Conditioning with Fludarabine, BCNU, and Melphalan in Allogeneic Stem Cell Transplantation Results in Reduced Toxixcity and High Activity Against Advanced Hematologic Malignancies.
Authors: Marks Reinhard , Potthoff Karin , Hahn Joachim , Ihorst Gabriele , Bertz Hartmut , Spyridonidis Alexandros , Holler Ernst , Finke Jurgen 
Published: October 2019

Abstract
Conditioning with reduced intensity regimens have been proven problematic for the control of advanced hematologic diseases. Therefore we applied a new protocol (FBM) in a prospective, two-center, phase II trial in 133 patients (median age: 55.6 years, 23–73) undergoing allogeneic cell transplantation (HCT). FBM contains fludarabine (5×30mg/m2), BCNU (2×200mg/m2) and melphalan (140mg/m2). Patients >=55 years received dose reduction in BCNU (2×150mg/m2) and melphalan (110mg/m2). Diagnoses and patients included AML (58), MDS (23), CML (11), MPS (9), ALL (3), myeloma (9), lymphoma (13) and CLL (7). Most patients (n=106) had advanced disease (AD) defined as ≥ CR2/CP2, refractory, relapsed or untreated. Only 27 patients presented with early disease (ED): CR1, CP1 or MDS RA/RARS. The stem cell graft was BM in 15 and PBSCT in 116 patients. Related (SIB) donors were used in 68, unrelated (MUD) donors in 65 cases. GvHD prophylaxis was CsA+MTX (23pts) and CsA+MMF (110pts) with additional ATG in MUD HCT. Median time to leukocyte engraftment (WBC >1×10e9/L) was 12.7 (1–41) days. One primary graft failure occurred. Platelet count >= 20×10e9/L was reached median day 17.4 (5–113). Complete donor chimerism at day 30 was reported in 95.7% of patients. Grade 3 organ toxicity according to Bearman et al. was observed in 21 cases, three patients died due to toxic complications. After a median follow up of 58.5 months, non-relapse mortality (NRM) was 15.8% (95%CI 10.7–23.4) and 27.8% (95%CI 21.2–36.6) at day 100 and 2 years. The relapse rate was 14.3% (95%CI 9.4–21.7) at 2 years. Acute GvHD III-IV developed in 23.3%, extensive chronic GvHD in 32.3% of all evaluable patients. Overall survival (OS) after 3 years was 53.0% (95%CI 44.5–61.6) and 46.1% (95%CI 36.9–55.2) after 5 years. Cases with ED had an OS of 63.0% (95%CI 44.7–81.2) and patients with AD experienced a 50.4% (95%CI 40.8–60.1) OS after 3 years. Event free survival (EFS) after 3 years was 46.4% (95%CI 37.9–54.9) and 41.9% (95%CI 33.1–50.7) after 5 years. EFS for ED patients was 55.6% (95%CI 36.8–74.3), for patients with AD 44.0% (CI 34.5–53.5) after 3 years. Interestingly, patients allografted from female donors showed a significant reduction in EFS with increased incidence of chronic GvHD in uni- and multivariate analyses. No significant differences were observed between patients >= 55 years and < 55 years or MUD/SIB donors. The subgroup of AML/MDS patients (n=81) showed a 5-year OS/EFS of 52.9% (95%CI 29.2–76.7)/47.1% (95%CI 23.3–70.8) for ED and 42.4% (95%CI 29.9–54.9)/38.6% (95%CI 26.5–50.7) for AD patients. There were no relapses in ED patients after HCT. NRM after 100 days was 17.3% (95%CI 10.7–27.8). Patients age and donor choice did not show statistically significance for OS and EFS in AML/MDS cases. Among cases with advanced disease, patients (n=33) with circulating blasts (median 21,1%) at the time of HCT, showed an OS of 44.4% after 5 years. We conclude that FBM conditioning prior to allogeneic HCT is especially effective in cases of advanced myeloid disease and can be safely administered to older or comorbid patients.