Addition of Melphalan to Fludarabine/Busulfan (FLU/BU4/MEL) Provides Survival Benefit for Patients with Myeloid Malignancy Following Allogeneic Bone Marrow Transplantation/Peripheral Blood Stem Cell Transplantation
Authors: Ueda Tomoaki , Maeda Tetsuo , Fukushima Kentaro , Fujita Jiro , Kusakabe Shinsuke , Yokota Takafumi , Shibayama Hirohiko , Tomiyama Yoshiaki , Kanakura Yuzuru 
Published: October 2019

Abstract
A combination regimen of fludarabine and myeloablative busulfan (FLU/BU4) has been widely used as a myeloablative conditioning regimen with reduced intensity for myeloid malignancies. However, FLU/BU4 has two major disadvantages. A disadvantage is the insufficient anti-leukemic effect in advanced cases. Although the overall survival (OS) after FLU/BU4 treatment is approximately 50-80% for myeloid malignancies in the 1st complete remission (CR), the regimen could result in unsatisfactory outcomes with 19-32% OS in patients with advanced disease (Shimoni 2010; Alatrash 2011). Another disadvantage is the slow achievement of complete donor-type chimerism, especially T-cell chimerism (Rambaldi 2015), which also affects the outcome of allogeneic hematopoietic stem cell transplantation (allo-HCT), particularly relapse (Peterlin 2015).
To overcome these issues, we designed a combination regimen with FLU, intravenous (IV) BU, and melphalan (FLU/BU4/MEL) and conducted retrospective analyses in this study. The FLU/BU4/MEL regimen consisted of 30 mg/m2 FLU for 5 days (150 mg/m2), 3.2 mg/kg BU for 4 days (12.8 mg/kg), and 50 mg/m2 MEL for 2 days (100 mg/m2) administered by IV infusion. A total body irradiation of 3 Gy was given in cases of unrelated transplantation, and 5 mg/kg anti-thymocyte globulin (Thymoglobuline®) was given for human leukocyte antigen-mismatched transplantation.
Between January 2009 and March 2016, 42 patients, including 33 with acute myeloid leukemia and 9 with myelodysplastic syndromes, received allogeneic bone marrow transplantation or peripheral blood stem cell transplantation (allo-BMT/PBSCT) with the FLU/BU4/MEL regimen in our institute. The median patient age at transplantation was 46.5 years (range: 20-63 years), and the median follow-up time was 1513.5 days (214-2975 days). At transplantation, 29 (69%) patients were in hematological CR, and 13 (31%) patients were not in CR. Most of the patients received standard prophylaxis for graft-versus-host disease (GVHD) with IV tacrolimus or cyclosporin A and methotrexate. The rate of neutrophil and platelet engraftment was 100% and 95.2% (95% CI: 81.6-98.8%), respectively, and the median time for their engraftment was 19 days (13-30 days) and 25 days (14-108 days), respectively. Among the patients who were examined for chimerism in the whole blood or T-cell fraction at day 28 after transplantation (n=32 in whole blood; n=16 in T-cell fraction), complete donor chimerism was achieved. Febrile neutropenia and severe (≧grade 3) oral/pharyngeal mucositis occurred in more than 80% of the patients. Although sinusoidal obstruction syndrome did not occur, thrombotic microangiopathy (TMA) occurred in 4 (10%) patients. The cumulative incidence of grade II-IVacute GVHD at day +100 was 42.2% (25.0-55.6%), and the cumulative incidence of moderate-to-severe chronic GVHD was 33.0% (14.4-53.0%).
At the last follow-up, 28 of 42 patients were alive, and 14 patients died because of infection (n=9; bacterial: 8, viral: 1), relapse (n=2), interstitial pneumonia (n=2), and TMA (n=1). The 1-year OS, disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) of all patients were 73.7% (57.5-84.5%), 66.7% (50.3-78.7%), 19.0% (8.8-32.2%), and 14.3% (5.7-26.7%), respectively, and the 4-year OS, DFS, NRM, and RR were 66.0% (49.4-78.3%), 59.5% (43.2-72.6%), 19.0% (10.2-32.1%), and 21.4% (10.5-34.9%), respectively. Among patients who were not in CR at allo-HCT, the 4-year OS and DFS were 49.4% (19.7-73.6%) and 38.5% (14.1-62.8%), respectively. These results indicated an improvement in the OS of patients with uncontrolled disease after the addition of MEL to FLU/BU4. In contrast, although the RR among patients who were in CR at allo-HCT was exceedingly low (1-year: 0.0% (0.0-0.0%); 4-year: 3.4% (0.2-15.4%)), the NRM after HCT in this group was relatively high (day +100: 13.8% (4.2-28.9%); 1-year: 24.1% (10.4-40.9%); 4-year: 27.6% (12.8-44.6%)). The most frequent cause of NRM in this group was bacterial infection, which was closely related to the high incidence of mucositis. Given the extremely low RR, the FLU/BU4/MEL regimen can be modified to reduce NRM in such cases.
In conclusion, FLU/BU4/MEL had curative potential even for patients with advanced myeloid malignancies, accompanied by the rapid complete chimerism achievement after allo-BMT/PBSCT. The NRM should be minimized to further improve the outcomes.

Disclosures
Yokota: Bristol-Myers Squibb: Research Funding; Pfizer Inc.: Research Funding; MSD K.K.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Shibayama:Bristol-Meyer Squibb K.K: Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria, Research Funding; Fujimoto Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical Co.,LTD: Honoraria, Research Funding; Jansen Pharmaceutical K.K: Honoraria; Mundipharma K.K.: Honoraria, Research Funding; Takeda Pharmaceutical Co.,LTD.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding. Tomiyama:Sysmex Corporation: Consultancy; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Kanakura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.