The utility of pharmacogenetics in clinical routine has turned to be lower than anticipated, as numerous barriers to implementing individualized medicine have appeared over the years (Agundez et al., 2012
). Cases in which a genetic test is sufficient to significantly affect a given therapy are discouragingly uncommon (Groenen, 2011
) and the leukemia setting is not an exception. Indeed, only 1–2% of marketed drugs have pharmacogenomic-based recommendations (Agundez et al., 2012
) and amongst the drugs commonly used in the chemotherapy of pediatric ALL, only 6-MP, thioguanine and azathioprine labels include genetic testing (TPMT
) as a recommendation to help individualize therapy. However, steps are being taken in order to revert this situation. The increasing availability of low-cost, high-throughput genetic platforms that allow the simultaneous screening of hundreds of polymorphisms, the education of health practitioners or the implementation of multicenter networks aimed to improve the safety of new drugs, are some of the measures that hopefully will help improve the impact of pharmacogenetics on clinical routine. It should also be pointed out that genetic variability in several of the targets for which genetic testing is recommended by the FDA and other corporations has been shown to modify the risk of acute leukemia (Agundez, 2004
), which certainly enhances the utility of these tests.
The body of work on the clinical impact of TPMT
polymorphisms on ALL does not mirror the limited current knowledge on the pharmacogenetics of the other drugs that constitute the core of chemotherapy for this disease. Thus, significantly less information is available with regard to vincristine, asparaginase, cyclophosphamide etc. The TPMT
gene polymorphism provides the best example of the value of applied pharmacogenetics in ALL and clinical oncology in general. It is now widely acknowledged that the initial dose of 6-MP treatment should be based on the TPMT
genotype (Relling et al., 2011
), thus allowing the clinician to identify patients at higher risk of toxicity. However, as it was described in the 6-MP chapter, there is still some interindividual variability in the response to this drug that cannot be explained only by the TPMT
genotype (Palmieri et al., 2007
). Therefore, the implementation of additional genetic analyses to identify polymorphisms in the ITPA
and other genes in the 6-MP intracellular pathway, as well as the study of their epistatic interactions seem to be reasonable steps to take in order to better adjust 6-MP doses in ALL patients. Furthermore, pharmacogenomics alone may not be sufficient to explain all the interindividual variability in 6-MP response and efforts should be undertaken in the coming years to create more precise algorithms that can help predict drug response.
With regard to MTHFR, the reasons for the present controversy regarding the influence of its genetic variation on MTX-induced toxicity are diverse. For instance, the wide variety of diseases in which MTX has been proved useful has paradoxically hampered the reproducibility of the results of genetic association studies, because of the heterogeneity of the patients analyzed. Moreover, other unknown variants in the same gene, epistatic interactions with other genes and, most likely, the combination of these factors, may result in genetic backgrounds with different susceptibilities to MTX-induced toxicity. The challenge seems to be to identify which genetic factors and genetic combinations are those in specific populations.
Some ALL chemotherapy regimens contemplate MTX dose reductions for subjects homozygous for the 677T variant or for those carrying both 677CT and 1298AC heterozygous genotypes. One could consider at least premature to make this kind of dose adjustments based on data that are still controversial. In fact, MTX was not included in the list of drugs mentioned in the Table of Pharmacogenomic Biomarkers in Drug Label
issued by the Food and Drug Administration (FDA) last year (FDA, 2011
It is probably naive to believe that the determination of SNPs in just one gene (MTHFR
) belonging to a highly complex intracellular pathway, such as that of MTX, is enough to accurately anticipate the occurrence of adverse effects.
As a general rule, it would be logical to think that the identification of combinations of mutations in several genes along the pathway of a given drug must be more helpful in terms of identifying subjects at-risk of toxicity than a single-SNP approach (Vagace et al., 2011
). This is crucial in the case of drugs with intricate intracellular routes as it is the case of MTX or 6-MP. Genome-wide approaches such as the ones reported by (Huang et al., 2007
), Bleibel et al. (2009)
, and Chen et al. (2011)
are able to evaluate whole pathways to identify key routes that can be later studied in detail. In addition, the inclusion of other clinical and demographic factors may increase the predictive value of pharmacogenetic models (Wessels et al., 2007