Easix Application in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Prophylaxis

INTRODUCTION

The Endothelial Activation and Stress Index (EASIX) is a biomarker-based laboratory formula applicable in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) which has been proposed to predict non-relapse mortality (NRM), overall survival (OS), and thrombotic microangiopathy (TMA) incidence when measured during the pre-transplant evaluation, and sinusoidal obstruction syndrome (SOS), when measured on day 0.

The use of post-transplant cyclophosphamide (PTCY) for graft vs. host disease (GVHD) prevention has become a standard in haploidentical hematopoietic cell transplantation (HCT) and it is increasingly used for allo-HCT performed with unrelated (UD) and matched sibling donors. PTCY-based prophylaxis was incorporated at our Institution between 2014 and 2018. Since then, lower rates of endothelial complications including acute GVHD (aGHVD) have been documented.

The predictive ability of EASIX has been validated mainly in patients receiving GVHD prophylaxis that did not contain PTCY. Considering that fewer endothelial complications have been diagnosed at our Institution since the use of PTCY-based prophylaxis, and that EASIX is considered a surrogate parameter of endothelial activation, this study investigates whether the dynamics of EASIX differ between patients receiving PTCY vs. other prophylaxis, and if the predictive ability of EASIX persists in PTCY-based allo-HCT.

METHODS

Between 2014 and 2020, 328 consecutive adults underwent first allo-HCT at our Institution and were included in the study. EASIX [(creatinine*LDH)/platelets] was calculated based on the information provided at the bloodwork collected at the pre-transplant assessment, on days 0, +7, +21, +28, +100, and +180. EASIX was transformed to a base-2 logarithm to perform the statistical analysis. The ability of EASIX to predict outcomes (OS and NRM) and post-transplant complications (SOS, TMA, and grade 2-4 aGVHD) was explored using landmark and regression analyses. Patients who died or who were diagnosed with the study time-dependent adverse event before each landmark point were excluded from the next time point.

RESULTS

The study cohort was divided into two groups according to the GVHD prophylaxis (PTCY n=201 vs. others n=127). Median age was 52 years and 81 patients (40.4%) received myeloablative conditioning regimens. One hundred and nine patients (65.2%) received transplants from mismatched donors [68 (44.8%) from mismatched UD and 41 (20.4%) haploidentical]. The dynamics of EASIX, in conjunction to creatinine, LDH, and platelets counts consecutively recorded from day 0 to +180 are depicted in Figure 1. As reported, the values of EASIX differed significantly from day 0 to day +28 between the two groups. These differences were attributed to lower LDH levels from day 0 to day +180, a lower platelet count documented between days +14 and +180 in patients receiving PTCY.

The ability of EASIX to predict outcomes and complications was explored in patients receiving PTCY. The cumulative incidence functions of SOS, TMA, and grade 2-4 aGVHD day +100 were 2.0%, 3.5%, and 21.4%, respectively. The 2-years OS and NRM were 69.0% and 16.4%, respectively. As reported in Table 1, higher values of EASIX , measured at the pre-transplant assessment, days 0, +7, +14, +28, and +180 were associated with a higher probability of NRM and lower OS. Moreover, increased values of EASIX, measured at the pre-transplant assessment, days 0, +7, and +14 were predictors for TMA, and higher values of EASIX, measured before allo-HCT, on days +21 and +28 were predictors for grade 2-4 aGVHD. No association was observed between EASIX and SOS prediction.

CONCLUSIONS

The dynamic of EASIX differs between patients receiving PTCY and those that did not. However, despite this difference, the ability of pre-transplant EASIX to predict NRM and OS persists in patients receiving PTCY.

Higher values of EASIX, measured not only at the pre-transplant evaluation, but also on days 0, +7, +21, +28 and +180 were associated with higher NRM and lower OS in patients receiving PTCY. In addition, pre-transplant EASIX was found to be a useful predictor for TMA and grade 2-4 aGVHD in these patients.

This analysis validates the predictive ability of EASIX in patients receiving PTCY for GVHD prevention, and enhances the relevance of the assessment of endothelial dysfunction markers for the prognosis of PTCY-based allo-HCT.