Germline mutations in B-cell non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) and patient outcomes

Abstract

Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence implicates germline mutations as potential contributors to hematologic abnormalities, suggesting a genetic predisposition in affected individuals. We conducted whole-exome sequencing (WES) on a cohort of 12 LA-HLH patients, with detailed analysis of 3 representative cases exhibiting coexisting genetic disorders. These cases were comprehensively evaluated for their clinical management strategies and therapeutic outcomes. Our study revealed that gene mutations were detected in 6 patients (6/12), including 2 had somatic mutations, 3 had germline mutations, and 1 had both somatic and germline mutations. Among the 4 patients harbored germline mutations, 3 were diagnosed with concurrent genetic disease. Most patients (11/12) responded to immunochemotherapy for a short time and then progressed or relapsed, even after autologous hematopoietic stem cell transplantation (ASCT). Interestingly, two patients received CAR-T-cell therapy and achieved extremely good responses. One patient received CD19 CAR-T-cell infusion and had a PFS of 26 months. The other patient received double CAR-T infusions and has remained in complete remission for more than 2 years (until now). This study proposes that LA-HLH may constitute a novel genetic subtype of lymphoma. Systematic genetic sequencing should be prioritized to guide precision treatment approaches in selected cases, including immunotherapies such as CAR-T-cell therapy. These insights redefine our understanding of LA-HLH pathogenesis and clinical intervention strategies.

Keywords: B-cell non-Hodgkin lymphoma; CAR-T-cell therapy; Germline mutation; Lymphoma-associated hemophagocytic lymphohistiocytosis; Whole-exome sequencing.