Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

In individualized medicine, physicians seek to balance treatment to obtain optimal clinical effect and minimal adverse reactions by taking patient variability into consideration. Drug dosing has traditionally been adjusted by age, weight or side effects. Thus, in its broadest sense, individualized medicine is not new, but the options and perspectives have become vastly expanded and scientifically established within the last decade [1]. The increased focus largely reflects the expanded number of potential adjustment parameters, including single nucleotide polymorphisms (SNPs) available with the completion of the human genome project and the potential of such markers in predicting patient responses. Interest has focused on variants in (or haplotypes linked to) genes involved in drug absorption, metabolism, transport, and excretion or in drug target pathways. However, variants not related to pharmacogenetics may also be important. In ALL for example, variants of genes encoding proteases, angiogenic factors, hematopoietic cytokines, bone marrow stroma factors, or structural proteins in epithelia may influence disease progression, expansion, or susceptibility to specific toxicities. Technical advances in proteomics and pharmaceutical measurements or in-vitro sensitivity testing provide another set of potential adjustment parameters.The clinical perspectives of individualized medicine have been emphasized and outlined in numerous publications, but in spite of extensive research within almost all areas of medicine, few outcome predictors are implemented in routine clinical decision-making [2]. Hence, re-evaluation of the strategies and feasibility of individualized medicine is warranted to identify clinical settings and logistic requirements, where the expectations are likely to be met.The therapeutic outcome of any disease is determined by the interaction between the patient, the disease, and the therapy (figure 1). The relative impact of patient and disease variants diff