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Treosulphan versus busulphan: pros and cons

Allogeneic haematopoietic cell transplantation (HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute leukaemias. The success of this therapy depends not only on the alloimmune effect but also on the potent anti-leukaemic activity of the pretransplant conditioning regimen. The alkylating agent busulphan was initially adopted in myeloablative conditioning (MAC) regimens following preclinical work by Santos and Tutchka. More recently, lower doses of busulphan have been utilized in reduced-intensity conditioning (RIC) and non-myeloablative transplants (NMA) in order to reduce regimen-related toxicity and transplant-related mortality (TRM). Recent randomized studies have confirmed the longheld belief that relapses can be mitigated with higher conditioning intensity, although at the expense of TRM and other toxicities. In acute myeloid leukaemia (AML), especially in the presence of minimal residual disease at the time of HCT, the potential for improved disease control and longer overall survival (OS) outweighs these risks. The goal of allogeneic HCT remains augmenting the graft-versus-leukaemia effect and increasing the anti-leukaemic activity of the conditioning regimen while minimizing TRM. Treosulphan has recently been utilized, mostly in Europe, in the place of busulphan in conditioning regimens. Although treosulphan is an alkylator derivative of busulphan, there are distinct differences observed with this drug compared to busulphan that are worth mentioning. Treosulphan is a prodrug, which is non-enzymatically converted under low pH conditions to epoxy derivatives. These in turn are thought to be the active DNA alkylators that exert the clinical effects of the drug. Preclinical studies demonstrated equal or greater anti-leukaemic efficacy compared to busulphan. Furthermore, treosulphan may lead to more profound lymphodepletion and induce a more favourable cytokine milieu, resulting in less graft-versus-host disease (GVHD). These preclinical data led to a number of prospective studies evaluating treosulphan-based conditioning in AML and MDS, with doses ranging from 10 to 14 mg/m for three consecutive days, combined with standard-dose fludarabine. A single randomized trial comparing fludarabine/treosulphan 10 mg/m (FT10) with reduced-intensity fludarabine/busulphan (FB2) in patients with AML or MDS not eligible for MAC transplant was terminated early when FT10 showed a significant improvement in event-free survival (64 0% vs 50 4%) resulting from a decreased rate of TRM (12 1% vs 28 2%). Of note, this study initially used a treosulphan dose of 14 mg/m (FT14) but was amended to a lower dose due to excess infections and prolonged neutropenia. The European Society for Blood and Marrow Transplant (EBMT) has now assessed FT regimens in a variety of AML studies. FT regimens demonstrated comparable outcomes to MAC (FB4, 12.8 mg/kg) and RIC (FB2) regimens, with lower GVHD rates and TRM when administered at a dose of 12 mg/m. In addition, compared to other regimens, conditioning with FT14 had a superior OS in patients with advanced disease. Two further EBMT analyses have compared FT to FLAMSA (fludarabine, cytarabine, amsacrine)-based regimens in primary refractory AML and in older patients with AML. Both analyses confirmed similar outcomes across conditioning regimens although in older patients the sequential regimen of FLAMSA/TBI (total body irradiation) was associated with less relapse and FT with less risk of GVHD. Shimoni et al. build on the existing literature to specifically describe outcomes in patients with MDS comparing FT with other RIC and MAC regimens. In their analysis they confirm that FT has comparable non-relapse mortality (NRM) to RIC regimens but at the same time less risk of relapse compared to both RIC and MAC regimens resulting in an improved OS. Collectively, these data show that FT is positioned as a reduced-toxicity yet MAC regimen. Importantly Shimoni et al. Correspondence: Pritesh Patel, Division of Hematology/Oncology, University of Illinois at Chicago, 840 South Wood Street, Chicago IL 60612, USA. E-mail: prpatel8@uic.edu commentary