Insights into the Natural History and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis (HLH): The into-HLH Registry

Purpose: Hemophagocytic Lymphohistiocytosis (HLH) is a complex, hyperinflammatory syndrome resulting from the interplay of genetic predisposition and various environmental factors. In the last 25 years, scientific insights and treatments have evolved substantially with novel targeted therapies. However, approximately 30% of patients do not respond to therapy despite available treatment options. Thus, there is an unmet need for a deeper understanding of the natural history, clinical/ etiologic diversity, complications, and treatment outcomes of HLH patients, specifically from North America. Therefore, we established a robust registry to better understand the natural history, treatment patterns, and outcomes of HLH syndrome.

Methods: To address these knowledge gaps, we established a non-interventional, observational study with a dual-enrollment method for maximum engagement (NCT05277272) modeled after the ACCELERATE Castleman disease natural history registry. Patients are consented and enrolled in the study via the traditional Physician Driven Arm (PDA) and a Patient-Powered Arm (PPA), in which patients are directly recruited through the Registry's website (www.hlhregistry.org). The Registry is a collaboration between Cincinnati Children's Hospital Medical Center (the academic sponsor), Texas Children's Hospital, The North American Consortium for Histiocytosis (NACHO), and Sobi Inc. (the industry sponsor). Anticipated enrollment is > 200 patients with clinically suspected or confirmed HLH, including familial and all other subtypes of HLH. Medical records are acquired and abstracted by the INTO-HLH Registry Team (IHRT) at Cincinnati Children's Hospital Medical Center into pre-specified electronic case report forms (eCRF). HLH-related data is abstracted from initial disease presentation to diagnosis, through treatment until Hematopoietic Stem Cell Transplantation (HSCT) or end of HLH-directed treatments. Patients are followed for at least five years to assess short- and long-term outcomes. Discrete HLH episodes are captured separately. Physicians at the PDA sites perform minimal data abstraction reflecting their subjective narrative regarding patients' treatments and responses. In addition, the patients are offered to answer optional patient-reported outcomes questionnaires and participate in correlative biology studies. The INTO-HLH steering committee adjudicates specific diagnoses and reviews adverse treatment events and causes of mortality.

Results: Enrollment is ongoing with pediatric patients with familial HLH and adult patients with other subtypes of HLH already consented. The primary objective of the research is to describe the natural history of patients with HLH, and the secondary objective is to describe treatment patterns, responses, and outcomes. In addition, health-related quality of life, disease-related health burden, and the relationship between biologic variability and clinical outcomes will be assessed as exploratory objectives.

Conclusion: The INTO-HLH Registry aims to advance clinical understanding and improve treatment outcomes in patients with HLH.

Zoref-Lorenz:Sobi: Consultancy. Fajgenbaum:EUSA Pharma: Consultancy, Research Funding. Oladapo:Sobi, Inc.: Current Employment. Yee:Sobi, Inc.: Current Employment. Gulati:Sobi: Research Funding. Allen:sobi: Consultancy. Jordan:Sobi, Inc.: Consultancy, Research Funding.