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No impact of CD34+ cell dose on outcome among children undergoing autologous hematopoietic stem cell transplant for high-risk neuroblastoma

Bone Marrow Transplantation volume 58, pages 1390–1393 (2023)Cite this article

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The impact of the autologous graft (autograft) CD34+ cell dose on outcomes among patients undergoing autologous hematopoietic stem cell transplantation (HSCT) for high-risk neuroblastoma is currently unknown. Pediatric transplant physicians regularly have the option to administer CD34+ doses higher than required for hematopoietic recovery, with few published studies to guide practice when surplus CD34+ cells are available. In adult patients undergoing autologous HSCT, higher CD34+ cell doses are associated with improved survival and more rapid neutrophil engraftment [1, 2]. However, infusions of larger grafts may be associated with an increased incidence of endothelial injury complications (EIC), as greater numbers of immune effector cells are infused with the graft [3]. Such complications are mediated by interactions between activated endothelial cells and immune effector cells (IECs) and are a major cause of non-relapse mortality (NRM) [4]. In the current study, we, therefore, sought to determine whether large CD34+ cell doses were advantageous or deleterious by examining the relationship between CD34+ dose and engraftment, relapse rates, EICs, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) in children undergoing autologous HSCT for high-risk neuroblastoma.

Data were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) where all data are de-identified and reported on standardized forms, with patients consenting to the use of their data in research. This study was approved by the National Marrow Donor Program’s Institutional Review Board. Patients included children aged <10 years undergoing autologous peripheral blood transplant (single or tandem) for neuroblastoma in the United States or Canada between 2008 and 2018. Patients were excluded if their CD34+ cell count was not reported, or if their pre-transplant disease status was reported as stable disease (SD), progressive disease (PD), or unknown (UNK). Patients who underwent more than one autologous HSCT were analyzed based on the CD34+ cell dose of their first transplant, with the assumption that CD34+ cell dose was equivalent across all transplants. The primary study endpoint was PFS, with secondary endpoints including time-to-neutrophil-engraftment, EIC incidence, relapse, NRM, and OS. EICs were studied as a composite variable that included VOD/SOS, engraftment syndrome, idiopathic pneumonia syndrome, thrombotic microangiopathy, and diffuse alveolar hemorrhage. The Kaplan-Meier estimator was utilized to calculate OS and PFS. A Cox regression model was built to examine factors associated with relapse, NRM, PFS, and OS. Optimal cut-points for TNC and CD34+ dose were determined using the maximum likelihood method as binary variables (above/below cut-point), for PFS. P-values ≤ 0.05 were considered statistically significant. Analyses were done using SAS version 9.4 (Cary, NC).

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Fig. 1: Outcomes of patients with high-risk neuroblastoma receiving autologous transplant, stratified by CD34+ cell dose (×106/kg).

Data availability

CIBMTR supports accessibility of research in accord with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute (NCI) Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases de-identified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Prior presentations Portions of the data in this manuscript were previously presented as abstracts at the Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR (“Tandem”), April 22nd–26th 2022.

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Acknowledgements

The authors would like to acknowledge the membership of the CIBMTR’s Pediatric Cancer Working Committee for their valuable and insightful input into this manuscript.

Funding

The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research; Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, Gateway for Cancer Research, Pediatric Transplantation and Cellular Therapy Consortium and from the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc.; Adaptimmune; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Allogene; Allovir, Inc.; Amgen, Inc.; Angiocrine; Anthem; Astellas Pharma US; Atara Biotherapeutics; BeiGene; bluebird bio, inc.; Bristol Myers Squibb Co.; CareDx Inc.; CRISPR; CSL Behring; CytoSen Therapeutics, Inc.; Elevance Health; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd.; GlaxoSmithKline; HistoGenetics; Incyte Corporation; Janssen Research & Development, LLC; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc.; Karius; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt Pharmaceuticals; Medexus Pharma; Merck & Co.; Mesoblast; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; MorphoSys; Novartis Pharmaceuticals Corporation; Omeros Corporation; Orca Biosystems, Inc.; Ossium Health, Inc.; Pfizer, Inc.; Pharmacyclics, LLC, An AbbVie Company; Pluristem; PPD Development, LP; Regimmune; Sanofi; Sanofi-Aventis U.S. Inc.; Sobi, Inc.; Stemcyte; Takeda Pharmaceuticals; Talaris Therapeutics; Vertex Pharmaceuticals; Vor Biopharma Inc.; Xenikos BV.

