Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Muna Qayed; Tao Wang; Michael T. Hemmer; Stephen Spellman; Mukta Arora; Daniel Couriel; Amin Alousi; Joseph Pidala; Hisham Abdel-Azim; Mahmoud Aljurf; Mouhab Ayas; Menachem Bitan; Mitchell Cairo; Sung Won Choi; Christopher Dandoy; David Delgado; Robert Peter Gale; Gregory Hale; Haydar Frangoul; Rammurti T. Kamble; Mohamed Kharfan-Dabaja; Leslie Lehman; John Levine; Margaret MacMillan; David I. Marks; Taiga Nishihori; Richard F. Olsson; Peiman Hematti; Olov Ringden; Ayman Saad; Prakash Satwani; Bipin N. Savani; Kirk R. Schultz; Sachiko Seo; Shalini Shenoy; Edmund K. Waller; Lolie Yu; Mary M. Horowitz; John Horan

doi:10.1016/j.bbmt.2017.11.004

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Muna Qayed, Tao Wang, Michael T. Hemmer, Stephen Spellman, Mukta Arora, Daniel Couriel, Amin Alousi, Joseph Pidala, Hisham Abdel-Azim, Mahmoud Aljurf, Mouhab Ayas, Menachem Bitan, Mitchell Cairo, Sung Won Choi, Christopher Dandoy, David Delgado, Robert Peter Gale, Gregory Hale, Haydar Frangoul, Rammurti T. KambleMohamed Kharfan-Dabaja, Leslie Lehman, John Levine, Margaret MacMillan, David I. Marks, Taiga Nishihori, Richard F. Olsson, Peiman Hematti, Olov Ringden, Ayman Saad, Prakash Satwani, Bipin N. Savani, Kirk R. Schultz, Sachiko Seo, Shalini Shenoy, Edmund K. Waller, Lolie Yu, Mary M. Horowitz, John Horan

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

24 Scopus citations

Abstract

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

Original language	English (US)
Pages (from-to)	521-528
Number of pages	8
Journal	Biology of Blood and Marrow Transplantation
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.bbmt.2017.11.004
State	Published - Mar 2018

Bibliographical note

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455, to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government.

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI) , the National Heart, Lung and Blood Institute (NHLBI) , and the National Institute of Allergy and Infectious Diseases ; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration ; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research ; and grants from * Actinium Pharmaceuticals, Inc. ; Alexion ; * Amgen, Inc. ; Anonymous donation to the Medical College of Wisconsin ; Astellas Pharma US ; AstraZeneca ; Atara Biotherapeutics, Inc. ; Be the Match Foundation ; * Bluebird Bio, Inc. ; * Bristol Myers Squibb Oncology ; * Celgene Corporation ; Cellular Dynamics International, Inc. ; Cerus Corporation ; * Chimerix, Inc. ; Fred Hutchinson Cancer Research Center ; Gamida Cell Ltd. ; Genentech, Inc. ; Genzyme Corporation ; Gilead Sciences, Inc. ; Health Research, Inc. Roswell Park Cancer Institute ; HistoGenetics, Inc. ; Incyte Corporation ; Janssen Scientific Affairs, LLC ; * Jazz Pharmaceuticals, Inc. ; Jeff Gordon Children's Foundation ; The Leukemia & Lymphoma Society ; Medac, GmbH ; MedImmune ; The Medical College of Wisconsin ; * Merck & Co, Inc. ; * Mesoblast ; MesoScale Diagnostics, Inc. ; * Miltenyi Biotec, Inc. ; National Marrow Donor Program ; Neovii Biotech NA, Inc. ; Novartis Pharmaceuticals Corporation ; Onyx Pharmaceuticals ; Optum Healthcare Solutions, Inc. ; Otsuka America Pharmaceutical, Inc. ; Otsuka Pharmaceutical Co, Ltd. – Japan ; PCORI ; Perkin Elmer, Inc. ; Pfizer, Inc ; * Sanofi US ; * Seattle Genetics ; * Spectrum Pharmaceuticals, Inc. ; St. Baldrick's Foundation ; * Sunesis Pharmaceuticals, Inc. ; Swedish Orphan Biovitrum, Inc. ; Takeda Oncology ; Telomere Diagnostics, Inc. ; University of Minnesota ; and * Wellpoint, Inc . This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455 , to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government.

