A final confirmatory analysis of results of a phase 3 trial comparing 2 reduced-toxicity conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who were older or had comorbidities showed that treosulfan plus fludarbine was noninferior to busulfan plus fludarabine with respect to efficacy and safety. The findings from this study were published in Lancet Haematology.

Although allo-HSCT must be preceded by a conditioning regimen, it is currently recognized that, when necessary, less aggressive chemotherapy combinations, such as reduced-intensity busulfan and fludarabine, can be substituted for myeloablative chemotherapy regimens that prevent autologous hematologic recovery.

The former approach is particularly relevant for patients with AML or MDS who are aged 50 to 75 years and/or have comorbidities that increase intolerance to myeloablation. However, there is some evidence that the risk of disease relapse may be higher for patients receiving reduced-intensity busulfan plus fludarabine compared with myeloablative conditioning.

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Treosulfan, like busulfan, is an alkylating agent, although the combination of treosulfan with fludarabine, unlike the busulfan/fludarabine regimen, has been classified as a “reduced-toxicity but myeloablative conditioning regimen.”

In this open-label, multicenter, noninferiority study, 476 adult patients with AML or MDS considered to be poor candidates for standard myeloablative conditioning were randomly assigned in a 1:1 ratio to receive fludarabine with either treosulfan or busulfan prior to undergoing allo-HSCT. The primary end point of the study was 2-year event-free survival (EFS).

At a median follow-up period of 15.4 months and 17.4 months for the groups receiving treosulfan- or busulfan-based conditioning, respectively, 2-year EFS was 64.0% (treosulfan arm) vs 50.4% (busulfan arm; hazard ratio [HR], 0.65; 95% CT, 0,47-0.90; P <.0001 for non-inferiority; P =.0051 for superiority).

Grade 3 or higher abnormal blood chemistry results were reported in 15% of patients in both treatment arms, with 11% and 16% of patients receiving treosulfan- and busulfan-based conditioning, respectively, experiencing grade 3 or higher gastrointestinal adverse events. The serious adverse event rate was 8% for patients treated with tresulfan and 7% for those receiving busulfan.

Notably, rates of all transplantation mortality were considerably higher in the busulfan arm (19%) compared with the tresulfan arm (10%), as were rates of late transplantation mortality (more than 6 months following allo-HSCT) which were 11% and 2% in the busulfan and treosulfan arms, respectively.  

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These results led the study authors to conclude that the large difference in 2-year EFS observed between the 2 study arms was “predominantly attributable to the substantial reduction of transplantation-related mortality (with treosulfan)”

They further commented that “this regimen [tresulfan plus fludarabine] has the potential to become a standard preparative regimen before allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome at increased mortality risk for myeloablative conditioning.”


Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomized, non-inferiority, phase 3 trial [published online October 9, 2019]. doi: 10.1016/S2352-3026(19)30157-7