Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

doi:10.1016/j.jaci.2018.12.1010

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

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Abstract

Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow–derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Original language	English
Pages (from-to)	2238-2253
Number of pages	16
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	6
DOIs	https://doi.org/10.1016/j.jaci.2018.12.1010
Publication status	Published - 1 Jun 2019

Keywords

CD40 ligand
hematopoietic stem cell transplantation
primary immunodeficiency
X-linked hyper-IgM syndrome

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10.1016/j.jaci.2018.12.1010

ferruaFinal published version, 2.22 MBLicence: CC BY-NC-ND

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@article{14dac99c1c6849729932147f083750d3,

title = "Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study",

abstract = "Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow–derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.",

keywords = "CD40 ligand, hematopoietic stem cell transplantation, primary immunodeficiency, X-linked hyper-IgM syndrome",

author = "Francesca Ferrua and Stefania Galimberti and Virginie Courteille and Slatter, {Mary Anne} and Claire Booth and Despina Moshous and Benedicte Neven and Stephane Blanche and Marina Cavazzana and Alexandra Laberko and Anna Shcherbina and Dmitry Balashov and Elena Soncini and Fulvio Porta and Hamoud Al-Mousa and Bandar Al-Saud and Hasan Al-Dhekri and Rand Arnaout and Renata Formankova and Yves Bertrand and Andrzej Lange and Joanne Smart and Beata Wolska-Kusnierz and Aquino, {Victor M.} and Dvorak, {Christopher C.} and Anders Fasth and Fanny Fouyssac and Carsten Heilmann and Manfred Hoenig and Catharina Schuetz and Jadranka Kele{\v c}i{\'c} and Bredius, {Robbert G.M.} and Lankester, {Arjan C.} and Lindemans, {Caroline A.} and Felipe Suarez and Sullivan, {Kathleen E.} and Albert, {Michael H.} and Krzysztof Ka{\l}wak and Vincent Barlogis and Monica Bhatia and Victoria Bordon and Wojciech Czogala and Laura Alonso and Figen Dogu and Jolanta Gozdzik and Aydan Ikinciogullari and Gergely Kriv{\'a}n and Per Ljungman and Isabelle Meyts and Boelens, {Jaap Jan}",

note = "Funding Information: F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. We thank data managers of the different centers for their support in data collection. We are grateful to all medical and nurse personnel of the participating clinical and transplant centers for patients' care. We are indebted to all the patients and their families for their participation in the study and trust. F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jun,

day = "1",

doi = "10.1016/j.jaci.2018.12.1010",

language = "English",

volume = "143",

pages = "2238--2253",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "6",

}

TY - JOUR

T1 - Hematopoietic stem cell transplantation for CD40 ligand deficiency

T2 - Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

AU - Ferrua, Francesca

AU - Galimberti, Stefania

AU - Courteille, Virginie

AU - Slatter, Mary Anne

AU - Booth, Claire

AU - Moshous, Despina

AU - Neven, Benedicte

AU - Blanche, Stephane

AU - Cavazzana, Marina

AU - Laberko, Alexandra

AU - Shcherbina, Anna

AU - Balashov, Dmitry

AU - Soncini, Elena

AU - Porta, Fulvio

AU - Al-Mousa, Hamoud

AU - Al-Saud, Bandar

AU - Al-Dhekri, Hasan

AU - Arnaout, Rand

AU - Formankova, Renata

AU - Bertrand, Yves

AU - Lange, Andrzej

AU - Smart, Joanne

AU - Wolska-Kusnierz, Beata

AU - Aquino, Victor M.

AU - Dvorak, Christopher C.

AU - Fasth, Anders

AU - Fouyssac, Fanny

AU - Heilmann, Carsten

AU - Hoenig, Manfred

AU - Schuetz, Catharina

AU - Kelečić, Jadranka

AU - Bredius, Robbert G.M.

AU - Lankester, Arjan C.

AU - Lindemans, Caroline A.

AU - Suarez, Felipe

AU - Sullivan, Kathleen E.

AU - Albert, Michael H.

AU - Kałwak, Krzysztof

AU - Barlogis, Vincent

AU - Bhatia, Monica

AU - Bordon, Victoria

AU - Czogala, Wojciech

AU - Alonso, Laura

AU - Dogu, Figen

AU - Gozdzik, Jolanta

AU - Ikinciogullari, Aydan

AU - Kriván, Gergely

AU - Ljungman, Per

AU - Meyts, Isabelle

AU - Boelens, Jaap Jan

N1 - Funding Information: F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. We thank data managers of the different centers for their support in data collection. We are grateful to all medical and nurse personnel of the participating clinical and transplant centers for patients' care. We are indebted to all the patients and their families for their participation in the study and trust. F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2019 The Authors

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow–derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

AB - Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow–derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

KW - CD40 ligand

KW - hematopoietic stem cell transplantation

KW - primary immunodeficiency

KW - X-linked hyper-IgM syndrome

UR - http://www.scopus.com/inward/record.url?scp=85063982597&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2018.12.1010

DO - 10.1016/j.jaci.2018.12.1010

M3 - Article

C2 - 30660643

AN - SCOPUS:85063982597

SN - 0091-6749

VL - 143

SP - 2238

EP - 2253

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

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