Association Between Busulfan First-Dose Pharmacokinetics and Outcome in Children Receiving Myeloablative Busulfan-Based Conditioning Before Unrelated Umbilical Cord Blood Transplantation for Malignancies

Abstract 4143

Myeloablative unrelated cord blood transplantation (MAC-UCBT) is an alternative to transplant in children with acute leukemia or myelodisplastic syndrome (MDS) when a donor is not available. Intravenous (iv) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used and is associated with higher EFS, lower transplant-related mortality (TRM) and toxicity. Even if iv Bu has a more predictable bioavailability comparing with oral Bu, there is still an important variation in Bu pharmacokinetics (PK) between patients that may cause treatment failure and toxicity.

In order to analyze the impact of PK parameters of the first iv Bu dose on the different outcomes of MAC-UCBT for acute leukemia and MDS, we analyzed 34 consecutive transplants performed in children between dec/2000 and dec/2011. Patients or parents provided an informed consent. Median age at transplant was 5.9 (0.6–19) years, and 19 (56%) were male. There were 20 AML, 2 ALL and 12 MDS. A total of 10 and 12 patients with acute leukemia were transplanted in first remission (CR1), second remission (CR2)/advanced phase of disease, respectively. Thirty-one patients received a single UCBT. Eight, and twelve patients received a 6/6, or 5/6HLA-matched graft. Median infused nucleated cells and CD34+ cells were 5.5 × 10^⋀7/kg and 2.1 × 10^⋀5/kg, respectively. Cyclosporin A and steroids were used as graft versus host disease (GvHD) prophylaxis for all patients and 33 patients received ATG. Conditioning regimen consisted of first-dose PK-adapted Bu (targeted steady-state concentration - Css - between 600–900 ng/ml) and Cy 200 mg/kg (n=30), Melphalan 135 mg/m2 (n=2) or Cy 120 mg/kg and etoposide 30 mg/kg (n=2). Median follow-up was 36 months. After iv Bu first dose, median Css was 555 ng/ml, AUC was 188,901 min*ng/ml and clearance was 4.61 ml/min/kg. Cumulative incidence (CI) of neutrophil (>0.5×10^⋀9/L) at D+60 and platelet recovery (>50×10^⋀9/L) at D+150 were both 87%. Median time to neutrophil and platelet recovery was 20 days and 67 days, respectively. There were six primary or secondary graft failure. CI of acute GVHD grade II-IV at D+180 was 16%. There were two cases of VOD. Five-years CI of transplant-related mortality (TRM) was 12%. CI of relapse at 5 years was 25%. Estimated event-free survival (EFS) at 5 years was 49%. Estimated overall survival (OS) at 5 years was 64%. First dose Css significantly influenced neutrophil recovery (100% vs. 70% for Css < and > 600 ng/ml, respectively - P=0.002), TRM (0% vs. 27% for Css < and > 600 ng/ml, respectively - P=0.02), EFS (73% vs. 18% for Css < and > 600 ng/ml, respectively- P<0.001) and OS (82% vs. 43% for Css < and > 600 ng/ml, respectively - P=0.005). There was no influence of Css on the incidence of platelet recovery, grade 2–4 aGVHD or relapse.

In conclusion, first dose iv Bu PK seems to be a significant prognostic factor after UCBT for malignancies in children, influencing neutrophil recovery, TRM, EFS and OS. A direct toxic effect of Bu and/or a synergistic toxic effect with Cy might explain the worst outcome when first dose iv Bu has a Css higher than 600 ng/ml. It will be important to validate these results in a multicentre study and also to compare these results with patients that received a fixed dose of Bu. Finally, our data reinforces the importance of Bu therapeutic drug monitoring-guided dosing in pediatric HSCT patients.