Busulfan-cyclophosphamide versus cyclophosphamide-busulfan as conditioning regimen before allogeneic hematopoietic cell transplantation: a prospective randomized trial

Abstract

Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.

Impact of busulfan pharmacokinetics on outcome in adult patients receiving an allogeneic hematopoietic cell transplantation

“…The differences in Bu_PK seen in this study here, seem to benefit CyBu over BuCy. In a previous randomized trial analyzing the hepatic toxicity of CyBu versus BuCy, we found that CyBu had a lower NRM even though pharmacokinetics did not differ according to conditioning regimen [ 21 ], but the population was smaller and differed slightly because it was not limited to myeloid neoplasm. Hassan et al conducted a study on 36 patients who received BuCy and showed that a short time interval <24 h between Bu and Cy could lower the Cy clearance and therefore increase incidence of hepatic toxicity and mucositis [ 22 ], this time interval was respected in our study.…”

“…In young patients (<55 years) with few co-morbidities, CyBu or BuCy regimen was preferred with Bu given for 4 days, followed or preceded by i.v. Cyclophosphamide for 2 days as published [ 21 ], with a time interval >24 h between the two drugs [ 22 ]. TBF was given to patients with HLA haploidentical or high-risk one-antigen mismatched unrelated donors, consisting of Thiotepa 2 days, followed by Bu and Fludarabine for 2 days.…”

“…The resulting AUC and concentration at steady state (Css) were calculated using the trapezoidal rule and permit to deduce Bu clearance (Bu/AUC). The target values for the Bu-AUC were 900–1350 µmol/l*min for Bu-4 and of 4680–5848 µmol/l*min for Bu-1 [ 21 , 24 ]; Bu clearance normal range comprised clearance from 2.1 to 3.5 ml/min/kg [ 25 ]. This AUC-target range was set to assure myeloablation and engraftment without increasing the risk of serious treatment-related toxicities [ 23 , 26 ].…”

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients

“…MDS posttransplant relapse still remains the leading cause of failure after allotransplantation [ 80 , 81 ] and even posttransplant donor lymphocyte infusions are considered as a possible prophylactic strategy [ 81 ]. Busulfan-based conditioning is associated with a different risk of nonrelapse mortality in allotransplant recipients compared with other conditioning regimens [ 82 , 83 , 84 , 85 , 86 ]. For this reason, we did not include comparisons of posttransplant survival for the patient subsets identified in the cluster analysis based on the total levels of various lipid classes ( Figure 1 ), because survival would then be reflected not only by differences in pretransplant lipid levels but possibly also by differences in conditioning therapy.…”

Is there any difference between busulfan-cyclophosphamide and cyclophosphamide-busulfan in patients underwent allogeneic transplantation?

“…In this study, clinical outcomes of 33 patients given Bu-Cy and 37 patients given Cy-Bu prior to allogeneic transplantation and toxicities of the regimens were compared. 5 In this study, a 24-h interval was left between Bu and Cy administration, as it was determined in previous studies that shortening the time interval between Bu and Cy can reduce toxicity. 2 While the baseline characteristics of the groups were similar, liver toxicity, SOS incidence, and 4-year non-relapse mortality in patients receiving the Cy-Bu regimen were found to be lower than those who received Bu-Cy (all p ≤ 0.05).…”