Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT

Abstract

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Allogeneic stem cell transplantation following relapse post autologous stem cell transplantation in adult patients with acute myeloid leukemia: A retrospective analysis of 537 patients from the Acute Leukemia Working Party of the EBMT

“…Although the use of ASCT to consolidate patients with AML in CR1 has decreased over time, recent studies and guidelines have indicated that ASCT remains an interesting therapeutic option in good and intermediate risk patients, especially if minimal residual disease (MRD) is undetectable and/or molecular remission is documented . The combination of IV Busulfan and high dose Melphalan as conditioning regimen has been shown to be associated with a lower RI . The advantage of ASCT over allo‐HSCT short term relies on a lower NRM after ASCT and on a long term basis on the absence of severe chronic GVHD.…”

“…Recent data regarding ASCT have shown improvements with a new high dose conditioning regimen pre ASCT taking advantage of the intravenous formulation of Busulfan (BU) and the combination of BU with high dose Melphalan (BUMEL) . Also, the outcome of ASCT can be improved by a better selection of patients: for instance, a recent comparison of the outcome of patients transplanted in first molecular remission, using the 2010 European Leukemia Net (ELN) classification, has shown that the overall survival (OS) post ASCT was superior to the OS post transplantation with matched unrelated donors (MUD) in good risk patients, identical in intermediate 2 risk patients and worse in intermediate 1 risk patients …”

Autologous Hematopoietic Stem Cell Transplantation in Acute Myelogenous Leukemia

“…In contrast, in a previous study, in patients with high-risk AML undergoing ASCT in CR1 with a busulfan and melphalan (BuMel) conditioning regimen, LFS was 53% at 2 years and 42% at 5 years [27], consistent with a study in which autografted CR1 patients, even those with high-risk AML, showed high 8year DFS and OS (56% and 62%, respectively) [28]. Therefore, further studies are needed to determine whether CR1 patients with high-risk AML should be excluded from ASCT.…”

Is There Still a Role for Autologous Stem Cell Transplantation for the Treatment of Acute Myeloid Leukemia?

“…The historical conditioning regimen is represented by the "Tutschka regimen" [48], based on the combination of oral busulfan 16 mg/kg with cyclophosphamide 120 mg/kg (BUCY). However, two recent retrospective studies, on behalf of the Italian Group for Blood and Marrow Transplantation and European Society for Blood and Marrow Transplantation (EBMT), respectively, have suggested that the association of busulfan with high-dose of melphalan (BUMEL) may led to improved outcomes in AML [49,50]. Furtherly, in 2017 Gorin et al [51] reported a retrospective multicenter analysis, from the EBMT database, comparing BUMEL to BUCY as preparative regimens before ASCT for patients with AML in complete remission (CR).…”