Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level?

The antifolate drug methotrexate (MTX) was introduced into clinical practice about 60 years ago and remains an important component of different acute lymphoblastic leukemia (ALL) treatment protocols. It acts by inhibiting several enzymes in the folate pathway, thereby resulting in the disruption of folate homeostasis. To date, treatment regimens have not been personalized despite there being experimental evidence that gene polymorphisms of folate metabolizing enzymes affect MTX response. The aim of this review was to evaluate the influence of genetic polymorphisms of the enzymes involved in the MTX pathway on ALL treatment outcomes and identify factors underlining the failure to personalize MTX therapy. We conducted a literature search in PUBMED and Goggle scholar using the following key words: methotrexate, polymorphism, acute lymphoblastic leukemia, pharmacogenetics, pharmacogenomics and personalized mediciner. The reasons for the failure to personalize MTX therapy may be due to (1) most studies involving single-center, small-sized cohorts, (2) differences in MTX dose across different protocols, (3) failure to consider minimal residual disease as a risk factor for post-induction treatment, (4) differences in outcome criteria between studies and (5) failure to consider the folate levels of a patient before initiation of MTX therapy. Although high-throughput techniques allow the mapping of thousands of genetic polymorphisms in a single run, it remains a major challenge to dissect out folate-metabolizing enzymes which have a high impact on the efficacy and toxicity of MTX and which, therefore, could be the targets for intervention. Prospective pharmacogenetic studies which consider all of the above-mentioned factors should be undertaken to facilitate the design of personalized MTX treatment for ALL patients.