Reduced Risk of Relapse for Total Body Irradiation + Fludarabine Compared to Busulphan + Fludarabine As "Reduced-Toxicity" Conditioning for Patients with Acute Myeloid Leukemia Treated with Allohsct in First Complete Remission. a Study By the Acute Leukemia Working Party of the EBMT
Authors: Giebel Sebastian , Labopin Myriam , Sobczyk Kruszelnicka Malgorzata Maria , Stelljes Matthias , Byrne Jenny , Fegueux Nathalie , Beelen Dietrich W. , Rovira Montserrat , Spyridonidis Alexandros , Blaise Didier , Bornhäuser Martin , Karadoğan Ihsan , Savani Bipin N. , Nagler Arnon , Mohty Mohamad 
Published: February 2020

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard of care for patients with acute myeloid leukemia (AML) being at high risk of relapse. However, the procedure using conventional myeloablative conditioning regimens based on either busulphan (Bu) or total body irradiation (TBI) in combination with cyclophosphamide is associated with significant risk of non-relapse mortality (NRM). The use of reduced-intensity or non-myeloablative conditioning regimens results in improved tolerance but increased incidence of disease recurrence. In order to reduce toxicity while maintaining the efficacy, alternative approaches have been proposed including the use of moderately reduced doses of Bu or TBI in combination with fludarabine (Flu). The goal of this retrospective study to compare BuFlu and TBI/Flu reduced-toxicity regimens.
Patients and methods: Adult patients with AML treated in CR1 with alloHSCT from either HLA-matched sibling or unrelated donor between January 2006 and June 2018 were included in the analysis. The following conditioning regimens have been selected for the comparison: intravenous Bu at a total dose 9.6 mg/kg (3 days) + Flu (Bu3Flu, N=350) or TBI at a total dose of 8 Gy + Flu (TBI8Flu, N=168). In both groups the proportion of patients with intermediate risk karyotype was 74% while high risk - 24%. The proportion of patients with secondary AML was also the same (14%). Patients in the Bu3Flu group were significantly older, were treated more frequently with alloHSCT from unrelated donors and were treated in more recent period.
Results: The engraftment rate was 99% for both regimens. In a univariate analysis the use of TBI8Flu was associated with reduced incidence of relapse (20% vs. 30% at 2 years, p=0.01) and tendency to increased leukemia-free survival (LFS; 66% vs. 60%, p=0.15) and overall survival (OS; 74% vs. 58%, p=0.051) as well as reduced incidence of grade III-IV acute graft-versus-host disease (GVHD, 4% vs. 9%, p=0.03). The effects on non-relapse mortality (NRM), grade II-IV acute GVHD and chronic GVHD were not significant. In a multivariate analysis a chance of LFS was reduced for patients with high risk karyotype and secondary AML, with no effect of donor type. Due to significant interaction between type of conditioning and age, further analyses were performed stratifying patients above or below 50 years.
For patients ≤50 y.o. the use of TBI8Gy was associated with reduced incidence of relapse (21% vs. 35%; Cox model: HR=0.49, p=0.049), tendency to improved NRM (4% vs. 7%,; HR=0.17; p=0.1), significantly improved LFS (75% vs. 58%, p=0.02; HR=0.45, p=0.02), improved OS (84% vs. 60%; HR=0.29, p=0.002) improved survival free from both GVHD and relapse (GRFS; 56% vs. 46%; HR=0.53, p=0.02) and reduced incidence of grade II-IV acute GVHD (15% vs. 26%; HR=0.53, p=0.02).
For patients &gt;50 y.o. the effect of TBI8Flu on relapse was not statistically significant (19% vs. 29%; HR=0.64, p=0.21) while this regimen was associated with increased risk of NRM (26% vs. 11%; HR=3.98, p=0.0006) leading to a tendency to decreased OS (59% vs. 63%; HR=1.53, p=0.1).
Conclusion: Reduced-toxicity regimens using either TBI8Flu or Bu3Flu for patients with AML in CR1 are associated with relatively low risk of relapse and NRM leading to enhancing survival rates after alloHSCT. The use of TBI8Flu appears more effective compared to Bu3Flu and may be advised in younger patients where reduced risk of relapse translates into improved survival. In older individuals it should be used with caution due to increased risk of NRM. Prospective studies are needed to verify our findings.

Disclosures
Labopin: Jazz Pharmaceuticals: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.