Pharmacogenomics Applied to Acute Leukemias: Identifying Clinically Relevant Genetic Variants

Area of Science:

• Hematology
• Pharmacogenomics
• Oncology

Background:

• Acute leukemias (AML and ALL) require intensive chemotherapy, but drug toxicity limits treatment success.
• Pharmacogenomics, by analyzing genetic variants, offers a strategy to optimize chemotherapy efficacy and minimize toxicity.
• Single-nucleotide variants (SNVs) can influence drug metabolism, response, and adverse events in leukemia patients.

Purpose of the Study:

• To identify and analyze clinically relevant genetic variants affecting chemotherapy response and toxicity in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL).
• To evaluate the frequency and clinical significance of specific variants, including those in ABCB1, TPMT, and NUDT15, within leukemia patient cohorts.

Main Methods:

• Utilized the ClinPGx/PharmGKB database for curated, clinically annotated genetic variants.
• Analyzed variant data for AML and ALL, categorizing them by type (synonymous, nonsynonymous, intronic) and clinical significance.
• Focused on variants associated with drug metabolism, efficacy, and toxicity, including those in ABCB1, TPMT, NUDT15, ABCC1, SLC28A3, and RARG.

Main Results:

• Curated 24 variants for AML and 57 for ALL, with nonsynonymous variants more frequent in ALL and synonymous in AML.
• Identified clinically significant variants in ABCB1 in 12.5% of AML and 10.5% of ALL cases, suggesting a role in chemotherapy resistance.
• Associated variants in TPMT, NUDT15, ABCC1, SLC28A3, and RARG with severe adverse events like myelotoxicity, mucositis, cardiotoxicity, and hepatotoxicity.

Conclusions:

• Genetic variants play a crucial role in modulating chemotherapy response and toxicity in acute leukemias.
• ABCB1 variants may serve as resistance markers, while pre-treatment genotyping of TPMT and NUDT15 is recommended to prevent severe toxicities.
• Consolidating pharmacogenetic data and prospective validation are essential for integrating precision medicine into routine acute leukemia management.