Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation

Bernard Ng, Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Andrew C. Harris, MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY.
Sayeh Abdossamadi, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Geraldine Aubert, Repeat Diagnostics Inc, North Vancouver, BC, Canada.
Rajinder Bajwa, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.
Monica Bhatia, Pediatric Stem Cell Transplant Program, Morgan Stanley Children's Hospital, Columbia University, New York, NY.
Henrique Bittencourt, Pediatric Hematology-Oncology Division, Saint-Justine University Hospital Centre, Montreal, QC, Canada.
Nataliya P. Buxbaum, Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
Emi H. Caywood, Nemours Children's Health, Thomas Jefferson University, Wilmington, DE.
Sonali Chaudhury, Department of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL.
Joseph H. Chewning, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.
Sung Won Choi, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI.
Ashley Chopek, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
Julia Chu, Pediatric Blood and Marrow Transplant Program, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
Donald Coulter, Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE.
Shahinaz M. Gadalla, Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Richard T. Hogg, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
David A. Jacobsohn, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.
Amanda K. Johnson, Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, University of Utah/Primary Children's Hospital, Salt Lake City, UT.
Michael Joyce, Department of Pediatrics, Nemours Children's Health, Jacksonville, FL.
Kimberly A. Kasow, Department of Pediatric Bone Marrow Transplant, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Michael Kent, Center for Cancer and Blood Disorders, Atrium Health/Levine Children's Hospital, Charlotte, NC.
Carrie L. Kitko, Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN.
Donna Lau, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Anita Lawitschka, Stem Cell Transplant Unit, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
Victor A. Lewis, Department of Pediatric Oncology and Transplant, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
Amanda M. Li, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Laura McLaughlin, Department of Bone Marrow Transplantation and Cellular Therapeutics, Children's Hospital Colorado, Denver, CO.
David Mitchell, Division of Pediatric Hematology-Oncology, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
Eneida R. Nemecek, Department of Pediatric Blood and Marrow Transplantation, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR.
Vaishnavi Parthasarathy, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Anna B. Pawlowska, Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplant, City of Hope, Duarte, CA.

Document Type

Journal Article

Publication Date

1-15-2026

Journal

Blood

Volume

147

Issue

3

DOI

10.1182/blood.2025028625

Abstract

Chronic graft-versus-host-disease (cGVHD) is the primary nonrelapse limitation to a successful hematopoietic cell transplantation and is largely treated as a single biological entity. We hypothesized that there exist different biological subtypes of cGVHD. Using the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) network database, which is derived from the largest pediatric cGVHD cohort worldwide, we applied clustering analysis to subtype patients with cGVHD from the ABLE1.0 and 2.0 studies (51 patients with cGVHD and 158 with non-cGVHD). We found 3 distinct cGVHD subtypes: cGVHD-1 was characterized by an effector memory T-cell, cytotoxic natural killer cell, and early precursor B-cell predominant pattern; cGVHD-2 was phosphatidylcholine, cytokine, and plasma cell predominant; and cGVHD-3 had more naïve CD4+ T cells and naïve regulatory T cells, had later onset, and was the only subtype with measurable T-cell receptor excision circles. We partially replicated these subtypes using metabolomic data from a separate pediatric cohort of the Children's Oncology Group trial ASCT0031 (33 patients with cGVHD and 39 with non-cGVHD). Furthermore, cGVHD-1 was associated with serotherapy (predominantly antithymocyte globulin) exposure, and cGVHD-3 was associated with receiving peripheral blood stem cells from donors, total body irradiation, and no previous acute GVHD. cGVHD-2 was associated with liver involvement and cGVHD-2 and -3 with de novo cGVHD. Overall, none of the subtypes were closely associated with organ involvement. Contrasting each subtype against patients with non-cGVHD, the 3 subtypes shared common markers, all of which were used in our previous cGVHD diagnostic classifier. These findings suggest the presence of distinct biological subtypes of cGVHD that may help guide therapeutic strategies.

Department

Pediatrics

Link to Full Text

Share

COinS