Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation

Abstract Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity, and sought to determine whether the Endothelial Activation and Stress Index (EASIX), (defined as lactate dehydrogenase (U/L)   ×   creatinine (mg/dL)/ platelets (109 cells per L), correlates with grade ≥2 FO in two cohorts of recipients of AHCT at our institution. Methods: We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors, and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors transplanted between 2010-2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis, and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on Receiver Operating Characteristics (ROC) curve analysis. Results: Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) in the two respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥ 2 FO in the study (cutoff: 4.4, HR=4.8, p 55 years (HR=4.5, p 60 years (HR=9.6, p=0.04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% vs 17%, p=0.9) was not different between the diabetics and non-diabetics. Conclusions: EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.