Publisher Copyright:
© 2017 The American Society for Blood and Marrow Transplantation

Keywords

Children
GVHD
Leukemia
Matched sibling donor transplantation
Recipient age

Publisher link

10.1016/j.bbmt.2017.11.004

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826854

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Cite this

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., ... Horan, J. (2018). Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis. Biology of Blood and Marrow Transplantation, 24(3), 521-528. https://doi.org/10.1016/j.bbmt.2017.11.004

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia : Implications for Prophylaxis. / Qayed, Muna; Wang, Tao; Hemmer, Michael T. et al.

In: Biology of Blood and Marrow Transplantation, Vol. 24, No. 3, 03.2018, p. 521-528.

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

Qayed, M, Wang, T, Hemmer, MT, Spellman, S, Arora, M, Couriel, D, Alousi, A, Pidala, J, Abdel-Azim, H, Aljurf, M, Ayas, M, Bitan, M, Cairo, M, Choi, SW, Dandoy, C, Delgado, D, Gale, RP, Hale, G, Frangoul, H, Kamble, RT, Kharfan-Dabaja, M, Lehman, L, Levine, J, MacMillan, M, Marks, DI, Nishihori, T, Olsson, RF, Hematti, P, Ringden, O, Saad, A, Satwani, P, Savani, BN, Schultz, KR, Seo, S, Shenoy, S, Waller, EK, Yu, L, Horowitz, MM & Horan, J 2018, 'Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis', Biology of Blood and Marrow Transplantation, vol. 24, no. 3, pp. 521-528. https://doi.org/10.1016/j.bbmt.2017.11.004

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title = "Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis",

abstract = "Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.",

keywords = "Children, GVHD, Leukemia, Matched sibling donor transplantation, Recipient age",

author = "Muna Qayed and Tao Wang and Hemmer, {Michael T.} and Stephen Spellman and Mukta Arora and Daniel Couriel and Amin Alousi and Joseph Pidala and Hisham Abdel-Azim and Mahmoud Aljurf and Mouhab Ayas and Menachem Bitan and Mitchell Cairo and Choi, {Sung Won} and Christopher Dandoy and David Delgado and Gale, {Robert Peter} and Gregory Hale and Haydar Frangoul and Kamble, {Rammurti T.} and Mohamed Kharfan-Dabaja and Leslie Lehman and John Levine and Margaret MacMillan and Marks, {David I.} and Taiga Nishihori and Olsson, {Richard F.} and Peiman Hematti and Olov Ringden and Ayman Saad and Prakash Satwani and Savani, {Bipin N.} and Schultz, {Kirk R.} and Sachiko Seo and Shalini Shenoy and Waller, {Edmund K.} and Lolie Yu and Horowitz, {Mary M.} and John Horan",

note = "Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455, to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government. Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI) , the National Heart, Lung and Blood Institute (NHLBI) , and the National Institute of Allergy and Infectious Diseases ; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration ; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research ; and grants from * Actinium Pharmaceuticals, Inc. ; Alexion ; * Amgen, Inc. ; Anonymous donation to the Medical College of Wisconsin ; Astellas Pharma US ; AstraZeneca ; Atara Biotherapeutics, Inc. ; Be the Match Foundation ; * Bluebird Bio, Inc. ; * Bristol Myers Squibb Oncology ; * Celgene Corporation ; Cellular Dynamics International, Inc. ; Cerus Corporation ; * Chimerix, Inc. ; Fred Hutchinson Cancer Research Center ; Gamida Cell Ltd. ; Genentech, Inc. ; Genzyme Corporation ; Gilead Sciences, Inc. ; Health Research, Inc. Roswell Park Cancer Institute ; HistoGenetics, Inc. ; Incyte Corporation ; Janssen Scientific Affairs, LLC ; * Jazz Pharmaceuticals, Inc. ; Jeff Gordon Children's Foundation ; The Leukemia & Lymphoma Society ; Medac, GmbH ; MedImmune ; The Medical College of Wisconsin ; * Merck & Co, Inc. ; * Mesoblast ; MesoScale Diagnostics, Inc. ; * Miltenyi Biotec, Inc. ; National Marrow Donor Program ; Neovii Biotech NA, Inc. ; Novartis Pharmaceuticals Corporation ; Onyx Pharmaceuticals ; Optum Healthcare Solutions, Inc. ; Otsuka America Pharmaceutical, Inc. ; Otsuka Pharmaceutical Co, Ltd. – Japan ; PCORI ; Perkin Elmer, Inc. ; Pfizer, Inc ; * Sanofi US ; * Seattle Genetics ; * Spectrum Pharmaceuticals, Inc. ; St. Baldrick's Foundation ; * Sunesis Pharmaceuticals, Inc. ; Swedish Orphan Biovitrum, Inc. ; Takeda Oncology ; Telomere Diagnostics, Inc. ; University of Minnesota ; and * Wellpoint, Inc . This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455 , to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government. Publisher Copyright: {\textcopyright} 2017 The American Society for Blood and Marrow Transplantation",

year = "2018",

month = mar,

doi = "10.1016/j.bbmt.2017.11.004",

language = "English (US)",

volume = "24",

pages = "521--528",

journal = "Biology of Blood and Marrow Transplantation",

issn = "1083-8791",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia

T2 - Implications for Prophylaxis

AU - Qayed, Muna

AU - Wang, Tao

AU - Hemmer, Michael T.

