Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation
Abstract
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.
Article Details
Authors (47)
Bernard Ng
1Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Andrew C. Harris
2MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY
Sayeh Abdossamadi
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Geraldine Aubert
4Repeat Diagnostics Inc, North Vancouver, BC, Canada
Rajinder Bajwa
5Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH
Monica Bhatia
6Pediatric Stem Cell Transplant Program, Morgan Stanley Children’s Hospital, Columbia University, New York, NY
Henrique Bittencourt
7Pediatric Hematology-Oncology Division, Saint-Justine University Hospital Centre, Montreal, QC, Canada
Nataliya P. Buxbaum
8Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
Emi H. Caywood
9Nemours Children’s Health, Thomas Jefferson University, Wilmington, DE
Sonali Chaudhury
11Department of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children’s Hospital, Northwestern University, Chicago, IL
Joseph H. Chewning
12Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
Sung Won Choi
13Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI
Ashley Chopek
14Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
Julia Chu
Donald Coulter
16Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE
Shahinaz M. Gadalla
Richard T. Hogg
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
David A. Jacobsohn
18Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
Amanda K. Johnson
19Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, University of Utah/Primary Children’s Hospital, Salt Lake City, UT
Michael Joyce
20Department of Pediatrics, Nemours Children’s Health, Jacksonville, FL
Kimberly A. Kasow
21Department of Pediatric Bone Marrow Transplant, University of North Carolina at Chapel Hill, Chapel Hill, NC
Michael Kent
22Center for Cancer and Blood Disorders, Atrium Health/Levine Children’s Hospital, Charlotte, NC
Carrie L. Kitko
23Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN
Donna Lau
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Anita Lawitschka
24Stem Cell Transplant Unit, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
Victor A. Lewis
25Department of Pediatric Oncology and Transplant, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
Amanda M. Li
British Columbia Children’s Hospital, University of British Columbia, Vancouver
Laura McLaughlin
26Department of Bone Marrow Transplantation and Cellular Therapeutics, Children’s Hospital Colorado, Denver, CO
David Mitchell
Eneida R. Nemecek
28Department of Pediatric Blood and Marrow Transplantation, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR
Vaishnavi Parthasarathy
Anna B. Pawlowska
30Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplant, City of Hope, Duarte, CA
Filip Pirsl
18Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
Michael A. Pulsipher
Muna Qayed
Jacob Rozmus
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Süreyya Savaşan
32Department of Pediatric Hematology and Oncology, Children’s Hospital of Michigan, Detroit, MI
Tal Schechter
33Department of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Central Michigan University, Mount Pleasant, Michigan
Shalini Shenoy
34Department of Pediatric Hematology-Oncology, Saint Louis Children’s Hospital–Washington University School of Medicine, St. Louis, MO
Alima Suleimenova
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Dong Jun Zheng
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Elena Ostroumov
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Andrew Gilman
35Medical Monitoring Support Center, ICON Biotech, Center for Cell and Gene Therapy, Charlotte, NC
Ramon I. Klein Geltink
36Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Daniel Wolff
Geoffrey D. E. Cuvelier
25Department of Pediatric Oncology and Transplant, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
Kirk R. Schultz
3Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada