Abstract
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.