Combination therapy involving azacitidine for acute myeloid leukemia patients ineligible for intensive chemotherapy.

Abstract

Acute myeloid leukemia (AML) is a complex hematological malignancy predominantly affecting the elderly, with a median diagnosis age of 68 years. Despite advances in treatment, elderly AML patients face suboptimal survival outcomes, with an estimated 5-year survival rate below 20 %. Epigenetic dysregulation, notably DNA methylation, is a key factor in the progression of myelodysplastic syndromes (MDS) to AML. This review examines various combination regimens involving azacitidine (AZA), including those with lenalidomide, histone deacetylase inhibitors (HDACi), kinase inhibitors, metabolic enzyme inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and anti-apoptotic protein inhibitors. Notable among these are the combinations with venetoclax, which has demonstrated remarkable efficacy in phase III trials, and the emerging IDH inhibitors ivosidenib and enasidenib, which have shown significant clinical benefits in patients with IDH mutations. While combination therapies with AZA hold great promise, challenges persist, including translating in vitro synergies to in vivo efficacy and identifying optimal regimens for specific patient populations. Cumulative toxicities may also offset clinical benefits, necessitating rigorous clinical trial design. Future research must focus on refining combination strategies, optimizing dosages and sequences, and thoroughly evaluating therapeutic efficacy and safety to advance the treatment of AML and improve patient outcomes.