Comparative outcomes of fludarabine-melphalan versus fludarabine-busulfan reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies: A systematic review and meta-analysis Free

Background: Reduced-intensity conditioning (RIC) regimens with fludarabine plus melphalan (FluMel) or busulfan (FluBu) are common in allogeneic stem cell transplants, especially for older or comorbid hematologic malignancy patients. While widely used, the optimal RIC regimen regarding disease control and toxicity is still debated.

Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines to compare clinical outcomes between FluMel and FluBu reduced intensity regimens in adult patients undergoing allo-HSCT. A comprehensive search of Ovid MEDLINE, Embase and Cochrane library was conducted from inception through July 22^nd, 2025. Eligible studies were identified based on predefined inclusion criteria: they involved adult patients aged 18 years or older with hematologic malignancies, compared outcomes of allo-HSCT using Flu-Mel (melphalan dose of 100-140 mg/m²) versus fludarabine combined with busulfan (busulfan dose of 3.2-4 mg/kg/day for 2 days or equivalent AUC), included a cohort of more than 50 patients, and providing data on transplant outcomes including overall survival (OS), progression free survival (PFS), treatment-related mortality (TRM), relapse rates and graft-versus-host disease (GVHD). Studies not published in English were excluded. Data extraction and quality assessment were independently performed by two reviewers. Meta-analyses were conducted in R (v4.3.2) using the random-effects model with the DerSimonian and Laird method to estimate pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Heterogeneity was assessed with the I² statistic. Publication bias was evaluated through funnel plots and Egger's test.

Results: A total of 17 studies comprising 10,396 patients were included, covering various hematologic malignancies: acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (n=7), lymphoid malignancies (n=7), myelofibrosis (n=2), and multiple myeloma (n=1). In the overall pooled analysis, the FluMel regimen demonstrated a significant improvement in PFS compared to FluBu (HR 0.89; 95% CI 0.82–0.97). This benefit was primarily driven by lower relapse rates (HR 0.78; 95% CI 0.63–0.97) and a reduction in chronic GVHD (HR 0.88; 95% CI 0.78–0.99), while there were no significant differences observed in OS (HR 1.01; 95% CI 0.86–1.18), TRM (HR 1.35; 95% CI 1.00–1.81), or grade III–IV acute GVHD (HR 0.88; 95% CI 0.42–1.82). Heterogeneity across outcomes was moderate to high (I² range: 35.7%–87.4%), reflecting variability in study design, populations, and regimens.

Subgroup analyses revealed in patient with AML/MDS (n=7, 4,969 patients), FluMel was associated with significantly improved OS (HR 0.82; 95% CI 0.73–0.92) and PFS (HR 0.83; 95% CI 0.75–0.91) compared to FluBu group. However, it was associated to a significantly higher TRM (HR 1.32; 95% CI 1.01–1.71). Differences in relapse (HR 0.67; 95% CI 0.43–1.03) and chronic GVHD (HR 0.70; 95% CI 0.40–1.21) did not reach statistical significance. Among elderly patients aged 60 years or older (N=6; 5,475 patients), FluMel was associated with significantly better OS (HR 0.83; 95% CI 0.74–0.94), and PFS (HR 0.83; 95% CI 0.75–0.92). However, there were no significant differences in TRM (HR 1.05; 95% CI 0.73–1.51), relapse rate (HR 0.79; 95% CI 0.50–1.25), chronic GVHD (HR 0.73; 95% CI 0.42–1.28), or grade III–IV acute GVHD (HR 0.87; 95% CI 0.31–2.40). For patients with lymphoma (n=7, 4,171 patients), FluMel was associated with significantly lower OS (HR 1.29; 95% CI 1.02–1.64) due to higher TRM (HR 1.73; 95% CI 1.10–2.73) compared to FluBu. No statistically significant differences were observed in PFS (HR 0.99; 95% CI 0.89–1.11) or relapse rate (HR 0.85; 95% CI 0.69–1.05). Heterogeneity within these subgroups was similarly variable (I² range: 34.1%–80.8%).

Conclusion: The evidence from this meta-analysis robustly indicates that the FluMel regimen offers a significant survival benefit, particularly in patients with AML/MDS and elderly populations due to lower relapse, while was associated with higher TRM and lower OS for patients with lymphoma. FluMel stands out as a preferred reduced-intensity conditioning regimen for AML/MDS patients, while lower intensity regimens appear to be needed for lymphoma patients due to higher TRM, in order to maximize long-term survival in allogeneic hematopoietic stem cell transplantation.