Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation

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.

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Publication Details

Journal
Blood
Published
2025-10-08
DOI
https://doi.org/10.1182/blood.2025028625
Citations
3
Primary Topic
Hematopoietic Stem Cell Transplantation
Type
article
Field-Weighted Citation Impact
5.31

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article

Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation

Donald W. Coulter, Rajinder Bajwa, Jacob Rozmus, Michael A. Pulsipher et al.
3 citations
Blood
Hematopoietic Stem Cell Transplantation
5.31
article

Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation

Donald W. Coulter, Rajinder Bajwa, Jacob Rozmus, Michael A. Pulsipher, Vaishnavi Parthasarathy, Geoff D.E. Cuvelier, Ashley Chopek, Nataliya P. Buxbaum, Andrew L. Gilman, Michael L. Kent, Kimberly A. Kasow, Süreyya Savaşan, Andrew C. Harris, Dennis H. Lau, Emi Caywood, Monica Bhatia, Eneida R. Nemecek, Robert S. Hogg, Muna Qayed, Daniel Wolff, Tal Schechter, Laura McLaughlin, Sayeh Abdossamadi, Dong Jun Zheng, Victor Lewis, Ánita Lawitschka, Geraldine Aubert, Amanda Johnson, Sung Won Choi, Filip Pirsl, Bernard Ng, Kirk R. Schultz, Amanda M. Li, Shalini Shenoy, Ramon I. Klein Geltink, Carrie L. Kitko, David A. Jacobsohn, Shahinaz M. Gadalla, Sonali Chaudhury, Anna Pawłowska, Joseph H. Chewning, David Mitchell, Elena Ostroumov, Julia Chu, Henrique Bittencourt, Michael Joyce, Alima Suleimenova
article en
3 citations

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.

BloodVol. 147(3)
Intermountain Healthcare (US), University of North Carolina at Chapel Hill (US), Roswell Park Comprehensive Cancer Center (US), Lurie Children's Hospital (US), Morgan Stanley Children's Hospital (US), National Institutes of Health (US), City Of Hope National Medical Center (US), Nationwide Children's Hospital (US), National Marrow Donor Program (US), St. Louis Children's Hospital (US), Primary Children's Hospital (US), Alfred I. duPont Hospital for Children (US), Memorial Sloan Kettering Cancer Center (US), Children's National (US), University of British Columbia (CA), Thomas Jefferson University (US), Emory University (US), Central Michigan University (US), Oregon Health & Science University (US), University of California, San Francisco (US), Wayne State University (US), Washington University in St. Louis (US), University of Utah (US), University of Michigan (US), Montreal Children's Hospital (CA), Huntsman Cancer Institute (US), Hospital for Sick Children (CA), Alberta Children's Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), University Hospital Regensburg (DE), University of Alabama at Birmingham (US), CancerCare Manitoba (CA), Gene Therapy Laboratory (FR), Children's Hospital Colorado (US), Levine Cancer Institute (US), Cell Biotech (South Korea) (KR), Nemours Children's Health System (US), City of Hope (US), Center for Cancer and Blood Disorders (US), Michigan United (US), Aflac (United States) (US), Michigan Medicine (US), National Cancer Institute (UA), St Anna Children's Hospital (AT), Lurie Children's Hospital (US), Levine Children's Hospital (US), Children's Hospital of Michigan (US), UCSF Benioff Children's Hospital (US), Allen Institute (US), National Cancer Institute (US), Children's Healthcare of Atlanta (US), CS Diagnostics (DE), BC Children's Hospital (CA), Doernbecher Children's Hospital (US), Nemours Children's Clinic (US), Department of Health and Human Services (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Nebraska Medical Center (US), Columbia University (US), Vanderbilt University Medical Center (US), University of Colorado Denver (US)
Pfizer, Sanofi, Incyte, National Institutes of Health, Canadian Institutes of Health Research, National Cancer Institute
Openalex Percentile: Top 4%
Hematopoietic Stem Cell Transplantation
5.31
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