Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered unfit to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of FLT3, IDH1, IDH2, or menin for patients with NPM1MUT or KMT2A rearrangements (KMT2Ar). Response rates (CR/CRi:40-90%) and overall survival outcomes (3-year: 0–67%) following Ven-HMA therapy are highly variable and depend primarily on tumor genetics while achievement of complete response with (CR) or without count recovery (CRi) and consolidation with allogeneic stem cell transplant (ASCT) are essential in securing long-term survival. Favorable genomic predictors of response to Ven-HMA include NPM1MUT, IDH2MUT, and DDX41MUT, and unfavorable TP53MUT, FLT3-ITD, and K/NRASMUT. Favorable predictors of overall survival include IDH2MUT, and unfavorable TP53MUT, FLT3-ITD, K/NRASMUT, and KMT2Ar. Whether or not triplet regimens provide significant survival gain over Ven-HMA in genetically targetable subgroups remains to be determined. Particularly frail patients who are considered unfit for Ven-HMA might benefit from monotherapy targeting FLT3MUT, IDH1/2MUT, NPM1MUTor KMT2Ar. Future research projects should focus on incorporating patient-reported outcomes in clinical trials, optimization of Ven-HMA dosing and treatment duration especially in triplet combinations and broadening the use of ASCT and clarification of its timing.
对于不适合接受强化化疗的新诊断急性髓系白血病（ND-AML）患者，其治疗模式随着对疾病生物学认识的加深而不断发展。在此背景下，治疗需明确界定目标，其中应包括保持生活质量（QoL）。维奈克拉联合去甲基化药物的方案是目前大多数情况下的标准治疗，在药物剂量、治疗时长以及联合用药（三联方案）或靶向治疗替代方案上具有灵活性，例如针对NPM1突变或KMT2A重排患者使用FLT3、IDH1、IDH2或menin抑制剂。维奈克拉联合去甲基化药物治疗的缓解率和总生存率差异显著，主要取决于肿瘤遗传学特征；而通过完全缓解（伴或不伴血象恢复）及异基因干细胞移植巩固治疗对确保长期生存至关重要。对维奈克拉联合方案反应良好的基因组预测因子包括NPM1突变、IDH2突变和DDX41突变，而不良预测因子包括TP53突变、FLT3-ITD和K/NRAS突变。总生存期良好的预测因子包括IDH2突变，而不良预测因子包括TP53突变、FLT3-ITD、K/NRAS突变和KMT2A重排。在基因靶向亚组中，三联方案是否比维奈克拉联合方案显著提高生存率仍有待确定。特别虚弱且不适合维奈克拉联合方案的患者可能受益于针对FLT3突变、IDH1/2突变、NPM1突变或KMT2A重排的单药治疗。未来研究应关注将患者报告结局纳入临床试验，优化维奈克拉联合方案的剂量和治疗时长（尤其在三联方案中），扩大异基因干细胞移植的应用并明确其时机。
Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms
肿瘤(癌症)患者之家