Plasma ST2 Concentrations Predict Acute Gvhd Development and Non-Relapse Mortality

Acute GVHD is the primary limitation of allogeneic HSCT. We have previously reported that plasma concentrations of suppressor of tumorigenicity 2 (ST2) at the onset of GVHD therapy predicted response at day (D) 28 and non-relapse mortality (NRM) at D180 after therapy initiation. We hypothesized that ST2 measured early in HSCT would predict GVHD occurrence by D100 and D180 NRM after HSCT. 

We measured ST2 in plasma taken at D0, D14 and D21 after HSCT in a pilot set. ST2 concentrations at D14 were most different between patients who developed GVHD and those without GVHD, and were twice higher in patients receiving full intensity conditioning (FIC) compared to those receiving reduced intensity conditioning (RIC). We then measured ST2 concentrations at D14 in two independent sets: 1) 598 patients from the University of Michigan (UM), 69% receiving FIC (15% receiving TBI) and 31% receiving RIC HSCT, 2) 75 patients receiving unrelated, FIC (92% receiving TBI) HSCT from the Dana Farber Cancer Institute (DFCI). 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. As ST2 concentrations differed between conditioning intensities, we used 3 models for prediction using the median ST2 concentrations for UM FIC, UM RIC, and DFCI FIC as cutpoints.

In multivariate analysis including the age, disease status, donor source, and HLA match, high ST2 predicted the development of GVHD in UM FIC, and trended toward significance in the DFCI set (Table 1 Top). Patients with high ST2 at D14 were at increased risk of D180 NRM for all conditioning intensities, independent of the clinical characteristics (Table 1 Bottom). High ST2 was not associated with increased risk of relapse mortality 1 year after HSCT.

In conclusion, high ST2 early in HSCT identifies patients at high risk for acute GVHD and NRM following HSCT. This has therapeutic consequences including increased monitoring and potential preemptive interventions.

Table.  ST2 concentrations at D14 predict GVHD development by D100 and predict D180 NRM
	UM FIC (n = 414)		UM RIC (n = 184)		DFCI (n = 75)
	Hazard Ratio (HR)	p-value	HR	p-value	HR	p-value
Age (55 and Over vs. Under 55)	1.5	0.01	0.8	0.4	0.1	0.02
Disease Status (High vs. Low risk)	1.0	0.99	1.8	0.02		n/a
Donor (Unrelated vs. Related)	1.9	<0.001	0.9	0.7		n/a
HLA match (Mismatched vs. Matched)	2.1	<0.001	1.0	0.9	2.7	0.09
ST2 Concentration (High vs. Low)*†	1.5	0.004	1.3	0.3	2.0	0.08
Age	3.1	<0.001	0.7	0.4	0.7	0.5
Disease Status	1.1	0.6	2.7	0.02		n/a
Donor	1.5	0.1	1.1	0.8		n/a
HLA match	1.7	0.06	0.5	0.3	1.9	0.2
ST2 Concentration	2.8	<0.001	4.8	0.005	2.6	0.04
*Effect of ST2 calculated with regression models adjusting for age, disease status, donor, and HLA match †High defined as ST2 concentration >600 pg/mL for UM FIC, >300 pg/mL for UM RIC, >1660 pg/mL for DFCI