. 2023 Dec 14;142(24):2105-2118.

doi: 10.1182/blood.2022019586.

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

Jennifer W Leiding^{1

2}, Danielle E Arnold³, Suhag Parikh⁴, Brent Logan⁵, Rebecca A Marsh⁶, Linda M Griffith⁷, Ruizhe Wu⁵, Sharon Kidd⁸, Kanwaldeep Mallhi⁹, Deepak Chellapandian¹⁰, Stephanie J Si Lim¹¹, Eyal Grunebaum^{12

13}, E Liana Falcone^{14

15}, Luis Murguia-Favela¹⁶, Debbi Grossman¹⁵, Vinod K Prasad¹⁷, Jennifer R Heimall¹⁸, Fabien Touzot¹⁹, Lauri M Burroughs⁹, Jack Bleesing⁶, Neena Kapoor²⁰, Jasmeen Dara⁸, Olatundun Williams^{21

22}, Malika Kapadia²³, Benjamin R Oshrine¹⁰, Jeffrey J Bednarski²⁴, Ahmad Rayes²⁵, Hey Chong²⁶, Geoffrey D E Cuvelier²⁷, Lisa R Forbes Satter²⁸, Caridad Martinez²⁹, Mark T Vander Lugt³⁰, Lolie C Yu³¹, Shanmuganathan Chandrakasan⁴, Avni Joshi³², Susan E Prockop^{23

33}, Blachy J Dávila Saldaña³⁴, Victor Aquino³⁵, Larisa A Broglie³⁶, Christen L Ebens³⁷, Lisa M Madden³⁸, Kenneth DeSantes³⁹, Jordan Milner⁴⁰, Hemalatha G Rangarajan⁴¹, Ami J Shah⁴², Alfred P Gillio⁴³, Alan P Knutsen⁴⁴, Holly K Miller⁴⁵, Theodore B Moore⁴⁶, Pamela Graham¹⁵, Andrea Bauchat¹⁷, Nancy J Bunin⁴⁷, Pierre Teira¹⁹, Aleksandra Petrovic⁹, Sharat Chandra⁶, Hisham Abdel-Azim^{20

48}, Morna J Dorsey⁸, Olga Birbrayer²³, Morton J Cowan⁸, Christopher C Dvorak⁸, Elie Haddad¹⁹, Donald B Kohn⁴⁶, Luigi D Notarangelo¹⁵, Sung-Yun Pai³, Jennifer M Puck⁸, Michael A Pulsipher²⁵, Troy R Torgerson⁴⁹, Harry L Malech¹⁵, Elizabeth M Kang¹⁵

Affiliations

¹ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD.
² Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL.
³ National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁴ Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA.
⁵ Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
⁶ Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
⁷ Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
⁸ Pediatric Allergy, Immunology, and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA.
⁹ Fred Hutchinson Cancer Research Center, Department of Pediatrics, University of Washington, and Seattle Children's Hospital, Seattle, WA.
¹⁰ Center for Cell and Gene Therapy for Non-Malignant Conditions, Johns Hopkins All Children's Hospital, St Petersburg, FL.
¹¹ Department of Pediatrics, John A. Burns School of Medicine, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, HI.
¹² Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
¹³ Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁴ Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada.
¹⁵ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
¹⁶ Section of Hematology/Immunology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
¹⁷ Division of Pediatric Transplant and Cellular Therapy, Department of Pediatrics, Duke University Medical Center, Durham, NC.
¹⁸ Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA.
¹⁹ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
²⁰ Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital, Los Angeles, CA.
²¹ Division of Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL.
²² Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Morgan Stanley Children's Hospital, New York-Presbyterian/Columbia University Irving Medical Center, New York, NY.
²³ Division of Hematology-Oncology, Boston Children's Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
²⁴ Washington University, St. Louis Children's Hospital, St. Louis, MO.
²⁵ Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT.
²⁶ UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
²⁷ Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
²⁸ Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX.
²⁹ Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital Center for Gene and Cell Therapy, Houston, TX.
³⁰ Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI.
³¹ Louisiana State University, Children's Hospital, New Orleans, LA.
³² Division of Pediatric Allergy and Immunology, Mayo Clinic, Rochester, MN.
³³ Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁴ Division of Blood and Marrow Transplantation, Children's National Hospital-George Washington University School of Medicine and Health Sciences, Washington, DC.
³⁵ Division of Hematology and Oncology, Department of Pediatrics, UT Southwestern Medical Center Dallas, Dallas, TX.
³⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
³⁷ Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN.
³⁸ Pediatric Bone Marrow Transplant Program, Texas Transplant Institute, San Antonio, TX.
³⁹ American Family Children's Hospital, University of Wisconsin, Madison, WI.
⁴⁰ Hematology and Oncology, Maria Fareri Children's Hospital, New York Medical College, Valhalla, NY.
⁴¹ Nationwide Children's Hospital, Columbus, OH.
⁴² Pediatric Stem Cell Transplantation Program and Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA.
⁴³ Institute for Pediatric Cancer and Blood Disorders, Hackensack University Medical Center, Hackensack, NJ.
⁴⁴ Pediatric Allergy and Immunology, Saint Louis University and SSM Health Cardinal Glennon Children's Hospital, St. Louis, MO.
⁴⁵ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, and The University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
⁴⁶ Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
⁴⁷ Division of Oncology, Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA.
⁴⁸ Cancer Center, Children's Hospital and Medical Center, Loma Linda University School of Medicine, Loma Linda, CA.
⁴⁹ Allen Institute for Immunology, Seattle, WA.

