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

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) is a significant source of morbidity and mortality and most commonly targets the gastrointestinal (GI) tract after CBT. We evaluated whether plasma biomarkers predict aGVHD severity and transplant-related mortality (TRM) after CBT. 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. Conditioning was myeloablative (n = 37), reduced intensity (n = 47), or non-myeloablative (n = 29), and CB units were 4-6/6 HLA-matched to the recipient. The median follow-up was 44 months (range 14-84). Batched samples blinded to transplant outcomes were analyzed by ELISA for levels of suppressor of tumorigenicity 2 (ST2), IL-2Rα, TNFR1, HGF, IL-8, elafin, and REG3α. Patients were grouped according to being above or below the median biomarker value. 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 (Table). IL2Rα, elafin, and HGF were not significant. ST2 was the only biomarker associated with both day 100 aGVHD and TRM. 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 increased 6-month TRM, and GVHD was the most common cause of transplant-related death. High concentrations of TNFR1, IL-8, and REG3a were significantly associated with 6-month TRM and the most common cause of death in these patients was GVHD or lung toxicity. Conclusions: This is the first biomarker analysis conducted in CBT recipients. As with adult donor allografts (NEJM, 2013), high day 28 ST2 levels is associated with a subsequent increased risk of grade II-IV and III-IV aGVHD, and 6-month TRM. GVHD onset is after day 28 in the majority of the patients which would permit potential therapeutic intervention. Thus, our findings have significant practical implications. Our results warrant further prospective evaluation with the ultimate aim of future interventions to ameliorate severe aGVHD and improve CBT survival.

Table.

Biomarker (ng/ml)	Day 100 Grade II-IV aGVHD (95%CI)	p-value	6-month TRM (95% CI)	p-value
ST2 ≤ 33.9 ST2 > 33.9	48% (35-61) 64% (49-76)	0.045	5% (1-13) 23% (13-35)	0.001
TNFR1 < 4792 TNFR1 > 4792	57% (42-69) 54% (40-67)	0.660	5% (1-13) 23% (13-35)	0.005
IL8 < 51 IL8 > 51	56% (41-68) 56% (41-68)	0.652	5% (1-13) 23% (13-35)	0.005
REG3α ≤ 42 REG3α > 42	57% (42-69) 55% (40-67)	0.938	5% (1-13) 24% (13-36)	0.032