Plasma ST2 Concentrations Predict Development of Acute Gvhd and Non-Relapse Mortality
Authors: Vander Lugt Mark T. , Braun Thomas M. , Hanash Samir , Ferrara James L.M. , Ritz Jerome , Ho Vincent T. , Antin Joseph H. , Zhang Qing , Chin Alice , Gomez Aurelie , Harris Andrew C. , Levine John E. , Choi Sung W. , Couriel Daniel , Reddy Pavan , Paczesny Sophie 
Published: October 2019

Abstract
Abstract 466
Acute graft-versus-host disease (GVHD) is a major limitation of allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that plasma concentrations of suppressor of tumorigenicity 2 (ST2) measured at the onset of GVHD therapy predicted response at day (D) 28 after therapy initiation, as well as non-relapse mortality (NRM) at 6 months after therapy. We hypothesized that ST2 measured early in HSCT would predict GVHD development by D100 and NRM at 6 months after HSCT.
We first measured ST2 in plasma taken at 0, 14, and 21 days after HSCT in a pilot set of 296 patients without GVHD at D35. ST2 concentrations at D14 were most different between patients who developed GVHD and those without GVHD, and were two times higher in patients receiving full-intensity conditioning (FIC) compared to patients receiving reduced intensity conditioning (RIC). We therefore measured ST2 concentrations at D14 in two independent sets: (i) 598 patients from the University of Michigan (UM), 69% receiving FIC (85% with chemotherapy only) and 31% receiving RIC HSCT: 313 who developed GVHD between D18 and D100, and 285 without GVHD, and (ii) 75 patients from the Dana Farber Cancer Institute (DFCI), all receiving unrelated, FIC (92% receiving TBI) HSCT: 29 who developed GVHD between D18 and D100, and 46 without GVHD. UM patients who developed GVHD were older and more likely to receive mismatched or unrelated donor HSCT. Median day of GVHD onset was D35 in FIC and D42 in RIC (p=0.08). DFCI patients who received sirolimus as GVHD prophylaxis were over-represented in the no-GVHD group. Because ST2 concentrations differed between conditioning intensities, we used 3 models for prediction using the median ST2 concentrations for UM FIC, UM RIC, and DFCI TBI-based FIC as cutpoints.
In multivariate analysis including the clinical characteristics of age, disease status, donor source, and HLA match, high ST2 predicted the development of GVHD in UM patients receiving FIC, but not RIC, and trended toward significance in the DFCI patient set, independent of the clinical characteristics (Hazard Ratio [HR] 1.5, p=0.004; HR 1.3, p=0.3; HR 2.0, p=0.08, respectively) (Table 1). Patients with high ST2 concentrations at D14 were also at increased risk of NRM at 6 months for all conditioning intensities independent of the clinical characteristics (UM FIC: HR 2.8, p<0.001; UM RIC: HR 4.8, p=0.005; DFCI: HR 2.6, p=0.04) (Table 1). High ST2 was not associated with increased risk of relapse mortality 1 year after HSCT (UM FIC: HR1.1, p=0.6; UM RIC: HR 0.7, p=0.6; and DFCI: HR 1.2, p=0.8).
In conclusion, high ST2 concentrations early in the course of HSCT identify a group of patients at high risk for acute GVHD and NRM following HSCT. Early identification of these patients may warrant increased monitoring and potential preemptive interventions.
Table 1. ST2 concentrations at D14 predict GVHD development by D100 (Top) and predict NRM at 6 months (Bottom) UM Full Intensity (n = 414) UM Reduced Intensity (n = 184) DFCI (n = 75) Univariate Multivariate Univariate Multivariate Univariate Multivariate HR p-value HR p-value HR p-value HR p-value HR p-value HR p-value Age (55 and Over vs. Under 55) 1.6 0.003 1.5 0.01 0.9 0.5 0.8 0.4 0.1 0.04 0.1 0.02 Disease Status (High vs. Low/Intermediate risk) 1.1 0.6 1.0 0.99 1.9 0.01 1.8 0.02 n/a n/a Donor (Unrelated vs. Related) 2.4 <0.001 1.9 <0.001 1.0 0.9 0.9 0.7 n/a n/a HLA match (Mismatched vs. Matched) 2.7 <0.001 2.1 <0.001 1.1 0.7 1.0 0.9 2.4 0.08 2.7 0.09 ST2 Concentration (High vs. Low)*† 1.8 <0.001 1.5 0.004 1.3 0.3 1.3 0.3 2.3 0.03 2.0 0.08 Age (55 and Over vs. Under 55) 3.5 <0.001 3.1 <0.001 0.9 0.7 0.7 0.4 0.7 0.5 0.7 0.5 Disease Status (High vs. Low/Intermediate risk) 1.4 0.1 1.1 0.6 2.8 0.02 2.7 0.02 n/a n/a Donor (Unrelated vs. Related) 1.8 0.01 1.5 0.1 1.4 0.4 1.1 0.8 n/a n/a HLA match (Mismatched vs. Matched) 21 0.004 1.7 0.06 0.6 0.4 0.5 0.3 2.0 0.2 1.9 0.2 ST2 Concentration (High vs. Low)*† 3.4 <0.001 2.8 <0.001 4.7 0.005 4.8 0.005 2.8 0.02 2.6 0.04 * Effect of ST2 calculated using regression models adjusting for age, disease status, donor, and HLA match. #x2020; High defined as ST2 concentration >600 pg/mL for UM full intensity, >300 pg/mL for UM reduced intensity, and >1660 pg/mL for DFCI.

Disclosures:
No relevant conflicts of interest to declare.