Pharmacokinetics of a Test Dose of Intravenous Busulfan Guide Dose Modifications to Achieve an Optimal Area Under the Curve of a Single Daily Dose of Intravenous Busulfan in Children Undergoing a Reduced-Intensity Conditioning Regimen with Hematopoietic Stem Cell Transplantation

AbstractWe studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 μmol·min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 μmol·min. The median test dose AUC was 953 μmol·min (range, 439-1315 μmol·min). The median AUC of single daily doses was 3798 μmol·min (range, 1511-7254 μmol·min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children

Excellent local tumor control regardless of extent of surgical resection after treatment on the Chicago Pilot II protocol for neuroblastoma.

BACKGROUND: Our aim was to investigate the impact of the extent of surgical resection on local recurrence and survival in high-risk patients treated with the Chicago Pilot II protocol. METHODS: Retrospective chart review was performed on 30 patients enrolled in the Chicago Pilot II protocol between 1995 and 2003. Variables studied were location of tumor, extent of resection, timing and location of recurrence, MYCN amplification, surgical complications, event-free survival, and overall survival (OS). Operative reports and postoperative meta-iodobenzylguanidine scans were used to assess extent of resection. Complete resection (CR) was defined as no gross residual tumor including primary and nodal disease. RESULTS: Three-year event-free survival and OS of this cohort of 30 patients was 58% and 82%, respectively. Only 1 patient developed a local recurrence, whereas metastatic recurrent disease was observed in 13 (43%) of the 30; and this subset had a significantly worse OS (23% vs 94%, P = .001). The most common relapse location was in bone. Patients with incomplete resection (IR) (11/30) and CR (19/30) had recurrence rates of 64% (7/11) and 32% (6/19, P = .12), respectively. Event-free survival was significantly better for patients with CR (68%) vs IR (27%; P = .05; odds ratio, 2.9). Overall survival rates for patients with CR vs IR were 68% vs 55%, respectively (P = .25). CONCLUSIONS: Recurrence rate was the significant determinant of survival. Patients with CR had lower recurrence rates; however, they did not have improved local control. Final outcome of patients with unfavorable neuroblastoma will be determined by metastatic recurrence, not by extent of resection