The Curative Potential Of Fludarabine125, Melphalan100, and Busulfan4 As a Conditioning Regimen For Myeloid Malignancies Of Elderly Patients
Authors: Ueda Tomoaki , Sato Aki , Sakai Kazuya , Muranushi Hiroyuki , Okamoto Yusuke , Tsukamoto Taku , Sugiura Hiroyuki , Matsui Hiroyuki , Jo Tomoyasu , Okada Kazuya , Maeda Takeshi , Onishi Tatsuhito , Kunitomi Akane , Ueda Yasunori 
Published: October 2019

Introduction
The prognosis of elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is poor, even in the patients who achieved good response after induction therapy. In order to undertake allogeneic stem cell transplantation (allo-SCT) with reduced toxicity and without total body irradiation (TBI), we conducted a combination regimen consisted of fludarabine, busulfan, and melphalan (Flu/Mel/Bu) for reduced intensity stem cell transplantation (RIST) conditioning.

Patients and methods
Among a total of 50 patients who underwent Flu/Mel/Bu conditioning between 2004 and 2012 in our institute, 32 patients with myeloid malignancies were retrospectively reviewed. Disease status was defined by WHO classification 2008. Therapy consisted of fludarabine 25 mg/m2 for five days (125mg/m2) and melphalan 50mg/m2 for two days (100mg/m2), both by intravenous infusion. Busulfan 2 mg/kg was administered orally for two days (4mg/kg) between 2004 and 2006, and intravenously at 1.6 mg/kg for two days (3.2mg/kg) between 2007 and 2012.

Results
Among the 32 eligible patients, 18 were female and 14 male. Seventeen patients were diagnosed with AML, 14 with MDS and one with chronic myelomonocytic leukemia (CMML). Median age was 59 years (32-66 years), and the median follow-up period was 1337 days (12-3043 days).Disease status of AML was complete remission (CR)1 (5), CR2 (10), CR3 (1) and CR4 (1), respectively, and all CR1 patients had poor risk factors. Disease status of MDS was RA (4), RARS (2), RCMD (1), RAEB-1 (5) and RAEB-2 (2), respectively. Three patients of RAEB conducted induction chemotherapy and two patients achieved CR. Donor sources consisted of 22 of unrelated bone marrow (URBM), 5 of related bone marrow (RBM), 3 related peripheral blood (RPB), and 2 of unrelated cord blood (URCB), respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus short term methotrexate (TAC+sMTX) (25) and cyclosporin plus methotrexate (CsA+sMTX) (7). The cumulative incidence of grade II-IV acute GVHD was 31.7% and chronic GVHD was 85.9%. Five-year non-relapse mortality (NRM) was 15.9% and the 5-year relapse rate was 18.8%. One-year overall survival (OS) was 81.2% (95%CI 62.9-91.1), 5-year OS was 74.6% (95%CI 55.5-86.4), one-year progression free survival (PFS) was 78.1% (95%CI 59.5-88.9), 5-year PFS was 65.4% (95%CI 44.2-80.2). Fourteen patients were older than 60 years, and both 5-year OS and PFS of this group were 85.7% (95%CI 53.9-96.2). For AML, one-year OS was 82.4% (95%CI 54.7-93.9), 5-year OS 70.1% (95%CI 42.3-86.3), one-year PFS was 76.5% (95%CI 48.8-90.4) and 5-year PFS was 61.8% (95%CI 32.9-81.2). Five-year NRM was 11.8% and the 5-year relapse rate was 26.5%. For MDS, both one-year OS and 5-year OS were 78.6% (95%CI 47.2-92.5), and both one-year PFS and 5-year PFS were 69.8% (95%CI 37.8-87.6). Five-year NRM was 21.4% and the 5-year relapse rate was 8.7%.On the other hand, we conducted 32 allo-SCT for myeloid malignancies (22 of AML in CR and 10 of MDS) with conventional conditioning regimens of cyclophosphamide (Cy) and TBI or Bu and Cy between 2004 and 2012. Median age was 36.5 years (20-54 years), and the median follow-up period was 1191 days (38-3366 days).Disease status of AML was CR1 (14), and CR2 (8), respectively. Disease status of MDS was RA (3), RARS (2), RCMD (1), RAEB-1 (4), RAEB-2 (1), and MDS-U (1), respectively. Four patients of RAEB conducted induction chemotherapy and achieved CR. Donor sources were URBM (15), RBM (11), CB (5) and RPB (1), respectively. GVHD prophylaxis consisted of TAC+sMTX (17) and CsA+sMTX (15).The outcomes of Flu/Mel/Bu were not statistically inferior to those of conventional regimens with one-year OS of (81.2% vs. 87.1%, p=0.564) and 5-year OS of (74.6% vs. 78.0%, p=0.564), and one-year PFS of (78.1% vs. 83.9%, p=0.183) and 5-year PFS of (65.4% vs. 80.4%, p=0.183).

Conclusions
Flu/Mel/Bu was tolerable, and produced good outcomes and may be a candidate for curative conditioning regimen of RIST, especially for patients with myeloid malignancies in controlled status.

Disclosures:
No relevant conflicts of interest to declare.