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An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia

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Abstract

Purpose

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton’s tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients.

Methods

XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes.

Results

In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50–95%), and the 1-year discontinuation rate of IgRT was 89%.

Conclusion

Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.

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Data Availability

The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.

Abbreviations

XLA:

X-linked agammaglobulinemia

BTK:

Bruton’s tyrosine kinase

Ig:

Immunoglobulin

IgRT:

Immunoglobulin replacement therapy

CLD:

Chronic lung disease

HCT:

Hematopoietic cell transplantation

OS:

Overall survival

EFS:

Event-free survival

PBSC:

Peripheral blood stem cell

RT-MAC:

Reduced toxicity myeloablative conditioning

RIC:

Reduced intensity conditioning

Flu:

Fludarabine

Treo:

Treosulfan

BU:

Busulfan

GVHD:

Graft-versus-host disease

PTCY:

Post-transplantation cyclophosphamide

IEI:

Inborn errors of immunity

IBD:

Inflammatory bowel disease

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Acknowledgements

We would like to thank the patients, families, and Ms. Sawako Ito (Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University) for support of the ethical review.

Funding

This work was supported by MEXT/JSPS KAKENHI (Grant Number: 22K07887) to HK and Medical Research Council (UKRI) (Grant Number: MR/W01677X/1) to VB. IM is a Senior Clinical Investigator at the Research Foundation (EBD-D8974-FKM) - Flanders. She is supported by the KU Leuven C1 Grant C16/18/007, by the FWO Grant G0E8420N, G0B5120N, and by the Jeffrey Modell Foundation. IM and MA are members of the ERN-RITA European Reference Network.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Akira Nishimura & Tomohiro Morio

  2. Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India

    Ramya Uppuluri, Revathi Raj & Venkateswaran Vellaichamy Swaminathan

  3. Institute of Hematology, People’s Hospital, Peking University, Beijing, China

    Yifei Cheng

  4. Pediatric Blood and Marrow Transplant Program, Nationwide Children’s Hospital, Columbus, OH, USA

    Rolla F. Abu-Arja

  5. Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

    Bin Fu

  6. Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Alexandra Laberko

  7. Department of Pediatrics, Dr von Hauner Children’s Hospital, University Hospital, LMU, Munich, Germany

    Michael H. Albert & Fabian Hauck

  8. Department of Pediatrics, University Hospital Leuven, Leuven, Belgium

    Giorgia Bucciol & Isabelle Meyts

  9. Department of Immunology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    Venetia Bigley & Suzanne Elcombe

  10. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Venetia Bigley

  11. Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, India

    Gaurav Kharya

  12. Childhood Cancer Center, Skåne University Hospital, Lund, Sweden

    Cornelis Jan H Pronk

  13. Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany

    Claudia Wehr & Klaus Warnatz

  14. Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France

    Bénédicte Neven

  15. Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany

    Klaus Warnatz

  16. Department of Immunology, University Hospital Zurich, Zurich, Switzerland

    Klaus Warnatz

  17. Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium

    Isabelle Meyts

  18. Translational and Clinical Research Institute, Newcastle University, and Paediatric Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, UK

    Andrew R. Gennery

  19. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Hirokazu Kanegane

Authors
  1. Akira Nishimura
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  2. Ramya Uppuluri
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  3. Revathi Raj
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  4. Venkateswaran Vellaichamy Swaminathan
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  5. Yifei Cheng
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  6. Rolla F. Abu-Arja
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  7. Bin Fu
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  8. Alexandra Laberko
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  9. Michael H. Albert
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  10. Fabian Hauck
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  11. Giorgia Bucciol
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  12. Venetia Bigley
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  14. Gaurav Kharya
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  15. Cornelis Jan H Pronk
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  16. Claudia Wehr
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  17. Bénédicte Neven
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  18. Klaus Warnatz
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  19. Isabelle Meyts
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  20. Tomohiro Morio
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  21. Andrew R. Gennery
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  22. Hirokazu Kanegane
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Contributions

AN and HK wrote the manuscript, and AG edited the manuscript. FH, IM, and TM supervised this study. AN, RU, RR, VVS, YC, RFA, BF, AL, MA, GB, AG, VB, SE, GK, CJP, BN, KW, CW, and HK established diagnoses, collected clinical data, and subedited the manuscript. HK conceptualized the study.

Corresponding author

Correspondence to Hirokazu Kanegane.

Ethics declarations

Ethics Approval

This study was conducted in accordance with the Helsinki Declaration and approved by the ethics boards of the Tokyo Medical and Dental University (M2021-040).

Consent to Participate

Informed consent was obtained from all patients and their parents included in this study.

Competing Interests

The authors declare no competing interests.

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Nishimura, A., Uppuluri, R., Raj, R. et al. An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia. J Clin Immunol 43, 1827–1839 (2023). https://doi.org/10.1007/s10875-023-01551-2

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