Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine/Treosulfan Conditioning Regimen Compared with Busulfan-Based Myeloablative and Reduced-Intensity Conditioning in Patients with AML and Mds; Relative Outcomes Depend On Disease Status at Transplantation.
Authors: Shimoni Avichai , Rand Avital , Shem-Tov Noga , Hardan Izhar , Volchek Yulia , Maayaan Hannah , Yerushalmi Ronit , Nagler Arnon 
Published: October 2019

Abstract
Abstract 3358
Poster Board III-246
Allogeneic stem-cell transplantation (SCT) with both myeloablative (MAC) and reduced-intensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different busulfan (Bu)- based regimens (Leukemia 2006). We showed that survival was similar with MAC and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. The combination of fludarabine and treosulfan (FT) has been reported as an effective regimen in AML/MDS with limited toxicity. However, the relative dose intensity and expected outcomes with FT in the different SCT settings, compared with Bu-based regimens is not well defined. We now extend the analysis to a group of 298 pts with AML/MDS, given allogneic SCT from sibling (n=153) or unrelated/mismatched donors (n=145) and included the more recently introduced FT regimen. Pts meeting standard eligibility criteria for myeloablative conditioning were given high dose iv Bu and cyclophosphamide (BuCy, n=81). Pts with a risk factor for MAC, mainly due to advanced age, were given fludarabine (F) and reduced doses of Bu (6.4 mg/kg, FB2, n=91), F with high dose Bu (12.8 mg/kg, FB4,n=63) or FT (treosulfan 30-36 gr/m2). Protocol allocation was not randomized, resulting in a younger age for pts in the BuCy group; median age 37 years compared with 60, 50, and 58 for FB2, FB4 and FT, respectively. BuCy and FT groups included more pts with active disease at SCT, while the BuCy group had less unrelated donors. Non-relapse mortality (NRM) was 17%,18%,18% and 20% with FB2,FB4,FT and BuCy, respectively (p=NS). However, pts were selected to regimens other than BuCy based on a high estimated risk for NRM. With a median follow-up of 38 months (range, 1-115), estimated 5-yr overall survival (OS) was 38% (95%CI, 31-44). OS rates were 36%,33%,43% and 41% after FB2, FB4, FT and BuCy, respectively (p=NS). Multivariate analysis (MVA) defined age>50 [HR 1.5 (1-2.2), p=0.05)], active disease at SCT [HR 2.3 (1.6-3.2), p<0.001)] and unrelated donor [HR 1.5 (1-2.0), p=0.02)], as risk factors for shorter OS. The conditioning regimen used was not predictive in the entire group. When the analysis was limited to pts in first or subsequent remission (n=126), OS was 51%,43%,58%, and 43%, respectively. MVA identified age>50 as an adverse factor, while SCT using FB2 or FT was associated with prolonged OS [HR 0.3 (0.2-0.7), p=0.002)]. When the analysis was limited to pts with active disease (n=172) either chemo-refractory to induction or subsequent therapy (n=93) or untreated [n=79; untreated relapsed AML (n=15) or MDS with excess of blasts (n=64)], OS was 12%,25%,32%, and 36%, respectively. MVA identified chemo-refractory disease as the major adverse factor; OS [HR 2.2 (1.5-3.3), p=0.001), while SCT using BuCy or FT was associated with prolonged OS [HR 0.7 (0.5-1.0), p=0.06)]. The advantage of FT was observed mainly in pts with active untreated disease (mostly MDS). OS was 57% (95%CI, 32-82) in a group of 25 pts given FT for advanced, previously untreated MDS. Only BuCy and to a lesser degree FB4 (OS 27%) were effective in the truly refractory pts. FB2 and FT, were associated with a grim outcome in this setting (OS 6%, p=0.04). In conclusion, dose intensity is associated with different outcomes in the different transplant setting. In pts in remission at SCT, outcome is mostly related to SCT toxicity, thus there is an advantage to less intensive regimens, such as FB2, while FT shares this characteristic. When outcome is dominated by the risk for relapse, such as in pts with active disease at SCT, there is an advantage to a more intensive regimen, such as BuCy. FT shares this characteristic mainly in pts with no true chemo-refractoriness, and has an advantage over FB2 in this setting. FT should be considered as a reduced toxicity myeloablative conditioning, that is feasible in pts ineligible for MAC, rather than a reduced-intensity regimen. In pts in CR toxicity is comparable to FB2 while in pts with active untreated MDS its anti leukemic activity is comparable to BuCy.

Disclosures:
No relevant conflicts of interest to declare.