Precision Oncology in Hematological Malignancies: Pharmacogenomics for Enhanced Therapeutic Efficacy and Diminished Toxicity

Abstract

Hematological malignancies, including acute and chronic leukemias, lymphomas, and multiple myeloma, continue to present clinicians with diverse responses to traditional chemotherapies and kinase inhibitors due to myelosuppression, off-target effects, and acquired resistance. Pharmacogenomics lets you choose the right dose and regimen by showing how changes in important genes in the germ line affect pharmacokinetics, transporter activity, and target engagement. Critical pharmacogenes encompass ABC transporters (ABCB1, ABCC1) linked to multidrug efflux and relapse risk; cytochrome P450 isoforms (e.g., CYP2C19, CYP3A5) that affect tyrosine kinase inhibitor clearance; and TPMT and NUDT15, which are involved in thiopurine metabolism in acute lymphoblastic leukemia (ALL), where deficient variants lead to severe neutropenia. Pre-emptive genotyping has proven effective in diminishing toxicity rates, as evidenced by juvenile acute lymphoblastic leukemia datasets, achieving a 40–60% reduction in thiopurine-related events and enhancing event-free survival through tailored dosing. High initial costs, low-quality assays, limited access in low-resource areas, and equity disparities among diverse ancestries where NUDT15 variations are common continue to be challenges. Emerging multigene panels, AI-enhanced interpretation, and real-world data from initiatives such as the 100,000 Genomes Project promise improved remission rates and quality of life, indicating potential for further integration. Keywords: Reducing drug toxicity, Variations in TPMT/NUDT15, Precision oncology, Pharmacogenomics, Blood cancers