Clinical and Molecular Characteristics of Acute Myeloid Leukemia (AML) Patients with TP53 Mutations and TP73 Mutations
Authors: Mims Alice S. , Kohlschmidt Jessica , Eisfeld Ann-Kathrin , Mrózek Krzysztof , Blachly James S. , Orwick Shelley , Papaioannou Dimitrios , Nicolet Deedra , Sampath Deepa , Stone Richard M. , Powell Bayard L. , Kolitz Jonathan E. , Byrd John C. , Bloomfield Clara D. 
Published: October 2019

Abstract
Introduction: Patients (pts) with AML who harbor TP53 mutations (TP53m) have a poor prognosis, with complete remission (CR) rates of 20-30% with standard intensive cytarabine/daunorubicin induction regimens (7+3) and median disease-free survival (DFS) of 4-6 months. There is a high risk of relapse after allogeneic stem cell transplantation (allo SCT) with 3-year overall survival (OS) of 10-12%. Another member of the p53 family is TP73, expressed as multiple protein isoforms that range in function from tumor suppressive activity to promoting oncogenic activities through control of cell survival and cell renewal. The TP73 gene resides in the short arm of chromosome 1; although this region is frequently deleted in a broad range of tumors, TP73 is rarely mutated in cancer. In the era of next-generation sequencing (NGS), TP73 mutations (TP73m) have not yet been described in AML to our knowledge. Herein we describe AML pts with TP73m and compare their outcomes with those of pts with TP53m and pts without TP73m or TP53m.
Methods: Mutational assessment of 81 leukemia- and/or cancer-associated genes using a customized NGS approach was performed on samples from 1165 pts (age ≥18 years) with newly diagnosed AML, treated with standard 7+3 followed by cytarabine +/- anthracycline based consolidation (Eisfeld et al., Leukemia 2017;31:2211-8).
We identified 3 groups of pts: wild-type (wt) for both TP53 and TP73,TP53m (including 2 pts with TP73m), and TP73m/TP53wt (TP73m). We made statistical comparisons between groups regarding co-mutations, mutational functional groupings, and outcomes using Fisher's exact test, Kruskal Wallis test, Kaplan-Meier curves, and log rank test.
Results: We identified 106 pts with TP53m and 11 pts with TP73m; 1048 pts were confirmed to be wt for both. TP73m pts were all found to have missense mutations, with the majority of variant allele frequencies (VAF) >20%, suggesting these mutations likely represent early mutational events similar to TP53m. Evaluation of mutations in other genes in TP73m pts revealed that most frequent were FLT3-ITD (27%) and mutations in ASXL1 (18%), DNMT3A (18%), IDH2 (18%), NPM1 (36%), RUNX1 (18%), STAG2 (18%), TET2 (27%), and U2AF1 (18%) genes. Frequencies of these mutations were similar to those seen in wt pts, except for higher frequencies of STAG2 (P=.05) and U2AF1 (P=.05) mutations in TP73m pts. No mutation occurred in TP53m pts with a significantly higher frequency than that found in wt pts. However, FLT3-ITD (P<.001), FLT3-TKD (P<.001), and mutations in DNMT3A (P<.001), GATA2 (P=.02), NPM1 (P<.001), SMC1A (P=.04), and WT1 (P<.001) were less frequent in TP53m pts than in wt pts. Compared with TP53m pts, TP73m pts carried NPM1 (P=.005) and U2AF1 (P=.02) mutations more often than TP53m pts.
Pretreatment characteristics of pts with TP73m were similar to those of wt pts, except for lower white blood cell counts (WBC) in the former (P=.05). No differences were seen between TP73m and TP53m pts. In contrast, compared with wt pts, TP53m pts were older (P<.001) and presented with lower platelet count (P=.05), WBC (P<.001) and blast percentage of both blood and bone marrow (P<.001 for both), and had less frequent extramedullary involvement (P=.04). Assessment of mutational functional group involvement showed that mutations in chromatin remodeling (P=.004), methylation (P=<.001), and NPM1 (P<.001) were less frequent in TP53m pts than in both TP73m and wt pts. TP53m pts also had fewer mutations in the kinases (P<.001) and RAS pathway (P<.006) compared to wt pts. TP73m pts had more cohesion group mutations than either TP53m (P=.01) or wt pts (P=.04).
There were no significant differences in CR, DFS or OS between TP73m and wt pts. However, compared to both TP73m and wt pts, TP53m pts had shorter DFS (P=.005 for TP73m and P<.001 for wt, respectively), event-free survival (EFS) (P=.001 for TP73m and P<.001 for wt, respectively) and OS (P<.001 for both). CR rates of TP53m pts were worse than those of wt pts (P<.001), but there was no significant difference in CR rates between TP53m and TP73m pts (P=.12).
Conclusion: TP73m are recurrently found in adult AML pts, albeit with a lower frequency than TP53m. TP73m does not appear to portend the poor prognosis seen in TP53m pts in regards to DFS, EFS and OS and have outcomes that appear to be similar to wt pts.
Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171; ClinicalTrials.gov Ids: NCT00048958, NCT00900224
Figure. Figure.

Disclosures
Mims: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria.