EASIX and mortality after allogeneic stem cell transplantation

Abstract

Allogeneic stem cell transplantation (alloSCT) is an effective immunotherapy in patients with hematological malignancies. Endothelial dysfunction was linked to major complications after alloSCT. We asked the question if the "Endothelial Activation and Stress Index" (EASIX; [(creatinine × LDH) ÷ thrombocytes]) can predict mortality after alloSCT. We performed a retrospective cohort analysis in five alloSCT centers in the USA and Germany. EASIX was assessed prior to conditioning (EASIX-pre) and correlated with mortality in 755 patients of a training cohort in multivariable models. The predictive model established in the training cohort was validated in 1267 adult allo-recipients. Increasing EASIX-pre predicted lower overall survival (OS) after alloSCT, and successful model validation was achieved for the validation cohort. We found that EASIX-pre predicts OS irrespective of established scores. Moreover, EASIX-pre was also a significant prognostic factor for transplant-associated microangiopathy. Finally, EASIX-pre correlated with biomarkers of endothelial homeostasis such as CXCL8, interleukin-18, and insulin-like-growth-factor-1 serum levels. This study establishes EASIX-pre based on a standard laboratory biomarker panel as a predictor of individual risk of mortality after alloSCT independently from established clinical criteria.

Figure 1.. Visualization of the univariable outcome analysis according to EASIX-pre quartiles A) training cohort, n=755, B) validation cohort (adult cohorts II-IV, n=1267).

Overall survival (OS), non-relapse mortality (NRM) and time to relapse (TTR) are shown according to the EASIX-pre quartiles raised in the respective cohorts. The high quartiles 4 (blue) and 3 (green) associate with lower OS and higher NRM in the training cohort and with lower OS, higher NRM and higher TTR in the validation cohort.

Figure 2.. Model validation of EASIX as predictor of overall mortality

(A) Univariable model: The prediction error curve for EASIX-pre (red curve) developed in the Heidelberg training cohort of adult alloSCT recipients was computed for 36 months after alloSCT and compared with the reference (marginal Kaplan-Meier estimate, black curve). (B) Multivariable model: Confounders were adjusted to the validation cohort. The prediction error of EASIX-pre (green curve) developed in the multivariable Heidelberg training cohort was computed for 36 months and compared to the prediction error of the multivariable model without EASIX-pre (blue curve). A lower prediction error curve in the model including EASIX (red curve below black curve / green curve below blue curve) supports the usefulness of EASIX for predicting prognosis. C) Time-dependent concordance indices for overall survival. Color coding as in A and B: Highest concordance indices are found in the models including EASIX-pre (red: univariable, green: multivariable model with confounders adjusted to validation cohort and EASIX-pre, blue: multivariable model with confounders adjusted to validation cohort and without EASIX-pre). A concordance index of 0·5 (dotted line) implies random concordance. A concordance index above 0·6 is regarded as acceptable.