Prognostic and Therapeutic Implications of Mutant TP53 Variant Allelic Frequency in Adults with Newly Diagnosed TP53-Mutated Acute Myeloid Leukemia
Authors: Short Nicholas J. , Montalban-Bravo Guillermo , Hwang Hyunsoo , Ning Jing , Franquiz Miguel , Kanagal-Shamanna Rashmi , Patel Keyur , Dinardo Courtney D. , Ravandi Farhad , Garcia-Manero Guillermo , Takahashi Koichi , Konopleva Marina , Daver Naval , Jabbour Elias , Yilmaz Musa , Issa Ghayas C. , Andreeff Michael , Kadia Tapan M. 
Published: November 2020

Background: TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 variant allelic frequency (TP53mut VAF) in AML is not well-established, nor is how this information might guide optimal frontline therapy.
Methods: We performed a retrospective study of 202 patients (pts) with TP53-mutated AML receiving frontline therapy and evaluated the impact of TP53mut VAF on cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS) and its interaction with type of therapy received. In cases of multiple TP53 mutations , the highest TP53mut VAF was used for analysis. Treatments were divided into 4 categories: 1.) intermediate or high-dose cytarabine (IDAC/HDAC)-based, 2.) low-dose cytarabine (LDAC)-based, 3.) HMA-based (excluding venetoclax), and 4.) HMA plus venetoclax. Groups 1 and 2 ("cytarabine" group) and groups 3 and 4 ("HMA" group) were combined for some analyses. Response was defined as achievement of CR or CRi.
Results: Baseline characteristics of the study population are shown in Table 1. The median TP53mut VAF was 43% (range, 1%-100%), and 48 pts (24%) had &gt;1 TP53 mutation.
The impact of TP53mut VAF on response rates was treatment-dependent. In the HMA group, no baseline variables were associated with response. In contrast, by multivariate analysis, independent predictors for response in the cytarabine-treated group included older age (odds ratio [OR] 0.87; P=0.001), &gt;1 TP53 mutation (OR 0.07; P=0.02) and TP53mut VAF &gt;40% (OR 0.09; P&lt;0.001). Among pts with TP53mut VAF &gt;40%, response rates were higher in those who received HMA-based therapy compared to those who received cytarabine-based therapy (54% and 28%, respectively; P=0.008), whereas response rates were not significantly different among pts with VAF ≤40% (44% and 61%, respectively; P=0.12).
In the whole cohort stratified by TP53mut VAF &gt;40% vs. ≤40%, the 1-year CIR rates were 85% and 48%, the 1-year RFS rates were 10% and 44%, and the 1-year OS rates were 19% and 35%, respectively. By multivariate analysis, TP53mut VAF &gt;40% vs. ≤40% remained a significant predictor for higher CIR (hazard ratio [HR] 2.25, P=0.003) and worse RFS (HR 2.21, P=0.001) and OS (HR 1.61, P=0.003).
The worse outcomes for pts with TP53mut VAF &gt;40% were driven primarily by those who received cytarabine-based therapy. Among pts treated with a cytarabine-based regimen, those with a TP53mut VAF &gt;40% had significantly worse outcomes than those with VAF ≤40% (median OS: 4.8 vs. 7.3 months, respectively; P=0.006), whereas there was no significant difference in outcomes according to VAF among HMA-treated pts (median OS: 5.7 months vs. 7.0 months, respectively; P=0.22) (Figure 1). Pts with VAF ≤40% who received IDAC/HDAC had a median OS of 18.1 months and 2-year OS of 41%; in contrast, those with VAF &gt;40% who received IDAC/HDAC had a median OS of only 5.0 months and 2-year OS of 14% (P=0.02). Among those with TP53mut VAF ≤40%, pts treated with a cytarabine-based regimen had superior OS compared to those who received an HMA-based regimen (1-year OS rates of 44% and 31%, respectively; P=0.04), with the best outcomes in those pts who received IDAC/HDAC-based therapy. Among those with TP53mut VAF &gt;40%, outcomes were similar among the treatment groups, and survival was universally poor with 1-year OS &lt;25% in all groups.
Overall, 20 pts with TP53-mutated AML underwent hematopoietic stem cell transplantation (HSCT) in first remission, with a median time to HSCT of 3.6 months. Using a landmark analysis at 3.6 months, HSCT in first remission was associated with a significant improvement in OS (median OS 17.6 months and 2-year OS 50% vs. median OS 9.1 months and 2-year OS 12%, respectively; P=0.006). By multivariate analysis including HSCT as a time-dependent variable, HSCT in first remission was independently associated with improved CIR, RFS, and OS (P&lt;0.001 for all). Transplanted pts with TP53mut VAF ≤40% had a trend towards better OS compared to transplanted pts with VAF &gt;40% (P=0.07).
Conclusions: TP53mut VAF is highly prognostic for response, relapse and survival in pts with TP53-mutated AML, particularly for those treated with conventional cytotoxic chemotherapy. Given the treatment-dependent impact of TP53mut VAF on clinical outcomes, VAF should be assessed when considering frontline therapy options. Further development of effective novel therapies is needed for this poor risk subgroup of pts.

Disclosures
Short: Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Honoraria. Dinardo:Takeda: Honoraria; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding. Konopleva:Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Ablynx: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Kadia:Cellenkos: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Amgen: Research Funding; Astra Zeneca: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding.