Assessment of ST2 for Risk of Death Following Graft-versus-Host Disease in the Pediatric and Adult Age Groups

Background: To address the need for establishing prognostic markers of Non-Relapse Mortality (NRM) and acute graft-versus-hostdisease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group, we conducted a prospective study (NCT02194439). Methods: 415 patients at six U.S. centers including 170 children ≤10 years were accrued from 2013 to 2018. Four biomarkers [stimulation-2 (ST2), interleukin-6, regenerating-islet-derived-3-alpha (REG3α) and tumornecrosis-factor-receptor-1 (TNFR1)] were assessed in the plasma pre-HCT (day -7), and at days +7, +14, +21 post-HCT. We performed landmark analyses for NRM and grade II-IV aGVHD, dichotomizing the cohort at ≤10 years and using each biomarker median as a cutoff for high and low risk groups. The multivariable analyses included the significant covariates. Findings: The NRM was not different among children ≤10 years compared to subjects >10 years. Landmark analyses using post-HCT assays showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in both children 10 years [HR (CI): ST2: 2.60 (1.15-5.86), p=0.021; TNFR1: 2.09 (0.96-4.58), p=0.06; REG3α: 2.57 (1.19-5.55), p=0.016]. When pre-HCT biomarkers were included, ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, GVHD prophylaxis), ST2 remained associated with NRM only in recipients ≤10 years [HR(CI): 4.82 (1.89-14.66), p=0.0056]. ST2 was also associated with grade II-IV aGVHD in both ≤10 years and >10 years groups (p=0.0059, and p<0.0001). Interpretation: Assays of ST2, TNFR1, REG3α in the first 3 weeks following HCT have prognostic value for NRM and aGVHD in both children and adults. ST2 prior to HCT is a prognostic biomarker for NRM and severe aGVHD in children ≤10 years allowing for additional stratification. Trial Registration: Clinicaltrial.gov under NCT02194439. Funding Statement: The Eunice Kennedy Shriver National Institute of Child Health and Human Development of Health from the National Institutes of Health R01HD074587, the National Cancer Institute R01CA168814, the Leukemia and Lymphoma Society (grant 1293-15), and the Lilly Physician Scientist Initiative Award. Declaration of Interests: S.P. is an inventor on a patent on “Methods of detection of graft-versus-host disease” (US- 13/573,766). K.R.C. is on the advisory board of Jazz pharmaceuticals. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by the respective Institutional Review Boards at six adult and pediatric centers: Children's National Medical Center, Texas Children's Hospital, Fred Hutchinson Cancer Research Center, Boston Children’s/Dana Farber Cancer Institute, Johns Hopkins, and Indiana University. Informed consent was obtained from all patients or their legal guardians.