Gene polymorphisms in drug metabolic pathways

TPMT. Patients with variant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes,[198] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression, infection, and second malignancies.[199,200] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this variant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[201,202]

NUDT15. Germline pathogenic variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[201,203] The NUDT15 variants are most common in East Asian and Hispanic patients, and they are rare in European and African patients. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[201,204]

CEP72. Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[205]

Single nucleotide polymorphisms. Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of interleukin-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[206] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[207,208] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations. It is unknown whether individualized dose modification on the basis of these findings will improve outcomes.