Emapalumab for Treatment of Impending Graft Failure

Introduction: Immune-mediated graft failure (also termed graft rejection) is a feared complication of hematopoietic stem cell transplant (HSCT) and there is no effective intervention. Multiple pre-transplant risk factors for graft failure are known and recent studies from our groups identified interferon gamma (IFNγ) as a mechanistically important and pharmacologically targetable cytokine involved in graft failure pathophysiology. CXCL9, a downstream marker of IFNγ production, was also identified as a biomarker. We describe an international multicenter retrospective pooled analysis of emapalumab (EMA), an IFNγ neutralizing agent, for the prevention/treatment of immune-mediated graft failure after HSCT. Methods: The safety and preliminary efficacy of EMA were studied in predominantly pediatric patients who received EMA using two different strategies: 1) graft failure treatment and 2) graft failure prophylaxis. Patients at US centers were treated with EMA if they developed clinical and laboratory signs of graft failure after HSCT. All treatment patients met 2 or more of the following criteria: 1) HLA mismatched donor and/or prior graft failure, 2) unexplained fever >39°C (or >38°C if prior history of graft failure) after HSCT, 3) absolute neutrophil count decline after initial engraftment, 4) delayed neutrophil engraftment after HSCT, 5) real-time CXCL9 > 2.5x upper limit of normal (ULN). Temperature and CXCL9 cutoffs were based on a prior graft failure biomarker publication (Sabulski et al, Blood Advances 2021). Patients treated at European centers received prophylactic EMA to prevent graft failure if they were deemed at high-risk prior to transplant. High-risk patients had a prior history of graft failure after HSCT or had two or more of the following established risk factors: a) affected by a disease with high risk of graft failure, including acquired severe aplastic anemia, thalassemia, primary HLH; b) ex-vivo T cell-depleted stem cell product; c) transplant from unrelated cord blood unit or mismatched related/unrelated donor. Results: Thirty-six HSCTs used EMA for graft failure treatment or prophylaxis and were included in this study.EMA was used for graft failure treatment in 25 HSCTs wherein patients developed clinical and laboratory signs of graft failure (Table 1). Most HSCTs in the treatment cohort were performed for bone marrow failure syndromes (n=16). All patients tolerated EMA without complications and no side effects or infections were attribu