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IDENTIFYING HARMFUL HYPERINFLAMMATION IN DIFFUSE LARGE B‐CELL LYMPHOMA USING THE OHI (OPTIMIZED HLH INFLAMMATORY) INDEX—DISCOVERY AND VALIDATION IN REAL‐WORLD PATIENTS
Abstract   Peer reviewed

IDENTIFYING HARMFUL HYPERINFLAMMATION IN DIFFUSE LARGE B‐CELL LYMPHOMA USING THE OHI (OPTIMIZED HLH INFLAMMATORY) INDEX—DISCOVERY AND VALIDATION IN REAL‐WORLD PATIENTS

A. Zoref-Lorenz, E. J. Cahn, E. Mou, G. Cholack, Y. Wang, M. Maurer, A. L. Feldman, B. J. Negaard, R. Mwangi, G. Itchaki, …
Hematological oncology, Vol.43(S3)
06/2025
DOI: 10.1002/hon.70093_122

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Abstract

Background: The OHI Index (Zoref-Lorenz et al., Blood, 2022) utilizes serum soluble CD25 (sCD25) and ferritin to identify HLH-associated inflammation and predict early mortality risk. Previous studies were limited to HLH-enriched cohorts and retrospective analyses. Here, we assessed the prognostic utility of the OHI Index in an unselected cohort of patients with diffuse large B-cell lymphoma (DLBCL), regardless of HLH suspicion, to determine its broader clinical applicability in risk stratification and outcome prediction. Methods: We analyzed newly diagnosed DLBCL patients from the Molecular Epidemiology Resource (MER) prospective cohort (2002–2015), all treated with standard chemoimmunotherapy. The study included 331 patients in the discovery cohort and 335 in the validation cohort. Soluble CD25 (sCD25) and ferritin levels were measured prior to treatment using ELISA, and receiver operating characteristic (ROC) curves were applied to determine optimal thresholds for risk stratification. We assessed the original OHI and DLBCL-optimized thresholds for their ability to predict 500-day mortality. Additionally, we evaluated event-free (EFS) and overall (OS) survival through univariate and multivariate analyses to assess the prognostic significance of the OHI Index in this population. Results: The discovery cohort's median age was 64, and 51% were male. Using the original OHI thresholds (sCD25 ≥ 3900 U/mL; ferritin ≥ 1000 ng/mL), 4.2% (n = 14) of patients were classified as OHI+, exhibiting a 5.6-fold higher risk of 500-day mortality (95% CI: 1.6–17). Applying optimized thresholds (sCD25 > 2400 U/mL; ferritin > 250 ng/mL), 24% (n = 78) of patients were identified as OHI+, with a 9.2-fold increased risk of 500-day mortality (95% CI: 4.0–24), as well as longer-term inferior EFS (HR = 2.4; 95% CI: 1.6–3.5) and OS (HR = 2.3; 95% CI: 1.5–3.4). After adjusting for age and the international prognostic index (IPI), OHI+ status remained an independent predictor of increased risk of 500-day mortality (OR = 5.0; 95% CI: 1.9–13) and inferior EFS (HR = 2.2; 95% CI: 1.1–4.3) and OS (HR = 2.0; 95% CI: 1.0–4.0). In the validation cohort, 21% (n = 70) were classified as OHI+, with a 4.0-fold increased risk of 500-day mortality; the Figure shows the 500-day EFS and OS curves for the discovery and validation sets. Furthermore, over the longer term (median follow-up of 9.8 years in living patients), OHI+ patients continued to show inferior EFS (HR = 2.5; 95% CI: 1.7–3.7) and OS (HR = 1.8; 95% CI: 1.2–2.8). Conclusions: The OHI index thresholds optimized for real-world DLBCL patients identified a large risk group with inferior outcomes, which was robustly validated in an independent cohort. The OHI index is a powerful predictor of inferior early and longer-term outcomes in DLBCL patients, highlighting hyperinflammation’s role in poor outcomes. These findings support its use in routine management and as a tool to study mechanisms, design targeted therapies, and conduct trials to improve outcomes.

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