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. 2024 Jun 25;8(12):3284-3292.
doi: 10.1182/bloodadvances.2023011049.

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

Aaron Etra  1 , Najla El Jurdi  2 , Nikolaos Katsivelos  1 , Deukwoo Kwon  3 , Stephanie Gergoudis  1 , George Morales  1 , Nikolaos Spyrou  1 , Steven Kowalyk  1 , Paibel Aguayo-Hiraldo  4 , Yu Akahoshi  1 , Francis Ayuk  5 , Janna Baez  1 , Brian C Betts  2 , Chantiya Chanswangphuwana  6 , Yi-Bin Chen  7 , Hannah Choe  8 , Zachariah DeFilipp  7 , Sigrun Gleich  9 , Elizabeth Hexner  10 , William J Hogan  11 , Ernst Holler  9 , Carrie L Kitko  12 , Sabrina Kraus  13 , Monzr Al Malki  14 , Margaret MacMillan  2 , Attaphol Pawarode  15 , Francesco Quagliarella  16 , Muna Qayed  17 , Ran Reshef  18 , Tal Schechter  19 , Ingrid Vasova  20 , Daniel Weisdorf  2 , Matthias Wölfl  21 , Rachel Young  1 , Ryotaro Nakamura  14 , James L M Ferrara  1 , John E Levine  1 , Shernan Holtan  2
Affiliations

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

Aaron Etra et al. Blood Adv. .

Abstract

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.

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Conflict of interest statement

Conflict-of-interest disclosure: B.C.B. is a coinventor of a CD83 CAR T cell licensed to CRISPR Therapeutics; received consulting fees from CTI BioPharma and Incyte; received research funding from Vitrac Therapeutics and CTI BioPharma; and is the current Director of Laboratory Science for American Society of Transplantation and Cellular Therapy. Y-B.C. received consulting fees from Incyte, Takeda, Vor Biopharma, Celularity, Equilium, and Pharmacosmos. H.C. received consulting fees from Incyte, Sanofi, Actinium, and REGiMMUNE, and research funding from Opna. C.L.K. received consulting fees from Horizon Therapeutics. M.A.M. received consulting fees from NexImmune, TScan, Hansa Biopharma, Stemline Therapeutics, CarDx, and Incyte; participated in a speakers’ bureau for Sanofi; and received research funding from NexImmune and Gilead. M.Q. received honoraria from Novartis and Vertex. R.R. received consulting fees from Atara Biotherapeutics, Allogene, Gilead Sciences, Takeda, Incyte, Instil Bio, TScan, Synthekine, Orca, Quell Therapeutics, Capstan, and Jasper; served in an expert witness role with Bayer; and received research funding from Atara Biotherapeutics, Incyte, Sanofi, Immatics, AbbVie, TCR2, Takeda, Gilead Sciences, CareDx, TScan, Synthekine, Bristol Myers Squibb, Johnson & Johnson, Genentech, and Precision BioSciences. T.S. received consulting fees from Moderna. J.L.M.F. and J.E.L. are coinventors of a GVHD biomarker patent and receive royalties from its licensure. J.E.L. received consulting fees from bluebird bio, Editas, Equillium, Incyte, Inhibrx, Kamada, Mesoblast, Sanofi, and X4 Pharmaceuticals, and research support from Genentech, Incyte, and Mesoblast. S.H. received consulting fees from Ossium Health; fees for clinical trial adjudication from CSL Behring; and research funding from Vitrac Therapeutics and Incyte. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Twelve-month NRM by risk classification for AREG and ST2 + REG3α biomarker algorithms (validation cohort). Pie charts show the proportion of patients classified as high-risk (HR, red border) and low-risk (LR, blue border). The proportions correctly classified as HR or LR are shaded in red and blue, respectively. The proportion incorrectly classified is shaded in gray. The cumulative incidence curves show the 12-month NRM, with shaded regions representing 95% confidence intervals. (A and B): All validation cohort patients (C and D): systemically treated subset. (A) ST2 + REG3α: NRM 39% vs 10%, P < .001; (B) AREG: NRM 29% vs 11%, P < .001; (C) ST2 + REG3α: NRM 39% vs 12%, P < .001; (D) AREG: NRM 31% vs 13%, P < .001.
Figure 2.
Figure 2.
Twelve-month NRM by Minnesota risk and further stratification using ST2 + REG3α and AREG algorithms in the validation cohort. The cumulative incidence curves show 12-month NRM with shaded regions representing the 95% confidence intervals. (A) Minnesota high-risk acute GVHD: NRM, 42%. (B) Minnesota high-risk stratified by ST2 + REG3α: NRM 45% vs 24%, P = .083; (C) Minnesota high-risk stratified by AREG: 50% vs 8%, P = .013. (D) Minnesota standard-risk acute GVHD: NRM, 15%. (E) Minnesota standard risk stratified ST2 + REG3α: NRM 34% vs 9%, P < .001; (F) Minnesota standard risk-stratified by AREG: NRM 21% vs 11%, P = .003.
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