Author information

Authors and Affiliations

  1. Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, USA

    Tristan E. Knight

  2. Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

    Tristan E. Knight & Neel S. Bhatt

  3. Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI, USA

    Kwang Woo Ahn

  4. CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Kwang Woo Ahn, Kyle M. Hebert, Rasha Atshan, Larisa Broglie & Mary Eapen

  5. Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Donna A. Wall

  6. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Kanhatai Chiengthong

  7. King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand

    Kanhatai Chiengthong

  8. Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, USA

    Troy C. Lund

  9. Blood and Cancer Centre, Starship Children’s Hospital, Auckland, New Zealand

    Tim Prestidge

  10. Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Nationwide Children’s Hospital, Columbus, OH, USA

    Hemalatha G. Rangarajan

  11. Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA

    Christopher C. Dvorak

  12. CIBMTR® (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN, USA

    Jeffery J. Auletta

  13. Hematology/Oncology/BMT and Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH, USA

    Jeffery J. Auletta

  14. Atrium Health Levine Children’s, Charlotte, NC, USA

    Michael Kent

  15. Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation, King Hussein Cancer Center, Amman, Jordan

    Hasan Hashem

  16. Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    Julie-An Talano

  17. Department of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, OH, USA

    Seth J. Rotz

  18. Division of Pediatric Hematology, Oncology, and Cellular Therapy, The Children’s Hospital at Montefiore, Bronx, NY, USA

    Ellen Fraint

  19. Department of Pediatrics, University of Cincinnati College of Medicine, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Kasiani C. Myers

  20. Duke-NUS Medical School, Singapore, Singapore

    Wing Leung

  21. Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Akshay Sharma

  22. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Neel S. Bhatt

  23. Duke University Pediatric Transplantation and Cellular Therapy, Durham, NC, USA

    Timothy A. Driscoll

  24. Division of Hematology/Oncology & HSCT, The Center for Cancer and Blood Disorders, Children’s Hospital, Louisiana State University Medical Center, New Orleans, LA, USA

    Lolie C. Yu

  25. Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, British Columbia’s Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada

    Kirk R. Schultz

  26. Aflac Cancer and Blood Disorders Center, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Muna Qayed

  27. Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Larisa Broglie

  28. Mott Children’s Hospital, University of Michigan Medical Center, Ann Arbor, MI, USA

    Gregory A. Yanik

Authors
  1. Tristan E. Knight
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  2. Kwang Woo Ahn
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Contributions

TEK was responsible for designing and writing the study protocol, analyzing data and interpreting results, and writing and editing the manuscript. KWA, KMH, and RA assisted in study protocol design, analyzed the data, designed and created study tables and figures, and provided statistical analysis and support. DAW and KC assisted in the study protocol design and critically reviewed the manuscript and provided formative commentary. TCL, TP, HGR, CCD, JJA, MK, HH, HT, SJR, EF, KCM, WL, AS, NSB, TAD, and LCY critically reviewed the manuscript and provided formative commentary. KRS and MQ assisted in the interpretation of results, critically reviewed the manuscript, and provided formative commentary. LB, ME, and GAY assisted in protocol design, analyzing data and interpreting results, writing and editing the manuscript, and providing formative commentary.

Corresponding author

Correspondence to Larisa Broglie.

Ethics declarations

Competing interests

No funding was secured specifically for this project. Dr. Knight reports partial salary support from Hold’Em for Life Oncology Fellowship, Garron Family Cancer Center Research Fellowship, and BMO Financial Group Oncology Fellowship. Dr. Wall reports steering committee participation for CRISPR/Vertex Pharmaceuticals and Editas Medicine; acting as a study advisor for CRISPR/Vertex Pharmaceuticals and Editas Medicine; acting as a clinical trial site-PI for CRISPR Therapeutics, Vertex Pharmaceuticals, and Novartis; and research funding from CRISPR Therapeutics, Vertex Pharmaceuticals, and Novartis. Dr. Rangarajan reports serving as the BMT Medical Monitor for NMDP (no financial reimbursements); and having served as honorary consultant for Medexus. Dr. Dvorak reports consulting for Jazz Pharma, and Alexion Inc. Dr. Auletta reports employment with National Marrow Donor Program (NMDP); and advisory council participation for Ascella Health. Dr. Talano reports research funding from Miltenyi. Dr. Rotz reports acting as a resource for Clinical Investigation in Blood and Marrow Transplantation (RCI BMT) (employment). Dr. Myers reports research funding for an investigator initiated clinical trial from Incyte and sponsored research from Elixirgen Therapeutics. Dr. Sharma reports consulting for Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, and Sangamo Therapeutics; research funding from CRISPR Therapeutics. Clinical Trial site-PI: CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Magenta Therapeutics, Beam Therapeutics, Honoraria: Vindico Medical Education. Dr. Qayed reports honoraria from Vertex and Novartis.

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Knight, T.E., Ahn, K.W., Hebert, K.M. et al. No impact of CD34+ cell dose on outcome among children undergoing autologous hematopoietic stem cell transplant for high-risk neuroblastoma. Bone Marrow Transplant 58, 1390–1393 (2023). https://doi.org/10.1038/s41409-023-02092-3

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