Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD

TY - JOUR

T1 - Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD

AU - Etra, Aaron

AU - El Jurdi, Najla

AU - Katsivelos, Nikolaos

AU - Kwon, Deukwoo

AU - Gergoudis, Stephanie

AU - Morales, George

AU - Spyrou, Nikolaos

AU - Kowalyk, Steven

AU - Aguayo-Hiraldo, Paibel

AU - Akahoshi, Yu

AU - Ayuk, Francis

AU - Baez, Janna

AU - Betts, Brian C

AU - Chanswangphuwana, Chantiya

AU - Chen, Yi-Bin

AU - Choe, Hannah

AU - DeFilipp, Zachariah

AU - Gleich, Sigrun

AU - Hexner, Elizabeth

AU - Hogan, William J

AU - Holler, Ernst

AU - Kitko, Carrie L

AU - Kraus, Sabrina

AU - Al Malki, Monzr

AU - MacMillan, Margaret

AU - Pawarode, Attaphol

AU - Quagliarella, Francesco

AU - Qayed, Muna

AU - Reshef, Ran

AU - Schechter, Tal

AU - Vasova, Ingrid

AU - Weisdorf, Daniel

AU - Wölfl, Matthias

AU - Young, Rachel

AU - Nakamura, Ryotaro

AU - Ferrara, James L M

AU - Levine, John E

AU - Holtan, Shernan

N1 - © 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

PY - 2024/6/25

Y1 - 2024/6/25

N2 - Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

AB - Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

KW - Humans

KW - Graft vs Host Disease/blood

KW - Interleukin-1 Receptor-Like 1 Protein/blood

KW - Biomarkers/blood

KW - Pancreatitis-Associated Proteins/blood

KW - Algorithms

KW - Male

KW - Female

KW - Middle Aged

KW - Adult

KW - Amphiregulin/blood

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Aged

KW - Prognosis

KW - Antigens, Neoplasm/blood

KW - Acute Disease

KW - Adolescent

KW - Young Adult

U2 - 10.1182/bloodadvances.2023011049

DO - 10.1182/bloodadvances.2023011049

M3 - SCORING: Journal article

C2 - 38640195

VL - 8

SP - 3284

EP - 3292

JO - BLOOD ADV

JF - BLOOD ADV

SN - 2473-9529

IS - 12

ER -