Reduced-Intensity Conditioning with Fludarabine/Busulfan Versus Fludarabine/Low-Dose Melphalan in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background Allogeneic hematopoietic stem cell transplantation (HCT) is a curative treatment for patients with relapsed and refractory non-Hodgkin lymphoma (NHL). Although reduced-intensity conditioning (RIC) regimens are the standard treatment, the optimal regimen remains unknown. Fludarabine plus a reduced dose of busulfan (Flu/Bu2) and intermediate-dose melphalan (140 mg/m²; Flu/Mel140) are commonly used in RIC regimens for patients with NHL. In contrast, fludarabine plus low-dose melphalan (80-100 mg/m²; Flu/Mel80-100) is expected to reduce non-relapse mortality (NRM), and the Flu/Mel100 regimen appears to be at least as effective as the Flu/Mel140 regimen in a single-center cohort. Several studies have compared the use of Flu/Bu2 and Flu/Mel140 in patients with NHL and reported that Flu/Bu2 was associated with a lower NRM and higher overall survival (OS) compared to Flu/Mel140. However, no studies have compared Flu/Bu2 and Flu/Mel80-100 in patients with NHL. Therefore, this study aimed to compare Flu/Bu2 and Flu/Mel80-100 in patients with NHL undergoing allogeneic HCT.

Methods This study included 523 adult patients with NHL who underwent allogeneic HCT following Flu/Bu2 (269 patients) or Flu/Mel80-100 (254 patients) for the first time between January 2009 and December 2020. We excluded patients whose donor source was cord blood or whose graft versus host disease prophylaxis was posttransplant cyclophosphamide. Flu/Bu2 consisted of fludarabine (125-180 mg/m²) and intravenous busulfan (6.4 mg/kg), while Flu/Mel80-100 consisted of fludarabine (125-180 mg/m²) and intravenous melphalan (80-100 mg/m²). Administration of total body irradiation at a low dose (≤ 4 Gy) and anti-thymocyte globulin were permitted. Missing data were imputed using a single-imputation method. The primary endpoint was 5-year OS, and the secondary endpoints were 5-year progression-free survival (PFS), 5-year cumulative incidence of relapse, and 5-year cumulative incidence of NRM. OS and PFS were evaluated using the log-rank test. The other endpoints were evaluated using Gray's method. Multivariable analyses were performed to estimate the treatment effects of Flu/Bu2 compared with those of Flu/Mel80-100 using the Cox proportional hazards model, to adjust for potential confounding factors between Flu/Bu2 and Flu/Mel80-100 that could influence the outcomes. In addition, an inverse probability of treatment weighting (IPTW) approach that was based on a propensity score was used for OS. The endpoints are shown as hazard ratios (HRs) and 95% confidence intervals (CIs).

Results The median age was 56 years (interquartile range, 49-62 years), and 307 patients (59%) were male. There were 313 (60%) patients with B-cell NHL and 210 (40%) patients with natural killer/T-cell NHL. Regarding disease status at transplant, 297 patients (57%) had complete or partial response, and 226 (43%) patients had no response. Significantly more patients in the Flu/Mel80-100 group had Eastern Cooperative Oncology Group Performance Status > 2, total body irradiation administration, and > 3 chemotherapy lines before allogeneic HCT. Regarding the primary endpoint, the 5-year OS were 55.5% (95% CI, 49.1-61.4) and 43.2% (95% CI, 36.2-50.0) in the Flu/Bu2 and Flu/Mel80-100 groups, respectively (p = 0.011). In the multivariable analysis, the HR of 5-year OS was 1.38 (95% CI, 1.06-1.81) compared to the Flu/Bu2 and Flu/Mel80-100 groups (p = 0.018). After applying IPTW, the 5-year OS were 55.2% (95% CI, 48.7-61.7) and 43.5% (95% CI, 36.3-50.6) in the Flu/Bu2 and Flu/Mel80-100 groups, respectively (p = 0.031) (Figure). The adjusted HR of 5-year OS was 1.46 (95% CI, 1.13-1.90) compared to that of the Flu/Bu2 and Flu/Mel80-100 groups (p = 0.004). Regarding the secondary endpoint, the Flu/Bu2 group had a similar 5-year PFS, with an adjusted HR of 1.12 (95% CI, 0.88-1.43, p = 0.34), similar 5-year cumulative risk of relapse, with an adjusted HR of 0.82 (95% CI, 0.63-1.06, p = 0.13), and lower cumulative risk of NRM, with an adjusted HR of 1.58 (95% CI, 1.05-2.38, p = 0.027).

Conclusion In this population, the 5-year OS was better in patients who received Flu/Bu2 than in those who received Flu/Mel80-100.

Kusumoto:Abbvie: Honoraria, Research Funding; Amgen BioPharma: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; One Pharmaceutical: Honoraria, Patents & Royalties; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Takeda: Honoraria, Research Funding. Ueda:Sanofi Otsuka Pharmaceutical: Honoraria. Atsuta:Novartis Pharma KK: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; AbbVie GK: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria.