.7-72.7). Survival probability of patients with progressive disease (88% TP53- mutated, 1 not tested) was comparable to BMF with transfusion dependency (20% TP53-mutated, 7 not tested), while the prognosis of patients identified with excess blasts at any time before HSCT (100% TP53-mutated, 2 not tested) was dire (Figure 1). Donor or graft type did not affect HSCT outcomes. None of the tested related donors carried mutations in ERCC6L2 (n=5). CIN of acute graft-versus-host-disease (GvHD) grades 2-4 at day 100 and chronic GvHD at 3 years were 30.4% (95% confidence interval [CI] 16.3-44.5)? and 45.0% (95% CI 25.4-64.6), respectively. Notably, grade 3-5 endothelial toxicities, e.g. thrombotic microangiopathy or hepatic veno-occlusive disease, were observed in 12 (27%) patients. They were associated with increased TRM (HR 7.7, 95% CI 1.5-38.8, p =0.016). Non-treosulfan-based myeloablative conditioning (MAC) resulted in a 4.9-fold (95% CI 1.1-22.0, p =0.04) increased risk for potentially fatal endothelial complications compared to reduced intensity conditioning (RIC). Treosulfan-based MAC and RIC showed similar outcomes. Summary/Conclusion Our results support HSCT for ED prior to the development of TP53-mutated myeloid malignancies with excess blasts. Given the poor predictability of the ED progression by blood counts, we recommend active surveillance including regular bone marrow examinations with cytogenetic and next-generation sequencing analyses for all ED patients. Treosulfan-based MAC or, when appropriate, RIC regimens appear to reduce the remarkable risk of endothelial complications. The elevated incidence of endothelial toxicity in ED patients underscores the need for careful selection of the conditioning regimen, close follow-up, and increased observation during the HSCT period.
Journal
HemaSphere