Pharmacogenomics of adverse effects of anti-leukemic agents in children.

I am honored to receive the 2011 Yaffe Award from the Pediatric Pharmacy Advocacy Group. Dr. Yaffe’s contributions to pediatric clinical pharmacology were enormous. In our own research, we have sought to improve the effectiveness of therapy for children with cancer through our research and by constantly working to translate research findings into the clinic. Pharmacogenetics of childhood acute lymphoblastic leukemia (ALL) includes determining the inherited basis for important drug-induced phenotypes in this disease. Phenotypes include efficacy phenotypes such as ex vivo drug sensitivity, minimal residual disease, and the risk of relapse. The disease also includes toxicity phenotypes such as thiopurine-induced myelosuppression, asparaginase-induced allergy, and glucocorticoid-induced osteonecrosis or methotrexate-induced gastrointestinal toxicity. I will review several examples of important pharmacogenetic relationships that have been elucidated in children with ALL. The approaches that we have taken to elucidate pharmacogenetic relationships in ALL include candidate gene approaches and genome-wide approaches. The first example of a candidate gene approach involves the gene for the enzyme thiopurine methyltransferase (TPMT). We have shown that polymorphisms in thiopurine methyltransferase affect mercaptopurine acute toxicity, mercaptopurine chronic toxicity, and the probability of cure. At St. Jude, we have been individualizing the dose of thiopurines based on the inherited genotype for TPMT since the early 1990s. For the 1 in 400 individuals who is homozygous for variant TPMT alleles, the thiopurine is decreased dramatically, with over a 10-fold decrease in the daily dose compared to patients with normal TPMT activity. The 10% of the population who are heterozygous, carrying one wild-type and one variant allele, normally require somewhat reduced doses of thiopurines. The 90% of patients who are homozygous for wild-type TPMT alleles are usually able to tolerate normal doses of the drug. Individuals who are homozygous for variant alleles are at high risk of life-threatening myelosuppression if they are treated with normal doses of the drug, whereas those patients who are homozygous for wild-type alleles tend to be at a lower risk of acute myelosuppression but also at a slightly increased risk of relapse. The proportion of patients with ALL who can avoid a dose decrease of 6-mercaptopurine is based on their TPMT status, that is, patients who carry the wild-type alleles are more able to avoid a dose decrease (Figure 1) than those who are heterozygotes or homozygous-bearing individuals. These findings were closely mimicked by a murine model of TPMT status in which the knockout mice were unable to tolerate full doses of 6-mercaptopurine without experiencing fatal toxicity. Using this knowledge at St. Jude, we began to adjust the doses of mercaptopurine in patients based on a combination of their TPMT genotype and their clinical tolerance. After we introduced genotype-adjusted dosing for thiopurines, we observed no change in the cumulative incidence of acute adverse effects in individuals who were carrying variant alleles for TPMT compared to that of those who were wild-type for TPMT, consistent with the notion that adjusting doses of thiopurines could attenuate or abrogate the adverse effect of thiopurines that is attributable to TPMT status. We also showed that this approach to adjusting thiopurine doses based on TPMT genotype and acute myelosuppression did not result in any increased risk of relapse in the patients who