It is difficult to compare the relative efficacy of different conditioning regimens in the treatment of patients with leukaemia as most studies are retrospective reviews and there are few direct comparisons in randomised clinical trials. In addition, it is likely that patient selection has a large impact on the results obtained, making it difficult to assess the impact of any given preparative regimen from the large number of phase II trials reported in the literature.
Acute lymphoblastic leukaemia (ALL)
While there is no standard conditioning regimen for acute lymphoblastic leukaemia (ALL), most regimens are based on total body irradiation (TBI) 12 Gy combined with either cyclophosphamide (Cy) or etoposide (VP16). The European Society for Blood and Marrow Transplantation (EBMT) registry analysis showed no difference in outcome for sibling blood and marrow transplant (BMT) with Cy/TBI or VP16/TBI when transplant was done in first complete response (CR1) but a lower relapse rate with VP16/TBI when transplant was done in second complete remission (CR2). Clearly, inferior results were reported for busulfan (Bu) based preparative regimens compared to TBI based regimens.r In childhood ALL, the recent updated evidence based review from the American Society for Blood and Marrow Transplantation (ASBMT) still recommends TBI based myeloablative conditioning.r In adult ALL, particularly those under the age of 35, myeloablative BMT is recommended in CR1 for all disease risk groups.r For adults who are not fit for myeloablative conditioning, reduced intensity conditioning has resulted in comparable outcomes.r
Acute myeloid leukaemia (AML)
A number of retrospective and randomised trials, including one meta-analysis, have previously compared Bu/Cy to TBI/Cyrr with results then favouring Cy/TBI. However, those patients received oral busulfan, with its varied pharmacokinetics. More recent availability of intravenous (IV) Bu required renewed comparison of these most commonly used myeloablative regimens. Two recent studies comparing Cy/TBI with IV Bu/Cy in mainly adult patients with myeloid leukaemias have shown that the IV Bu containing regimen was associated with improved outcome.rr In the retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) registry studyr involving 1230 AML CR1 patients receiving HLA-matched sibling or unrelated donors (URD) allografts from the years 2000 - 2006, non-relapse mortality (NRM) and relapse were both reduced in IV Bu/Cy resulting in improved leukaemia-free survival (LFS) and overall-survival (OS) in comparison to oral Bu/Cy or Cy/TBI. In contrast, the EBMT retrospective registry study involving 1659 HLA-matched sibling allografts between 2004 - 2010 for adult AML in CR1 (85% of patients) and CR2 showed no difference in outcome between IV Bu/Cy and Cy/TBI.r In a prospective multicentre cohort study accruing 1483 patients from March 2009 - February 2011 with myeloid leukaemia (AML, chronic myeloid leukaemia (CML) and myelodysplastic syndrome (MDS) IV Bu based myeloablative conditioning was found to result in superior survival compared to TBI based myeloablative conditioningr, particularly in early disease. Over two thirds of patients in this latter study had AML. Thus IV Bu/Cy is currently the preferred myeloablative conditioning regime for adult AML in CR1. In patients with advanced or refractory AML, outcomes were similar between Cy/TBI and IV Bu/Cy.r
Chronic myeloid leukaemia (CML)
BMT for CML in the tyrosine kinase inhibitor (TKI) era usually involves patients at a more advanced stage of disease, or those who have failed TKI. Although Cy/TBI was previously the preferred myeloablative conditioning regime, a recent CIBMTR retrospective registry study of CML patients in first chronic phase from 2000 - 2006 has shown the superiority of IV Bu/Cy over Cy/TBI. In 438 HLA-matched sibling and 235 URD allografts, multivariate analysis showed less relapse in patients receiving IV Bu compared to TBI, with subsequent improved LFS, particularly in HLA-matched sibling allografts. However, NRM and OS were similar between the patient groups.r In a prospective multicentre cohort study in chronic phase and advanced phase CML, Cy/TBI has equivalent results to IV Bu/Cy.r
Efficacy
Figure 1: Probabilities of LFS (A) and OS (B) for patients receiving IVBu/Cy vs oral Bu/Cy vs Cy/TBI for AML in CR1.r
© Blood 2013
Figure 2: Survival after BMT with IV-Bu or TBI conditioning stratified on diagnosis (A) and disease status (B).r
© Blood 2013
Toxicity
The following table displays multivariate analysis of transplant outcomes in HLA-identical sibling or URD allografts in AML CR1 patients.r
Table 1: multivariate analysis of transplant outcomes in HLA-identical sibling or URD allografts in AML CR1 patients.r
© Blood 2013