High-Risk TP53-Mutated Acute Myeloid Leukemia in Puerto Rico: Elevated Variant Allele Frequency and Clinical Implications

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with poor prognosis, particularly in patients with TP53 mutations. TP53 mutations disrupt tumor suppressor gene function, causing genomic instability, chemoresistance, and adverse clinical outcomes. Variant allele frequency (VAF) of TP53 mutations carries prognostic significance, with higher VAF (>40%) being linked to worse outcomes. Despite extensive research on TP53 mutations in AML, there is a lack of knowledge regarding their prevalence and specific characteristics in the Puerto Rican community.

Methods: This is a retrospective study of newly diagnosed AML patients with TP53 mutations detected via next-generation sequencing (NGS) at San Juan City Hospital, a primary referral center for AML in Puerto Rico. We analyzed patient demographics, cytogenetics, molecular markers, and VAF of TP53 mutations. This study is compliant with the Declaration of Helsinki for Studies.

Results: Among the 184 newly diagnosed AML patients identified during the study period (2020-2024), 14% (N = 25) exhibited TP53 mutations. Within this subset, 64% were male, with a median age of 66 years. The average TP53 VAF was 47%, higher than reported in previous studies, with 65% of cases exhibiting a VAF >40%. We identified complex cytogenetics in 72% of cases, with 36% having co-occurring RUNX1 mutations and 40% having 5q deletions. Additionally, 57% of the cohort had biallelic TP53 mutations. Outcome data showed only 4 patients surviving, with 2 having undergone allogeneic stem cell transplant and the other 2 currently receiving treatment.

Conclusion: This study is the first to describe TP53 mutated AML in patients from Puerto Rico. There is an elevated prevalence of TP53 VAF, biallelic mutations, and concurrent RUNX1 and 5q deletions compared to the general population. These findings suggest that Puerto Rican patients with TP53 mutated AML form a high-risk subgroup burdened by TP53 mutations. Further investigations are required to understand the reasons behind the elevated VAF in this community, considering the unique sociostructural factors influencing health on the island and existing health inequalities. Additionally, our findings highlight the necessity for targeted treatments and personalized therapeutic strategies for this high-risk group due to their connection with chemoresistance and poor prognosis. Tackling these challenges through appropriate and fair healthcare interventions is essential for improving outcomes for this vulnerable population.

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