Shifting Treatment Paradigms and Clinical Outcomes in TP53 Mutated Acute Myeloid Leukemia

Introduction:

Treatment for AML had remained stagnant for many decades prior to 2017, with the “7+3” regimen of cytarabine and anthracycline comprising the lone option for fit patients. Since then, there has been introduction of several novel and targeted therapies exploiting disease-specific pathophysiology. Our previous work showed improvement in medial overall survival (mOS) in AML patients from 8.8 months in 2015 to 19.7 months in 2019 (p = 0.003) in association with evolving treatment options. Here, we examine whether the expanding therapeutic options improved outcomes specifically in TP53 mutated AML, which represents one of the most unfavorable genetic subtypes with estimated mOS of 2-10 months.

Methods:

We identified 86 AML patients with a TP53 mutation and 150 patients with adverse-risk AML but wild-type TP53 who were treated at our institution from 2015 to 2024. Those in the TP53 mutated group were subdivided into those diagnosed in or prior to 2017 (-2017) and those diagnosed in 2018 and after (2018+). In addition, we performed subgroup analysis based on variant allele frequency (VAF), comparing those with <50% and >50% VAF. We collected data including demographics, cytogenetic and molecular profile, treatment regimens, best response, stem cell transplantation status (HCT), PFS, and survival. OS and PFS analysis completed and compared using the Kaplan-Meier method. Categorical variables were analyzed using Fisher's exact test.

Results:

The median age at diagnosis of AML was 66 years in the TP53 mutated group (TP53) and 63 years in the TP53 Wild Type (WT) group. The median Charlson Comorbidity Index (CCI) was 5 in both groups. Median progression free survival (mPFS) in the TP53 group was 77 days and in the WT group 78 days (p=0.833). mOS was 198 days in the TP53 group and 335 days in the WT group (p=0.0003). A complete response (CR) or CR with incomplete hematologic recovery (CRi) following induction was seen in 32.2% of the TP53 group compared with 36.9% in the WT group (p= 0.610). Overall response rate (ORR), including CR, CRi, PR, or morphologic leukemia free state, in TP53 group was 40.7% compared to 54.4% in the WT group (p=0.105).

In the subgroup analysis based on year of diagnosis, median PFS was 34 days and 101 days in the -2017 and 2018+ groups, respectively (p=0.022). However, median OS in the two groups was not meaningfully different as it was 193 days and 183 days in the -2017 and 2018+ groups, respectively (p=0.469). The short median PFS but longer mOS in the -2017 group could be attributed to outlying examples of successful reinduction and response to transplant. CR rate was numerically higher in the 2018- group with 37.2% compared to 18.8% in the -2017 group (p=0.222). Statistically significant improvement was seen with ORR, 48.8% in 2018- versus 18.8% in -2017 (p=0.036).

Subgroup analysis was performed based on VAF (>50% and <50%). The median PFS in the <50% group was 159 days and in the >50% group 38.5 days (p= 0.016 by Gehan-Breslow-Wilcoxon method). Interpretation of Kaplan-Meier analysis suggests this is largely due to early mortality (first 200 days) in the high VAF group. Median OS did not differ statistically between the two groups, although strongly numerically favoring the low VAF group, with 217 days and 121.5 days, respectively(p=0.2131). A significant difference in CR rates favoring the low VAF TP53 group was noted (55.6% and 5.9% respectively) (p=0.003), as did ORR (66.7% and 17.6% respectively) (p=0.006).

Conclusions:

With the advent of multiple new AML therapies since 2017, we have begun to see an improvement in PFS and response rates in even the highest-risk patient. Our data suggests that those with lower VAF <50% at diagnosis shows a better initial response to therapy with significantly higher CR rate. Improvement in exploitation of leukemic drivers in therapeutic decision making have improved outcomes even for this sub-group with a particularly dismal prognosis, however, further therapeutic advances are crucial to maintain the initial treatment response and improve overall survival in TP53 mutated AML.

No relevant conflicts of interest to declare.