Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia.

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.