During the 66th American Society of Hematology Annual Meeting and Exposition, Shivani Handa, MD, of the Division of Hematology at The Ohio State University Wexner Medical Center in Columbus, presented findings showing that TP53 alterations (TP53+) have a stronger association with overall survival (OS) and risk of leukemic progression in patients with myeloproliferative neoplasms (MPN) than previously validated high-molecular risk (HMR) mutations used in the MIPSS70v.2 scoring system.
“We are trying to shed light on the prognostic significance of TP53+, particularly single-hit TP53+ where there may be a scope for early intervention with selecting candidates for transplant,” Dr. Handa said.
The retrospective study included 74 total patients (median age = 61; 60% male) with TP53+ MPN (40 single-hit TP53+, 34 multi-hit TP53+). Most patients (78%; 37/40 single-hit, 21/34 multi-hit) had detectable TP53+ before transformation to MPN-accelerated/blast phase (AP/BP). The comparator arm included 87 patients with HMR mutations (ASXL1, EZH2, IDH1/2, U2AF1, SRSF2).
Researchers compared patient characteristics, leukemic transformations, and OS. They also sought to determine the cut-point of variant allele frequency (VAF) associated with the highest risk of progression to MPN-AP/BP.
VAF greater than 36% was identified as the optimal cut-point associated with the highest risk of transformation (p=0.002). “As expected, the risk continues to increase with higher VAF levels; every 10% increase in VAF was associated with a 16% increase in the risk of evolution,” Dr. Handa said.
One year after mutation detection, patients with both single-hit and multi-hit TP53+ experienced significantly inferior OS than patients with HMR mutations (75% and 55%, respectively, vs. 99%; p≤0.001).
Additionally, patients with multi-hit TP53+ had a significantly higher incidence of transformation to MPN-AP/BP than single-hit patients (64.7% vs. 17.5%; p=0.0015). When compared with patients with HMR mutations, the multi-hit but not single-hit TP53+ cohort had a significantly higher risk of transformation to MPN-AP/BP (p=0.00354).
“Patients who were in the chronic phase only transformed to acute leukemia when they acquired that second hit. However, when it comes to patients with myelofibrosis, single-hit TP53+ — especially with a high VAF between 40% to 50% — can be a risk factor for transformation to leukemia,” Dr. Handa said. She recommends “testing all patients with newly diagnosed MPN at baseline and then retesting at regular intervals to potentially intervene prior to leukemic transformation.”
Researchers cited heterogeneity in the timing of next-generation sequencing as a limitation because it “limits our ability to clearly determine when patients transformed into accelerated or blast phase,” said senior author Bridget Marcellino, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York. “Thinking prospectively, we’d like to evaluate TP53+ at defined clinical timepoints in sub-cohorts of specific MPN diagnosis to confirm these findings.”
“Single-hit TP53+ is a high-risk group with worse OS, often with a more myelodysplastic syndromes (MDS)-like phenotype,” Dr. Handa said. “One could argue that these patients should be included under the same umbrella of TP53 myeloid neoplasms, and then hopefully they can be included in future clinical trials that are designed for TP53-mutated MDS or acute myeloid leukemia, where currently patients with MPN are not included.”
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Handa S, Riazat-Kesh Y, Marcellino B, et al. TP53 alterations confer increased risk of leukemic transformation and worse survival as compared to high molecular risk mutations in patients with myeloproliferative neoplasms. Abstract 243. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.
