1. ¹Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
2. ²Division of Pathology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
3. ³Division of Hematology, Department of Oncology, Azienda Ospedaliera S. Giovanni Battista, Turin, Italy
4. ⁴Division of Hematology, Department of Clinical and Preventive Medicine, University of Milano Bicocca, Monza, Italy
5. ⁵Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
6. ⁶Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland

Correspondence: Dr D Rossi, Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, Novara 28100, Italy. E-mail: rossidav@med.unipmn.it

⁷These authors contributed equally to this work.

Received 9 September 2008; Revised 15 December 2008; Accepted 19 December 2008; Published online 29 January 2009.

Abstract

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.