SPECIAL CONSIDERATIONS IN THE DIAGNOSIS AND MANAGEMENT OF CHRONIC GRAFT-VERSUS-HOST DISEASE IN PEDIATRIC PATIENTS
Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for a variety of pediatric hematologic and non-malignant disorders, yet chronic graft-versus-host disease (cGVHD) remains the primary cause of long-term non-relapse morbidity and mortality. The incidence of cGVHD in children has been increasing, a trend associated with the expanded use of peripheral blood stem cells and unrelated donors. Despite generally lower rates than adults, cGVHD remains a significant and growing clinical problem with profound long-term implications for pediatric survivors, who have a much greater life expectancy.
Objective: This review aims to provide a focused and much-needed overview of cGVHD in children. Specifically, it delineates the unique epidemiological, pathobiological, and clinical characteristics that distinguish the disease in this population, including immunological distinctions, diagnostic challenges, and special considerations for long-term effects. This report highlights the pressing questions in treatment and research, addressing the historical lack of specialized data and emphasizing the principle that "children are not small adults" in the context of this complex condition.
Methods: This review was conducted by systematically analyzing and synthesizing peer-reviewed articles, clinical guidelines, and consensus statements related to pediatric cGVHD. A comprehensive literature search was performed across databases including PubMed, Scopus, and Embase using a combination of keywords such as "pediatric," "chronic GvHD," "children," "hematopoietic stem cell transplantation," "management," "diagnosis," and "long-term effects."
Summary: The lower incidence and severity of cGVHD in children are attributable to distinct biological factors, including superior thymic function and a greater use of bone marrow or cord blood grafts. However, diagnostic challenges persist due to non-specific symptoms and the limitations of adult-derived criteria. The profound and age-specific impacts of the disease and its treatments on growth, neurocognitive development, and infectious risk underscore the disproportionate long-term burden on pediatric survivors. The review discusses therapeutic strategies that prioritize steroid-sparing regimens and the integration of novel targeted inhibitors and cellular therapies.
Conclusion: A paradigm shift is necessary, advocating for dedicated pediatric research, age-adapted diagnostic tools, and a multidisciplinary, holistic approach to long-term survivorship care to optimize the functional status and quality of life for children with cGVHD.
References
Baird, K., Cooke, K., & Schultz, K. R. (2010, Feb). Chronic graft-versus-host disease (GVHD) in children. Pediatric Clinics of North America, 57(1), 297-322. https://doi.org/10.1016/j.pcl.2009.11.003
Beer, S. A., Blattel, J., Reuss, K., Maier, C. P., Faul, C., Vogel, W., Bethge, W., & Lengerke, C. (2025, May). Long-term patient-reported outcomes following allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation, 60(5), 617-624. https://doi.org/10.1038/s41409-025-02540-2
Bosi, A., Bartolozzi, B., & Guidi, S. (2005, Jul-Aug). Allogeneic stem cell transplantation. Transplant Proc, 37(6), 2667-2669. https://doi.org/10.1016/j.transproceed.2005.06.087
Cuvelier, G. D. E., Li, A., Drissler, S., Kariminia, A., Abdossamadi, S., Rozmus, J., Chanoine, J. P., Ng, B., Mostafavi, S., Brinkman, R. R., & Schultz, K. R. (2020). "Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation". Frontiers in Immunology, 11, 571884. https://doi.org/10.3389/fimmu.2020.571884
