Pharmacogenomics Applied to Acute Leukemias: Identifying Clinically Relevant Genetic Variants

TL;DR

This paper explores how genetic variants affect chemotherapy outcomes in acute leukemias, highlighting genes like ABCB1 and TPMT that influence drug response and toxicity.

Contribution

The study identifies clinically relevant genetic variants in AML and ALL using the ClinPGx/PharmGKB database, emphasizing their role in drug response and toxicity.

Findings

Nonsynonymous variants are more frequent in ALL compared to AML.

ABCB1 variants are linked to chemotherapy resistance in acute leukemias.

TPMT and NUDT15 variants are associated with severe drug toxicities.

Abstract

Acute leukemias are highly aggressive hematologic malignancies that demand intensive chemotherapy regimens. However, drug toxicity remains a major barrier to treatment success and patient survival. In this context, pharmacogenomics offers a promising strategy by identifying single-nucleotide variants (SNVs) that influence drug metabolism, efficacy, and toxicity, ultimately impacting treatment outcomes. This study analyzed data from the ClinPGx/PharmGKB database to identify clinically annotated variants related to chemotherapy response in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). A total of 24 variants were curated for AML and 57 for ALL. Among these, nonsynonymous variants were most frequent in ALL (31.6%), while synonymous variants predominated in AML (33.3%). Although traditionally considered neutral, synonymous and intronic variants may influence gene expression through regulatory or splicing mechanisms. The analysis revealed clinically significant variants associated with chemotherapy response, particularly in the ABCB1 gene, observed in 12.5% of AML and 10.5% of ALL cases. Several variants, particularly TPMT, NUDT15, ABCC1, SLC28A3, and RARG, were associated with severe adverse effects such as myelotoxicity, mucositis, cardiotoxicity, and hepatotoxicity. This study reinforces the importance of genetic variants in modulating the therapeutic response and toxicity to chemotherapy drugs in acute leukemias. Analysis of ClinPGx/PharmGKB data emphasizes ABCB1 as a potential resistance marker and supports pre-treatment genotyping of genes like TPMT and NUDT15 to prevent severe toxicities. Future advances should include the expansion of pharmacogenetic studies in underrepresented populations and the clinical validation of new markers in prospective trials, aiming to consolidate precision medicine as a routine part of the therapeutic management of acute leukemias.

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