PMID: 37562003
PMCID: PMC10862239
DOI: 10.1182/blood.2022019586

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

Jennifer W Leiding et al. Blood. 2023.

. 2023 Dec 14;142(24):2105-2118.

doi: 10.1182/blood.2022019586.

Authors

Affiliations

¹ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD.
² Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL.
³ National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁴ Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA.
⁵ Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
⁶ Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
⁷ Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
⁸ Pediatric Allergy, Immunology, and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA.
⁹ Fred Hutchinson Cancer Research Center, Department of Pediatrics, University of Washington, and Seattle Children's Hospital, Seattle, WA.
¹⁰ Center for Cell and Gene Therapy for Non-Malignant Conditions, Johns Hopkins All Children's Hospital, St Petersburg, FL.
¹¹ Department of Pediatrics, John A. Burns School of Medicine, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, HI.
¹² Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
¹³ Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁴ Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada.
¹⁵ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
¹⁶ Section of Hematology/Immunology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
¹⁷ Division of Pediatric Transplant and Cellular Therapy, Department of Pediatrics, Duke University Medical Center, Durham, NC.
¹⁸ Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA.
¹⁹ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
²⁰ Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital, Los Angeles, CA.
²¹ Division of Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL.
²² Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Morgan Stanley Children's Hospital, New York-Presbyterian/Columbia University Irving Medical Center, New York, NY.
²³ Division of Hematology-Oncology, Boston Children's Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
²⁴ Washington University, St. Louis Children's Hospital, St. Louis, MO.
²⁵ Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT.
²⁶ UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
²⁷ Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
²⁸ Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX.
²⁹ Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital Center for Gene and Cell Therapy, Houston, TX.
³⁰ Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI.
³¹ Louisiana State University, Children's Hospital, New Orleans, LA.
³² Division of Pediatric Allergy and Immunology, Mayo Clinic, Rochester, MN.
³³ Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁴ Division of Blood and Marrow Transplantation, Children's National Hospital-George Washington University School of Medicine and Health Sciences, Washington, DC.
³⁵ Division of Hematology and Oncology, Department of Pediatrics, UT Southwestern Medical Center Dallas, Dallas, TX.
³⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
³⁷ Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN.
³⁸ Pediatric Bone Marrow Transplant Program, Texas Transplant Institute, San Antonio, TX.
³⁹ American Family Children's Hospital, University of Wisconsin, Madison, WI.
⁴⁰ Hematology and Oncology, Maria Fareri Children's Hospital, New York Medical College, Valhalla, NY.
⁴¹ Nationwide Children's Hospital, Columbus, OH.
⁴² Pediatric Stem Cell Transplantation Program and Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA.
⁴³ Institute for Pediatric Cancer and Blood Disorders, Hackensack University Medical Center, Hackensack, NJ.
⁴⁴ Pediatric Allergy and Immunology, Saint Louis University and SSM Health Cardinal Glennon Children's Hospital, St. Louis, MO.
⁴⁵ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, and The University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
⁴⁶ Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
⁴⁷ Division of Oncology, Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA.
⁴⁸ Cancer Center, Children's Hospital and Medical Center, Loma Linda University School of Medicine, Loma Linda, CA.
⁴⁹ Allen Institute for Immunology, Seattle, WA.

