Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation (SCT) with Fludarabine and Intravenous Busulfan Is Associated with Improved Toxicity Profile and Longer Survival Than Conditioning with Fludarabine and Melphalan in Patients with Chemo-Sensitive Hematological Malignancies.
Authors: Shimoni Avichai , Hardan Izhar , Rand Avital , Shem-Tov Noga , Yerushalmi Ronit , Nagler Arnon 
Published: April 2020

Abstract
Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic SCT. They are more effective when the underlying malignancy is in remission at the time of SCT. Various RIC regimens have been designed, yet there is no defined data as to whether any of the regimens has an advantage over the others. To answer this question we retrospectively analyzed SCT outcomes in 100 consecutive patients (pts) given RIC for various hematological malignancies including AML/MDS (n=45), ALL (n=8), CML (n=6), multiple myeloma (MM, n=18), various lymphomas (n=19), others (n=4). All pts were considered not eligible for myeloablative conditioning and were required to have chemo-sensitive disease at SCT. The median age was 56 years (23–75). Donors were HLA-matched siblings (n=53) or matched unrelated (n=47). RIC consisted of fludarabine with intravenous busulfan (6.4 mg/kg; FB, n=62) or with melphalan (100–140 mg/m2; FM, n=38). The FB group included older pts; median age 59(23–75) compared with 51(27–66) years in the FM group (p&lt;0.001). The FB group included more pts with acute leukemia (66% vs 32%) while the FM group included more pts with MM (42% vs 2%, p&lt; 0.0001) and also more pts with a prior autologous SCT (42% vs. 21%, p=0.02). Donor type was not different between the regimens. 93 pts engrafted, 2 died early and 5 had primary graft failure, 3 after FB and 2 after FM (p=NS). The median time to engraftment was not different among groups. NCI grade III–IV organ toxicity occurred in 13 (21%) and 17 pts (45%) after FB and FM, resulting in 4 and 1 deaths, respectively (p=0.04). The cumulative incidence of acute GVHD grade II–IV were 20% and 43% (p=0.004) and the rates of grade III–IV were 6% and 19% (p=0.03), respectively. The cumulative incidence of chronic GVHD was 44%; not different between the regimens. The 1-year non-relapse mortality (NRM) rate was 10% after FB (6 pts; 1 graft failure, 1 organ toxicity, 2 GVHD, 2 infections) and 27% after FM (10 pts; 1 graft failure, 4 organ toxicity, 4 GVHD, 1 infection)(p=0.03). Relapse rate was not statistically different between the regimens; 38% and 50% after FB and FM, respectively (p=NS). With a median follow-up of 28 months (1–80), 58 pts are alive and 42 have died (18 NRM including 2 late events in the FB group, 24 of relapse). 43 FB and 15 FM recipients are alive with an estimated 3-yr survival rate of 59%(95CI, 43–75) and 26%(95CI, 8–44, p=0.007). Disease-free survival rates were 46%(95CI, 31–61) and 28%(95CI, 12–43, P=0.03), respectively. Multivariable analysis determined that FM conditioning was associated with shorter survival (HR, 2.9 (1.2–7.0), p=0.02) while SCT from an unrelated donor was of borderline significance (HR, 1.8 (1.0–3.3), p=0.06). Age, disease type and prior autologous SCT were not predictive of survival in this cohort. 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 toxic. It was associated with higher incidence of NRM due to increased risk of both organ toxicity and acute GVHD. FM offered no advantage in disease control in pts with chemo-sensitive disease, thus reduced toxicity with FB translated into improved survival. These observations merit further study in more homogeneous pt population and in prospective studies.