Efficacy and safety of salvage therapies in relapsed/refractory Acute Myeloid Leukemia: A systematic review and network meta-analysis

Abstract Background: Relapsed or refractory acute myeloid Leukemia (R/R AML) poses significant therapeutic challenges due to its aggressive nature, patient heterogeneity, and the limited efficacy of standard treatments. With numerous salvage therapies available—ranging from conventional chemotherapy to novel targeted agents—clinicians often face uncertainty regarding optimal treatment selection. This network meta-analysis (NMA) aimed to compare the efficacy and safety of available salvage regimens for relapsed or refractory acute myeloid Leukemia (R/R AML) to inform clinical decision-making. Methods: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted according to PRISMA guidelines to identify randomised controlled trials and observational studies evaluating salvage therapies in patients with relapsed or refractory acute myeloid leukaemia (R/R AML). Primary efficacy outcomes included overall survival (OS), event-free survival (EFS), and complete remission rate (CRR); safety outcomes included adverse events (AEs) and treatment-related mortality. A Bayesian NMA was performed using placebo as the reference comparator, and treatments were ranked using Surface Under the Cumulative Ranking (SUCRA) values. Results: A total of 20 studies comprising 4,196 patients were included. Among the evaluated interventions, Gemtuzumab Ozogamicin ranked highest for OS (SUCRA = 0.85), Gilteritinib for EFS (SUCRA = 0.81), and Apamistamab for CRR (SUCRA = 0.85). For safety, Cytarabine showed the lowest incidence of AEs (SUCRA = 0.71), while Enasidenib demonstrated the best profile in reducing mortality (SUCRA = 0.87). Gilteritinib consistently exhibited superior efficacy across multiple endpoints with a manageable safety profile, particularly in patients with FLT3 mutations. Conclusion: This NMA highlights Gilteritinib as the most effective and safest salvage therapy for R/R AML, particularly in patients with FLT3-mutated disease. Gemtuzumab Ozogamicin, Apamistamab, and Enasidenib also showed favorable outcomes, depending on molecular profiles and clinical priorities. These findings underscore the importance of individualized therapy selection based on efficacy, safety, and molecular characteristics. Further studies are warranted to validate these results and optimize combination strategies. Keywords: Relapsed acute myeloid Leukemia, refractory AML, salvage therapy, network meta-analysis, Gilteritinib, survival, adverse events, SUCRA.