Pathological Subtyping, Outcomes, and Survival Trends of Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: A Multicenter Analysis of 464 Patients

Introduction: Lymphoma is the most common underlying cause of secondary hemophagocytic lymphohistiocytosis (HLH). The detailed pathological subtypes of lymphomas presenting with HLH remain less well-defined. The prognostic role of pathological subtypes in patients with lymphoma-associated HLH (LA-HLH) has not been studied in a large cohort. Survival trends of patients with LA-HLH has not been explored. Whether the advent of novel therapies and better supportive care improves the outcomes of patients with LA-HLH remains to be determined. Methods: Patients with LA-HLH were included. The diagnosis of HLH was established according to the HLH-2004 criteria. Only patients with a histological diagnosis and follow-up were included. The subtyping was based on the 2016 World Health Organization classification of lymphoid neoplasms. Results: A total of 464 cases of LA-HLH were included in this study. Two-hundred and twenty-six cases were diagnosed from 2010-2019 (Era 1) and 238 patients were diagnosed from 2020-2024 (Era 2). Two-hundred and forty-three cases were T/NK cell lymphoma (52.4%), 206 B cell lymphoma (44.3%), 12 Hodgkin lymphoma (HL, 2.6%), and 3 composite lymphoma (0.6%). The most common lymphoma subtypes included large B cell lymphoma (LBCL, n=190, 40.9%), aggressive NK cell leukemia (ANKL, n=66, 14.2%), extranodal NK/T cell lymphoma, nasal type (n=64, 13.8%), peripheral T cell lymphoma, not otherwise specified (n=28, 6.0%), and angioimmunoblastic T cell lymphoma (n=28, 6.0%). Patients with B cell LA-HLH had better outcomes than those with T/NK cell LA-HLH (median survival: 418 days vs. 72 days, p<0.0001; 60-day survival: 68.8% vs. 53.4%, p=0.0012). For specific subtypes, patients with ANKL-associated HLH showed the worst outcome with a median survival of only 39 days (60-day survival: 43.7%). Patients with LBCL-associated HLH had a median survival of 420 days. Survival of B cell LA-HLH improved remarkably in recent years (median survival: 238 days in Era 1 vs. Undefined in Era 2, p=0.0019; 60-day survival: 61.8% in Era 1 vs. 74.2% in Era 2, p=0.0441). The survival of T/NK cell LA-HLH also improved (median survival: 54 days in Era 1 vs. 97 days in Era 2, p=0.0177; 60-day survival: 47.3% in Era 1 vs. 60.5% in Era 2, p=0.0402). The outcomes for patients with NK cell LA-HLH also improved in recent years (median survival: 39 days in Era 1 vs. 105 days in Era 2, p=0.0171; 60-day survival:40.6% in Era 1 vs. 66.4% in Era 2, p=0.0074). Conclusions: To our knowledge, we presented the largest cohort of LA-HLH. T/NK cell LA-HLH is more common than B cell LA-HLH in China. The most common lymphoma subtypes related to HLH included LBCL, ANKL, and ENKL. The pathological subtypes had significant impacts on the survival outcomes of patients with LA-HLH. Patients with T/NK cell LA-HLH had poorer outcomes, especially those with ANKL. The survival of both B cell LA-HLH and T/NK cell LA-HLH improved recently, probably due to novel agents and better supportive care.