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Busulfan and Subsequent Malignancy: An Evidence-Based Risk Assessment
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  • Janel Long-Boyle,
  • Donald Kohn,
  • Ami Shah,
  • Sueli Marques Spencer,
  • Julian Sevilla,
  • Claire Booth,
  • Jose Luis López-Lorenzo,
  • Eileen Nicoletti,
  • Arpita Shah,
  • Meredith Reatz,
  • Joana Matos,
  • Jonathan Schwartz
Janel Long-Boyle
University of California San Francisco
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Donald Kohn
University of California Los Angeles
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Ami Shah
Lucile Packard Children’s Hospital, Stanford University School of Medicine
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Sueli Marques Spencer
Rocket Pharmaceuticals, Inc.
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Julian Sevilla
Hospital Infantil Universitario Niño Jesús
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Claire Booth
University College London Great Ormond Street Institute of Child Health
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Jose Luis López-Lorenzo
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Hospital Universitario Fundación Jiménez Díaz
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Eileen Nicoletti
Rocket Pharmaceuticals, Inc.
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Arpita Shah
Rocket Pharmaceuticals, Inc.
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Meredith Reatz
Rocket Pharmaceuticals, Inc.
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Joana Matos
Rocket Pharmaceuticals, Inc.
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Jonathan Schwartz
Rocket Pharmaceuticals, Inc.

Corresponding Author:[email protected]

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The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in non-malignant hematologic and related disorders, more precise characterization of busulfan’s potential contribution to subsequent malignant risk is warranted. We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches and selecting those reporting at least 3 years of follow-up. We identified 8 pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2,076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from 8 publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with non-malignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with Sickle Cell Disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12 years. The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for non-malignant conditions other than SCD.
14 Aug 2023Submitted to Pediatric Blood & Cancer
14 Aug 2023Submission Checks Completed
14 Aug 2023Assigned to Editor
21 Aug 2023Review(s) Completed, Editorial Evaluation Pending
22 Aug 2023Reviewer(s) Assigned
11 Sep 2023Editorial Decision: Revise Minor
22 Sep 20231st Revision Received
22 Sep 2023Submission Checks Completed
22 Sep 2023Assigned to Editor
25 Sep 2023Review(s) Completed, Editorial Evaluation Pending
25 Sep 2023Reviewer(s) Assigned