Endothelial Activation and Stress Index (EASIX) to Predict Survival in T or NK Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

Introduction: Lymphoma is the most common underlying cause of secondary hemophagocytic lymphohistiocytosis (HLH). In Asian countries, T or NK-cell lymphoma-associated HLH (T/NK-LAHLH) is more common than B-cell lymphoma-associated HLH. There are no established prognostic markers for T/NK-LAHLH. Endothelial Activation and Stress Index (EASIX) is a marker of endothelial activation and could predict mortality in patients treated with allogeneic stem cell transplantation. Whether EASIX could predict survival in T/NK-LAHLH remains to be determined. Materials and Methods: Patients with T/NK-LAHLH were included. EASIX was calculated by the formula: lactate dehydrogenase (U/L)×creatinine (mg/dL)/thrombocytes (10⁹ cells per L). The diagnosis of HLH was based on the HLH-2004 criteria. Only patients with a histological diagnosis and follow-up were included. The subtyping was based on the 2016 World Health Organization classification of lymphoid neoplasms. X-tile was used to determine the best cutoff of EASIX for survival prediction. Results: A total of 212 cases of T/NK-LAHLH were identified. The most common subtype of T/NK cell malignancy was extranodal NK/T cell lymphoma, nasal type (57, 26.9%) followed by aggressive NK cell leukemia (55, 25.9%) and peripheral T cell lymphoma, not otherwise specified (29, 13.7%). The best cutoff of EASIX for predicting 60-day survival was 40.1. Patients with high EASIX values (>40.1) had a significantly poorer 60-day survival than those with low EASIX values (≤40.1) (60-day survival rate: 15.6% vs. 63.9%, p<0.0001). Patients with high EASIX also showed significantly poorer overall survival (median survival: 14 days vs. 79 days, p<0.0001). For patients with NK cell malignancies, a higher EASIX also significantly predicted a reduced 60-day survival rate (p<0.0001) and overall survival (p<0.0001). Patients with high EASIX values showed significantly lower levels of hemoglobin, neutrophil count, albumin, and fibrinogen and higher levels of aspartate aminotransferase, alanine aminotransferase, and triacylglycerol (p values all < 0.05). EASIX>40.1 (hazards ratio[HR] 3.60, 95%CI: 2.31-5.60; p<0.0001), fibrinogen≤1.5g/L (HR 1.67, 95%CI: 1.07-2.58; p=0.023), and age>60 (HR 1.76, 95%CI:1.14-2.71; p=0.011) were identified as independent predictors of worse 60-day survival in multivariate analysis. A prognostic index was established by combining these three independent predictors. We assigned a weighted score of 1 to fibrinogen and age, and 2 to EASIX. Finally, a prognostic index for T/NK-LAHLH (T/NK-LAHLH-PI) ranged from 0 to 5 was established (T/NK-LAHLH-PI: low-risk 1, intermediate-risk 2, high-risk ≥2). T/NK-LAHLH-PI significantly predicted different 60-day survival rates (low-risk 77.3% vs. intermediate-risk 50.1% vs. high-risk 24.9%, p<0.0001) and overall survival (median survival: low-risk 340 days vs. intermediate-risk 63 days vs. high-risk 20 days, p<0.0001). Conclusions: Our study demonstrated that EASIX was a robust marker for predicting outcomes in patients with T/NK-LAHLH. T/NK-LAHLH-PI, a prognostic index containing EASIX, could be used to predict the outcomes of patients with T/NK-LAHLH.