Real-world comprehensive single-institution analysis of AML with TP53-mutation

Abstract

Abstract Intro Acute myeloid leukemia (AML) with TP53 mutations (TP53m) are associated with dismal outcomes with median overall survival (OS) 5-6 months for both intensive and non-intensive chemotherapy regimens. There are high rates of treatment resistance and optimal treatment strategies for this high-risk group remain undefined. For younger/fit patients (pts), intensive induction therapy is often considered while hypomethylating agents (HMA's) with or without venetoclax remains the standard for older/unfit pts. However, it is unclear whether intensive chemotherapy improves outcomes in younger/fit pts. We set out to assess and compare clinical outcomes of newly diagnosed TP53m AML pts treated with intensive versus low-intensity therapy within a uniform single-institutional cohort. Methods We conducted a retrospective analysis of 125 pts with newly diagnosed TP53m AML treated at the University of North Carolina between 2015-2024 including demographic and clinical variables (age, sex, race, BMI, comorbidities, smoking, treatments, and outcomes). All pts received a next generation sequencing (NGS) mutational panel at diagnosis consisting of 49 variants including TP53. BiallelicTP53m AML was defined by 2 or more TP53m, TP53m variant allele fraction (VAF) >50%, or TP53m with loss of 17p by cytogenetics or FISH consistent with 2022 WHO criteria. All other TP53m were classified as monoallelic or unknown (if VAF was unknown). Frontline treatment regimens were stratified by intensive induction therapy (IIT) including 7+3 with or without cladribine, CPX-351, or clofarabine, cytarabine, G-CSF (CLAG) with or without investigational therapies. Low-intensity therapy (LIT) was defined as HMA's with or without venetoclax or other targeted therapies including investigational agents. Categorical variables were compared using the Chi-square test or Fisher's exact test, as appropriate. Kaplan-Meier survival analysis was used to estimate overall survival, with group comparisons performed using the log-rank test. Analyses were conducted using SAS software. Results Of all 125 pts with TP53m AML, 65 (52.0%) were male and 94 (75.2%) were Caucasian, 21 (16.8%) were African American, 4 (3.2%) patients were Asian and 4 (3.2%) were Hispanic ethnicity. Median age was 68.5 years (range 35-93). The majority of pts (n=109: 87.2%) had complex karyotype while 30 (24%) had therapy-related AML. Most pts were classified as biallelic TP53m (n=78: 62.4%) vs. monoallelic (n=25: 20.0%) vs. unknown: (n=22: 17.6%). Overall, there was a trend for worse OS in pts with biallelic vs monoallelic TP53m (median OS 5.2 months (mo) vs 8.2mo, p=0.07). 60-day mortality was 20.5% of the cohort, with significantly higher rate in pts with biallelic TP53m (20.5% vs 4%, right-sided p=0.04). 51 (40.8%) pts underwent treatment with IIT (median OS = 6.9mo), with the remaining 74 (59.2%) treated with LIT (median OS = 4.6mo). Composite CR (CRc) was significantly higher in pts treated with IIT vs. LIT (49.0% vs 16.2%, respectively; p<0.001). There was no statistically significant association between initial treatment type and median OS. 20 (16.1%) of patients were treated with novel agents on clinical trial and demonstrated improved median OS compared to those treated with standard of care regimens (9.5 mo vs 5.1mo p=0.01), including without proceeding to alloHCT (8.8 mo vs 4.5 mo, p=0.01). 12 (9.6%) pts underwent allogenic stem cell transplant (alloSCT) and had significantly improved median OS compared with those who did not undergo alloSCT (median OS 25.0 months vs 5.1 months, range p<0.001). Among 5 pts with biallelic TP53m who underwent alloSCT, the median OS was 27.3 months, including one pts with TP53 VAF of 87% with OS 30mo. Conclusion In this single-institution cohort of patients with TP53-mutated AML, OS remained poor across treatment approaches with improved outcomes with investigational therapies. AlloSCT was associated with improved OS outcomes, although a limited proportion of patients were able to proceed to alloSCT as consistent with previously published data. These findings underscore the urgent need to develop novel therapeutic strategies, prioritize clinical trial options, and optimize alloSCT selection and timing for patients with TP53m AML.