Patients with TP53 aberrations comprise the highest risk subset of all myeloid malignancies. The managerial conundrum of TP53-mutant myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) stems from refractoriness to or relapse after conventional chemotherapy, as well as the limited translational success of investigational therapies targeting TP53-mutant cells. Thus far, no targeted therapies have been commercially approved for this mutational subset. As a result, management plans for patients with TP53-mutant MDS and AML are often driven by clinical judgment and/or physician preference rather than consensus guidelines backed by a rigorous evidence basis. This clinical case-based, evidence-driven review highlights the most salient data that guides the management of commonly encountered patient prototypes. This review discusses the therapeutic menu of first-line options that derive from multi-institutional experiences as well as from disease-centric consortia and discusses how these first-line options can be optimally tailored to heterogeneous groups of patients. The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents – eprenetapopt, magrolimab, sabatolimab, and idasanutlin – and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.

TP53 畸变患者是所有髓系恶性肿瘤中风险最高的亚组。TP53 突变型骨髓增生异常肿瘤 （MDS） 和急性髓性白血病 （AML） 的管理难题源于常规化疗难治性或复发性，以及针对 TP53 突变细胞的研究性疗法的转化成功有限。到目前为止，尚未针对该突变亚群的靶向治疗获得商业批准。因此，TP53 突变 MDS 和 AML 患者的管理计划通常由临床判断和/或医生偏好驱动，而不是由严格证据基础支持的共识指南驱动。这项基于临床病例、循证驱动的综述突出了指导常见患者原型管理的最重要数据。本综述讨论了源自多机构经验以及以疾病为中心的联盟的一线选择治疗方案，并讨论了如何针对异质性患者群体优化这些一线治疗方案。总结了关于是否应该向这些患者提供同种异体干细胞移植的争论。最后，这篇综述探讨了最近领先的研究药物 eprenetapopt、magrolimab、sabatolimab 和 idasanutlin 临床试验暂停的不幸消息，并为在 2025 年重振精准治疗管道提供了解决方案。