High Day 28 ST2 Biomarker Levels Predict Severe Day 100 Acute Graft-Versus-Host Disease and Day 180 Transplant-Related Mortality After Double-Unit Cord Blood Transplantation
Authors: Ponce Doris M , Hilden Patrick , Mumaw Christy , Devlin Sean , Lubin Marissa N , Evans Katherine L , Prockop Susan , Scaradavou Andromachi , Kernan Nancy A. , Giralt Sergio A , van den Brink Marcel R.M. , Paczesny Sophie , Barker Juliet N 
Published: October 2019

Abstract

Background
Cord blood transplantation (CBT) is a proven therapy for high-risk hematologic malignancies. However, severe grade III-IV acute graft-versus-host disease (aGVHD) has emerged as a significant source of morbidity and mortality and most commonly targets the gastrointestinal (GI) tract after CBT. Plasma biomarkers have been found to predict aGVHD onset, aGVHD therapy response, and transplant-related mortality (TRM) after adult donor hematopoietic stem cell transplantation. However, whether plasma biomarkers are informative in CBT recipients has not been investigated.

Methods
Plasma biomarkers were measured 28 days after unrelated donor double-unit CBT in 113 consenting patients (median age 41 years, range 1.7-69) transplanted at a single center between 5/2006 and 5/2012 for the treatment of high-risk hematologic malignancies. Conditioning was myeloablative (n = 37), reduced intensity (n = 47), or non-myeloablative (n = 29), and CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient. The median follow-up was 44 months (range 14-84). Batched samples blinded to transplant outcomes were analyzed by enzyme-linked immunosorbent assay for levels of suppressor of tumorigenicity 2 (ST2), IL-2 receptor-α (IL-2Rα), tumor necrosis factor receptor-1 (TNFR1), hepatocyte growth factor (HGF), IL-8, elafin, and regenerating islet-derived protein 3-α (REG3α). Patients were grouped according to being above or below the median day 28 value for each biomarker. The cumulative incidence of aGVHD and TRM from day 28 landmark was estimated for each biomarker and significance was assessed using Gray's test. Patients who had aGVHD onset prior to day 28 (n = 7) were excluded from aGVHD evaluation.

Results
We found significant associations between day 28 plasma biomarkers and grade II-IV aGVHD and/or 6-month TRM, which are shown in Table. IL2Rα, elafin, and HGF were not significant for either outcome (data not shown). ST2 was the only biomarker associated with day 100 grade II-IV aGVHD with high ST2 patients having a median aGVHD onset of 42 days (range 28-93). Notably, patients with high day 28 ST2 had significantly increased day 100 grade III-IV aGVHD of 27% (95%CI:16-40) versus 11% (95%CI:4-20) in patients with low ST2 levels, p = 0.025. High ST2 was also associated with substantially increased 6-month TRM, and GVHD was the most common cause of transplant-related death [11/19 (58%) of deaths] with a median time to GVHD death of 170 days (range 70-400). High concentrations of TNFR1, IL-8, and REG3a were also significantly associated with 6-month TRM. Notably, aGVHD and organ failure due to lung toxicity were the most common causes of TRM in patients with high TNFR1, IL8, and REG3α levels.

Conclusions
This is the first biomarker analysis conducted in CBT recipients. We demonstrate that a high day 28 ST2 level is associated with a subsequent increased risk of grade II-IV and III-IV aGVHD, as well as 6-month TRM. These findings are consistent with those recently reported in adult unmodified (T-replete) allograft recipients (Vander Lugt et al, NEJM, 2013). GVHD is the predominant mechanism of death in high ST2 patients and the day of onset is after day 28 in the majority which would permit time for therapeutic intervention. Thus, our findings have significant practical implications. Whether the other biomarkers offer additional prognostic information remains to be determined. They were not associated with the overall grade II-IV aGVHD incidence, but where associated with mortality from GVHD and organ failure. Overall, our promising results warrant further prospective evaluation in a large patient cohort with the ultimate aim of future interventions to ameliorate severe aGVHD and improve survival after CBT.

Disclosures:
No relevant conflicts of interest to declare.