Long-Term Outcomes of Busulfan, Fludarabine and 400 Cgy Total Body Irradiation Versus Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Hematologic Diseases: A Large Single Center Experience
Authors: Malinou Justin N. , Alkhaldi Hanan , Dahiya Saurabh , Goloubeva Olga , Bukhari Ali , Lutfi Forat , Sanchez-Petitto Gabriela , Samanta Santanu , Rapoport Aaron P. , Hardy Nancy M. , Minas Nicolette , Ruehle Kathleen , Gahres Natalie , Ridge Linda , Mohindra Pranshu , Molitoris Jason , Yared Jean A. 
Published: February 2021

Background:
Nonmyeloablative (NMA) and reduced-intensity conditioning (RIC) regimens are offered for patients with hematologic malignancies requiring allogeneic stem cell transplantation (HSCT) but are not candidates for myeloablative conditioning (MAC). The intensity of the conditioning regimen (CR) is important and contributes to the ability of HSCT to provide a cure. There is no consensus regarding the best RIC regimen and efficacy is not equal amongst RIC regimens. The combination of 2 days of intravenous Busulfan (total of 6.4 mg/Kg) and Fludarabine (total of 120-160 mg/m2) (Flu/Bu2) has been validated and widely adopted. While this regimen is well tolerated, relapses are common and remain the leading cause of death. Total body irradiation (TBI) has been widely used in the CR and provides the advantage of potent anti-cancer effect, immunosuppression and the ability to reach certain 'sanctuary sites' for chemotherapy (i.e. CNS). The 2 most commonly used TBI levels are 1200 cGy in MAC regimens and 200 cGy in NMA and RIC regimens. We hypothesize that the addition of 400 cGy (200 cGy two fractions per day, 6 hours apart) TBI to Flu/Bu2 will reduce the relapse rate without increasing its toxicity. In this retrospective study, we compared the safety and efficacy of Flu/Bu2/TBI400 with Flu/Bu2 CR amongst a diverse group of hematologic diseases.
Methods:
From 2006 to 2018, 137 adult patients with different hematological diseases were treated using one of two RIC regimens, either Flu/Bu2/TBI400 or Flu/Bu2 followed by HSCT from HLA-matched related or unrelated donors.
The primary endpoint was OS defined as the time from the date of transplant to death from any cause. The secondary endpoints included PFS, relapse rate, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), causes of death, aGVHD, cGVHD and engraftment. PFS was defined as the time from the date of transplant to disease progression as documented by the treating physician, based on pathological, imaging or clinical findings of the individual disease, or death from any cause. NRM was defined as time of death without evidence of progressive disease with relapse or progressive disease as a competing risk event (data not shown in the abstract). Relapse was defined as progression or disease relapse with NRM as a competing risk event. These endpoints were censored at the time of last follow-up.
Results:
A total of 137 patients were included in this study. 74 patients were treated with Flu/Bu2/TBI400 and 63 patients were treated with Flu/Bu2. The 2 groups were comparable in terms of patient-, disease- and transplant-related characteristics; however, Flu/Bu2/TBI400 patients had a higher HCT-CI score and a lower KPS. CNI-MTX GVHD prophylaxis was used in a higher proportion in Flu/Bu2/TBI400. Most of the Flu/Bu2 transplants occurred from 2006 to 2012. The median age was 62 in both groups and patients had comparable disease type distribution and DRI (Table 1). The median follow-up time was 4.62 years.
Flu/Bu2/TBI400 showed improvement of PFS over Flu/Bu2; the 5-year PFS was 50% in the TBI arm vs. 34% in the no-TBI arm (p=0.06 of marginal statistical significance). There was a numerical improvement of OS in favor of the TBI arm but this was not statistically significant; The 5-year OS was 53% with TBI vs. 39% without TBI (p=0.13). Cumulative incidence of relapse was not different between the 2 groups (p=0.29), see figures 1, 2 and 3. There was no difference in aGVHD incidence between the 2 groups (p=0.21). The TBI arm had significantly lower incidence of cGVHD compared to no-TBI arm (29% vs. 54%, p=0.005). Advanced DRI, grade III-IV aGVHD, cGVHD, use of ATG and MUD were associated with worse OS (univariate analysis). The same factors, with the exception of cGVHD, were associated with worse PFS. Multivariable Cox regression model revealed that grade III-IV aGVHD was associated with worse OS (p=0.001) while advanced DRI was associated with marginally inferior OS (p=0.07) (Table 2).
Conclusion:
This is the largest retrospective study of RIC Flu/Bu2/TBI400 regimen for HSCT with a median follow-up approaching 5 years. Our data suggests that RIC Flu/Bu2/TBI400 is safe and efficacious for different hematological malignancies. When compared to Bu/Flu2 without TBI, Flu/Bu2/TBI400 had lower incidence of cGVHD and showed a strong trend towards improved PFS and OS though not statistically significant at this time. Grade III-IV aGVHD was associated with poor OS in both groups.

Disclosures
Hardy: Incyte Corporation: Other: Advisory Board Member; Kite/Gilead: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member.