Single Nucleotide Polymorphisms in ABCB1 and CBR1 Predict Toxicity to R-CHOP Type Regimens in Patients with Diffuse Non Hodgkin's Lymphoma

Abstract 1616

We analyzed single nucleotide polymorphisms (SNPs) in patients with diffuse large B-cell lymphoma treated in the prospective GELA LNH 2003 studies. Peripheral blood DNA samples collected at diagnosis before chemotherapy were obtained from 760 patients (among a total of 1367 accrued) including 441 randomized to received R-CHOP or modified R-CHOP (LNH 03–7B) and 319 who received R-ACVBP. The median age was 59 years (range 18–93) and there were 441 males and 319 females. 429 were IPI 0–2 (56.4%) and 331 were IPI 3–5 (43.6%). 119 patients had an ECOG performance status >1 (15.7%). B symptoms were present in 261 cases (34.4%). Serum albumin was below 35 g/L in 190 patients (27.7%). 489 patients (66.9%) had complete or unconfirmed complete response after induction therapy and 167 (22%) had partial response. At 5 years the overall survival was 73.9% (95% C.I. 69.7–77.6) and the progression free survival was 64.4% (95% CI 60.1–68.4). A total of 17 SNPs in 13 genes involved in drug metabolism or apopotosis were genotyped by TaqMan SNP Genotyping Assays (Applied Biosystems) on a LC480 (Roche) and correlated with toxicity occurring during treatment. Toxicity was evaluated prospectively using the NCI CTC V3 scale and associations were determined between specific genotypes and grade 3 or 4 toxicities. The studied genes were ABCB1, CAT, CBR1, FGFR4, IL10, NRG1, SLC22A16, SOD2, UGT1A1, CYP3A4, GSTP1, GSTM1 and GSTT1. Among these, 4 SNPs located in ABCB1 and CBR1 were found to be significantly associated with treatment-induced toxicity. The two SNPs localized in the ABCB1 gene were rs2032582 which was correlated with thrombocytopenia (p=0.04) and rs2229109 which was correlated with vomiting (p=0.003) and diarrhoea (p=0.007). The two SNPs localized in the CBR1 gene were rs20572 and rs9024 which were both correlated with anemia, thrombocytopenia and diarrhoea (p=0.02). ABCB1 codes for the drug efflux pump Pgp which has mainly been evaluated for its role in chemoresistance, is also known to be a key regulator of drug elimination and a determinant of pharmacokinetics. CBR1 codes for carbonyl reductase 1 which is involved in the first step of the metabolism of doxorubicin. These results suggest that genotyping of peripheral blood cells could help predict severe toxicity in patients receiving R-CHOP type regimens.