Survival Advantage with Comparable Complete Chimerism Patterns in Reduced Toxicity Treosulfan-Based Vs Reduced Intensity Busulfan-Based Conditinioning Regimen in AML/MDS Patients Undergoing Allogeneic Haematopoietic Cell Transplantation
Authors: Batsis Ioannis , Sakellari Ioanna , Papalexandri Apostolia , Mallouri Despina , Charalampidou Sofia , Kaliou Maria , Afisidis Achilleas , Gavriilaki Eleni , Constantinou Varnavas C , Yannaki Evangelia , Kaloyannidis Panayotis , Apostolou Chrysa , Sotiropoulos Damianos , Vadikolia Chrysanthi , Smias Christos , Anagnostopoulos Achilles 
Published: October 2019

Abstract
Introduction: The optimal regimen for patients not fitting criteria for myeloablative conditioning has not yet been established. Treosulfan-based conditioning emerges as a potent antileukemic regimen with high efficacy and low toxicity in acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS) patients. The current prospective study was designed to explore both safety and efficacy of FluTreo (fludarabine 150mg/m2, treosulfan 14 gr/m2/d ×3d) in medically infirm patients. Furthermore, we compared the outcome with a control similar population treated with FluBuATG (fludarabine 150mg/m2, busulfex 6.4mg/Kg, thymoglobulin-ATG 5-7.5mg/kg) reduced intensity conditioning.
Method: A total of 20 patients, aged 54.5 (34-64) years, suffering from AML (14), MDS (2) and MDS related AML (4), after 3 (1-6) lines of treatment, received a FluTreo conditioning (plus ATG 5 mg/Kg in the setting of unrelated donor, MUD) from 10/2013-06/2015. They received peripheral grafts, CD34+ 7.0×106/kg from siblings (6 patients), 8/8 (9 patients) or 7/8 matched (5 patients) unrelated donors. The historic group consisted of 26 consecutive patients treated with FluBuATG during 2002-2012 for AML (20), MDS (5), MDS related AML (1). Chimerism evaluation in unfractionated bone marrow with STR (short tandem repeat) fragment analysis was performed regularly (on day + 14, + 30, +60, + 90) in both groups. Donor chimerism ≥99% was considered as complete donor chimerism (CDC).
Results: The two groups were similar in terms of age, disease phase and risk group, lines of treatment or HCT-CI, except for more MUD in FluTreo. In the FluTreo group, neutrophil engraftment was achieved at day +10 (8-11) and platelet +12 (9-20), with 6 median days of neutropenia. Both groups experienced early engraftment: median time to CDC for both groups was + 30 days (range 12-69 in the Flutreo and 12-205 in the historic group). No significant difference was found between the two groups with respect to CDC on days +14 (30% vs 28%) or +30 (69% vs 57% respectively). Among patients receiving Flutreo 6 experienced CMV reactivation (2 infections), 7 EBV (1 PTLPD) and 1 tuberculosis. No grade III-IV organ associated toxicities were noted. Until last follow-up, 6 patients developed grade ≥II aGVHD and 9 cGVHD. Sixteen patients are alive in CR, while 4 died: 2 aGVHD grade III/IV, 1 cGVHD and 1 disease progression. With a median follow-up of 14 (2-130) for FluBuATG and 8.1 (2-20) months for FluTreo, 1-year disease-free survival was significantly higher in FluTreo (49% vs 88% respectively, p=0.009). Similarly, FluTreo showed a significant advantage in 1-year overall survival (OS) too (39% vs 77% respectively, p=0.006). In multivariate analysis, the regimen (FluBuATG vs FluTreo), age, disease phase, donor, lines of treatment, GVHD and HCT-CI were incorporated. In terms of OS, only the regimen (FluTreo) was recognized as a significantly favorable factor (p=0.029). FluTreo was also significant for superior DFS (p=0.016) along with less lines of treatment pre-transplant (p=0.026). Treatment related mortality (TRM), in univariate analysis, was significantly associated with MDS, time from diagnosis to transplant and previous lines of treatment, but none in multivariate analysis.
Conclusions: This treosulfan-based reduced toxicity regimen seems safe and efficacious providing balanced immunosuppression that retains a graft-versus-leukemia effect with myeloablative activity and acceptable toxicity profile. Despite similar patterns of complete chimerisms compared to standard reduced intensity regimens, this regimen favors durable complete chimerism with low relapse rate. Prospective studies with longer follow-up are necessary to establish the advantages of this treosulfan-based regimen that render it a favorable alternative option in patients unfit for conventional regimens.

Disclosures
No relevant conflicts of interest to declare.