Pharmacogenetics in diffuse large B-cell lymphoma treated with R-CHOP: Still an unmet challenge.

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP. Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting. This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a genome-wide association study (GWAS) analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to genes involved in drug transport (i.e., ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis. Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively. Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed.