Comparison between Two Reduced-Intensity Conditioning Regimens Prior to Allogeneic Stem Cell Transplantation: Fludarabine and Melphalan Is Associated with Higher Incidence of Acute Graft-Versus-Host Disease and Non-Relapse Mortality and Lower Incidence of Relapse Than Fludarabine and Busulfan.
Authors: Shimoni Avichai , Hardan Izhar , Shem-Tov Noga , Yerushalmi Ronit , Bar-Natan Michal , Tsolakis Friderikos , Nagler Arnon 
Published: October 2019

Abstract
Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem cell transplantation (SCT). Various RIC regimens have been designed and much clinical experience has been gained over the last decade with their use, yet, there is no data as to whether any of the regimens has an advantage over the others and in what SCT settings. To answer this question we retrospectively analyzed SCT outcomes in 151 consecutive patients (pts) given RIC for various hematological malignancies. All pts were considered not eligible for myeloablative conditioning. The median age was 53 (16–70). The donor was an HLA-matched sibling (n=90) or matched unrelated (n=61). 72 pts were given conditioning with fludarabine and intravenous busulfan (6.4 mg/kg; FB group), while 79 pts were conditioned with fludarabine and melphalan (100–140 mg/m2; FM group). Sixty percent of pts had active disease at the time of SCT. The median time to engraftment was not different among FB and FM groups. However, there was significant difference in chimerism kinetics. At one month after SCT, 77% of FB recipients had compelete chimerism compared to 96% after FM (p=0.003). There was no difference between the regimens in chimerism at 3 months after SCT. NCI Grade III-V organ toxicity (excluding mucositis) occurred in 31% and 53% of FB and FM recipients, respectively (p=0.005). The cumulative incidence of acute GVHD grade II-IV were 33% and 53% (p=0.01) and the rates of grade III-IV were 17% and 42% (p=0.003) after FB and FM, respectively. In all, non- relapse mortality (NRM) was 16% and 40%, respectively (p=0.003). This was related to both increased risk of organ toxicity and acute GVHD after FM. With median follow-up of 26 months (1–60), 66 pts are alive and 85 died; 41 of NRM and 43 of disease relapse. The actuarial 2-year OS was 34%. The status of disease at SCT was the most significant predictor of outcome. Pts in remission had OS of 54% compared with 24% in pts with active disease at SCT (p=0.0003). Multivariable analysis confirmed the adverse effect of active disease (HR 2.2, p=0.003) and a prior autologous SCT within 1 year (HR 1.7, p=0.04). The type of conditioning was not predictive of OS. However, when the analysis of outcome is limited to pts in remission at SCT the conditioning regimen used had a significant impact. OS was 72% and 36% after FB and FM, respectively (p=0.03). This difference was related to marked difference in the cumulative incidence of NRM, 7% and 32% (p=0.03), but no significant difference in the incidence of relapse mortality, 21% and 33%(p=NS), respectively. Among pts given SCT in active disease, FM recipients had higher incidence of NRM, but lower incidence of relapse, such that OS was equivalent to FB recipients. In conclusion, there are marked differences in SCT outcomes between RIC regimens that are theoretically equivalent in dose intensity. The FM regimen in the doses used is more intensive. It is more myelosuppressive and associated with higher incidence of organ toxicity and GVHD, but better disease control in pts with active disease. In patients in remission at SCT, where the graft-versus-malignancy effect may be the most significant factor, the reduced toxicity associated with FB is translated to better OS. These observations merit further study in prospective studies.