Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age at diagnosis of 68 years. Estimated 5-year survival differs significantly by age and is <10% for patients older than 60 years (1). Older patients represent highly heterogeneous group and require careful evaluation of comorbidities and frailty. When selecting a treatment plan for older patients, physicians must carefully weigh the risk of adverse events and the potential impact on quality of life (QOL) against possible survival benefits. They are generally unsuitable for curative treatment options such as intensive chemotherapy and hematopoietic stem cell transplantation. Consequently, treatment strategies aimed at improving outcomes and patient compliance continue to evolve.

Lower intensity regimens include hypomethylating agents (HMA), such as azacitidine or decitabine, or low-dose cytarabine (LDAC). The introduction of azacitidine in 2012 and decitabine in 2015 significantly transformed the treatment landscape for these patients (2-4). However, HMA monotherapy has been associated with remission rates of 30% or less and survival of under one year (2, 5). As HMA therapy is considered the standard backbone for AML patients unfit for intensive chemotherapy, the majority of phase III trials have been designed to evaluate novel agents in combination with HMA versus HMA alone. In 2018, azacitidine and venetoclax combination was approved for patients with newly diagnosed AML aged ≥75 years old or ineligible for intensive chemotherapy (6). The VIALE-A trial demonstrated improved overall survival (OS) with venetoclax-azacitidine versus plasebo-azacitidine (14.7 and 9.6 months, respectively). Moreover, with long term follow-up, patients achieving CR/CRi with measurable residual disease (MRD) negativity had a longer median OS (34.2 months) compared to those without MRD response (18.7 months) (7). Profound cytopenias accompanied by concurrent infections, bone marrow evaluations during treatment cycles to evaluate cellularity, treatment delays, and prolonged hospitalizations are frequently observed. Nevertheless, due to its manageable side effect profile and a protocol allowing dose and schedule modifications, venetoclax-azacitidine has become a first-line treatment for elderly AML patients worldwide who are unfit for intensive therapy. Similarly, the VIALE-C trial, which randomized patients to LDAC/venetoclax versus LDAC/placebo, demonstrated improved CR/Cri (48% vs 13%) and OS (8.4 vs 4.1 months) in the venetoclax arm.(8)

The combination of HMAs with other agents, together with the establishment of genetic risk profiles and identification existing mutations, underscores the importance of individualized therapy. Among promising agents, Ivosidenib monotherapy or its combination with HMA has shown superiority in OS, CR/Cri, and EFS for IDH- 1mutated de novo AML (AGILE trail) (9). Patients with TP53 alterations, however, continue to experience significantly worse survival outcomes (10). The CD47 monoclonal antibody magrolimab has demonstrated clinical efficacy when combined with azacitidine or with azacitidine/venetoclax (11).Several multiple novel agents and combinations are under investigation, including fromtline FLT3i, oral HMAs, and triplets combining HMA, venetoclax and targeted agents (12). Considering that none of these regimens are curative, it remains a matter of debate whether dynamically assessing patient frailty and using non-intensive therapies can provide a bridge to allogenic stem cell transplantation.