Cuvelier, G. D. E., Nemecek, E. R., Wahlstrom, J. T., Kitko, C. L., Lewis, V. A., Schechter, T., Jacobsohn, D. A., Harris, A. C., Pulsipher, M. A., Bittencourt, H., Choi, S. W., Caywood, E. H., Kasow, K. A., Bhatia, M., Oshrine, B. R., Flower, A., Chaudhury, S., Coulter, D., Chewning, J. H., Joyce, M., Savasan, S., Pawlowska, A. B., Megason, G. C., Mitchell, D., Cheerva, A. C., Lawitschka, A., West, L. J., Pan, B., Al Hamarneh, Y. N., Halevy, A., & Schultz, K. R. (2019, Jul 18). Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria. Blood, 134(3), 304-316. https://doi.org/10.1182/blood.2019000216
Cuvelier, G. D. E., Ng, B., Abdossamadi, S., Nemecek, E. R., Melton, A., Kitko, C. L., Lewis, V. A., Schechter, T., Jacobsohn, D. A., Harris, A. C., Pulsipher, M. A., Bittencourt, H., Choi, S. W., Caywood, E. H., Kasow, K. A., Bhatia, M., Oshrine, B. R., Chaudhury, S., Coulter, D., Chewning, J. H., Joyce, M., Savaşan, S., Pawlowska, A. B., Megason, G. C., Mitchell, D., Cheerva, A. C., Lawitschka, A., Ostroumov, E., & Schultz, K. R. (2023). A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study. Blood Advances, 7(14), 3612-3623. https://doi.org/10.1182/bloodadvances.2022007715
Fujii, H., Cuvelier, G., She, K., Aslanian, S., Shimizu, H., Kariminia, A., Krailo, M., Chen, Z., McMaster, R., Bergman, A., Goldman, F., Grupp, S. A., Wall, D. A., Gilman, A. L., & Schultz, K. R. (2008, Mar 15). Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood, 111(6), 3276-3285. https://doi.org/10.1182/blood-2007-08-106286
Giralt, S., & Bishop, M. R. (2009). Principles and overview of allogeneic hematopoietic stem cell transplantation. Cancer Treat Res, 144, 1-21. https://doi.org/10.1007/978-0-387-78580-6_1
Haroun, E., Agrawal, K., Leibovitch, J., Kassab, J., Zoghbi, M., Dutta, D., & Lim, S. H. (2023, Jul). Chronic graft-versus-host disease in pediatric patients: Differences and challenges. Blood Reviews, 60, 101054. https://doi.org/10.1016/j.blre.2023.101054
Ifversen, M., Meisel, R., Sedlacek, P., Kalwak, K., Sisinni, L., Hutt, D., Lehrnbecher, T., Balduzzi, A., Diesch, T., Jarisch, A., Gungor, T., Stein, J., Yaniv, I., Bonig, H., Kuhlen, M., Ansari, M., Nava, T., Dalle, J. H., Diaz-de-Heredia, C., Trigoso, E., Falkenberg, U., Hartmann, M., Deiana, M., Canesi, M., Broggi, C., Bertaina, A., Gibson, B., Krivan, G., Vettenranta, K., Matic, T., Buechner, J., Lawitschka, A., Peters, C., Yesilipek, A., Yalcin, K., Lucchini, G., Bakhtiar, S., Turkiewicz, D., Niinimaki, R., Wachowiak, J., Cesaro, S., Dalissier, A., Corbacioglu, S., Willasch, A. M., & Bader, P. (2021). Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT). Front Pediatr, 9, 705179. https://doi.org/10.3389/fped.2021.705179
Inagaki, J., Moritake, H., Nishikawa, T., Hyakuna, N., Okada, M., Suenobu, S.-i., Nagai, K., Honda, Y., Shimomura, M., Fukano, R., Noguchi, M., Kurauchi, K., Tanioka, S., & Okamura, J. (2015). Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation, 21(11), 1973-1980. https://doi.org/10.1016/j.bbmt.2015.07.025
Jandin, A., Pochon, C., Campidelli, A., D'Aveni, M., Kicki, C., Notarantonio, A. B., Roth Guepin, G., Mbuyi, T. A., Feugier, P., Chastagner, P., Schweitzer, C., de Carvalho Bittencourt, M., Rubio, M. T., & Pagliuca, S. (2023, Jul). Age-related immune cell dynamics influence outcomes after allogeneic haematopoietic cell transplantation. British Journal of Haematology, 202(1), 122-134. https://doi.org/10.1111/bjh.18822
Janeczko-Czarnecka, M., Rybka, B., Ryczan-Krawczyk, R., KaLwak, K., & Ussowicz, M. (2020). Thymic activity in immune recovery after allogeneic hematopoietic stem cell transplantation in children. Cent Eur J Immunol, 45(2), 151-159. https://doi.org/10.5114/ceji.2019.89843
Keesler, D. A., St Martin, A., Bonfim, C., Seber, A., Zhang, M. J., & Eapen, M. (2018, Dec). Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia. Biology of Blood and Marrow Transplantation, 24(12), 2487-2492. https://doi.org/10.1016/j.bbmt.2018.08.010
Khandelwal, P., Fish, J. D., Gorfinkel, L., Guilcher, G. M. T., Howell, J., Nishitani, M., Nuechterlein, B., Obeng, E., Shah, A. J., Cuvelier, G. D. E., Rotz, S., Williams, K. M., & Duncan, C. N. (2025, May). Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part III. Long-Term Impact of Chronic Graft-versus-Host Disease on Endocrinologic, Cardiovascular, and Metabolic Outcomes in Survivors of Pediatric Hematopoietic Cell Transplantation. Transplant Cell Ther, 31(5), 297 e291-297 e215. https://doi.org/10.1016/j.jtct.2025.01.891
Lawitschka, A., Gueclue, E. D., Januszko, A., Kormoczi, U., Rottal, A., Fritsch, G., Bauer, D., Peters, C., Greinix, H. T., Pickl, W. F., & Kuzmina, Z. (2019). National Institutes of Health-Defined Chronic Graft-vs.-Host Disease in Pediatric Hematopoietic Stem Cell Transplantation Patients Correlates With Parameters of Long-Term Immune Reconstitution. Frontiers in Immunology, 10, 1879. https://doi.org/10.3389/fimmu.2019.01879
Lee, J. W., Lee, D. H., Jang, P. S., Yi, M. S., Chung, N. G., Cho, B., Jeong, D. C., & Kim, H. K. (2011, Sep). Prognostic implications of the NIH consensus criteria in children with chronic graft-versus-host disease. Yonsei Medical Journal, 52(5), 779-786. https://doi.org/10.3349/ymj.2011.52.5.779
Lee, S. J., & Flowers, M. E. D. (2008). Recognizing and Managing Chronic Graft-Versus-Host Disease. Hematology, 2008(1), 134-141. https://doi.org/10.1182/asheducation-2008.1.134
Lin, M., Epport, K., Azen, C., Parkman, R., Kohn, D. B., & Shah, A. J. (2009, Mar). Long-term neurocognitive function of pediatric patients with severe combined immune deficiency (SCID): pre- and post-hematopoietic stem cell transplant (HSCT). Journal of Clinical Immunology, 29(2), 231-237. https://doi.org/10.1007/s10875-008-9250-z
Luo, Y., Yang, P., Yang, Y., He, P., Qin, M., Wang, B., Zhu, G., Jia, C., Yan, Y., Zhou, Y., Wang, R., Wang, A., Zhou, X., & Peng, X. (2019, Sep). Cognitive and psychological outcomes of pediatric allogeneic hematopoietic stem cell transplantation survivors in a single center in China. Medicine (Baltimore), 98(39), e17307. https://doi.org/10.1097/MD.0000000000017307
Lynch, H. E., Goldberg, G. L., Chidgey, A., Van den Brink, M. R., Boyd, R., & Sempowski, G. D. (2009, Jul). Thymic involution and immune reconstitution. Trends in Immunology, 30(7), 366-373. https://doi.org/10.1016/j.it.2009.04.003
Meisel, R., Laws, H.-J., Balzer, S., Bernbeck, B., Kramm, C., Schönberger, S., Sinha, K., Tröger, A., Schmitz, M., Fischer, J., Göbel, U., Enczmann, J., & Dilloo, D. (2007). Comparable Long-Term Survival after Bone Marrow versus Peripheral Blood Progenitor Cell Transplantation from Matched Unrelated Donors in Children with Hematologic Malignancies. Biology of Blood and Marrow Transplantation, 13(11), 1338-1345. https://doi.org/10.1016/j.bbmt.2007.07.009
Milosevic, E., Babic, A., Iovino, L., Markovic, M., Grce, M., & Greinix, H. (2022). Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: A systematic review. Frontiers in Immunology, 13, 1033263. https://doi.org/10.3389/fimmu.2022.1033263
Miskiewicz-Bujna, J., Miskiewicz-Migon, I., Szmit, Z., Przystupski, D., Rosa, M., Krol, A., Kalwak, K., Ussowicz, M., & Gorczynska, E. (2022). Short- and long-term outcome of allogeneic stem cell transplantation in infants: A single-center experience over 20 years. Front Pediatr, 10, 956108. https://doi.org/10.3389/fped.2022.956108
Presland, R. B. (2016, Dec 24). Biology of chronic graft-vs-host disease: Immune mechanisms and progress in biomarker discovery. World J Transplant, 6(4), 608-619. https://doi.org/10.5500/wjt.v6.i4.608