AU - Spellman, Stephen

AU - Arora, Mukta

AU - Couriel, Daniel

AU - Alousi, Amin

AU - Pidala, Joseph

AU - Abdel-Azim, Hisham

AU - Aljurf, Mahmoud

AU - Ayas, Mouhab

AU - Bitan, Menachem

AU - Cairo, Mitchell

AU - Choi, Sung Won

AU - Dandoy, Christopher

AU - Delgado, David

AU - Gale, Robert Peter

AU - Hale, Gregory

AU - Frangoul, Haydar

AU - Kamble, Rammurti T.

AU - Kharfan-Dabaja, Mohamed

AU - Lehman, Leslie

AU - Levine, John

AU - MacMillan, Margaret

AU - Marks, David I.

AU - Nishihori, Taiga

AU - Olsson, Richard F.

AU - Hematti, Peiman

AU - Ringden, Olov

AU - Saad, Ayman

AU - Satwani, Prakash

AU - Savani, Bipin N.

AU - Schultz, Kirk R.

AU - Seo, Sachiko

AU - Shenoy, Shalini

AU - Waller, Edmund K.

AU - Yu, Lolie

AU - Horowitz, Mary M.

AU - Horan, John

N1 - Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455, to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government. Funding Information: Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI) , the National Heart, Lung and Blood Institute (NHLBI) , and the National Institute of Allergy and Infectious Diseases ; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration ; Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research ; and grants from * Actinium Pharmaceuticals, Inc. ; Alexion ; * Amgen, Inc. ; Anonymous donation to the Medical College of Wisconsin ; Astellas Pharma US ; AstraZeneca ; Atara Biotherapeutics, Inc. ; Be the Match Foundation ; * Bluebird Bio, Inc. ; * Bristol Myers Squibb Oncology ; * Celgene Corporation ; Cellular Dynamics International, Inc. ; Cerus Corporation ; * Chimerix, Inc. ; Fred Hutchinson Cancer Research Center ; Gamida Cell Ltd. ; Genentech, Inc. ; Genzyme Corporation ; Gilead Sciences, Inc. ; Health Research, Inc. Roswell Park Cancer Institute ; HistoGenetics, Inc. ; Incyte Corporation ; Janssen Scientific Affairs, LLC ; * Jazz Pharmaceuticals, Inc. ; Jeff Gordon Children's Foundation ; The Leukemia & Lymphoma Society ; Medac, GmbH ; MedImmune ; The Medical College of Wisconsin ; * Merck & Co, Inc. ; * Mesoblast ; MesoScale Diagnostics, Inc. ; * Miltenyi Biotec, Inc. ; National Marrow Donor Program ; Neovii Biotech NA, Inc. ; Novartis Pharmaceuticals Corporation ; Onyx Pharmaceuticals ; Optum Healthcare Solutions, Inc. ; Otsuka America Pharmaceutical, Inc. ; Otsuka Pharmaceutical Co, Ltd. – Japan ; PCORI ; Perkin Elmer, Inc. ; Pfizer, Inc ; * Sanofi US ; * Seattle Genetics ; * Spectrum Pharmaceuticals, Inc. ; St. Baldrick's Foundation ; * Sunesis Pharmaceuticals, Inc. ; Swedish Orphan Biovitrum, Inc. ; Takeda Oncology ; Telomere Diagnostics, Inc. ; University of Minnesota ; and * Wellpoint, Inc . This work is supported in part by the National Center for Advancing Translational Sciences (Grants UL1TR000454 and KL2TR000455 , to M.Q.). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration A) or any other agency of the US Government. Publisher Copyright: © 2017 The American Society for Blood and Marrow Transplantation

PY - 2018/3

Y1 - 2018/3

N2 - Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

AB - Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

KW - Children

KW - GVHD

KW - Leukemia

KW - Matched sibling donor transplantation

KW - Recipient age

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EP - 528

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

IS - 3

ER -

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

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