Comparative Study of Treosulfan Plus Fludarabine (FT14) with Busulfan Plus Fludarabine (FB4) for Acute Myeloid Leukemia in First or Second Complete Remission: An Analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)

Background: Treosulfan has been increasingly used in reduced toxicity regimens, especially in older or frail patients. Different doses of treosulfan plus fludarabine have shown an advantage over reduced intensity regimens, confirmed by a randomized phase 3 trial utilizing treosulfan 30 g/m² (or FT10) in the majority of patients. However, data comparing fludarabine with higher doses of treosulfan (FT14) to fludarabine combined with myeloablative doses of busulfan are limited.

Aims: We compared outcomes between treatment alternatives of similar conditioning intensity: FT14 (fludarabine 150 or 160 mg/m ² and treosulfan 42g/m ², or FT14) over FB4 (fludarabine 150 or 160 mg/m ² and busulfan 12.8 mg/kg).

Methods: We retrospectively studied consecutive patients from the European Society for Blood and Marrow Transplantation (EBMT) registry, meeting the following inclusion criteria: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated or sibling donor between 2010-2020, c) HSCT at first or second complete remission (CR), d) conditioning regimen with either FT14 or FB4. Patients with ex vivo manipulated grafts were excluded. A sub-group analysis was performed according to age (<55 years or ≥55 years).

Results: In total, 2703 patients were included in the analysis comprising 2025 (75%) transplanted with FB4, and 678 (25%) with FT14.

In the sub-group of patients younger than 55 years (n=1676), FT14 recipients (n=236) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), and peripheral blood grafts (p=0.026), but a lower percentage of female donors to male recipients (p=0.008), compared to FB4 recipients (n=1440). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV was higher in FT14 (9.3% versus 5.8%, p=0.044), but rates of chronic GVHD were similar. With a median follow-up of 24.4 months (range 23.4-25.6), 2-year CI of relapse was higher in FT14 (35.9% versus 27.5%, p=0.025, Figure 1A), while non-relapse mortality was similar between groups (NRM 11.9% versus 7.7%, p=0.28, 1B). This led to lower 2-year leukemia-free survival (LFS 52.2% versus 62.4%, p=0.002, 1C), overall survival (OS 63.2% versus 72.9%, p=0.038, 1D), and GVHD free, relapse free survival (GRFS 41.3% versus 50%, p=0.004) in FT14. In Cox-regression multivariate analysis, conditioning regimen remained an independent predictor of CI of relapse (p=0.011), and LFS (p=0.03).

Similar differences in patient characteristics were observed in patients aged ≥55 years (n=1027). FT14 recipients (n=442) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), adverse cytogenetics (p<0.0001), peripheral blood grafts (p=0.026), but a lower percentage of female to male combinations (p=0.008) compared to FB4 (n=585). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade II-IV was higher in FT14 (7.6% versus 6.5%, p=0.001), with similar rates of chronic GVHD. Nevertheless, with a median follow-up of 29.6 months (range 23.9-34.1), 2-year CI of relapse, NRM, as well as LFS, OS and GFRS were similar between groups.

Conclusion: With the limitations of a retrospective analysis, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients with AML transplanted in first or second CR. The same was not true for older patients (≥55 years). It should also be noted that FT14 has been selected by treating physicians for higher risk HSCT, including patients who are older, have secondary disease, adverse cytogenetics, and unrelated donors. Therefore, further studies are needed to determine the optimal conditioning regimen for such patient populations.

Figure 1

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Figure 1

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