PMID: 37562003
PMCID: PMC10862239
DOI: 10.1182/blood.2022019586

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

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Conflict of interest statement

Conflict-of-interest disclosure: J.W.L. is an employee and shareholder of bluebird bio; a speaker and advisory board member of Horizon Therapeutics and Sobi; and a consultant for Prime Medicine. R.A.M. serves as a section editor for UpToDate and is an advisory board member of Horizon Therapeutics and Sobi. J.R.H. receives research support from Regeneron, CSL-Behring, ADMA, Enzyvant and author royalties from UpToDate. L.M.B. has received clinical trial support from Medac GmbH; is a member of the data safety monitoring board for a clinical trial with Jasper Therapeutics; and has served on an advisory board for Horizon Therapeutics. J.J.B. is an advisory board member of Horizon Therapeutics and Sobi. G.D.E.C. is a consultant for Miltenyi Biotec. L.R.F.S. serves as a consultant for Takeda, Grifols, and ADMA and as an advisory board member for Horizon, CSL-Behring, Enzyvant, and Incyte. S.E.P. receives support for the conduct of sponsored trials through Boston Children’s Hospital from AlloVir, Atara, and Jasper Therapeutics; is a consultant for CellEvolve, Smart Immune, and Regeneron; and has intellectual property related to the development of off-the-shelf viral-specific cytotoxic T lymphocytes, with all rights assigned to Memorial Sloan Kettering Cancer Center. C.C.D. is a consultant for Alexion and Jazz Pharmaceuticals. E.H. is an advisory board member of Octapharma, Takeda, Jasper, Therapeutics, and Rocket Pharma. M.A.P. is an advisory board member for Novartis, Gentibio, bluebird bio, Vertex, Medexus, and Equillium; and has received study support from Miltenyi Biotec and Adaptive. J.M.P. receives royalties from UpToDate and their spouse is an employee of Invitae. H.L.M. is part of a cooperative agreement between NIAID and Prime Medicine. The remaining authors declare no competing financial interests.

Figures

**Figure 1.**
**Infection density, inflammatory disease, and treatment in CT (non-HCT) and HCT-treated patients.** Frequency of total infections (A), CGD infections (B), bacterial infections (C), and fungal infections (D); the use of antibacterial prophylaxis (E), antifungal prophylaxis (F), and IFN-γ (G); the frequency of total inflammatory disease (H) and inflammatory bowel disease (I); and the use of systemic steroids (J) are shown in CT (non-HCT) and HCT-treated patients before HCT and at 1, 2, and 3 to 5 years after HCT. P values compare CT (non-HCT) time point with pre-HCT (HCT baseline), CT with post-HCT time point of 3 to 5 years, and pre-HCT with post-HCT time point of 3 to 5 years.

**Figure 2.**
**Nutrition and growth assessments in CT (non-HCT) and in HCT-treated patients.** Frequency of low albumin level (A), need for supplemental nutrition via GT, NG tube, and TPN (B), weight z score (C), and height z scores (D) are shown in CT (non-HCT) and HCT-treated patients before HCT and 1, 2, and 3 to 5 years after HCT. P values compare CT (non-HCT) time point with pre-HCT (HCT baseline), CT with post-HCT time point of 3 to 5 years, and pre-HCT with post-HCT time point of 3 to 5 years. NG, nasogastric; GT, gastric tube; TPN, total parenteral nutrition NS, not significant.

**Figure 3.**
**GF and/or receipt of second HCT and donor chimerism with time after HCT.** (A) The cumulative incidence of GF and/or receipt of second HCT with 95% CI and (B) myeloid and (C) T-cell donor chimerism after HCT with median and interquartile range are shown.

**Figure 4.**
**OS and EFS after HCT in 240 patients with CGD.** The probability of OS and EFS after HCT with 95% CI (A) are shown. An event was defined as death, GF, or second HCT. The probability of EFS based on baseline performance status (B), EFS based on donor and recipient HLA match (C), OS based on conditioning intensity (D), EFS based on stem cell source (E), and EFS based on history of infection (F) and inflammatory disease (G) in the year before HCT and status at the time of HCT are shown. P values were obtained using log-rank test.

See this image and copyright information in PMC

Comment in

HCT alleviates disease burden in CGD.
Güngör T. Güngör T. Blood. 2023 Dec 14;142(24):2043-2045. doi: 10.1182/blood.2023021538. Blood. 2023. PMID: 38095925 No abstract available.

References

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1. Prince BT, Thielen BK, Williams KW, et al. Geographic variability and pathogen-specific considerations in the diagnosis and management of chronic granulomatous disease. Pediatric Health Med Ther. 2020;11:257–268. - PMC - PubMed
1. Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP. Noninfectious manifestations and complications of chronic granulomatous disease. J Pediatric Infect Dis Soc. 2018;7(suppl_1):S18–s24. - PMC - PubMed
1. LaBere B, Gutierrez MJ, Wright H, et al. Chronic granulomatous disease with inflammatory bowel disease: clinical presentation, treatment, and outcomes from the USIDNET registry. J Allergy Clin Immunol Pract. 2022;10(5):1325–1333.e5. - PMC - PubMed

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Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

Affiliations

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

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Conflict of interest statement

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