Busulfan and subsequent malignancy: An evidence‐based risk assessment

Abstract

BackgroundThe 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 nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted.ProcedureWe 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.ResultsWe identified eight pediatric and 13 adult publications describing long‐term follow‐up in 570 pediatric and 2076 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 eight publications evaluating lentiviral‐ and human promotor‐based HSC‐targeted gene therapy in 215 patients with nonmalignant 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.ConclusionThe 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 nonmalignant conditions other than SCD.

Donor Cell Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: A Case Report and Literature Review

“…Some of these postulate the presence of either occult leukemia or a predisposing disorder in the donor, and this seems not to be the case of our patient. Other possible mechanisms lie in the effects of previous myeloablative chemotherapy or irradiation of the patient prior to the HSCT, even if this myeloablative-regiment-related possibility is generally considered low [18]. We cannot postulate a mechanism truly suitable for the development of DCL in our patient; the only tenable statement is that DCL is probably a multifactorial process [1].…”