The diagnostic utility of the soluble CD25-to-ferritin ratio in lymphoma-associated hemophagocytic lymphohistiocytosis.

Lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS) is associated with high mortality, and rapid identification may enable timely lymphoma-directed therapy. The soluble interleukin-2 receptor alpha (sIL-2Rα), measured clinically as soluble CD25 (sCD25), to ferritin ratio has been proposed as a diagnostic biomarker to distinguish LAHS from non-lymphoma-associated HLH (N-LAHS), but validation in Western populations and across lymphoma subtypes remains limited. We performed a retrospective multicenter cohort study of adults diagnosed with HLH across three United States academic institutions between 2008 and 2024. HLH was defined using HLH-2004 criteria. Laboratory values were selected at first clinical suspicion of HLH. Patients were classified as LAHS or N-LAHS, and lymphoma subtypes were annotated using institutional records. Among 126 patients, 44 (34.9%) had LAHS. LAHS cases included aggressive B-cell/classical Hodgkin lymphoma, aggressive T/NK-cell lymphoma and indolent B-cell lymphoma. Median sCD25 was significantly higher in LAHS, whereas ferritin did not differ significantly. The median sCD25/ferritin ratio was elevated in LAHS (2.2 vs. 0.4; P < 0.001). Receiver-operating-characteristic analysis calculated from our analytic cohort demonstrated an area under the curve (AUC) of 0.7431, and the Youden index identified an optimal cutoff of > 1.02 with 73% sensitivity, 73% specificity, 59.3% positive predictive value and 83.3% negative predictive value. In logistic regression, each one-unit increase in log(sCD25/ferritin) was associated with increased odds of underlying lymphoma. The sCD25/ferritin ratio is best interpreted as a risk-enrichment tool that may prioritize evaluation for occult lymphoma, but it cannot replace tissue diagnosis.