A New Busulfan Fixed Dosing for Conditioning before Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children with Malignant and Non-Malignant Diseases: Pharmacokinetics, Toxicity and Clinical Outcomes.

Background: Oral busulfan (Bu) is a standard component of hematopoietic stem cell transplantation (HSCT) regimens in pediatric patients (pts). Bu exposure (AUC) has been correlated with outcomes, thus dose adjustment and therapeutic drug monitoring (TDM) were needed. An IV Bu formulation would allow to target AUC and improve outcomes of HSCT. We previously reported that a new IV Bu fixed dose based on body-weight calculation can successfully target a therapeutic AUC in children without any dose-adjustment and TDM

Methods: Children received Bu/Melphalan (Mel, 140 mg/m²) before autologous (auto-, n=27) or Bu/Cyclophosphamide (Cy, 200 mg/kg) before allogeneic (allo-, n=28) HSCT. Donors were mainly HLA-matched sibling (n=22). IV Bu was administered over 2 h at a dose of 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-< 16 kg, 16–23 kg, >23–34 kg, and >34 kg strata of weight, respectively. PK was performed at doses 1, 9 and 13 but no dose adjustment was allowed. Clonazepam was given as seizures prophylaxis. Indications for HSCT were: high risk neuroblastoma (n= 24), Ewing sarcoma (n=3) for auto-HSCT; AML (n= 14), CML (n= 3), ALL (n=1), MDS (n=1), hemoglobinopathy (n=6), and immunodeficiency (n=3) for allo-HSCT. Median age (range) was 4.0 y (0.7-14.9), and 7.2 y (0.3–17.2) for auto- and allo-HSCT, respectively.

Results: Bu PK analysis demonstrated that 91% of AUCs were in 900–1500 μM. min range, despite a large variability (CV= 50%) on Bu clearance among dose levels. IVBu based BuMel or BuCy regimens were well tolerated. VOD incidence was 15% (95% CI: 4–33.7%) and 7% (95% CI: 0.9–23.5%) in auto- and allo-HSCT recipients, respectively but none was severe. In all pts neutrophils (> 0.5 x 10⁹/L) and platelets (> 50.0 x 10⁹/L) recovery occurred at the expected time. Donor engraftment was documented in all recipients: 26/28 achieved complete chimerism, and 2/28 were mixed chimeras but had mainly donor cells (> 85%). There was no death at Day +100 post-transplant. One patient died due to chronic GVHD at 13 months. Cumulative incidence of TRM was 0% (auto-HSCT) and 3.8% ± 7.6% (allo-HSCT). Median follow-up was 31.6 months (range 20.1–41.2) and 28.0 months (range 18.2–38.2) after auto- and allo-HSCT, respectively. Event-free and overall survivals were as follows: 59% ± 18% and 70% ± 18%, respectively after auto-HSCT; and 85% ± 13% for both probabilities after allo- HSCT.

Conclusions: This new IV Bu fixed dosing can successfully target a therapeutic AUC without any dose-adjustment and TDM and results in a low incidence of transplant-related mortality. Complete chimerism was achieved by 93% of allo-recipients without any case of graft rejection.