Pharmacogenomics in pediatric leukemia

Abstract

Purpose of review: The therapeutic index of many medications, especially in children, is very narrow with substantial risk for toxicity at doses required for therapeutic effects. This is particularly relevant to cancer chemotherapy, when the risk of toxicity must be balanced against potential suboptimal (low) systemic exposure that can be less effective in patients with higher rates of drug clearance. The purpose of this review is to discuss genetic factors that lead to interpatient differences in the pharmacokinetics and pharmacodynamics of these medications.

Recent findings: Genome-wide agonistic studies of pediatric patient populations are revealing genome variations that may affect susceptibility to specific diseases and that influence the pharmacokinetic and pharmacodynamic characteristics of medications. Several genetic factors with relatively small effect may be combined in the determination of a pharmacogenomic phenotype and considering these polygenic models may be mandatory in order to predict the related drug response phenotypes. These findings have potential to yield new insights into disease pathogenesis, and lead to molecular diagnostics that can be used to optimize the treatment of childhood cancers.

Summary: Advances in genome technology, and their comprehensive and systematic deployment to elucidate the genomic basis of interpatient differences in drug response and disease risk, hold great promise to ultimately enhance the efficacy and reduce the toxicity of drug therapy in children.

Figure 1

Adjustment of mercaptopurine therapy on the basis of TPMT status allows reduction in toxicity with no decrease in efficacy. The upper panels depict the predominant TPMT variant alleles causing autosomal codominant inheritance of TPMT activity in humans. As depicted in the subsequent lower panels, when uniform conventional body surface based dosing of thiopurine medications are applied to patients, TPMT-deficient patients accumulate marked higher (10-fold) cellular concentrations of the active thioguanine nucleotides (TGN) and heterozygous patients accumulate approximately two-fold higher TGN concentrations, determining a significantly higher frequency of toxicity (lower left panel). As depicted in the lower right panel, personalization of therapy of mercaptopurine according to TPMT status, integrating assessment of TPMT genotype, TPMT activity and TGN levels, comparable cellular TGN concentrations are achieved and all three TPMT phenotypes can be treated without acute toxicity [–16]. Mercaptopurine individualized dosing has no detrimental effect on the efficacy of therapy [17]. At St. Jude Children’s Research Hospital, in the current treatment protocol for ALL, TPMT status is assessed in all patients as follows in order to individualize mercaptopurine dosing: TPMT genotype is assessed at diagnosis, while TPMT activity and TGN are measured at start of reinduction therapies; TGN and TPMT activity are measured subsequently in patients with high TGN level, suspected noncompliance, problems with toxicities or high blood counts. Figure modified with permission from Evans, 2002 [18].