Allogeneic Stem-Cell Transplantation for AML and MDS with Tresosulfan Compared with Busulfan-Based Regimens; Reduced Toxicity Vs. Reduced Intensity
Authors: Shimoni Avichai , Shem-Tov Noga , Danylesko Ivetta , Volchek Yulia , Yerushalmi Ronit , Nagler Arnon 
Published: October 2019

Abstract
Abstract 495
Allogeneic stem cell transplantation (SCT) is potentially curative therapy for AML and MDS. SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM) but higher relapse rate than myeloablative conditioning (MAC). Novel regimens with intensive anti-leukemia activity but limited toxicity will be of benefit. Treosulfan is a prodrug of a bifunctional alkylating agent with intensive myelosuppressive as well as immunosuppressive properties and relatively favorable toxicity profile, which make it an attractive candidate for the use in SCT. The combination of fludarabine and treosulfan (FT) has been introduced over the last few years as a relatively dose-intensive regimen with favorable toxicity. However, data on the relative merits of this regimen and the expected outcomes in different settings is still limited. The current analysis includes 276 patients (pts) with AML/MDS, non-eligible for MAC, given various regimens prior to SCT. 85 pts were enrolled on a prospective FT study (treosulfan dose 36 g/m2). Outcomes were compared to pts given fludarabine busulfan (Bu) RIC (FB2, Bu dose 6.4 mg/kg, n=106) or reduced-toxicity (RTC) conditioning (FB4, myeloablative Bu dose 12.8 mg/kg, n=85). Median age was 57 years (18–76). The donor was a sibling (n=127) or unrelated (n=149). 110 pts had advanced leukemia at SCT and 63 had comorbidity score (HCT-CI)>2. The FT and FB2 groups included older pts and more pts with comorbidities compared to the FB4 group. The FT group also had more pts with MDS/2AML and advanced leukemia compared with the other groups. The median time to engraftment was not different between the regimens. Complete chimerism was achieved by 1 month in 90, 78 and 93%, respectively (p=0.01). Grade III-V organ toxicity occurred in 41, 30 and 34% of FT, FB2 and FB4 recipients, respectively (p=NS). Severe mucositis occurred less frequently after FT and FB2; 8, 14 and 31%, respectively (p=0.001). Severe infections during the neutropenic phase were more frequent after FT, possibly due to longer duration of neutropenia with this regimen. The cumulative incidence of acute GVHD grade II-IV was 20, 25 and 37% (p=0.03) and of grade III-IV was 8, 7 and 19%, after FT, FB2 and FB4, respectively (p=0.01). Chronic GVHD rates were similar among the regimens. In all, 5-year NRM was 29, 20 and 18%, respectively (p=NS). Multivariate analysis (MVA) identified HCT-CI>2 (HR 2.5 p=0.002) and advanced disease (HR 1.9, p=0.04) as predicting NRM. No regimen was associated with excess NRM after adjusting for differences in pt characteristics. 5-year relapse rate was 36, 47 and 40% after FT, FB2 and FB4, respectively (p=NS). MVA identified advanced age (HR 1.7, p=0.08) and advanced leukemia (HR 4.3, p=0.001) as associated with increased risk. When adjusting for pt characteristics, FT was associated with lower relapse rate, HR 0.6 (p=0.03). With median follow-up of 36 months (1–122), 5-year overall survival (OS) rate was 37% (95 C.I. 31–44%). Disease status at SCT was the most significant predictor of OS. Pts with early-intermediate stage disease had OS of 46% whereas pts with advanced disease had OS of 25% (p<0.001). MVA confirmed advanced disease (HR 2.5, p=0.001), HCT-CI >2 (HR 1.6, p=0.02) and age ≥50 years (HR 1.7, p=0.04) as independent adverse factor. There was a trend for better OS with FT (HR 0.7, p=0.1). The correlation between OS and conditioning regimen was dependant on disease status at SCT. There was no significant difference among the regimens in pts with early-intermediate stage disease, 5-year OS been 46, 44 and 50 after FT, FB2 and FB4, respectively. However, among pts with advanced disease, OS was 33, 9 and 28%, respectively (p=0.02), mostly due to very high relapse rate after FB2 in this setting. In conclusion, FT and FB4 are both RTC regimens. Similarly to MAC they are associated with early achievement of complete chimerism and more intense anti-leukemia effect resulting in lower relapse rate. Therefore, they may have reasonable outcome also in advanced leukemia. In contrary, FB2 is a RIC regimen that may be effective only in pts with less advanced leukemia. FT is feasible in elderly pts and pts with comorbidities, with acceptable toxicity and GVHD rates, similarly to RIC. FB4 was also relatively well tolerated although with higher GVHD rate, but was tested in the current study predominantly in better risk pts. Randomized studies are needed to better define the role of the 3 regimens in different settings.

Disclosures:
No relevant conflicts of interest to declare.