Conditioning with Fludarabine, Myeloablative Doses of Busulfan, and Melphalan (Flu/Bu4/Mel) Achieves Comparable or Superior Outcomes to Conventional Myeloablative Conditioning in Allogeneic Bone Marrow and Peripheral Blood Stem Cell Transplantation
Authors: Nishino Shunsuke , Yamamoto Hisashi , Kuno Mika , Watanabe Otoya , Yamaguchi Kyosuke , Kageyama Kosei , Kaji Daisuke , Taya Yuki , Nishida Aya , Takagi Shinsuke , Ishiwata Kazuya , Yamamoto Go , Asano-Mori Yuki , Wake Atsushi , Uchida Naoyuki 
Published: December 2024

Background:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a crucial therapeutic approach for myeloid malignancies. To maximize the efficacy of allo-HSCT, optimizing conditioning regimens to maintain anti-leukemic effects while minimizing non-relapse mortality (NRM) is essential.
We have established a novel regimen of 180mg/m2 fludarabine, myeloablative doses (12.8mg/kg) of busulfan, and 80mg/m2 melphalan (Flu/Bu4/Mel) for relapse/refractory acute myeloid leukemia (AML) in single cord blood transplantation (sCBT), demonstrating its high anti-tumor efficacy without increasing NRM. Flu/Bu4/Mel is now widely used in sCBT in Japan, however, its efficacy and safety in non-CBT have not been established, and specific patient populations for whom Flu/Bu4/Mel regimen is optimal remain unclear.
Method:
We retrospectively analyzed patients who underwent their first allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) with myeloablative conditioning (MAC) for myeloid malignancies at our institution from 2010 to 2023. HLA-haploidentical transplants were excluded. Patients were divided into Flu/Bu4/Mel (FB4M) and conventional MAC (cMAC) groups. The primary endpoint was overall survival (OS); secondary endpoints included leukemia-free survival (LFS), relapse rate, NRM, and neutrophil engraftment. OS and LFS were evaluated using Kaplan-Meier method and compared with log-rank test. Multivariate analysis using Cox proportional hazards model was conducted to identify factors contributing to OS and LFS. Cumulative incidence of relapse, NRM, and neutrophil engraftment were compared using Gray's test. Fine-Gray proportional hazard regression was used to identify contributing factors for relapse and NRM.
Results:
A total of 140 patients (median age 45.3 years, range 17-70; 55 females) were analyzed: 106 cases of AML, 32 with myelodysplastic syndromes (MDS), 2 with myeloproliferative neoplasms (MPN). 71 unrelated donor and 69 non-remission transplants were included. FB4M group had 65 patients, and cMAC group 75. Median follow-up time was 2941 days (range, 221-5267). FB4M group had significantly more non-remission and post-2015 transplants. Other backgrounds were similar. The representative regimens in cMAC group included 21 cases of Cyclophosphamide (Cy)/Total Body Irradiation (TBI), 9 of Cy/Bu, and 28 of Flu/Bu/TBI. 5-year OS was 0.603 (95% confidence interval [CI], 0.465-0.715) for FB4M and 0.573 (95% CI, 0.414-0.647) for cMAC with no significant difference (p=0.82). 5-year LFS was 0.564 (95% CI, 0.430-0.678) for FB4M and 0.484 (95% CI, 0.327-0.558) for cMAC, also showing no significant difference (p=0.21). Cumulative incidence of relapse was 0.275 (95% CI, 0.170-0.389) for FB4M and 0.333 (95% CI, 0.226-0.443) for cMAC (p=0.50). NRM incidence was 0.162 (95% CI, 0.083-0.264) for FB4M and 0.221 (95% CI, 0.133-0.323) for cMAC (p=0.43). Neutrophil engraftment rates were 0.985 (95% CI, 0.896-0.998) for FB4M and 0.947 (95% CI, 0.864-0.980) for cMAC, with median time of 19 and 17 days, respectively. Multivariate analysis showed remission status, performance status (PS), unrelated donor, and transplantation era affected OS. LFS factors included these four plus Flu/Bu4/Mel conditioning. Relapse was influenced by remission status, unrelated donor, and transplantation era; NRM by remission status, PS, and transplantation era.
Subgroup analysis showed a trend towards improved OS and LFS in FB4M group for unrelated transplants, although not statistically significant, with similar relapse rates but lower NRM. In remission transplants, the FB4M group showed significantly better OS and LFS (p = 0.04 and 0.02, respectively) and a trend towards lower relapse rates.
Conclusion:
This study examined the efficacy of Flu/Bu4/Mel regimen for non-CBT in myeloid malignancies. From the perspectives of OS and LFS, Flu/Bu4/Mel was found to be comparable to other MAC regimens. Unrelated and remission transplants had significantly favorable outcomes with Flu/Bu4/Mel regimen. Despite a higher incidence of non-remission transplants, Flu/Bu4/Mel conditioning showed equal or lower relapse rates with a tendency for lower NRM, suggesting it maintains anti-leukemic efficacy while minimizing toxicity. These findings support Flu/Bu4/Mel as a promising conditioning regimen for allogeneic BMT/PBSCT in myeloid malignancies.