International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome - 05/01/22
Doi : 10.1016/j.jaci.2021.04.036
Dimana Dimitrova, MD a, ⁎∗ 
, Zohreh Nademi, MD, PhD b, c, ∗, Maria Elena Maccari, MD d, e, Stephan Ehl, MD d, e, Gulbu Uzel, MD f, Takahiro Tomoda, MD g, Tsubasa Okano, MD g, Kohsuke Imai, MD, PhD h, Benjamin Carpenter, MD i, Winnie Ip, MD j, k, Kanchan Rao, MD l, Austen J.J. Worth, MD, PhD j, k, Alexandra Laberko, MD m, Anna Mukhina, MD m, Bénédicte Néven, MD, PhD n, o, p, Despina Moshous, MD, PhD n, o, p, Carsten Speckmann, MD d, e, Klaus Warnatz, MD e, Claudia Wehr, MD e, q, Hassan Abolhassani, MD, MPH, PhD r, s, Asghar Aghamohammadi, MD s, Jacob J. Bleesing, MD, PhD t, Jasmeen Dara, MD u, Christopher C. Dvorak, MD u, Sujal Ghosh, MD v, Hyoung Jin Kang, MD w, Gašper Markelj, MD x, Arunkumar Modi, MBBS, MPH y, Diana K. Bayer, DO z, Luigi D. Notarangelo, MD f, Ansgar Schulz, MD aa, Marina Garcia-Prat, MD, MSc bb, Pere Soler-Palacín, MD, PhD, MSc bb, Musa Karakükcü, MD cc, Ebru Yilmaz, MD cc, Eleonora Gambineri, MD dd, ee, Mariacristina Menconi, MD ff, Tania N. Masmas, MD, PhD gg, Mette Holm, PhD hh, Carmem Bonfim, MD ii, Carolina Prando, MD, PhD jj, Stephen Hughes, MD, PhD kk, Stephen Jolles, MD, PhD ll, Emma C. Morris, MD, PhD mm, Neena Kapoor, MD nn, Sylwia Koltan, MD oo, Shankara Paneesha, MD pp, Colin Steward, MD, PhD qq, Robert Wynn, MD kk, Ulrich Duffner, MD rr, ss, Andrew R. Gennery, MD b, c, Arjan C. Lankester, MD, PhD tt, Mary Slatter, MD b, c, ‡, Jennifer A. Kanakry, MD a, ⁎, ‡
, Zohreh Nademi, MD, PhD b, c, ∗, Maria Elena Maccari, MD d, e, Stephan Ehl, MD d, e, Gulbu Uzel, MD f, Takahiro Tomoda, MD g, Tsubasa Okano, MD g, Kohsuke Imai, MD, PhD h, Benjamin Carpenter, MD i, Winnie Ip, MD j, k, Kanchan Rao, MD l, Austen J.J. Worth, MD, PhD j, k, Alexandra Laberko, MD m, Anna Mukhina, MD m, Bénédicte Néven, MD, PhD n, o, p, Despina Moshous, MD, PhD n, o, p, Carsten Speckmann, MD d, e, Klaus Warnatz, MD e, Claudia Wehr, MD e, q, Hassan Abolhassani, MD, MPH, PhD r, s, Asghar Aghamohammadi, MD s, Jacob J. Bleesing, MD, PhD t, Jasmeen Dara, MD u, Christopher C. Dvorak, MD u, Sujal Ghosh, MD v, Hyoung Jin Kang, MD w, Gašper Markelj, MD x, Arunkumar Modi, MBBS, MPH y, Diana K. Bayer, DO z, Luigi D. Notarangelo, MD f, Ansgar Schulz, MD aa, Marina Garcia-Prat, MD, MSc bb, Pere Soler-Palacín, MD, PhD, MSc bb, Musa Karakükcü, MD cc, Ebru Yilmaz, MD cc, Eleonora Gambineri, MD dd, ee, Mariacristina Menconi, MD ff, Tania N. Masmas, MD, PhD gg, Mette Holm, PhD hh, Carmem Bonfim, MD ii, Carolina Prando, MD, PhD jj, Stephen Hughes, MD, PhD kk, Stephen Jolles, MD, PhD ll, Emma C. Morris, MD, PhD mm, Neena Kapoor, MD nn, Sylwia Koltan, MD oo, Shankara Paneesha, MD pp, Colin Steward, MD, PhD qq, Robert Wynn, MD kk, Ulrich Duffner, MD rr, ss, Andrew R. Gennery, MD b, c, Arjan C. Lankester, MD, PhD tt, Mary Slatter, MD b, c, ‡, Jennifer A. Kanakry, MD a, ⁎, ‡ a Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md
b Children’s Bone Marrow Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom
c The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
d Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
e Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
f Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
g Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
h Department of Community Pediatrics, Perinatal, and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
i Department of Haematology, University College Hospital National Health Service Trust, London, United Kingdom
j Department of Immunology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom
k University College London Great Ormond Street Institute of Child Health, London, United Kingdom
l Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom
m Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
n Unité d’Immuno-hématologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
o Université de Paris, Paris, France
p Institut Imagine, Paris, France
q Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
r Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
s Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
t Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
