Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome; A More Favorable Outcome after Fludarabine and Treosulfan Conditioning. a Survey on Behalf of the Chronic Malignancies Working Party of the EBMT
Authors: Shimoni Avichai , Nagler Arnon , Iacobelli Simona , van Biezen Anja , Beelen Dietrich , Mufti Ghulam J. , Ciceri Fabio , Kanz Lothar , Volin Liisa , Richard Carlos , Blaise Didier , Ganser Arnold , Luft Thomas , Chevallier Patrice , Schwerdtfeger Rainer , de Witte Theo , Robin Marie , Kröger Nicolaus 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with myelodysplastic syndrome (MDS). So far, there is no proven advantage for any conditioning regimen over the others. Prior studies have shown that reduced-intensity conditioning (RIC) is associated with lower non-relapse mortality (NRM) compared with myeloablative conditioning (MAC), however, relapse rates are increased, resulting in similar survival. Novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal anti-leukemia effect will be of benefit. Fludarabine combined with treosulfan (FT) has been shown, in relatively small phase II studies, to be a reduced-toxicity regimen with intense anti leukemia activity and limited toxicity in patients with myeloid malignancies and possibly in particular in MDS. In this analysis we performed a retrospective analysis of all SCTs for MDS, performed between 2000 and 2011 and reported to the chronic malignancies working party (CMWP) of the EBMT (n=2516). We identified 480 patients given FT and compared their outcomes to patients given various MAC (n=1090) and RIC (n=946) regimens. FT and RIC recipients were older than MAC recipients, median age 59, 60 and 50 years, respectively (p=0.001). They were also more likely to have an unrelated donor, 56%, 57% and 50%, respectively (p=0.001) and to be given peripheral blood stem cell rather than bone marrow grafts, 92%, 94% and 79%, respectively (p=0.001). More FT recipients had previously untreated MDS at SCT, 33%, 20% and 24% while less had chemosensitive disease, 42%, 51% and 51%, respectively (p=0.001). The proportion of patients with chemo-refractory disease and with more than 10% marrow or peripheral blood blasts at SCT was similar in the three groups. More FT recipients had a prior history of transformation to AML, 15%, 9% and 9%, respectively (p=0.03). The proportion of patients with high and intermediate-risk cytogenetics was 13%, 21% and 18%, respectively (p=0.01). With a median follow-up of 21 months (range, 1-150), 1364 patients are alive, 456 patients died of relapse and 696 of NRM causes. The estimated 5 year overall (OS) and disease-free (DFS) rates for the entire group were 40% (95%CI, 37-43) and 35% (95%CI, 33-38), respectively. The 5-year OS rate of FT recipients was 47% (95%CI, 41-52). OS after the various RIC and MAC regimens was similar, 39% (95%CI, 34-43) and 38% (95%CI, 33-42), respectively, significantly shorter than after FT (p=0.02). DFS rates were 42% (95%CI, 37-47), 31% (95%CI, 27-36) and 35% (95%CI, 30-39), respectively (p=0.002). Relapse rates were similar after FT and MAC, 25% (95%CI, 21-30) and 29% (95%CI, 25-33), respectively, significantly lower than after RIC, 37% (95%CI, 33-41) (p=0.001). NRM was lower after FT and RIC than after MAC, 33% (95%CI, 28-38) and 32% (95%CI, 28-35), Vs. 36% (95%CI, 33-40), respectively (p=0.14). Multivariate analysis identified age> 55 years (HR 1.7, P=0.01), marrow blasts at SCT > 10% (HR 1.5, p=0.02), a history of transformation to AML (HR 1.7, p=0.01) and MDS refractory to prior therapy (HR 1.8, p=0.001) as poor prognostic factors for survival, while FT conditioning was protective (HR 0.6, p=0.02). Gender, cytogenetics, time from diagnosis to SCT, donor type and stem cell source were not predictive for survival. The predicting factors for increased relapse risk were RIC (HR 1.6, p=0.03), chemorefractory disease (HR 1.6, p=0.05), marrow blasts at SCT > 10% (HR 1.6, p=0.04), poor risk cytogenetics (HR 2.2, p=0.003) and prior transformation to AML (HR 1.8, p=0.0001). The predicting factors for increased NRM were MAC (HR 1.6, p=0.004), age > 55 years (HR 1.5, p=0.008), unrelated donor (HR 1.4, p=0.004), chemo-refractory disease (HR 1.5, p=0.05), marrow blasts > 10% (HR 1.6, p=0.01) and positive patient serology for CMV (HR 1.4, p=0.04). In conclusion, 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 regimens. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials.

Disclosures
Nagler*: MEDAC, Germany: Honoraria, Research Funding. Beelen:MEDAC, Germany: Research Funding. Ciceri:MEDAC, Germany: Honoraria, Research Funding. Kröger:MEDAC, Germany: Research Funding.