Qayed, M., Wang, T., Hemmer, M. T., Spellman, S., Arora, M., Couriel, D., Alousi, A., Pidala, J., Abdel-Azim, H., Aljurf, M., Ayas, M., Bitan, M., Cairo, M., Choi, S. W., Dandoy, C., Delgado, D., Gale, R. P., Hale, G., Frangoul, H., Kamble, R. T., Kharfan-Dabaja, M., Lehman, L., Levine, J., MacMillan, M., Marks, D. I., Nishihori, T., Olsson, R. F., Hematti, P., Ringden, O., Saad, A., Satwani, P., Savani, B. N., Schultz, K. R., Seo, S., Shenoy, S., Waller, E. K., Yu, L., Horowitz, M. M., & Horan, J. (2018, Mar). Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis. Biol Blood Marrow Transplant, 24(3), 521-528. https://doi.org/10.1016/j.bbmt.2017.11.004
Reynolds, G., Hall, V. G., & Teh, B. W. (2023, Nov). Vaccine schedule recommendations and updates for patients with hematologic malignancy post-hematopoietic cell transplant or CAR T-cell therapy. Transplant Infectious Disease, 25 Suppl 1(Suppl 1), e14109. https://doi.org/10.1111/tid.14109
Sakoda, Y., Hashimoto, D., Asakura, S., Takeuchi, K., Harada, M., Tanimoto, M., & Teshima, T. (2007, Feb 15). Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood, 109(4), 1756-1764. https://doi.org/10.1182/blood-2006-08-042853
Schoemans, H. M., Lee, S. J., Ferrara, J. L., Wolff, D., Levine, J. E., Schultz, K. R., Shaw, B. E., Flowers, M. E., Ruutu, T., Greinix, H., Holler, E., Basak, G., Duarte, R. F., Pavletic, S. Z., Party, E. T. C. W., & the, E.-N. I. H. C. G. T. F. (2018, Nov). EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplantation, 53(11), 1401-1415. https://doi.org/10.1038/s41409-018-0204-7
Schofield, H. T., Fabrizio, V. A., Braniecki, S., Pelletier, W., Eissa, H., Murphy, B., Chewning, J., Barton, K. D., Embry, L. M., Levine, J. E., Schultz, K. R., & Page, K. M. (2022, Oct). Monitoring Neurocognitive Functioning After Pediatric Cellular Therapy or Hematopoietic Cell Transplant: Guidelines From the COG Neurocognition in Cellular Therapies Task Force. Transplant Cell Ther, 28(10), 625-636. https://doi.org/10.1016/j.jtct.2022.06.027
Sobkowiak-Sobierajska, A., Lindemans, C., Sykora, T., Wachowiak, J., Dalle, J. H., Bonig, H., Gennery, A., & Lawitschka, A. (2022). Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan. Front Pediatr, 10, 808103. https://doi.org/10.3389/fped.2022.808103
Sprent, J., & Kishimoto, H. (2002, Jul). The thymus and negative selection. Immunological Reviews, 185, 126-135. https://doi.org/10.1034/j.1600-065x.2002.18512.x
van Lier, Y. F., Vos, J., Blom, B., & Hazenberg, M. D. (2023, Jan-Dec). Allogeneic hematopoietic cell transplantation, the microbiome, and graft-versus-host disease. Gut Microbes, 15(1), 2178805. https://doi.org/10.1080/19490976.2023.2178805
Wall, D. A. (2004, Dec 15). Allogeneic peripheral blood versus bone marrow transplantation: children are small adults and more. Journal of Clinical Oncology, 22(24), 4865-4866. https://doi.org/10.1200/JCO.2004.09.958
Whangbo, J. S., Kim, H. T., Mirkovic, N., Leonard, L., Poryanda, S., Silverstein, S., Kim, S., Reynolds, C. G., Rai, S. C., Verrill, K., Lee, M. A., Margossian, S., Duncan, C., Lehmann, L., Huang, J., Nikiforow, S., Alyea, E. P., 3rd, Armand, P., Cutler, C. S., Ho, V. T., Blazar, B. R., Antin, J. H., Soiffer, R. J., Ritz, J., & Koreth, J. (2019, Sep 10). Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. Blood Adv, 3(17), 2550-2561. https://doi.org/10.1182/bloodadvances.2019000631
Wynn, R., Nataraj, R., Nadaf, R., Poulton, K., & Logan, A. (2022). Strategies for Success With Umbilical Cord Haematopoietic Stem Cell Transplantation in Children With Malignant and Non-Malignant Disease Indications. Front Cell Dev Biol, 10, 836594. https://doi.org/10.3389/fcell.2022.836594
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