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Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency

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Abstract

ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive. Three received unconditioned bone marrow transplants from human leukocyte antigen (HLA)-matched siblings and achieved stable mixed donor-recipient T cell chimerism but low B cell (4–9 %) and absent to near-absent myeloid donor engraftment. Despite this, all three have normal immunoglobulin levels, have developed specific protective antibody responses to post-HSCT vaccinations, and have discontinued immunoglobulin replacement. Five patients received myeloablative conditioning (three T cell-depleted haploidentical and two unrelated cord blood) and have full donor chimerism for T and B cells and myeloid lineages. One patient experienced primary graft failure after serotherapy only. CD8 T cell count is normal in 5/8, high in 1/8, and low in 2/8. Infectious complications in 5/5 and autoimmune thrombocytopenia in one patient resolved post-HSCT. Mitogen proliferation to phytohemagglutinin was normal after HSCT in 8/8 patients. In total, seven have discontinued immunoglobulin replacement. In conclusion, HSCT using a variety of graft sources and approaches, including unconditioned matched sibling donor transplant, is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function and resolution of clinical problems.

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Abbreviations

AdV:

Adenovirus

ALC:

Absolute lymphocyte count

ANC:

Absolute neutrophil count

CMV:

Cytomegalovirus

FTT:

Failure to thrive

GI:

Gastrointestinal

GVHD:

Graft-versus-host disease

HLA:

Human leukocyte antigen

HSCT:

Hematopoietic stem cell transplant

ITP:

Immune thrombocytopenia purpura

IVIg:

Intravenous immunoglobulin

PBSCs:

Peripheral blood stem cells

PHA:

Phytohemagglutinin

PIDTC:

Primary Immune Deficiency Treatment Consortium

PJP:

Pneumocystis jiroveci

RSV:

Respiratory syncytial virus

SCID:

Severe combined immunodeficiency

TCR:

T cell receptor

TRECs:

T cell receptor excision circles

ZAP70:

Zeta chain-associated protein of 70 kDa

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Acknowledgments

We would like to thank Dr. Teresa Zelinski for performing the ZAP70 genetic testing and providing helpful suggestions on the manuscript. We would also like to thank the patients and their families who participated in this study. There was no funding for this study.

Authors’ Contributions

GC designed the study, collected the data, and had primary responsibility for the writing of the manuscript. TR summated the data, created tables, and helped with the writing and editing of the manuscript, including intellectual input into the interpretation. DW helped with writing and editing of the manuscript, including intellectual input into the interpretation. MS designed the study, collected the data, and helped with the writing and editing of the manuscript, including intellectual input into the interpretation.

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Authors and Affiliations

  1. Manitoba Blood and Marrow Transplant Program, Division of Pediatric Hematology-Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada

    Geoffrey D. E. Cuvelier, Donna A. Wall & Marlis L. Schroeder

  2. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada

    Geoffrey D. E. Cuvelier, Tamar S. Rubin, Donna A. Wall & Marlis L. Schroeder

  3. CancerCare Manitoba, ON2011-675 McDermot Avenue, Winnipeg, Manitoba, R3E 0V9, Canada

    Geoffrey D. E. Cuvelier

  4. Division of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada

    Tamar S. Rubin

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  1. Geoffrey D. E. Cuvelier
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  2. Tamar S. Rubin
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  4. Marlis L. Schroeder
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Correspondence to Geoffrey D. E. Cuvelier.

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The authors declare that they have no conflicts of interest.

Ethical Approval

This project was approved by the Health Research Ethics Board at the University of Manitoba. As a retrospective study, formal consent of participants was not required.

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Cuvelier, G.D.E., Rubin, T.S., Wall, D.A. et al. Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency. J Clin Immunol 36, 713–724 (2016). https://doi.org/10.1007/s10875-016-0316-z

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  • DOI: https://doi.org/10.1007/s10875-016-0316-z

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