The Clinical Significance and Prognostic Value of Serum Beta-2 Microglobulin in Adult Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: A Multicenter Analysis of 326 Patients

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by an excessive immune response. Beta-2 microglobulin (B2M) forms the light chain section of the major histocompatibility complex (MHC) class Ⅰ antigen. The prognostic role of B2M in lymphoma-associated HLH remains to be determined. This study was to investigate the prognostic role of serum B2M in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH).

Methods: The clinical and laboratory characteristics of adult patients in a multicenter cohort with lymphoma-associated HLH who had baseline serum B2M levels between August 2009 and June 2023 were retrospectively analyzed. The diagnosis of HLH was established according to the HLH-2004 criteria.

Results: A total of 326 cases were included and the median serum B2M level was 5.19 mg/L. The most common subtype of lymphoma was T/NK cell lymphoma (51.8%, 169/326), followed by B-cell non-Hodgkin lymphoma (45.4%, 148/227) and Hodgkin lymphoma 8/326 (2.5). The optimal cut-off value of serum B2M for predicting overall survival was 8.73 mg/L (p < 0.0001). Patients were divided into two subgroups by the optimal cut-off value. The median survival was 21 days for the high level subgroup, and 236 days for the low level subgroup (Figure 1). The 6-month survival rates were 22% and 54%, respectively. The subgroup with B2M level > 8.73 mg/L was older and had a higher proportion of stage IV. Patients with higher levels of B2M showed lower levels of platelets, albumin, and fibrinogen, and high levels of creatinine. A moderate correlation between creatinine and serum B2M was found (Spearman's ρ = 0.417, p < 0.001). The multivariate analysis showed that the high levels of serum B2M (> 8.73 mg/L) and creatinine (≥ 133 μmol/L), decreased fibrinogen (≤ 1.5 g/L), agranulocytosis (< 0.5×10 ⁹/L), severe thrombocytopenia (< 50×10 ⁹/L), and increased Epstein-Barr virus DNA were found to have significant prognostic values in all patients. The high serum B2M level (> 8.73 mg/L), severe thrombocytopenia (< 50×10 ⁹/L), agranulocytosis (< 0.5×10 ⁹/L), and high Epstein-Barr virus DNA copy number were independent prognostic factors in patients with creatinine < 133 μmol/L. Finally, a prognostic scoring system was established based on serum B2M levels as well as five other independent prognostic factors and divided the patients into three groups with significant prognostic differences (median survival: low-risk [score ≤ 1] 428 days vs. intermediate-risk [score = 2] 102 days vs. high-risk [score ≥ 3] 18 days, P < 0.0001) (Figure 2). The 6-month survival rates were 67%, 46% and 14%, respectively.

Conclusions: This study confirmed that the serum B2M level could be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.