AZA or LDAC combined with venetoclax likely improves mortality, remission, and quality of lifeNew combinations show promise for older adults with myeloid leukemia

Older adults with newly diagnosed acute myeloid leukemia (AML) are often ineligible for conventional "7+3" induction chemotherapy. Despite recent drug approvals, treatment outcomes remain poor in this population. We conducted an updated systematic review to inform the 2025 American Society of Hematology (ASH) AML update guidelines in older adults. This review compared the efficacy and safety of low-dose cytarabine (LDAC), azacitidine (AZA), 5- and 10-day decitabine (DEC), and gemtuzumab ozogamicin, alone or combined with drugs such as venetoclax (VEN), in older adults with AML ineligible for conventional chemotherapy. We included randomized controlled trials (RCTs) and nonrandomized studies (NRSs) of adults aged ≥55 years with AML, and synthesized evidence on mortality, remission, quality of life (QoL), functional status, and severe toxicity. We applied GRADE (grading of recommendations assessment, development, and evaluation) to assess the certainty of evidence. We included 47 studies (30 RCTs and 17 NRSs). AZA or LDAC combined with VEN probably reduces mortality and improves remission and QoL. AZA plus isocitrate dehydrogenase 1 (IDH1) inhibitors may reduce 1-year mortality and improve remission and survival in patients with IDH1-mutated AML. Compared with DEC alone, combining DEC with other agents showed inconsistent effects with mostly low certainty of conclusions. VEN combinations showed promising effects on mortality and remission but lacked data on QoL and functional status. In older adults with AML ineligible for conventional therapy, evidence suggests that hypomethylating agents or LDAC combined with VEN likely improves survival and remission outcomes. Treatment decisions should consider patient goals and functional status. These findings informed 8 recommendations in updated ASH-AML guidelines.