A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study

Geoffrey D. Cuvelier, Pediatric Blood and Marrow Transplantation, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
Bernard Ng, Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
Sayeh Abdossamadi, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
Eneida R. Nemecek, Pediatric Blood and Marrow Transplantation, Doernbechter Children's Hospital, Oregon Health and Sciences University, Portland, OR.
Alexis Melton, Pediatric Blood and Marrow Transplant Program, Benioff Children's Hospital, UC San Francisco, San Francisco, CA.
Carrie L. Kitko, Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN.
Victor A. Lewis, Pediatric Oncology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
Tal Schechter, Pediatric Hematology-Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
David A. Jacobsohn, Division of Blood and Marrow Transplantation, Children's National Hospital, School of Medicine and Health Sciences, The George Washington University, Washington, DC.
Andrew C. Harris, MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY.
Michael A. Pulsipher, Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine, The University of Utah, Salt Lake City, UT.
Henrique Bittencourt, Pediatric Hematology-Oncology, Saint-Justine University Hospital Centre, Montreal, QC, Canada.
Sung Won Choi, Blood and Marrow Transplant Program, Michigan Medicine, University of Michigan, Ann Arbor, MI.
Emi H. Caywood, Nemours Children's Health, Thomas Jefferson University, Wilmington, DE.
Kimberly A. Kasow, Pediatric Bone Marrow Transplant, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Monica Bhatia, Pediatric Stem Cell Transplant Program, Morgan Stanley Children's Hospital, Columbia University, New York, NY.
Benjamin R. Oshrine, Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL.
Sonali Chaudhury, Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL.
Donald Coulter, Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE.
Joseph H. Chewning, Division of Pediatric Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL.
Michael Joyce, Division of Pediatric Hematology-Oncology, Nemours Children's Specialty Care, Jacksonville, FL.
Süreyya Savaşan, Pediatric Hematology & Oncology, Children's Hospital of Michigan, Detroit, MI.
Anna B. Pawlowska, Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplant, City of Hope, Duarte, CA.
Gail C. Megason, Children's Hematology-Oncology, University of Mississippi Medical Center, Jackson, MS.
David Mitchell, Division of Pediatric Hematology-Oncology, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
Alexandra C. Cheerva, Pediatric Hematology, Oncology and Stem Cell Transplantation, Norton Children's Hospital, University of Louisville, Louisville, KY.
Anita Lawitschka, Stem Cell Transplant Unit, St. Anna Children's Hospital, Medical University, Vienna, Austria.
Elena Ostroumov, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
Kirk R. Schultz, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.

Document Type

Journal Article

Publication Date

7-25-2023

Journal

Blood advances

Volume

7

Issue

14

DOI

10.1182/bloodadvances.2022007715

Abstract

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Department

Pediatrics

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