Transplant for TP53-mutated MDS and AML: because we can or because we should?

Abstract

TP53 mutations impair the cellular response to genotoxic stress and drive intrinsic resistance to conventional cytotoxic therapies. Clinical outcomes in patients with TP53-mutated myeloid malignancies are poor and marked by high-risk clinical features, such as complex karyotype and prior exposure to leukemogenic therapies, and short survival due to a high risk of relapse after allogeneic transplantation. TP53 mutations are thus included as adverse markers in clinical prognostic models, including European LeukemiaNet recommendations and the Molecular International Prognostic Scoring System for myelodysplastic syndromes (MDS). Recent data indicate that the TP53 allelic state, co-occurring somatic mutations, and the position of the TP53 mutation within the clonal hierarchy define genetic heterogeneity among TP53-mutated MDS and acute myeloid leukemia that may influence clinical outcomes, thereby informing the selection of patients most suitable for transplantation. Further, novel therapeutic methods such as antibody-based agents (monoclonals or dual-affinity retargeting antibodies), cellular therapies (natural killer cells, chimeric antigen receptor T cells), or targeted agents (eprenetapopt) may offer opportunities to modify the approach to pretransplant conditioning or posttransplant maintenance and improve clinical outcomes.