Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome (MDS) Using Treosulfan Based Compared to Standard Reduced-Intensity or Myeloablative Conditioning Regimens. a Report of the Chronic Malignancies Working Party of EBMT

Abstract

<h3>Introduction</h3> Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with MDS. Prior studies have shown no overall-survival (OS) advantage of any conditioning regimen over the others. Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM) compared to myeloablative conditioning (MAC), however, relapse rates are higher, resulting in similar OS. Fludarabine and treosulfan (FT) is a reduced-toxicity regimen with intense anti leukemia activity in patients with myeloid malignancies. We explored outcomes following FT conditioning in comparison with other regimens. <h3>Methods</h3> We retrospectively analyzed SCT outcomes of MDS patients reported to the chronic malignancies working party of EBMT (n=1722). The conditioning regimens were defined according to standard EBMT criteria and included FT (n=367), RIC (n=687) or MAC (n=668). <h3>Results</h3> FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0.001). More FT recipients had untreated MDS at SCT, 45%, 26% and 36%, respectively (P < 0.001). Disease status at diagnosis, cytogenetics, secondary origin and prior transformation to AML, were not different between the regimens. With a median follow-up of 20 months (1-171), 807 patients are alive, 328 died of relapse and 587 had NRM. The 5-year rates of relapse, NRM and OS for the entire group were 21% (95%CI, 19-23), 35% (95%CI, 33-38) and 44% (95%CI, 42-437), respectively. Relapse rates were similar after FT and MAC, 16% (13-21) and 19% (16-22), respectively, significantly lower than after RIC, 25% (21-28) (P = 0.003). Multivariate analysis (MVA) identified age >55 years (HR 1.42), advanced histology (RAEB 1/2, HR 2.01/ 1.73), prior transformation to AML (HR 1.87), refractory disease to prior therapies (HR 1.75) secondary origin (HR 1.33) and poor cytogenetics (HR 2.83) as associated with higher relapse risk. FT conditioning was associated with a lower risk (HR 0.63, P = 0.006). NRM was lower after FT and RIC than after MAC, 34% (29-39), 33% (30-37) and 38% (35-40), respectively (P = 0.05). MVA identified age >55 years (HR 1.39) and MAC (HR 1.34) as associated with higher NRM, while SCT from sibling donor (HR 0.81) and in CR (HR 0.80) were associated with a lower risk. In all, 5-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), after FT, RIC and MAC, respectively (Figure 1, P = 0.03). MVA identified age >55 years (HR 1.39), advanced histology (RAEB 1/2, HR 1.35/ 1.10), prior transformation to AML (HR 1.37), and poor cytogenetics (HR 1.58) as associated with lower OS. FT conditioning was associated with better OS (HR 0.79, P = 0.01). <h3>Conclusions</h3> FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials.