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, where the risk of toxicity must be balanced against potential suboptimal (low) systemic exposure that can be less effective in patients with the 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 inter-patient differences in drug response and disease risk, hold great promise to ultimately enhance the efficacy and reduce the toxicity of drug therapy in children.

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

“…90 The case for complete omission of prophylactic cranial irradiation Studies of survivors of childhood ALL have found that prophylactic cranial irradiation can cause many late-occurring sequelae, including second cancers, neurocognitive impairment, and multiple endocrinopathy. 91,92 Recognizing the devastating complications of cranial irradiation, pediatric oncologists have steadily reduced the use of this treatment modality since the late 1970s.…”

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy

“…PEG-asparaginase demonstrates a prolonged half-life and decreased renal excretion relative to the parent compound [15]. In addition, the pegylated formulation increases efficacy and reduces the possibility of antibody generation by preventing reticuloendothelial uptake [16, 17]. The newly developed Erwinia asparaginase produced a lower rate of allergic reaction and has been demonstrated to produce effective asparaginase activity even in patients who had previously experienced an allergy to PEG-asparaginase [18].…”

“…Since 3–14% of patients are heterozygous for TPMT associated with lower enzyme activity, routine pre-treatment testing is suggested and once identified, these patients should start with a dose reduction in the 6-MP level by 30–70% [53]. Notably, the FDA now recommends testing for the most commonly identified inactive SNP genotype, which can prospectively predict patients at higher risk of developing 6-MP-induced hematopoietic toxicity [16, 49, 50]. It is most useful in ALL protocols containing high doses 6-MP (>50 mg/m 2 /day) [5].…”

Clinically Relevant Pharmacogenomic Testing in Pediatric Practice

“…Heterozygotes typically need a dose reduction between 35% and 50%, and homozygotes need a dose reduction of about 90%. 3,4 Expression of TPMT does not change significantly during development, 6 allowing use of these suggested dose reductions across the pediatric and adult spectrum. As azathiopurine is a prodrug of 6-MP, its pharmacokinetics involves TPMT, and prospective genotyping is recommended.…”