In 1983, Santos et al reported on the use of busulfan (Bu) in combination with cyclophosphamide (Cy) at 200 mg/kg (BuCy4) as an alternative to TBI based myeloablative conditioning.r51 patients with AML were conditioned using BuCy4 with stable long term remissions achieved in 44% patients transplanted in CR1. In an attempt to reduce the high TRM (73%) associated with BuCy4, Tutschka et al reduced the dose of Cy to 120 mg/kg (BuCy2). This regimen appeared equally effective but less toxic than BuCy4 with actuarial 3-year OS of 65% and reduced rates of hepatic veno-occlusive disease (VOD) and mucositis.r Marked inter-individual variation in the pharmocokinetics of oral busulfan has been well documented and it has been demonstrated that high busulfan levels are associated with increased risk of toxicity and lower levels have been associated with increased risk of graft rejection and relapse leading to the development of targeted busulfan dosing based on levels. rr Subsequently intravenous Busulfan has become available and demonstrates less individual variation and less hepatic toxicity.rr
A number of prospective and retrospective trials have compared Bu and TBI based regimens for acute and chronic myeloid leukaemia. Long-term follow up of 4 randomised trials comparing BuCy to CyTBI demonstrated similar overall and disease-free survival for 316 patients with chronic myeloid leukaemia with projected 10 year overall survival of 65% for BuCy and 63% for CyTBI; however, there was a non-significant inferior projected 10 year overall survival of 51% for BuCy compared to 63% for CyTBI for 172 patients with acute myeloid leukaemia. There was increased risk of cataracts in CyTBI conditioning and permanent alopecia in BuCy conditioning. r
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Fig. 1. Survival and DFS of patients with CML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.
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Fig 2. Survival and DFS of patients with AML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.
More recent registry studies have compared intravenous busulfan, oral busulfan and TBI in combination with cyclophosphamide conditioning regimens. There was improved leukaemia-free survival with IV BuCy compared to CyTBI (p = 0.0028) but not oral BuCy and improved overall survival in IV BuCy compared to CyTBI (p = 0.0034) in 1230 AML patients in first CR in the CIBMTR study. Also there was reduced relapse and non-relapse mortality after the first year in the IV BuCy arm.r An EBMT study comparing IV BuCy to CyTBI in 1659 AML patients in remission demonstrated increased relapse 26% vs 21% (p = 0.012), and less acute and chronic GVHD with IV BuCy with no difference in leukaemia-free survival or overall survival. r A CIBMTR study comparing IV BuCy with oral BuCy and CyTBI in 673 patients with chronic myeloid leukaemia demonstrated less relapse in the IV BuCy arm and improved leukaemia-free survival in HLA-matched sibling patients who received IV or oral busulfan compared to TBI conditioning regimens with no difference in overall survival or non-relapse mortality.r
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Fig.3 Adjusted probabilities of LFS and OS for all patients according to preparative regimen. LFS is represented in panel A. OS is represented in panel B.
An alternative myeloablative conditioning regimen with Fludarabine substituted for Cyclophosphamide in combination with intravenous Busulfan has been developed in an attempt to reduce risk of toxicity. There have been a number of randomised trials comparing IV BuFlu with BuCy with variable results.rrr There also have been 2 meta-analyses - the meta-analysis by Ben-Barouch et al reported a lower risk of non-relapse mortality at 100 days as well as lower rate of infection with IV BuFlu compared to BuCy and the meta-analysis by Lei et al reported increased risk of liver toxicity in BuCy arm.rr There was no difference in overall survival, event-free survival, relapse or GVHD in the meta-analyses.
Few studies have evaluated the optimal myeloablative conditioning regimen for acute lymphoblastic leukaemia, however most studies would suggest TBI containing regimens offer better disease control than those incorporating Bu. Granados et al reported the results of a retrospective study comparing BuCy2 vs CyTBI in 156 adult patients with ALL. 6-year EFS was 43% vs 22% (p=0.01) for TBI vs Bu conditioning with significantly higher 3-year relapse probability in the Bu group (71% vs 47%, p=0.01) and similar TRM.r Davies et al reported a large IBMTR cohort of outcomes for patients aged <20 years with ALL using either BuCy2 or CyTBI. OS, LFS were significantly higher in the CyTBI group, despite the relative risk of relapse being similar between the two groups. TRM was higher using BuCy2 (RR 1.68, p=0.012).r ASBMT guidelines published in 2012 reported that a TBI based conditioning regimen appeared superior in adult acute lymphoblastic leukaemia however acknowledged lack of data indicating superiority of any one conditioning regimen.r