Role of genetic polymorphisms on R-CHOP efficacy in diffuse large B-cell lymphoma patients: an interim analysis of a multicenter prospective pharmacogenetics study.

Background: Standard chemotherapy represented by the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is successful in about 60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). Pts who do not benefit from this treatment, due to the development of tumor drug resistance, have a very poor prognosis. Currently, knowledge on reasons of treatment related failures in DLBCL are scanty and predictive biomarker of response are largely unknown. Aims: We hypothesized that polymorphisms of gene involved in the pharmacokinetics and pharmacodynamics of drugs included in R-CHOP regimen may play a role in predicting the outcome in DLBCL pts. Thus, we designed a multicentre prospective pharmacogenetic trial aimed at identifying gene polymorphisms potentially predictive of drug efficacy/resistance in DLBCL pts treated with R-CHOP. We are reporting update data of an interim analysis on the first 80 enrolled pts. Methods: The study includes chemonaive DLBCL pts (Ann Arbour I-IV stages) candidate to an R-CHOP standard treatment. The Ethical Committee of each participating centre approved the pharmacogenetic protocol, and all pts signed a written informed consent. In this interim analysis, the impact of single nucleotide polymorphisms (SNPs) on R-CHOP efficacy was evaluated by objective response (OR) rate, progression-free survival (PFS) and overall survival (OS). The efficacy of R-CHOP was evaluated according to Cheson criteria by performing standard hematochemical and instrumental (TC and FDFG-PET) tests and defining complete remission (CR), partial remission (PR), non response or progressive disease (PD). Genomic DNA was extracted from peripheral blood of 80 pts. SNPs analysis was performed by an Affimetrix array. To date, 21 SNPs from 19 candidate genes (ABCB1, ABCC1, ABCC2, ABCG2, CYBA, CYP2C9, FCGR2A, GSTP1, IL2, MARCKS, MLH1, NCF4, NQO1, NQO2, RAC2, TNF, TOP2A, TP53, TUBB) involved in pharmacokinetics and pharmacodynamics of R-CHOP (www.pharmgkb.org) selected and analysed in relation to R-CHOP efficacy. Univariate and multivariate logistic regression analyses were performed to evaluate associations between SNPs and clinical/pathological characteristics or survival parameters (PFS and OS). Results: Median age was 63 years. There were 37 men and 43 women. 47.5% of pts were in stage I-II, 52.5% of pts in stage III-IV. 27.5% of pts had bulky disease, 43.8% of pts had involvement of extranodal site. 47.5% of pts had pathological LDH value. According to the revised IPI, 15% of pts were in the low risk group, 58.7% in the intermediate, and 26.3% in the high risk group. Overall, 468 courses of R-CHOP had been administered (mean: 5.85 courses, range: 4-6). 88,7% of pts had CR to R-CHOP whereas the remaining showed PR or SD (7.5%) or PD (3,8%). Multivariate analysis identified FCGR2A rs1801274 as a predictor of PFS (p=0.045). Pts with HR or RR genotypes showed shorter PFS than pts with HH genotype (HR: 2.437, CI95% 1.020-5,823). No statistically significant correlation was found between SNPs and OS. Summary/Conclusions: Our preliminary data obtained in a limited number of pts, show an association between a SNP of the low affinity FCGR2A gene involved in the activity of rituximab and PFS. Further insights will derive from the completion of pts accrual to reach the planned number of cases at the end of our study