EBMT 2018 | A phase III study comparing treosulfan-based conditioning versus busulfan-based conditioning before allo-HSCT in AML or MDS

At the 44^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Dietrich W. Beelen from the University Hospital of Essen, Essen, DE, presented interim data from the prospective open-label, multi-center phase III randomized study (NCT00822393), which is comparing the safety and efficacy of Treosulfan-based conditioning therapy with reduced intensity to busulfan-based conditioning in adult patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

The main objective of this phase III study was to demonstrate at least non-inferiority in event‑free survival (EFS) of the Treosulfan-based regimen as compared to the reduced-intensity busulfan-based regimen within 24 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The study also aims to compare the associated safety profiles of these two regimens.

In total, 476 patients (median age = 60 years) with AML or MDS in complete remission indicated for matched related donor (MRD) or matched unrelated donor (MUD) allo-HSCT were enrolled in this study and randomly assigned 1:1 to receive either intravenous (IV) treosulfan (10 g/m²/day [d‑4 to d‑2]) or IV busulfan (4 x 0.8 mg/kg/day [d‑4 to d‑3]), both in combination with IV fludarabine (30 mg/m²/day [d-6 to d-2]). After exclusion of patients that were not treated, an overall of 240 patients (median age = 61 years, range 31–70) were enrolled in the busulfan arm and 220 patients (median age = 60 years, range 37–70) in the treosulfan arm.

 Key findings in evaluable patients (n = 460):

• 2-year EFS in patients administered treosulfan based conditioning was significantly non‑inferior compared to patients in the busulfan group: 64.0% vs 50.4%, HR = 0.65, P = 0.000016
• 2-year overall survival in patients in the treosulfan and busulfan group: 71.3% vs 56.4%, HR = 0.61, P = 0.0082
• 2-year chronic GvHD- and relapse-free survival rate in patients in the treosulfan and busulfan group: 52.3% vs 38.5%, HR = 0.69, P = 0.0108
• 2-year transplantation-related mortality rate in patients in the treosulfan and busulfan group: 12.1% vs 28.2%, HR = 0.54, P = 0.0201
• 2-year relapse/progression rate in patients in the treosulfan and busulfan group: 24.6% vs 23.3%, HR = 0.87, P = 0.5017
• 100-day grade II–IV acute graft versus host disease (GvHD) in patients in the treosulfan and busulfan group: 6.4% vs 9.6%, P = 0.2099

The speaker, Dietrich Beelen, concluded that the findings of this study demonstrate the non-inferiority of the modified treosulfan (3 x 10 g/m²) /fludarabine (5 x 30 mg/m²) regimen compared to the RIC busulfan/fludarabine regimen for elderly or comorbid AML and MDS patients. Additionally, the clinical outcomes observed in this study “were consistently in favor of the treosulfan/fludarabine regimen thus confirm a major clinical benefit of this regimen as compared to the RIC busulfan/fludarabine regimen in this selected patient population”.

As a result of this interim data and the statistically proven non-inferiority of the treosulfan conditioning regimen, the phase III randomized study was terminated prematurely.