Research Report on Pre-HCT Emapalumab Therapy Improving Donor Chimerism in Children with HLH

Background and Objective of the Study

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune disorder caused by pathological immune activation. The primary mechanism involves the functional deficiency of cytotoxic activity in natural killer (NK) cells and CD8+ T cells, leading to uncontrolled T cell proliferation and excessive secretion of interferon gamma (IFN-γ), which drives disease progression. Thus, targeting IFN-γ is central to therapeutic interventions for HLH. Clinical trials have demonstrated that Emapalumab, an antibody drug, successfully neutralizes excessive IFN-γ and was approved by the U.S. Food and Drug Administration (FDA) in 2018 for treating refractory and recurrent primary HLH cases. While Emapalumab has shown efficacy in controlling disease activity, its long-term impact on outcomes following allogeneic hematopoietic stem cell transplantation (HCT) is unknown.

HCT remains the treatment of choice for HLH. However, the use of reduced-intensity conditioning (RIC) has been associated with reduced transplant-related mortality but an increased risk of low donor chimerism (mixed chimerism, defined as <95% donor chimerism post-transplant), which can further raise the risk of secondary graft failure. This study evaluates the effect of Emapalumab therapy before RIC-HCT on donor chimerism and transplant success in pediatric HLH patients.

Study Initiation and Publication Information

This study was published in the December 19, 2024 issue of Blood and conducted by a research team at Cincinnati Children’s Hospital Medical Center, with primary authors including Drs. Bethany Verkamp, Sonata Jodele, and Michael B. Jordan. The study analyzed clinical outcomes of pediatric HLH patients undergoing their first RIC-HCT from 2014 to 2022.

Methods and Study Design

Study Population and Treatment Procedures

The study conducted a retrospective analysis of 50 confirmed HLH patients who had undergone disease-directed initial therapy before transplantation. Of these, 22 patients received Emapalumab within 21 days prior to the RIC treatment regimen, forming the experimental group, while 28 patients who did not receive Emapalumab served as the control group.

During the HCT phase, patients received customized conditioning regimens, with fludarabine and melphalan as the core components. The stem cell sources included bone marrow (71%), cord blood (21%), and peripheral blood stem cells (PBSC, 8%). Donor types were categorized as HLA-matched or mismatched, and the donor distributions were comparable between the two groups.

Data Collection and Analysis

Key outcomes included donor chimerism rates, incidence rates of mixed chimerism, and severe mixed chimerism (<25% donor chimerism). Secondary outcomes included the 5-year intervention-free survival (IFS), defined as survival without requiring post-HCT interventions (e.g., donor lymphocyte infusions, donor CD34+ cell infusions, or a second HCT) or death. Statistical analyses were conducted using Chi-square tests, Mann-Whitney U tests, and Cox proportional hazard models.

Results

Significant Reduction in Mixed Chimerism

The study found that preconditioning use of Emapalumab significantly reduced the incidence of mixed and severe mixed chimerism post-HCT. Specifically:
- Mixed chimerism occurred in 48% of the Emapalumab group, significantly lower than the 77% in the control group (p=0.03).
- Severe mixed chimerism occurred in only 5% of the Emapalumab group, compared to 38% in the control group (p=0.007).

These results indicate that Emapalumab effectively reduces the competitive pressure on donor cells, improving donor chimerism quality.

Significant Improvement in 5-Year IFS

The 5-year IFS in the Emapalumab group was 73%, significantly higher than the 43% observed in the control group (p=0.03). Among high-risk infants (<12 months of age), the disparity was even greater—IFS was 75% in the Emapalumab group compared to 20% in the control group (p<0.01).

Overall Survival (OS) and Complications

Although Emapalumab-treated patients showed a higher overall survival (OS) rate (82%) compared to the control group (71%), this difference did not reach statistical significance (p=0.41), likely due to the small sample size. Additionally, the study found no significant increase in transplant-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), linked to Emapalumab use.

Study Implications and Value

Scientific Contributions

This study is the first to demonstrate that preconditioning Emapalumab therapy significantly enhances full donor chimerism (≥95%) in pediatric HLH patients undergoing RIC-HCT, improving overall intervention-free survival. It highlights the critical role of IFN-γ in donor cell engraftment failure and provides a mechanism-based intervention for its prevention.

Clinical Significance

Emapalumab is especially beneficial for high-risk infants (<12 months) with HLH, reducing post-HCT secondary complications and associated healthcare costs. The study underscores the inclusion of Emapalumab as part of pre-HCT protocols for HLH patients.

Highlights and Innovations

1. Innovative Therapy: The study provides the first substantial evidence demonstrating the long-term efficacy of Emapalumab in improving donor chimerism post-HCT.
   
2. Precision in High-Risk Populations: The findings highlight the pronounced benefits of Emapalumab for infants, a group with an inherently high risk of poor outcomes.
   
3. Mechanistic Insights: The study elucidates an IFN-γ-driven mechanism underlying post-HCT mixed chimerism and provides an effective preventive intervention.
   

These findings establish Emapalumab as a valuable option for improving donor-derived hematopoietic reconstitution in HLH patients undergoing transplantation. Future studies are necessary to optimize dosing regimens and further investigate its role in achieving full donor chimerism.