Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

Catherine J. Lee; Tao Wang; Karen Chen; Mukta Arora; Ruta Brazauskas; Stephen R Spellman; Carrie Kitko; Margaret L. MacMillan; Joseph A. Pidala; Jeffery J. Auletta; Sherif M. Badawy; Neel Bhatt; Vijaya R. Bhatt; Jean Yves Cahn; Zachariah DeFilipp; Miguel A. Diaz; Nosha Farhadfar; Shahinaz Gadalla; Robert P. Gale; Hasan Hashem; Shahrukh Hashmi; Peiman Hematti; Sanghee Hong; Nasheed M. Hossain; Yoshihiro Inamoto; Lazaros J. Lekakis; Dipenkumar Modi; Sager Patel; Akshay Sharma; Scott Solomon; Daniel R. Couriel

doi:10.1016/j.jtct.2022.07.014

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

Catherine J. Lee, Tao Wang, Karen Chen, Mukta Arora, Ruta Brazauskas, Stephen R Spellman, Carrie Kitko, Margaret L. MacMillan, Joseph A. Pidala, Jeffery J. Auletta, Sherif M. Badawy, Neel Bhatt, Vijaya R. Bhatt, Jean Yves Cahn, Zachariah DeFilipp, Miguel A. Diaz, Nosha Farhadfar, Shahinaz Gadalla, Robert P. Gale, Hasan HashemShahrukh Hashmi, Peiman Hematti, Sanghee Hong, Nasheed M. Hossain, Yoshihiro Inamoto, Lazaros J. Lekakis, Dipenkumar Modi, Sager Patel, Akshay Sharma, Scott Solomon, Daniel R. Couriel

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI,. 73 to 2.31; P =. 38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Original language	English (US)
Pages (from-to)	712.e1-712.e8
Journal	Transplantation and Cellular Therapy
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.jtct.2022.07.014
State	Published - Oct 2022

Bibliographical note

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government.

Funding Information:
The CIBMTR supports accessibility of research in accordance with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR releases only deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: C.J.L. D.R.C. M.A. and S.S. designed, directed, and performed research, analyzed data, and wrote the manuscript; K.C. M.A. and S.S. provided datasets for analysis; T.W. K.C. and R.B. performed statistical analysis; C.K. M.L.M. and J.P. reviewed data and the manuscript; and all authors critically reviewed the data and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 712.e7.

Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy

Keywords

Allogeneic hematopoietic cell transplantation
Children
Chronic GVHD
Hematologic malignancy
Late effects

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtct.2022.07.014

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Cite this

Lee, C. J., Wang, T., Chen, K., Arora, M., Brazauskas, R., Spellman, S. R., Kitko, C., MacMillan, M. L., Pidala, J. A., Auletta, J. J., Badawy, S. M., Bhatt, N., Bhatt, V. R., Cahn, J. Y., DeFilipp, Z., Diaz, M. A., Farhadfar, N., Gadalla, S., Gale, R. P., ... Couriel, D. R. (2022). Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy. Transplantation and Cellular Therapy, 28(10), 712.e1-712.e8. https://doi.org/10.1016/j.jtct.2022.07.014

Lee, CJ, Wang, T, Chen, K, Arora, M, Brazauskas, R, Spellman, SR, Kitko, C, MacMillan, ML, Pidala, JA, Auletta, JJ, Badawy, SM, Bhatt, N, Bhatt, VR, Cahn, JY, DeFilipp, Z, Diaz, MA, Farhadfar, N, Gadalla, S, Gale, RP, Hashem, H, Hashmi, S, Hematti, P, Hong, S, Hossain, NM, Inamoto, Y, Lekakis, LJ, Modi, D, Patel, S, Sharma, A, Solomon, S & Couriel, DR 2022, 'Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy', Transplantation and Cellular Therapy, vol. 28, no. 10, pp. 712.e1-712.e8. https://doi.org/10.1016/j.jtct.2022.07.014

