Emapalumab to Prevent Graft Failure in High-Risk Patients: The Experience of Stanford Children's Health

Introduction Graft failure (GF) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the pathophysiology of GF is not well understood, CXCL9, a chemokine induced by IFNγ, has been identified as a biomarker for GF. Emapalumab is an anti-IFNγ monoclonal antibody used for treatment of primary hemophagocytic lymphohistiocytosis (HLH). Emapalumab has been used off-label successfully following GF prior to 2nd HSCT. To test this hypothesis, we developed an algorithm (Figure 1) to identify patients at risk of imminent GF and administered emapalumab accordingly. Additionally, we administered emapalumab to patients with a history of HLH before their 1st HSCT to facilitate engraftment. Objectives The aim of this study is to assess the effectiveness and shortcomings of the current algorithm and gain valuable insights through the lessons learned so far. Methods A single-center retrospective chart review was conducted. All patients receiving allo-HSCT from October 2022 to September 2023 were included in analysis. Results A total of 45 patients received allo-HSCT during the study period at Stanford Children's Health; 12 patients (26.7%) were evaluated for GF due to persistent fevers and cytopenia, and 4 patients (8.9%) received 1-2 doses of emapalumab (Table 1). Two patients met our algorithm criteria and 2 met criteria except for underlying diagnosis of malignant disease. All 4 patients – who received an αβ T-cell depleted graft and a reduced intensity conditioning (RIC) regimens, ultimately experienced GF. Baseline ferritin, ferritinmax, CXCL9max, and SC5b9 were higher in GF patients. There was no difference in baseline CXCL9 between groups. Median Tmax was on Day +9.5 in the GF group and Ferritinmax lagged behind Tmax by 4.5 days and appears to be a late marker of GF. Three GF patients successfully engrafted after 2nd HSCT without needing further doses of emapalumab. The last GF patient was found to have persistent leukemia and did not receive 2nd HSCT. Additionally, 2 patients with history of HLH received emapalumab prior their 1st HSCT and successfully engrafted. Conclusion In this cohort, GF selectively occurred in patients receiving αβ T-cell depleted grafts and RIC regimens. Ferritin, CXCL9 and SC5b9 at time of fever are markers associated with rejection, as previously demonstrated. However, given the long turnaround time for CXCL9 and the lag of ferritinmax, timely administration of emapalumab with our current algorithm remains a challenge. The successful outcomes observed in 2 patients who received emapalumab prior to their 1st HSCT suggests that administering emapalumab earlier - potentially before the GF process initiates, may yield the greatest benefits. In this high-risk population, a synergistic approach combining emapalumab and eculizumab may hold promise in mitigating the risk of GF.