Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality

Abstract

Hepatic venoocclusive disease (HVOD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is a well-recognized dose-limiting toxicity of oral busulfan (Bu)-based preparative regimens. The unpredictable absorption of oral Bu from the gastrointestinal (GI) tract and hepatic first-pass effects have led to the development of an intravenous Bu preparation (i.v. Bu). The purpose of this retrospective comparison was to evaluate the incidence rate of HVOD and the 100-day mortality rate in patients treated with a busulfan/cyclophosphamide (BuCy2) regimen in which either oral Bu or i.v. Bu was administered. Data from 2 similar groups of patients treated between March 1995 and December 1997 were analyzed. Thirty patients were treated with oral Bu (1 mg/kg x 16 doses) at City of Hope and 61 patients were treated with i.v. Bu (0.8 mg/kg x 16 doses) in a multicenter trial involving 7 sites. Bu was followed by Cy (60 mg/kg x 2 days) and a histocompatible-sibling-donor HSCT. In the i.v. Bu treatment group, 48% of the patients were classified as heavily pretreated (> or = 3 prior chemotherapy regimens, prior radiation, or prior HSCT) with 13% having had a prior HSCT and 75% having active disease at the time of transplantation. According to the same classification criteria, 33% of the patients in the oral-Bu treatment group were considered heavily pretreated, with 23% having had a prior HSCT and 80% having active disease at the time of transplantation. The incidence rates of clinically diagnosed HVOD were 5/61 (8%) and 10/30 (33%) after i.v. and oral Bu, respectively. HVOD-related mortality occurred in 2 (3.3%) of 61 i.v. and 6 (20%) of 30 oral Bu patients. The (standardized) Jones criteria for HVOD were met by 4.9% of i.v. and 20% of oral Bu patients. Univariate logistic regression analysis identified oral versus i.v. Bu (P = .001) and a diagnosis of myelodysplastic syndrome (P = .04) as statistically significant factors in the development of HVOD, with prior extensive treatment identified as marginally significant (P = .25). No other demographic parameter was found to be significant. After adjustment for prior treatment, multivariate analyses showed that the use of oral versus i.v. Bu was the strongest predictor for development of HVOD (odds ratio, 7.5; 95% confidence interval, 2.1-27.2; P = .002). This study showed that the incidence rate of HVOD is significantly lower (P = .002) and the 100-day survival rate significantly higher (P = .002) in patients treated with i.v. Bu than in patients treated with oral Bu when Bu is used as part of a BuCy2 preparative regimen for allogeneic HSCT.

Busulfex (i.v. BU) and CY regimen before SCT: Japanese-targeted phase II pharmacokinetics combined study

“…BU showed satisfactory dose assurance with reliable predictability of pharmacokinetics without dose adjustment. 19 Hence, it is very probable that its use reduces the incidence of various risks at transplantation such as hepatic venoocclusive disease (VOD), as shown by Kashyap et al 21 Nevertheless, drug profiles of i.v. BU preparation have not been fully evaluated in different races, who may have different pharmacokinetics.…”

Efficacy of allogeneic and autologous hematopoietic SCT in patients with AML after first complete remission

“…This finding is unsurprising given that the other conditioning regimens, involving radiotherapy and/or chemotherapy, are associated with more pronounced toxicities and side effects. 15,16 Interestingly, we also found that the symptom of fever and the proportion of BM primitive cells were significant predictors of disease-free and overall survival. These are surprising findings that are difficult to explain.…”

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

“…In addition, high BU levels are documented to cause acute chemical hepatitis by depleting glutathione in hepatocytes, and, probably, predisposing to VOD. 17 Hence, i.v. BU was developed to counter the first pass effect of oral leading to much less variability in the pharmacokinetic profile and a decrease in the incidence and severity of VOD.…”

“…(0.8 mg/kg) BU is comparable to oral (1 mg/kg) BU dosage. 17 However, Slattery 24 noted in response that the comparison had failed to account for the differences in BU area under the plasma concentration time curve. The mean area under the curve (AUC) for i.v.…”

“…), the combination (BuCy or BuFlu) and the dosage (high dose or low dose) of BU-based conditioning regimens. [16][17][18] However, no reports have evaluated all the above mentioned factors in a single study. Hence, this study was performed to determine, in a single cohort, outcomes for different BU regimens that differ, based on route of administration (oral or i.v.…”