Comparison of fludarabine–melphalan and fludarabine–treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation—a registry study on behalf of the EBMT Acute Leukemia Working Party

Abstract

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients – A clinical trial to registry data comparison

“…For AML patients, the present results suggest that the FluTreo regimen as applied in the MC-FludT.14/L Trial II study is associated with significantly lower NRM compared with the intermediate intensity FluMel regimen. In contrast, one recent EBMT registry study comparing a total dose of 42 g/m² treosulfan to 140 mg/m² melphalan in otherwise similar AML patients, revealed only slightly lower NRM after FluTreo, which, however, appears substantially higher than in the present analysis [ 35 ]. Furthermore, this study revealed significantly lower RI after FluMel, which was not notable in the present analysis.…”

“…The substantially lower NRM together with comparable RI translated into significantly higher OS of FluTreo patients on multivariate analysis in the present analysis. In contrast, the lower RI obtained in FluMel patients of the EBMT registry study did not result in higher OS because it was counterbalanced by NRM [ 35 ]. Whether these differences actually reflect effects of treosulfan dose intensity cannot be clarified currently, but the present results at least argue against substantially stronger antileukemic properties of FluMel compared with the FluTreo regimen, even at a total treosulfan dose of 30 g/m².…”

Validation of the Transplant Conditioning Intensity (TCI) Index for Allogeneic Hematopoietic Cell Transplantation

“…The TCI score was calculated for every patient by adding the intensity weighted scores for each component given any day before the graft infusion, as shown in Supplementary Table 1, and as previously described. 8 Assignment to the low, intermediate, or high TCI category was performed according to the TCI score of [1][2], [2.5-3.5] and [4][5][6], as previously described. An online interface for calculating the TCI score and TCI group index is available at xxxx.…”

“…The myeloablative conditioning (MAC) versus the reduced intensity conditioning (RIC) classi cation has set for the last two decades a global standard to indicate transplant conditioning intensity and proved a reliable approach for clinical decisions and registry analyses. 1,2 As intensity represents a continuum and novel drugs and new conditioning regimens are now used, with some of them not being readily amenable to the RIC/MAC nomenclature, [3][4][5][6][7] we recently developed a tool which provided ner strati cation, better discriminating ability and more standardized assessment of the intensity of the preparative regimen. 8 Brie y, we assigned intensity weight scores for frequently used components in the conditioning regimen, we used their sum to generate the transplant conditioning intensity (TCI) score, and we built a discrete 3-category strati cation TCI index which was tested on a discovery cohort of 8255 patients with acute myeloid leukemia (AML) allografted between 2005 and 2017.…”

“…The internal validity of the TCI model was assessed using a bootstrapping technique, however, a formal validation conducted in a separate and more contemporary patient population was lacking, hence the current validation study. Using data reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, we included transplant recipients meeting inclusion criteria from the discovery study but who were allografted in a more recent period (2018 to June 2021), we assigned them to a TCI category (low, intermediate, high) according to the calculated TCI score ([1-2], [2.5-3.5], [4][5][6], respectively), as previously described, 8 and examined the validity of the TCI category in predicting early NRM, 2-year NRM and REL.…”