Phase II study of dose‐modified busulfan by real‐time targeting in allogeneic hematopoietic stem cell transplantation for myeloid malignancy

Abstract

We aimed to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation with targeted oral busulfan (BU) and cyclophosphamide (CY) in a phase II study. Busulfan (1.0 mg/kg) was given initially in six doses. Based on the estimated concentration at steady state after the first dose of BU, subsequent (7th-16th) doses were adjusted to obtain a targeted overall concentration at steady state of 700-900 ng/mL. The primary endpoint was 1-year overall survival (OS). Fifty patients were registered and 46 (median age, 53 years; range, 18-62 years) received planned transplant, including 24 with AML, 16 with myelodysplastic syndrome, and six with CML. Fourteen patients were categorized as standard risk. Nineteen patients received transplant from human leukocyte antigen-identical siblings, 27 from unrelated donors. The BU dose required reduction in 32 patients and escalation in six patients. One-year OS was 65% (95% confidence interval, 50-77%). Cumulative incidence of hepatic sinusoidal obstruction syndrome was 11%. One-year transplant-related mortality was 18%. Both OS and transplantrelated mortality were favorable in this study, including patients of older age and with high risk diseases. Individual dose adjustment based on BU pharmacokinetics was feasible and effective in the current phase II study. This trial is registered in the University Hospital Medical Information Network Clinical Trial Registry System (UMIN-CTR, ID:C000000156). (Cancer Sci 2012; 103: 1688-1694 B usulfan is an alkylating agent widely used in high-dose chemotherapy regimens for HSCT.(1,2) The BU level in serum has been shown to be an important factor for graft rejection and regimen-related toxicity such as SOS.(3-5) Unfavorable profiles of oral BU include delayed and variable absorptive characteristics and high variability in drug metabolism.(6) Individualized dose adjustment of BU using the LSM, and its transplantation results, have been investigated widely in Caucasian patients and pediatric populations, but few prospective studies have investigated results in Asian patients.(7) Prior to the current study, we carried out a prospective PK study to analyze BU concentration using gas chromatography-mass spectrometry. (8) Nine patients were enrolled in the study, and received preparative regimen containing oral BU 1 mg/kg every 6 h for eight or 16 doses. Out of nine patients, only three met the average steady-state plasma concentration levels in the safety range of 650-1000 ng/mL (4,9) after the first and 13th dose. From the results, we developed LSM to estimate the AUC using two different formulas in order to fit even delayed clearance. Subsequently, we carried out a pilot study that used the same targeting method as the current study, and six patients with myeloid malignancy received tBU+CY conditioning with a targeting AUC of Css 700-900 ng/mL. Four patients received dose reduction after the seventh dose of BU, and overall Css of three patients met the safety range of 786-905 ng/mL (Akio Kohno, Mariko Fukumoto, Hiroto Nari...

The Incidence and Severity of Oral Mucositis among Allogeneic Hematopoietic Stem Cell Transplantation Patients: A Systematic Review

“…A total of 20 were included based on the strict selection criteria outlined and were categorized according to conditioning regimen or GVHD prophylaxis (Tables 3-7). Seven of these studies included regimens that fit with more than 1 of our predefined categories [22][23][24]26,28,30,32] and 2 of these studies [23,26] included regimens that fell under 3 of our categories. Because of the lack of randomized controlled trials focusing on OM as the primary outcome and heterogeneity of scales used to measure OM, a meta-analysis could not be performed; however, pooled analysis indicated significant differences in incidence of OM with respect to different conditioning regimens.…”

Risk factors and implications of oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation

“…Oral mucositis (OM) is among the most common and debilitating toxicities of hematopoietic stem cell transplantation (HSCT) . Depending on the conditioning intensity, graft‐versus‐host disease (GVHD) prophylaxis regimen, and other factors, OM may be experienced by up to 60%‐100% of transplantation recipients .…”

FLT3 Inhibitors as Maintenance Therapy Post Hematopoietic Cell Transplantation for Acute Myeloid Leukemia (AML): A Systematic Review and Meta-Analysis

“…The main outcomes were the hazard ratio (HR) for overall survival (OS, de ned as time from inclusion in the study until death. [29,30]), non-relapse mortality (NRM, the deaths in the absence of persistent relapse [31]), the leukemia-free survival (LFS, the survival in a state of continuous complete remission [32]) and cumulative incidence of relapse (CIR, calculated from the date of CR to the rst relapse [33]). If HRs are not available, we calculated them from the available statistics according to Tierney and colleagues [34].…”