Clinical Pharmacogenetics in Pediatric Patients

Anwar Husain; Jennifer A. Loehle; David W. Hein


Pharmacogenomics. 2007;8(10):1403-1411. 

In This Article

Childhood Leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Only 50 years ago, childhood ALL was considered to be universally fatal. However, in perhaps one of the greatest success stories in pediatric oncology, long-term, event-free survival rates are currently almost 80%.[12,13] Nevertheless, many challenges still exist in treating ALL and individualizing treatment therapies. Better ways of predicting which patients require less toxic therapies and which patients would benefit from augmented therapy would allow for safer, more efficacious treatment plans. Development of novel treatment options for those nearly 20% of patients who do not respond to standard therapy must also be emphasized. Patients characterized as having ultra-low-risk ALL have begun to be treated with less intensive therapies, and those children at high risk for relapse are receiving transplantation less frequently. Differentiating patient groups prior to the initiation of treatment still remains challenging, since therapy for ALL ultimately remains highly toxic, nonspecific and, in some cases, lethal.[14]

Great interest has been placed on polymorphisms in drug-associating molecules as predisposing factors to the development of ALL or to risk for relapse or adverse affects from standard treatment options. Among the cytochrome P450 enzymes, the CYP1A1 2A (6235 T>C) SNP, located in the noncoding region of this gene, has been associated with a highly inducible phenotype, increased risk of ALL and a worse therapeutic outcome in some,[15,16] but not other,[17] studies.

Glutathione-S-transferase (GST) enzymes are highly polymorphic and have been associated with the risk of de novo cancer and therapy-related cancers following chemotherapy and with the efficacy and toxicity of cancer chemotherapy. The GSTT1-null genotype has been linked to favorable early response to prednisolone in childhood ALL.[18] A recent larger study of ALL children analyzed 16 common SNPs in 13 different candidate genes and their relation to treatment outcome.[14] In patients with high-risk ALL, the GSTM1 non-null genotype showed a greater risk of hematologic relapse, which was further increased in patients who had a genotype associated with high expression of the thymidylate synthase gene. The lower-activity GSTP1 polymorphism at 1578A>G (GSTP1*B), which results in the amino acid change Val105Ile, is associated with higher etoposide clearance in African–Americans treated with steroids, possibly by inducing ABCB1-medicated drug efflux [19] The homozygous GSTP1*B variant may also be associated with a better treatment outcome [20] and reduced incidence of CNS relapse.[21]

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of the thiopurine agents azathioprine, 6-mercaptopurine (6MP), and thioguanine. 6MP is one of the key medications for treatment of ALL. The drug is given in oral doses for most of the 2-3 years of maintenance therapy in standard treatment protocols. Clinical interest in TMPT pharmacogenetics is based on numerous studies that show that the TPMT genotype or phenotype identifies patients who are at risk of hematopoetic toxicity after thiopurine therapy. These studies have consistently shown that patients with TPMT deficiency are at very high risk of severe hematopoetic toxicity if treated with conventional doses of thiopurines.[22,23] Patients who are heterozygous at the TPMT gene locus are at intermediate risk of dose-limiting toxicity.[24] TPMT-deficient patients with ALL tolerated full does of 6-MP for only 7% of the scheduled weeks of therapy over 2.5 weeks of treatment, whereas TPMT-heterozygous or TPMT-homozygous wild-type patients tolerated full doses for 65 and 84% of the scheduled weeks, respectively. The percentage of weeks in which 6MP dosage had to be decreased to prevent toxicity in TPMT-homozygous common genotype patients was 2%, in TPMT-heterozygous genotypes was 16%, and TPMT-homozygous variant genotypes was 76%.[24] Cumulative incidence of 6MP dose reduction was highest among individuals homozygous for variant TPMT alleles at 100%, intermediate among those patients heterozygous for alleles at 35%, and lowest among those individuals with homozygous common alleles at 7%. When the doses of 6MP were reduced in patients possessing variant alleles, administration of full doses of other chemotherapy could then be initiated. In a separate series of patients treated at other centers, approximately 70% of those who experienced hematopoetic toxicity during treatment with combination chemotherapy containing thiopurines were found to be TPMT heterozygotes or TPMT deficient. The TPMT heterozygotes required a mean dose reduction of 35%, whereas the TPMT-deficient patients required a mean dose reduction of 90%. Once the thiopurine dosage was appropriately adjusted, these patients were generally able to tolerate full doses of their other chemotherapy. Therefore, the clinical benefits of ascertaining TPMT genotypes prior to the administration of thiopurine therapy in children with ALL translate into more efficient drug therapy and less potential of toxic adverse events for patients. TPMT deficiency has also been linked to the occurrence of drug-induced secondary malignancies among children with ALL. The incidence of brain tumors was significantly impacted by TPMT genotype (42 versus 8.3% in variant versus common TPMT genotypes, respectively). Among children with ALL, defective TPMT has been associated with the risk of topoisomerase II inhibitor-induced secondary myeloid malignancies.[25,26]

Methotrexate (MTX) is also an important chemotherapeutic drug in the treatment of ALL. Polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR) have been implicated in response to MTX treatment. Krajinovic et al. investigated the role of MTHFR and methylenetetrahydrofolate dehydrogenase (MTHFD1) polymorphisms in children of French–Canadian origin with ALL.[27] They reported that patients with either the MTHFR T677A1298 haplotype or the MTHFD1 A1958 variant had a lower probability of event-free survival, and this effect was more apparent when treatment was combined with genetic polymorphism associated with increased thymidylate synthase levels. These findings have been confirmed by a larger study reporting a statistically significant association between the MTHFR C677T variant allele and an increased risk of relapse.[28] Another study found that carriers of at least one MTHFR T677 variant had a significantly lower frequency of weeks with high-grade hematologic and liver toxicity during consolidation and maintenance treatment of pediatric ALL patients.[29]


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