TA-TMA and GVHD are distinct consequences of endothelial injury: A MIDAS consortium study.

Graft-versus-host disease (GVHD) is a major risk factor for transplant-associated thrombotic microangiopathy (TA-TMA), and the two conditions often co-occur; therefore, we evaluated biomarkers of endothelial injury to clarify their relationship. Our prospective MIDAS cohort study of 368 adult (18 years) patients measured biomarkers before and after first allogeneic HCT. We found post-transplant cyclophosphamide (PTCy) significantly reduced acute GVHD incidence but had no impact on reduction of TA-TMA incidence. Severe TA-TMA occurred in the absence of acute GVHD but also occurred more frequently with higher grades of acute GVHD. Pre-transplant serum creatinine and detectable placental growth factor (PlGF) were associated with post-HCT TA-TMA. In sex-stratified multivariable models, a 1 mg/dL increase in pre-transplant creatinine conferred a ~40-fold higher TA-TMA risk in females versus ~5-fold in males. Both landmark and association analyses identified day+28 creatinine and suppression of tumorigenicity 2 (ST2) as significant TA-TMA risk factors. Our study phenotyped TA-TMA and GVHD concurrently, and we show that ST2, previously linked to GVHD treatment response and non-relapse mortality (NRM), also predicts TA-TMA. Day+28 levels of ST2, soluble Fms-like tyrosine kinase-1 (sFLT-1), and epidermal growth factor (EGF) were associated with NRM and overall survival, whereas baseline or day+28 soluble C5b-9 (sC5b-9) was not associated with TA-TMA. Post-hoc analyses of the EASIX composite score at day+28 post-HCT found significant associations with severe TA-TMA, acute GVHD, NRM and OS. Overall, our data highlight distinct risk factors and biomarker profiles for TA-TMA and GVHD and also identify differences between adults and reported biomarkers of TA-TMA in children.