A prognostic score for acute graft-versus-host disease based on biomarkers: A multicentre study

John E. Levine, Thomas M. Braun, Andrew C. Harris, Ernst Holler, Austin Taylor, Holly Miller, John Magenau, Daniel J. Weisdorf, Vincent T. Ho, Javier Bolaños-Meade, Amin M. Alousi, James L M Ferrara

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

Background: Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately defi ne risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to defi ne clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers. Methods: Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the fi nal two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3a) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identifi ed thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD. Findings: In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality signifi cantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001). Interpretation: Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy.

Original languageEnglish (US)
Pages (from-to)e21-e29
JournalThe Lancet Haematology
Volume2
Issue number1
DOIs
StatePublished - 2015

Bibliographical note

Funding Information:
This study was supported by grant numbers P01CA039542, R21CA173459, and P30CA046592 from the National Cancer Institute, number U10HL069294 from the National Heart, Lung, and Blood Institute, the National Cancer Institute and the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, the Judith Devries Fund, and by contributions from Eisai Inc, Hospira Inc, Roche Laboratories Inc, and Immunex Corporation, a wholly owned subsidiary of Amgen Inc. This report was prepared with BMTCTN 0302 and BMTCTN 0802 Research Materials obtained from the NHLBI Biologic Specimen and Data Repository and the Information Coordinating Center, and the repository operated by the NMDP. It does not necessarily reflect the opinions or views of the BMTCTN 0302 or 0802 protocol teams or the NIH.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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