Timing of TP53 mutation acquisition as a determinant of outcomes in patients with myeloproliferative neoplasms and myeloproliferative neoplasms/myelodysplastic syndromes.

6587 Background: While TP53 mutations have been studied in MDS and AML, their clinical significance in MPN and MDS/MPN remains incompletely understood. Emerging evidence suggests that TP53 mutations are often not present at diagnosis, acquired over the disease course, and enriched in older patients (pts). The primary objective of this study was to evaluate whether the interval between diagnosis and the detection of TP53 mutation impacts OS and/or PFS. Methods: All patients with a TP53 mutation were identified via our in-house NGS panel between 2018–2024 were included (n=497). Spearman correlation, Kruskal–Wallis, and chi-square tests were used to evaluate associations between age, VAF, and the presence of co-mutations with the interval from diagnosis to TP53 detection. The Kaplan–Meier method and Cox proportional hazards models were used to analyze OS and PFS. Results: A total of 54 pts, including ET (n=27), PV (n=7), MF (n=9), and CMML (n=9) were identified. The median age at diagnosis was 65.1 yrs, 56% were males (n=30), 81% Caucasian (n=44). 22% (n=12) of pts were diagnosed with their MPN or MDS/MPN at the time of TP53 identification. 52% pts were treated with hydroxyurea prior to TP53 identification. At the time of TP53 detection, 13 pts had progressed to AML and 11 pts to MF. The most common co-mutations were JAK2 (n=19), CALR (n=11), TET2 (n=10) and ASXL1 (n=9). The median time from initial diagnosis to TP53 detection was 6.7 yrs (interquartile range [IQR], 0.8–13.4; range, 0–38 yrs). Pts were divided into 4 quartiles depending on timing of TP53 acquisition, with 13 pts in the <6-mo, 15 pts in the 6 mo–7 yrs, 13 in the 7.1-14 yrs and 13 pts in the >14 yrs quartiles. Older pts had a significantly shorter interval between diagnosis and TP53 detection (Spearman r = −0.61, p < 0.0001). In addition to older age in TP53 time < 6 months (Median 74,9 vs 64.0, p=0.005), pts in the <6-month group also had higher VAF (> median of 41: 69.2% vs 43.9%) and had higher number of co-mutations at diagnosis (≥3: 53.8% vs 26.8%), although this did not reach statistical significance. Older age at TP53 detection was associated with significantly worse OS (3.6 vs 27.2 mo; p=0.002) and PFS (3.6 vs 17.5 mo; p<0.001). After adjusting for age at the time of TP53 detection, a longer interval between diagnosis and TP53 detection was associated with worse OS (HR for the 2nd, 3rd, and 4th quartiles vs. the 1st quartile: 1.2, 2.5, and 4.3; p for trend = 0.002) and worse PFS (HR 1.2, 2.9, and 4.5, p for trend = 0.001). Conclusions: This study demonstrates that after adjusting for age, a longer interval between MPN or MDS/MPN diagnosis and TP53 detection is associated with worse OS and PFS. Older age has previously been identified as an adverse prognostic factor, however our findings suggest that timing of TP53 acquisition may also be an important predictor of clinical outcomes in pts with MPNs and MDS/MPNs.