Busulfan with Cyclophosphamide Versus Busulfan with Fludarabine for Myeloablative Conditioning in Acute Myeloid Leukemia and Myelodysplastic Syndrome in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplant- a Systematic Review and Meta-Analysis
Authors: Shahzad Moazzam , Khan Abat , Amin Muhammad Kashif , Singh Pramod , Akram Umar , Nihar Kainat , Ishaq Muhammad Uzair , Ismail Areeba , Sani Salman , Zahra Rubab , Shahbaz Usman , Shahani Javeria , Akram Fatima , Kaur Anmolpreet , Chaudhary Sibgha Gull , Anwar Iqra , Nelson Maggie , McGuirk Joseph P. , Mushtaq Muhammad Umair 
Published: December 2024

Background: Conditioning regimens significantly affect the outcomes of allogeneic hematopoietic cell transplantations (allo-HCT). Busulfan/Cyclophosphamide (BuCy) and Busulfan/Fludarabine (BuFlu) are both standard myeloablative conditioning (MAC) regimens for adult patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) undergoing allo-HCT. This systematic review and meta-analysis aimed to compare the outcomes with BuCy vs. BuFlu MAC allo-HCT in adult AML/MDS patients.

Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on four databases (PubMed, Cochrane Library, ClinicalTrials.gov and Embase)from date of inception through May 2024 using the MeSH and entry terms for (‘acute myeloid leukemia’ OR 'myelodysplastic syndrome') AND ('stem cell transplantation) AND ('myeloablative conditioning') AND ('outcome assessment'). A total of 4033 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 comparing outcomes following MAC with BuCy and BuFlu regimens. 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.

Results: Our study included adult AML and MDS patients (n=1102) undergoing MAC allo-HCT, divided into two groups based on MAC regimen: BuCy (n=533, 48.4%) and BuFlu (n=569, 51.6%). The median ages were 40 years (yrs) for the BuCy group (range: 18-66 yrs) and 46 years for the BuFlu group (range: 18-76 yrs); 55.4% and 56.4% were males in BuCy and BuFlu groups, respectively. When using MAC with BuCy vs. BuFlu, there was no statistically significant difference in the outcomes for 1-year overall survival (OS) (78.1% vs. 81.6%, 95% CI 0.89-1.04, p=0.30), 2-year OS (62.8% vs 56%, 95% CI 0.87-1.34, p=0.49) and 5-year OS (61.6% vs 63.3%, 95% CI 0.88-1.08, p=0.60) between BuCy vs. BuFlu groups. Similarly, there was no statistically significant difference in the disease-free survival rates (DFS) at 1-year (74.3% vs. 67.6%, 95% CI 0.91-1.30, P=0.37), at 2-year (59.4% vs. 55.0%, 95% CI 0.67-1.49, P= 0.99), and at 5-years (49.3% vs. 49.9%, 95% CI 0.75-1.26, P= 0.82) between BuCy vs BuFlu groups. There was no statistically significant difference in the 1-year relapse rates (RR) (14.5% vs. 21%, 95% CI 0.45-1.12 p=0.14), 2-year RR (26.7% vs 29.5%, 95% CI 0.69-1.23, p=0.57) and 5-year RR (23.5% vs 25.7%, 95% CI 0.72-1.21, p=0.60). There was no statistically significant difference in the rates of acute GVHD (33.8% vs. 30.8%, 95% CI 0.88-1.31, p=0.48) and chronic GVHD (37.2% vs. 33.3%, 95% CI 0.95-1.31 p=0.19) occurrence. A trend towards lower non-relapse mortality was seen with the BuFlu regimen as compared to BuCy.

Conclusion: Our study, which aimed to compare the outcomes of BuCy vs. BuFlu MAC allo-HCT in adult AML/MDS patients, demonstrates comparable outcomes in the two groups, including OS, DFS, RR, and GVHD. BuFlu showed a trend towards fewer toxicities than the more frequently used BuCy MAC regimen, providing a potential safety advantage. This underscores the importance of considering BuFlu as an alternative MAC regimen. Further prospective studies are warranted to explore the optimal regimen with post-transplant cyclophosphamide-based GVHD prophylaxis.