@article{9400d342a8d64403bb69364d70ea9485,

title = "Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy",

abstract = "Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI,. 73 to 2.31; P =. 38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.",

keywords = "Allogeneic hematopoietic cell transplantation, Children, Chronic GVHD, Hematologic malignancy, Late effects",

author = "Lee, {Catherine J.} and Tao Wang and Karen Chen and Mukta Arora and Ruta Brazauskas and Spellman, {Stephen R} and Carrie Kitko and MacMillan, {Margaret L.} and Pidala, {Joseph A.} and Auletta, {Jeffery J.} and Badawy, {Sherif M.} and Neel Bhatt and Bhatt, {Vijaya R.} and Cahn, {Jean Yves} and Zachariah DeFilipp and Diaz, {Miguel A.} and Nosha Farhadfar and Shahinaz Gadalla and Gale, {Robert P.} and Hasan Hashem and Shahrukh Hashmi and Peiman Hematti and Sanghee Hong and Hossain, {Nasheed M.} and Yoshihiro Inamoto and Lekakis, {Lazaros J.} and Dipenkumar Modi and Sager Patel and Akshay Sharma and Scott Solomon and Couriel, {Daniel R.}",

note = "Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. Funding Information: The CIBMTR supports accessibility of research in accordance with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR releases only deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: C.J.L. D.R.C. M.A. and S.S. designed, directed, and performed research, analyzed data, and wrote the manuscript; K.C. M.A. and S.S. provided datasets for analysis; T.W. K.C. and R.B. performed statistical analysis; C.K. M.L.M. and J.P. reviewed data and the manuscript; and all authors critically reviewed the data and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 712.e7. Publisher Copyright: {\textcopyright} 2022 The American Society for Transplantation and Cellular Therapy",

year = "2022",

month = oct,

doi = "10.1016/j.jtct.2022.07.014",

language = "English (US)",

volume = "28",

pages = "712.e1--712.e8",

journal = "Transplantation and Cellular Therapy",

issn = "2666-6367",

publisher = "Elsevier B.V.",

number = "10",

}

TY - JOUR

T1 - Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

AU - Lee, Catherine J.

AU - Wang, Tao

AU - Chen, Karen

AU - Arora, Mukta

AU - Brazauskas, Ruta

AU - Spellman, Stephen R

AU - Kitko, Carrie

AU - MacMillan, Margaret L.

AU - Pidala, Joseph A.

AU - Auletta, Jeffery J.

AU - Badawy, Sherif M.

AU - Bhatt, Neel

AU - Bhatt, Vijaya R.

AU - Cahn, Jean Yves

AU - DeFilipp, Zachariah

AU - Diaz, Miguel A.

AU - Farhadfar, Nosha

AU - Gadalla, Shahinaz

AU - Gale, Robert P.

AU - Hashem, Hasan

AU - Hashmi, Shahrukh

AU - Hematti, Peiman

AU - Hong, Sanghee

AU - Hossain, Nasheed M.

AU - Inamoto, Yoshihiro

AU - Lekakis, Lazaros J.

AU - Modi, Dipenkumar

AU - Patel, Sager

AU - Sharma, Akshay

AU - Solomon, Scott

AU - Couriel, Daniel R.

N1 - Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. Funding Information: The CIBMTR supports accessibility of research in accordance with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR releases only deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies, ADC Therapeutics, Adienne SA, Allogene, Allovir, Amgen, Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, BeiGene, bluebird bio, Bristol Myers Squibb, CareDx, CRISPR, CSL Behring, CytoSen Therapeutics, Eurofins Viracor, DBA Eurofins Transplant Diagnostics, Fate Therapeutics, Gamida-Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Kiadis Pharma; Kite Pharma/Gilead, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt Pharmaceuticals, Medac, Medexus Pharma, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi, Sanofi-Aventis US, Sobi, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Vertex Pharmaceuticals and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: C.J.L. D.R.C. M.A. and S.S. designed, directed, and performed research, analyzed data, and wrote the manuscript; K.C. M.A. and S.S. provided datasets for analysis; T.W. K.C. and R.B. performed statistical analysis; C.K. M.L.M. and J.P. reviewed data and the manuscript; and all authors critically reviewed the data and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 712.e7. Publisher Copyright: © 2022 The American Society for Transplantation and Cellular Therapy

PY - 2022/10

Y1 - 2022/10

N2 - Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI,. 73 to 2.31; P =. 38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

AB - Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI,. 73 to 2.31; P =. 38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

KW - Allogeneic hematopoietic cell transplantation

KW - Children

KW - Chronic GVHD

KW - Hematologic malignancy

KW - Late effects

UR - http://www.scopus.com/inward/record.url?scp=85136151813&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136151813&partnerID=8YFLogxK

U2 - 10.1016/j.jtct.2022.07.014

DO - 10.1016/j.jtct.2022.07.014

M3 - Article

C2 - 35863740

AN - SCOPUS:85136151813

SN - 2666-6367

VL - 28

SP - 712.e1-712.e8

JO - Transplantation and Cellular Therapy

JF - Transplantation and Cellular Therapy

IS - 10

ER -

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

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