Outcomes of Melphalan Versus Busulfan with Fludarabine Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis
Authors: Shahzad Moazzam , Khan Abat , Amin Muhammad Kashif , Rehman Gohar , Akram Umar , Nihar Kainat , Ishaq Muhammad Uzair , Ismail Areeba , Sadiq Muhammad Hamza , Shamoon Sheena , Mannan Muhammad Shaheer , Singh Pramod , Faisal Abdul Rafae , Chaudhary Sibgha Gull , Anwar Iqra , Nelson Maggie , Abdelhakim Haitham , McGuirk Joseph P. , Mushtaq Muhammad Umair 
Published: December 2024

Background: An optimal conditioning regimen before hematopoietic cell infusion is essential for improved outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Historically, myeloablative conditioning was used to eradicate disease, followed by allograft infusion to restore hematopoiesis. However, many patients with acute myeloid leukemia (AML) are elderly, with a median age of diagnosis of 69 years. Reduced-intensity conditioning (RIC) is used in elderly and less fit patients undergoing allo-HCT, and outcomes for these patients have improved over the years. We aimed to compare the outcomes after two commonly used RIC regimens, Melphalan versus Busulfan with Fludarabine (FluMel vs. BuFlu), in AML patients undergoing allo-HCT.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on five databases (PubMed, Cochrane Library, ClinicalTrials.gov, Medline, and Embase) from date of inception through June 2024 using the MeSH and entry terms for (“acute myeloid leukemia”) AND (“allogeneic stem cell transplantation” OR “Stem cell transplantation”) AND “reduced intensity conditioning chemotherapy”). A total of 5957 studies were identified, and primary and secondary screening was performed. After excluding reviews, editorials, opinion pieces, animal studies, and duplicate and non-relevant articles, we included six studies (five retrospective, one trial) reporting outcomes following RIC with either FluMel or BuFlu. The Joanna Briggs Institute critical appraisal checklist for studies reporting the prevalence data and randomized control trials was used for quality assessment, and all studies were reported as good. Review Manager (RevMan, version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analysis. We used a DerSimonian and Laird random effects model, with the Mantel-Haenszel method for dichotomous outcomes to calculate risk ratios (RR) and corresponding 95% CI. The random-effects model was used because of the estimated heterogeneity of the actual effect sizes. We used the Higgins I2 values to evaluate statistical heterogeneity, and a value above 50% was considered a cause for concern. Multiple arms were combined when two or more groups were present in intervention and control groups.Results: Our study included 4365 patients with the median ages in the late 50s to mid-60s (range 19-76 years). Male patients were 55-65% of the study population. Most patients had good performance status (ECOG PS 0-1 or Karnofsky's PS ≥90%). Neutrophil engraftment occurred around 13-17 days post-transplant, while platelet engraftment took place around 14-16 days post-transplant, with some ranges and specific regimens variations. Peripheral blood stem cells were the predominant graft source in most studies, along with mixed donor types, including matched related, unrelated, and mismatched donors. Analysis of the six studies comparing FluMel and BuFlu RIC regimens in AML patients undergoing allo-HCT showed no significant difference in overall survival (OS) between the two groups (RR 1.06, 95% CI 1.00-1.12, P=0.06). However, FluMel showed significantly lower relapse rates (RR 0.67, 95% CI 0.59-0.76, P&lt;0.00001), particularly at 1-, 3-, and 5-years post-transplant. Transplant-related mortality (TRM) was not significantly different overall (RR 1.31, 95% CI 0.98-1.75, P=0.07), but BuFlu showed a higher risk at 1 and 5 years. No significant differences were found in acute graft versus host disease (GVHD) (RR 1.05, 95% CI 0.81-1.37, P=0.70) or chronic GVHD (RR 0.81, 95% CI 0.57-1.16, P=0.25) between the two regimens.Conclusion: Our findings suggest that melphalan, compared to busulfan, with fludarabine RIC allo-HCT significantly decreases relapse rates; however, the overall survival is similar. This study underscores the need for additional investigation to identify the specific patient characteristics that could benefit the most from each regimen and to explore strategies to reduce transplant-related mortality.