Conditioning with Fludarabine, BCNU, and Melphalan in Allogeneic Stem Cell Transplantation Results in Reduced Toxixcity and High Activity Against Advanced Hematologic Malignancies.

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.