TP53 MULTIHIT alterations in myelodysplastic neoplasms show a reduced adverse impact in patients with isolated del(5q), with significantly improved survival and delayed progression compared with other subtypes.
TP53 Multihit in Myelodysplastic Neoplasms
Myelodysplastic neoplasms are a heterogeneous group of disorders, with prognosis strongly influenced by genetic alterations. TP53 multihit alterations are typically associated with poor outcomes. In contrast, myelodysplastic neoplasms with isolated del(5q) are generally linked to favourable prognosis and are defined by the absence of TP53 multihit alterations. Uncertainty has remained regarding whether TP53 multihit alterations confer the same negative prognostic effect in this specific genetic context.
Comparative Outcomes in Del(5q) Disease
A retrospective analysis evaluated 43 patients with myelodysplastic neoplasms with isolated del(5q) harbouring TP53 multihit alterations and compared them with 68 patients with low blast myelodysplastic neoplasms with TP53 multihit alterations without isolated del(5q). Patients in the del(5q) cohort demonstrated distinct clinical features, including higher platelet counts and a greater frequency of SF3B1 mutations. They were also less frequently classified as high risk according to established prognostic scoring systems.
Importantly, survival outcomes differed markedly between the groups. Patients with isolated del(5q) and TP53 multihit alterations had a median overall survival of 70.2 months compared with 13.9 months in the comparator group. Time to progression to acute myeloid leukaemia was also significantly prolonged at 31.9 months versus 7.2 months.
Prognostic Implications of Genetic Context
The survival advantage observed in the del(5q) group remained significant even when compared with patients without complex karyotype. In this analysis, overall survival was 70.2 months compared with 39.9 months, while time to acute myeloid leukaemia progression was 31.9 months compared with 11.4 months.
These findings suggest that the genetic context of isolated del(5q) may mitigate the otherwise adverse prognostic impact of TP53 multihit alterations. This challenges the conventional understanding of TP53 driven risk and highlights the importance of integrating cytogenetic context into risk stratification.
For clinicians, these data underscore the need for nuanced interpretation of TP53 alterations in myelodysplastic neoplasms. Patients with isolated del(5q) may experience more favourable outcomes despite the presence of high-risk molecular features, with implications for prognostic assessment and management strategies.
Reference
Montoro MJ et al. How should myelodysplastic neoplasms with isolated deletion 5q and TP53 multihit alterations be classified? Leukaemia. 2026; https://doi.org/10.1038/s41375-026-02939-w.
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