Background: In children busulfan (Bu) is often included in conditioning regimens prior to allogeneic (allo-) haematopoietic stem cell transplantation (HSCT). The IV Bu formulation represents a substantial improvement over the oral Bu form for the control of Bu-systemic drug exposure (AUCs) and for successful targeting, but the age-based dosing (3–4 years cut-off) is not likely to be the optimal strategy (L Nguyen et BMT 2004). We tested IVBu fixed dose body-weight (BW) based calculation combined with cyclophosphamide (Cy) as conditioning regimen prior to allo-HSCT.


  1. To validate and confirm the PK relevance of this new dosing strategy which allows to target AUC (900–1500 μM.min) in children,

  2. To investigate the safety especially the early non-relapse mortality (NRM),

  3. to evaluate the consequences of such IVBu administration modalities upon children clinical outcomes.

Methods: Thirty-six children (21 male/15 female) with a median age and weight of 7.5 y (range 0.3 to 17.2 y) and 27 kg (range 5.0 to 62.0) were enrolled. Indications for HSCT were: AML (n = 17: 14 CR1, 2 CR2, 1 PR), CML (n = 3), ALL (n = 1), MDS (n = 1), SAA (n = 1); hemoglobinopathy (n = 8), and immunodeficiency (n = 5). IVBu (Busilvex®) was given over 2 h q6h × 16 doses at: 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts with <9 kg, 9 to <16 kg, 16–23 kg, >23–34 kg, and >34 kg BW, respectively. Cy was given at 50 mg/kg qd×4. Donors were HLA-matched related (28/36) or unrelated (5/36). Pharmacokinetics (PK) of Bu at dose 1, 9, and 13, and regimen-related toxicity (RRT) were determined. Cumulative incidence (Ci) of relapse / NRM, and Kaplan-Meier EFS/OS were estimated.

Results: PK results are available in 28/36 pts. Although Bu clearance was highly variable (CV= 45%), the average AUCs after 1st and subsequent doses were similar whatever age and BW. In 75 % of pts AUC was within the target AUC. Mean AUC at dose 1 was 1205 ± 187 μM.min (range 963–1619 μM.min). All pts engrafted at 19 days (range 9–47) for neutrophils ≥ 0.5 ×109/L, and 30 days (range 16–111) for platelets ≥ 50 ×109/L. Donor cells (DC) were documented in all recipients: 31/36 achieved complete chimerism (> 99% DC), and 5/36 were mixed chimeras (> 85% DC). IVBu was well tolerated: one grade (G) IV toxicity (pulmonary), G III (mainly stomatitis) occurred in 14 pts. VOD occurred in 8% (95% CI: 1.8–22.5%) but none was severe. Grades II–IV a-GVHD rate was 42%. There was one death (3%) at day+100, and Ci of NRM was 6% ±8% (hemorrhage =1, c-GVHD =1). After a median follow-up of 36.7 months (range 3.9–49.1) the Ci of relapse, EFS and OS rates were: 12% ±11%, 82% ±13%, and 85% ±12%, respectively. For pts with malignancies (mainly AML) the results are excellent: neither VOD nor NRM, and EFS and OS rates were 82% ±16%, and 86% ±14%, respectively.

Conclusions: The new IVBu dosing optimises Bu treatment, confirming that IVBuCy is an efficacious, reduced-toxicity, myeloablative conditioning regimen for children undergoing standard HSCT.

Disclosure: No relevant conflicts of interest to declare.

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