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Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network

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Abstract

Purpose

Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS).

Methods

Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression.

Results

We identified 507 patients (66% CYBB mutants) diagnosed in 1953–2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1 years after diagnosis (0–45.8 years). OS was negatively associated with CYBB mutation (HR = 6.25; p = 0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR = 1.26; p = 0.65). Transplant at ≤ 14 years old was associated with improved TRS (93% v. 82% at T + 60 months) (HR = − 4.51; p = 0.035). Patients transplanted before 15 years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p = 0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p = 0.0010). Compared to non-HSCT patients ≥ 15 years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p = 0.0039) and lower frequency of disability (11% v. 52%; p = 0.014).

Conclusion

Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15 years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

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Acknowledgements

The United States Immunodeficiency Network (USIDNET) is supported by a cooperative agreement, U24AI86837, from the National Institute of Allergy and Infectious Diseases (NIAID)/National Institute of Health (NIH), which has been awarded to the Immune Deficiency Foundation.

The authors would like to thank the USIDNET Steering Committee (Dr. Charlotte Cunningham-Rundles, Dr. Luigi Notarangelo, and Dr. Jennifer Puck) and Marla Goldsmith (Registry Manager) for their contributions to this work.

Authorship Contributions

All coauthors have reviewed this manuscript and have contributed in a substantive and intellectual manner to this work.

Funding

The USIDNET is supported by a cooperative agreement (U24AI86837) from the National Institute of Allergy and Infectious Diseases (NIAID)/NIH, which has been awarded to the Immune Deficiency Foundation.

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Authors and Affiliations

  1. Cleveland Medical Center, Department of Pediatric Hematology-Oncology, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave., Cleveland, OH, 44106, USA

    Jennifer R. Yonkof, Ashish Gupta & Jignesh Dalal

  2. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Wood Bldg., Rm. WG-82P, 2109 Adelbert Rd., Cleveland, OH, 44106, USA

    Pingfu Fu

  3. National Institutes of Health, National Human Genome Research Institute, Bldg. 10/10C-103, MSC 1611, 10 Center Dr., Bethesda, MD, 20892, USA

    Elizabeth Garabedian

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Correspondence to Jignesh Dalal.

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Fig. S1

Kaplan-Meier estimate of post-diagnosis survival in CYBB mutants, compared by hematopoietic stem cell transplant (HCT) status. (PNG 103 kb)

High-resolution image (EPS 26 kb)

Fig. S2

Kaplan-Meier estimate of post-diagnosis survival in patients born between 2003 and 2016, compared by hematopoietic stem cell transplant (HSCT) status. (PNG 89 kb)

High-resolution image (EPS 22 kb)

Fig. S3

Kaplan-Meier estimate of post-diagnosis survival in CYBB mutants v. non-CYBB mutants S-PLUS (TIBCO Software Inc.) was used to create Figs. 1, 2, S1, S2, and S3. (PNG 105 kb) Microsoft Excel (Microsoft Inc.) was used to create Fig. 3.

High-resolution image (EPS 27 kb)

ESM 1

(DOCX 28 kb)

Appendix

Appendix

Table 5 Institutions and the number of CGD patients diagnosed in 1953–2016
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Yonkof, J.R., Gupta, A., Fu, P. et al. Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network. J Clin Immunol 39, 448–458 (2019). https://doi.org/10.1007/s10875-019-00635-2

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