TP53 Alterations Confer Increased Risk of Leukemic Transformation and Worse Survival As Compared to High Molecular Risk Mutations in Patients with Myeloproliferative Neoplasms
Authors: Handa Shivani , Amel Riazat-Kesh Yosef Joseph Rene , Butterfield Richard J , Sivakumar Ganesh , Venugopal Sangeetha , McGovern Erin , Feld Jonathan , Tremblay Douglas , Elghaity-Beckley Sebastian , Kremyanskaya Marina , Mascarenhas John O. , Langlais Blake , Mazza Gina L. , Nathan Daniel I. , Tripodi Joseph , Najfeld Vesna , Dueck Amylou C , Rampal Raajit , Hoffman Ronald , Marcellino Bridget Kelly 
Published: December 2024

Introduction
TP53 alterations (TP53+) are seen in &lt;5% of patients (pts) with chronic myeloproliferative neoplasms (MPNs) but are more common in accelerated/blast phase (MPN-AP/BP) [Luque Paz D, et al 2020]. While pts with low-burden TP53+ (Variant allele frequency (VAF) &lt;5%) may remain stable for years [Kubesova et al, 2018]; biallelic loss of TP53 is thought to confer higher risk for progression [Li et al, 2022] and worse overall survival (OS) than non-TP53+ pts [Rolles et al, 2023]. However, TP53 abnormalities have not been incorporated into currently utilized molecular based prediction models (MIPSS or MIPSS70) or compared with currently validated high molecular-risk (HMR) mutations (mut). We report the outcomes of the largest cohort of TP53+ MPN pts to date in comparison with HMR mut, and identify a VAF cut-off associated with highest risk of progression to MPN-AP/BP.
Methods
We retrospectively reviewed 2583 MPN pts from Mount Sinai Hospital (MSH) and Memorial Sloan Kettering Cancer Center (MSK) with at least one next generation sequencing (NGS) performed. Deidentified data from an additional cohort of 8 TP53+ MPN pts was received from University of Miami Sylvester Cancer Center (UMiami). Patient characteristics such as MPN subtype, gender, age at MPN diagnosis, driver mutation, thrombosis history were recorded. We also recorded date of transformation to MPN-AP/BP, dates of NGS testing, mutational and cytogenetic data, and survival status. We defined multi-hit TP53 as presence of =/&gt;2 TP53mut, VAF &gt; 50% or TP53 mutation + 17p deletion. Additional cohorts of pts with HMR mut (ASXL1, EZH2, IDH1/2, U2AF1, SRSF2 as per MIPSS70v.2) from MSH and non-TP53+ pts from the MPN-Research Consortium Tissue Bank were used as comparator arms. Patient characteristics were compared between TP53 single-hit and multi-hit using Chi-Sq test for categorical variables and Kruskal-Wallis test for continuous variables. Cumulative incidence function and Kaplan-Meier method were used to compare leukemic transformation and OS, respectively, between groups. Successive VAF levels with minimum groups of 25% of the total cohort were used to identify an optimal VAF cut-off.
Results
Of the 2583 MPN pts from MSH and MSK, 66 pts (2.6%) were found to have a TP53 mutation. Including 8 additional pts from UMiami, we analyzed a total of 74 TP53+ MPN pts; 40 single-hit and 34 multi-hit. Median age at MPN diagnosis was 61 years with a male predominance (60%). Distribution of driver mut was similar in single-hit vs multi-hit cohort with JAK2V617F being the most common (58%), whereas 11% of pts had triple negative disease . Thrombotic history was available for 45 TP53+ pts, with a high frequency of venous/arterial thrombosis (21/45 or 46.7%) in the TP53+ group as compared to 18.5% in the non-TP53+ MPN cohort (p= 0.0001). A significantly higher number of multi-hit TP53+ pts had a concurrent complex karyotype (79% vs 24% in single-hit; p&lt;.001).
MPN diagnosis at the time of detection of TP53+ was ET/PV (25.7%), MF (44.6%), MDS/MPN overlap syndrome (6.8%), MPN-U (2.7%) and MPN-AP/BP (20.3%), respectively. One or more genetic samples with TP53+ was available prior to transformation to MPN-AP/BP in 77% of pts (21/34 multi-hit; 36/40 single-hit) while a TP53+ was detected at the time of MPN-AP/BP diagnosis in the rest. Multi-hit TP53+ was associated with a significantly higher incidence of transformation to MPN-AP/BP as compared to single-hit; [65% vs 17.5%; HR=4.08 (1.71-9.71), p=0.0015]. Compared with HMR mut, multi-hit (HR=2.41; p=0.004) but not single-hit (HR=0.53; p=.277) TP53+ MPN pts were found to have a significantly increased risk of MPN-AP/BP transformation. One-year OS from the time of mutation detection was significantly inferior for both multi-hit (53.3%) and single-hit (75%) TP53+ pts as compared to HMR mut (98.8%, p=&lt;.001). Cut-point analysis identified VAF &gt;36% to be associated with the highest risk of transformation (HR=3.08) with lowest p-value (0.002).
Conclusions
Multi-hit TP53 alterations are associated with a significantly increased risk of leukemic evolution as compared to previously validated HMR mut, whereas both multi and single-hit TP53 mut are associated with worse OS highlighting the importance of TP53 in MPN disease progression.