Abstract 3366: Determinants of survival in hemophagocytic lymphohistiocytosis: A real-world database analysis

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterized by the uncontrolled activation of lymphocytes and macrophages, resulting in hyperinflammation and tissue damage. HLH manifests in two forms: primary (familial), driven by genetic mutations affecting cytotoxic function, and secondary (acquired), triggered by infections, malignancies, autoimmune disorders, or other conditions. This study aims to identify key prognostic factors, clinicopathologic characteristics, and therapeutic strategies that impact survival outcomes in HLH patients through a pooled database analysis. Methods: We analyzed a real-world database of confirmed HLH cases, evaluating demographic features, molecular and immunohistochemical profiles, potential prognostic indicators, treatment interventions, and survival outcomes. Kaplan-Meier survival curves were generated, and Cox proportional hazards models and Log-rank tests were applied to assess the effect of various clinicopathologic factors on overall survival (OS). Results: The study included 255 confirmed HLH patients, with a median age of 32 and a male-to-female ratio of 1.5. Primary HLH comprised 8% of cases, with PRF1 mutations present in 33%. Triggering etiologies included infections (49%), malignancies (19%), autoimmune conditions (8%), and unknown causes (24%). Tissue hemophagocytosis was observed in 56% of cases, while liver (58%), pulmonary (25%), renal (23%), neurological (15%), and cardiac (9%) dysfunction were also noted. Median OS for the entire cohort was 24 months. Factors significantly associated with worse OS included age >50 (p=0.003), splenomegaly (p=0.02), malignancy (p=0.0004), LDH >1000 U/L (p=0.003), sIL2R >5000 U/ml (p=0.03). Patients with pulmonary or renal dysfunction also had worse OS. Etoposide-based regimens and non-chemotherapy immunosuppression improved median OS compared to supportive care (24 vs. NR vs. 3 months, p=0.038). Of note, etoposide-based regimens arm had a greater percentage of high-risk patients. Complete responders had superior OS compared to those with partial and no response, respectively (NR vs. 18 vs. 0.75; p<0.0001). Moreover, patients with relapse <2months had worse survival (6 vs. NR months, p=0.01). Conclusion: This analysis, from the largest real-world HLH cohort, highlights key prognostic factors such as age, splenomegaly, malignant etiology, LDH, sIL2R, organ dysfunction, treatment approach, and quality of response as critical determinants of overall survival in HLH patients. Citation Format: Philip A. Haddad, Suma Chennapragada, Deepti Kantamani, S. Jashwanth Gaddam. Determinants of survival in hemophagocytic lymphohistiocytosis: A real-world database analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3366.