Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy.
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.
Chiesa
Robert
R
Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
Cappelli
Barbara
B
Crocchiolo
Roberto
R
Frugnoli
Ilaria
I
Biral
Erika
E
Noè
Anna
A
Evangelio
Costanza
C
Fossati
Marco
M
Roccia
Tito
T
Biffi
Alessandra
A
Finizio
Valentina
V
Aiuti
Alessandro
A
Broglia
Monica
M
Bartoli
Antonella
A
Ciceri
Fabio
F
Roncarolo
Maria Grazia
MG
Marktel
Sarah
S
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*
D007166:Immunosuppressive Agents; D002066:Busulfan