u Department of Pediatrics, Division of Allergy, Immunology, Blood and Marrow Transplantation, Benioff Children’s Hospital, University of California San Francisco, San Francisco, Calif
v Department of Pediatric Oncology, Hematology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
w Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Wide River Institute of Immunology, Seoul, Korea
x Department of Allergology, Rheumatology and Clinical Immunology, University Children’s Hospital, University Medical Center, Ljubljana, Slovenia
y University of Arkansas for Medical Sciences Department of Pediatrics, Little Rock, Ark
z Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa
aa Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
bb Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
cc Department of Pediatric Hematology and Oncology, Erciyes University, Kayseri, Turkey
dd Department of “NEUROFARBA”: Section of Child's Health, University of Florence, Florence, Italy
ee Department of Haematology-Oncology: BMT Unit, “Anna Meyer” Children's Hospital, Florence, Italy
ff Unità Operativa Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Pisana Santa Chiara, Pisa, Italy
gg Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Clinic, Copenhagen University Hospital, Copenhagen, Denmark
hh Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
ii Department of Immunology, Hospital Pequeno Principe, Curitiba, Brazil
jj Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
kk Department of Paediatric Immunology, Royal Manchester Children’s Hospital, Manchester, United Kingdom
ll Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
mm Institute of Immunity and Transplantation, University College London, London, United Kingdom
nn Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
oo Department of Pediatric Hematology and Oncology, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
pp Department of Haematology and Stem Cell Transplantation, Birmingham Heartlands Hospital, Birmingham, United Kingdom
qq School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
rr Blood and Bone Marrow Transplantation, Helen DeVos Children's Hospital, Grand Rapids, Mich
ss Department of Pediatrics and Human Development, Spectrum Health and Michigan State University, Grand Rapids, Mich
tt Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
∗Corresponding authors: Dimana Dimitrova, MD, or Jennifer A. Kanakry, MD, Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10-CRC, Room 3-3330, Bethesda, MD 20892.Experimental Transplantation and Immunotherapy BranchNational Cancer InstituteNational Institutes of Health10 Center DriveBuilding 10-CRCRoom 3-3330BethesdaMD20892
Abstract |
Background |
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).
Objectives |
This study sought to characterize HCT outcomes in APDS.
Methods |
Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.
Results |
Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.
Conclusions |
Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency, activated phosphoinositide 3-kinase delta syndrome, lymphoproliferation, allogeneic hematopoietic cell transplantation, graft failure, mTOR inhibitor, serotherapy
Abbreviations used : APDS, CMV, DCI, GF, GFFS, GVHD, HCT, HCT-CI, MAC, MSD, mTOR, mTORi, MUD, OS, PI3K, RIC, RT-MAC, SOS
Plan
| This research was funded in part from the Intramural Program of the National Cancer Institute, National Institutes of Health. The funding source had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication. |
|
| Disclosure of potential conflict of interest: C. C. Dvorak has consulted for Omeros Corp and Alexion, Inc. P. Soler-Palacin has received personal fees from UCB Pharma. S. Jolles has received support from Health and Care Research Wales, CSL Behring, Takeda, LFB, Biotest, Binding Site, Sanofi, GlaxoSmithKline, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex, Pharming, and Octapharma for projects, advisory boards, meetings, studies, speaking, Data Safety and Monitoring Boards, and clinical trials. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2021
Publié par Elsevier Masson SAS.
Vol 149 - N° 1
P. 410 - janvier 2022 Retour au numéro
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