Emapalumab Therapy Prior to Hematopoietic Stem Cell Transplant Is Associated with Improved Long-Term Chimerism and Event-Free Survival in Pediatric Patients with Hemophagocytic Lymphohistiocytosis

Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder driven by interferon-gamma (IFNγ) mediated immunopathology. Emapalumab, an anti-IFNγ human monoclonal antibody, was approved by the FDA in 2018 for refractory/recurrent HLH. Hematopoietic stem cell transplant (HSCT) is required for cure in primary (familial) HLH and other select cases. Use of reduced intensity conditioning (RIC) for HSCT in HLH has led to improved survival but higher incidences of mixed chimerism and graft failure. Post-HSCT outcomes after emapalumab therapy have not yet been described. Methods We conducted a retrospective study of pediatric patients with HLH who received a HSCT between July 1, 2014 and July 31, 2022 for HLH. Inclusion criteria included: active HLH (pre-HSCT) requiring treatment, receiving a first HSCT at CCHMC during this time period, and receiving a reduced intensity conditioning regimen. Interventions for mixed chimerism included rapid and premature weaning of immunosuppression, donor lymphocyte infusion, infusion of donor CD34 selected cells, and second HSCT (including a preparative regimen). The study follow up period included up to 5-years post-HSCT, time to second HSCT, or death when applicable. Results Fifty patients met inclusion criteria for analysis, 22 patients (44%) received emapalumab within 3-months prior to HSCT and 28 (56%) did not. Median age was 17.5 months (range 3-211) at time of HSCT, age distribution was similar between groups (p=0.42). Three patients were not assessable for chimerism (two died during conditioning (1 emapalumab, 1 no emapalumab) and one died day +9 (no emapalumab). Alemtuzumab, fludarabine, and melphalan was the most common preparative regimen of both groups (N=40, 80%). Chimerism was significantly higher in the emapalumab cohort at multiple timepoints (median minimum chimerism 90% (IQR 62-99) vs. 69% (IQR 10-94) in non-emapalumab patients, Figure 1). Use of emapalumab was associated with a lower risk of receiving intervention for mixed chimerism (p=0.007, Figure 2). Incidence of acute graft-versus-host disease (GVHD) was similar between groups (p= 0.78). Event-free survival (EFS), including chimerism ≤25% at last measurement, intervention for mixed chimerism, or, was significantly higher in patients receiving emapalumab (EFS 64% vs. EFS 32% in non-emapalumab patients, p=0.01, Figure 3A). There was a trend toward improved overall survival (OS) in the emapalumab cohort (OS 82% vs. no emapalumab OS 71%) but the difference was not statistically significant (p=0.39, Figure 3B). Conclusions This is the first study describing outcomes post-HSCT following emapalumab therapy in patients with HLH. Patients receiving pre-HSCT emapalumab had a lower rate of mixed chimerism, a common complication following RIC HSCT, and improved EFS compared to patients without pre-HSCT emapalumab therapy.