Prognostic and Therapeutic Implications of Mutant TP53 Variant Allelic Frequency in Adults with Newly Diagnosed TP53­-Mutated Acute Myeloid Leukemia

Background: TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 variant allelic frequency (TP53^mut 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 TP53^mut 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 TP53^mut 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 TP53^mut VAF was 43% (range, 1%-100%), and 48 pts (24%) had >1 TP53 mutation.

The impact of TP53^mut 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), >1 TP53 mutation (OR 0.07; P=0.02) and TP53^mut VAF >40% (OR 0.09; P<0.001). Among pts with TP53^mut VAF >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 TP53^mut VAF >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, TP53^mut VAF >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 TP53^mut VAF >40% were driven primarily by those who received cytarabine-based therapy. Among pts treated with a cytarabine-based regimen, those with a TP53^mut VAF >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 >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 TP53^mut 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 TP53^mut VAF >40%, outcomes were similar among the treatment groups, and survival was universally poor with 1-year OS <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<0.001 for all). Transplanted pts with TP53^mut VAF ≤40% had a trend towards better OS compared to transplanted pts with VAF >40% (P=0.07).

Conclusions: TP53^mut 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 TP53^mut 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.