title: Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy.
abstract: beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease.
authors: Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
authors: Robert
authors: R
authors: Chiesa
authors: Barbara
authors: B
authors: Cappelli
authors: Roberto
authors: R
authors: Crocchiolo
authors: Ilaria
authors: I
authors: Frugnoli
authors: Erika
authors: E
authors: Biral
authors: Anna
authors: A
authors: Noè
authors: Costanza
authors: C
authors: Evangelio
authors: Marco
authors: M
authors: Fossati
authors: Tito
authors: T
authors: Roccia
authors: Alessandra
authors: A
authors: Biffi
authors: Valentina
authors: V
authors: Finizio
authors: Alessandro
authors: A
authors: Aiuti
authors: Monica
authors: M
authors: Broglia
authors: Antonella
authors: A
authors: Bartoli
authors: Fabio
authors: F
authors: Ciceri
authors: Maria Grazia
authors: MG
authors: Roncarolo
authors: Sarah
authors: S
authors: Marktel
mesh_terms: D000293:Adolescent; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008877:Middle East; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome; D017086:beta-Thalassemia / Q000401:mortality / Q000628:therapy*
chemical_list: D007166:Immunosuppressive Agents; D002066:Busulfan