Total Body Irradiation (TBI) Added to Fludarabine/Busulfan/Antithymocyte Gobulin (FLUBUP/ATG) Conditioning Increases Overall Survival and Relapse-Free Survival in Patients with Acute Myeloid Leukemia (AML) Receiving Allogeneic Stem Cell Transplants.
Authors: Savoie Mary Lynn , Balogh Alexander , Chaudhry Ahsan , Stewart Douglas A. , Bahlis Nizar J. , Storek Jan , Brown Christopher , Quinlan Diana , Kmet Leanne , Larratt Loree M. , Turner A. Robert , Russell James A. 
Published: October 2019

Abstract
Myeloablative conditioning with FLUBUP (fludarabine 50mg/m2 i.v. days -6 to -2 and busulfan 3.2mg/kg i.v. once daily days -5 to -2) is convenient to administer and relatively well tolerated. The addition of ATG (Thymoglobulin 4.5mg/kg over 3 days) to cyclosporine and short course methotrexate appears to decrease the incidence and severity of graft-versus-host disease (GVHD) but may contribute to a still unacceptable relapse rate when this regimen is used in AML. We have added low dose TBI (200cGy x 2 day -1 or 0) to our standard FLUBUP/ATG conditioning regimen in all patients with AML in an effort to enhance cytotoxicity and reduce relapse rate. 135 patients (pts) received allogeneic stem cell transplants at our centre between 07/99 and 05/05. Ninety pts (66.7%), transplanted between 07/99 and 04/04 received FLUBUP/ATG while the remaining 45 (33.3%) received FLUBUP/ATG+TBI. Patient age was 16–65, median 42, in the FLUBUP/ATG group and 20–63, median 46, in the group with additional TBI. 71.1% of pts receiving TBI were in CR1 or CR2 compared to 62.2% of those not receiving TBI (p=ns). The remainder had more advanced disease. The distribution into standard cytogenetic risk groups between the two groups was also not statistically significant. More pts received peripheral blood stem cells in the TBI group (73.3% vs. 91.1%, p=0.02). In the TBI group 17 pts (37.8%) received a matched related donor transplant as opposed to 50 (55.6%) in the non-TBI group. The others were transplanted from mismatched related or volunteer unrelated donors. There was no difference between the groups with respect to neutrophil and platelet engraftment, rates of severe acute GVHD (6.6% Grade III-IV in the TBI group vs 7.8% for the non-TBI group) or chronic GVHD (51.1% in the TBI group vs 50.0 in the non TBI group). At one year non-relapse mortality was 12.2% vs.16.7% (p=ns) and relapse was 37.8% vs.13.3% (p=0.003) in the groups with and without TBI respectively. Overall survival (OS) at one year was 82% (95% CI 68%-91%) in the TBI group versus 61% (95% CI 50%-70%) in the non-TBI group (p=0.015). After adjusting for risk group, donor type and patient age the Cox proportional hazards ratio was 0.41 (0.19–0.90) in favour of the addition of TBI. Pts receiving FLUBUP/ATG+TBI were therefore 60% less likely to die within the first year than those receiving FLUBUP/ATG. When OS was assessed including all available observation time the statistical difference by log-rank test persisted, p=0.0237. Relapse-free survival was also improved by the addition of TBI (80% (65%-89% vs. 50% (39%-60%), p=0.001). After adjusting for risk group, donor type, patient age as well as cytogenetic risk group the Cox proportional hazards ratio was 0.23 (0.11–.0.50) in favour of additional TBI suggesting that pts receiving TBI were about 77% less likely to die or relapse within the first year compared to pts who did not receive TBI. The addition of TBI was well tolerated and helped overcome the risk of relapse associated with increased immunosuppression from ATG.