ASH 2024 | Increased risk of leukemic transformation and worse survival in patients with TP53-mutated MPNs

TP53 mutations are seen infrequently in patients with chronic myeloproliferative neoplasms like essential thrombocytosis or polycythemia vera. However, they are one of the most common mutations in the accelerated or blast phase disease. Now, it’s well known that biallelic TP53 mutations lead to leukemic transformation and confer worse overall survival in MPNs. However, the impact of single-hit TP53 mutations has not been clearly defined, and these are currently not included in most prognostic scoring systems. In order to better elucidate the prognostic impact of both multi-hit and single-hit TP53 mutations, we compared these to other validated high molecular risk mutations that include ASXL1, EZH2, IDH1 and 2, SRSF2, and U2AF1. So looking at the rate of leukemic transformation, as expected, this was significantly higher for the multi-hit TP53 patients at about 30% at one year from mutation detection, whereas these were similar at about 10% for the single-hit TP53 and other high molecular risk patients. However, when you look at the overall survival, both single hit and multi-hit TP53 patients had a significantly worse overall survival as compared to patients with other high molecular risk mutations. So at one year for mutation detection, patients with high molecular risk mutations had a nearly 100% overall survival versus 75% for the single hit patients and 55% for the multi-hit patients. So even when the single-hit patients had a relatively lower risk of leukemic transformation, they still had an increased risk of death, mostly attributable to advanced myelofibrosis, often overlapping with MDS and bone marrow failure. So I think our study has important clinical implications in selecting candidates for transplant, since we clearly show that the single-hit TP53 patients have a worse overall survival, even when compared to patients with high molecular risk mutations. So these patients should be prioritized for transplant. And then MPN patients with TP53 mutations should be included under the umbrella of TP53 mutated myeloid malignancies to foster targeted therapy development for these patients, which is a critical unmet need. I do want to mention one important limitation of our study is its retrospective nature. So some of the patients did not have mutation testing available prior to transformation. So it’s difficult to accurately describe clonal dynamics and predict when that transformation is going to occur. So it’ll be ideal to study this in a prospective manner.

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