The OHI index predicts early mortality from organ dysfunction and survival benefit from etoposide in lymphoma patients

• The excess mortality predicted by the OHI index in lymphoma patients is predominantly due to multi-organ dysfunction.

• Incorporation of etoposide into lymphoma-directed therapy for those deemed OHI+ at diagnosis is associated with improved overall survival

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that complicates hematologic malignancies. The Optimized HLH Inflammatory (OHI) index, based solely on the combined elevation of soluble CD25 (>3,900 U/mL) and ferritin (1,000 ng/mL) levels, predicts mortality more effectively than conventional HLH criteria. This study aimed to determine whether mortality in OHI+ patients is primarily due to lymphoma or inflammation-related causes. In a multicenter retrospective study of newly diagnosed lymphoma patients with sCD25 and ferritin measurements, patients were classified as OHI+ or OHI-. One-year and three-year overall survival (OS), event-free survival (EFS), and causes of death were analyzed, along with predicted vs. observed mortality based on other lymphoma-relevant prognostic indices. Among 135 lymphoma patients (70 OHI- and 65 OHI+), OHI+ patients had significantly lower OS at one year (33% vs. 81%, p < 0.0001), with a median survival of 190 days. OHI+ patients had a 13-fold increased mortality risk (OR 13.3; 95% CI 6.0-28.5) despite similar predicted OS based on conventional indices (72% vs. 65%, p = 0.46). Mortality causes differed significantly as 58% of OHI+ patients died from multiorgan failure, while only 6% died from progressive lymphoma, compared to 43% of OHI- patients who died from lymphoma progression. The incorporation of etoposide into lymphoma-directed treatment was associated with improved OS in OHI+ T/NK-cell lymphomas (p = 0.007). These findings underscore the clinical significance of the OHI index as a prognostic tool in lymphoma, elucidate mechanisms of mortality, and identify a high-risk subgroup where tailored treatments may lead to improved outcomes.