Favorable Outcome Of Hematopoietic Stem Cell Transplantation Using a Targeted Once-Daily IV Busulfan Fludarabine Etoposide Regimen In Pediatric and Infant ALL Patients

Conditioning regimens for pediatric acute lymphoblastic leukemia (ALL) usually include total body irradiation (TBI), but TBI may result in serious sequelae such as growth impairment, endocrinologic and metabolic problem, and secondary malignancies. Busulfan based conditioning regimen with cyclophosphamide has been used as an alternative to TBI based regimen in many diseases including pediatric ALL. Etoposide has been widely used in hematopoietic stem cell transplantation (HSCT) for lymphoid and myeloid malignancy because of its anti-leukemic effect, and a conditioning regimen containing busulfan, cyclophosphamide and etoposide (BuCyVP) was used in many studies including pediatric patients. But, toxicities have been reported in some studies using BuCyVP regimen. Recently, a reduced toxicity myeloablative regimen using busulfan and fludarabine showed promising results. Also, therapeutic drug monitoring (TDM) and administration of targeted dose of busulfan has been recommended to improve the outcome of HSCT. In this study, we evaluated the outcome of HSCT using a targeted once-daily intravenous (IV) busulfan fludarabine etoposide (BuFluVP) regimen in pediatric and infant ALL. The conditioning regimen was composed of busulfan, fludarabine (40 mg/m² once daily i.v. on days -8 ∼ -3) and etoposide (20 mg/kg once daily i.v. on days -4 ∼ -2). Busulfan (≥ 1 year-120 mg/m² and < 1 year-80 mg/m²) was administered once daily as the first dose on day -8, and targeted dose of busulfan was used according to the TDM results on day -7 ∼ -5. A total of 33 patients were evaluated. Donor-type neutrophil engraftment was achieved in all patients. Veno-occlusive disease occurred in 5 (15.2%) patients, but all of them were successfully treated. Grade II-IV acute GVHD developed in 11 patients (grade 2 in 9 patients, grade 3 in 1 and grade 4 in 1 patient) and the cumulative incidence was 33.6%. Chronic GVHD developed in 3 patients (2 extensive and 1 limited). Three patients died of treatment-related mortality (TRM) and the cumulative incidence was 9.1%. The causes of TRM were adenoviral pneumonia in 1, respiratory syncytial viral (RSV) pneumonia in 1 and interstitial lung disease in 1 patient. Relapse occurred in 3 patients and cumulative incidence was 9.1%. Overall survival (OS) and event free survival (EFS) of all patients were 84.9% and 81.8%, respectively. EFS showed no difference according to the type of HSCT (77.8% in related BMT/PBSCT, 82.4% in unrelated BMT/PBSCT, and 85.7% in CBT, P=0.95). Eleven patients (33.3%) were infants at diagnosis, and OS of these patients was 81.8%. Our study demonstrated that HSCT using a targeted once-daily IV BuFluVP regimen showed favorable outcome and could be one option for HSCT in pediatric and infant ALL.