FC RIIIA and FC RIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma

Abstract

FCγRIIIA and FCγRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphomaWe investigated the association of Fcγ γRIIIa and Fcγ γRIIa polymorphisms and response to R-CHOP in 58 patients with diffuse large B-cell lymphoma (DLBCL). Fcγ γRIIIa and Fcγ γRIIa polymorphisms did not influence response, event-free or overall survival. These results suggest that ADCC via Fcγ γRIIIa and Fcγ γRIIa may not be the major mechanism of activity of the R-CHOP combination in DLBCL. Haematologica 2007; 92:998-999 Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasm accounting for approximately 30-40% of all non-Hodgkin lymphomas (NHLs). Recently, the combination of rituximab (R) and CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) led to significant improvement in the outcomes of patients with DLBCL, establishing R-CHOP as the new standard treatment.1,2 The proposed mechanisms of rituximab activity include: antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), direct induction of apoptosis and chemosensitization of tumor cells to the cytotoxic effects of chemotherapy.3,4 The clinical importance of each is still a matter of debate. ADCC is mediated by effector cells that engage the Fc portion of the antibody via receptors for immunoglobulin (FcγRs). Three FcγR classes (FcγRI, II, III) and eight subclasses have been described with significantly different haplotype distribution between various ethnic groups.5 FcγRIIIa receptor is expressed on natural killer (NK) cells, macrophages, while FcγRIIa is expressed on neutrophils and macrophages. Genomic polymorphism of the FcγRIIIa receptor corresponding to phenotypic expression of valine (V) or phenylalanine (F) at position 158 influences the binding of IgG1 to this receptor.6 It has been shown that NK cells with valine homozygous FcγRIIIa receptors (V/V) have a higher affinity to rituximab than those with phenylalanine homozygous receptors (F/F) resulting in more effective ADCC.7 Several studies investigated the influence of FcγRIIIa and FcγRIIa polymorphisms on response to rituximab-containing treatment in different types of lymphoma. In follicular lymphoma (FL), patients with FcγRIIIa 158 V/V phenotype respond better than F carriers to rituximab monotherapy, 8,9 but not to R-CHOP. 10,11FcγRIIIa 158 V/V phenotype is associated with improved response to rituximab monotherapy in Waldenstrom's macroglobulinemia, 12 in contrast to chronic lymphocytic leukemia (CLL).13 A recently published study found that Korean DLBCL patients with FcγRIIIa 158 V/V phenotype respond better to R-CHOP than F carriers, although there were no differences in event-free survival (EFS) and overall survival (OS).14 In one series, patients with FL homozygous for histidine (H) on position 131 of FcγRIIa responded better to rituximab monotherapy than heterozygous patients or patients homozygous for arginine (R).9 Others failed to confirm this association. 8,10,13,14 We examined the cor...

E13 Non-Hodgkin lymphoma: how to proceed

“…The Fc portion of the antibody activates type 1 immunologic reactions. Presumably, these immunologic reactions are important for the activity of the drug but, surprisingly, this has not been proven yet (2).…”

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21

“…[9][10][11][12][13][14]16,20 These included SNPs affecting: (1) cytochrome P450 enzymes (CYP2C19 rs4244285, CYP3A5 rs776746); (2) glutathione S-transferase isoforms (GSTA1 rs3957357, GSTM1-null, GSTP1 rs1695, GSTP1 rs1138272); (3) ATP-binding cassette transporters (ABCC2 rs17222723, ABCC2 rs8187710, ABCB1 rs1045642, ABCB1 rs2229109, ABCG2 rs2231142, ABCG2 rs2231137); (4) NAD(P)H oxidase subunits (NCF4 rs1883112, RAC2 rs13058338, CYBA rs4673); (5) glucocorticoid receptor (GR rs41423247); (6) Fcg receptors (FCGR2A rs1801274, FCGR3A rs10127939) and (7) TP53 (TP53 rs1042522). DNA samples for genotyping were extracted from peripheral blood granulocytes collected at DLBCL diagnosis.…”

“…[9][10][11][12][13][14]16,20 SNPs were selected according to the following criteria: (1) nonsynonymous SNPs predicting alteration of protein function; (2) SNPs affecting regulatory regions and predicting altered expression of the gene; (3) SNPs known to be relevant for prediction of outcome or toxicity in other settings and (4) SNPs with a minor allele frequency in the study population 45%. 21 In fact, SNPs whose minor alleles do not reach a given frequency in the study population may not be informative for correlation studies.…”

“…[3][4][5] According to available evidence, genes that a priori may be involved in R-CHOP pharmacogenetics encode: (1) cytochrome P450 enzymes, which promote both cyclophosphamide conversion to active compounds and metabolism of vincristine and prednisone; 11 (2) glutathione S-transferase isoforms, which promote detoxification of cyclophosphamide and vincristine and also favor scavenging of doxorubicinderived reactive oxygen species (ROS) that contribute to anthracyclin cytotoxicity; 10,15 (3) ATP-binding cassette transporters, which increase efflux of doxorubicin, vincristine and prednisone from the cell cytoplasm to the extracellular compartment; 9 (4) nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits involved in ROS generation; 14 (5) glucocorticoid receptor 16 and (6) Fcg receptors involved in rituximab antibody-dependent cellular toxicity. 12,13 This study aimed at verifying whether SNPs modulating gene expression and/or function of enzymes involved in R-CHOP pharmacogenetics may contribute to the prognostic stratification and the prediction of toxicity in DLBCL patients treated with R-CHOP21.…”

“…[8][9][10][11] Scant information is available on the impact of pharmacogenetics as a predictor of outcome and toxicity in the context of DLBCL. [12][13][14] Rituximab-CHOP (R-CHOP) is the standard treatment for DLBCL. [3][4][5] According to available evidence, genes that a priori may be involved in R-CHOP pharmacogenetics encode: (1) cytochrome P450 enzymes, which promote both cyclophosphamide conversion to active compounds and metabolism of vincristine and prednisone; 11 (2) glutathione S-transferase isoforms, which promote detoxification of cyclophosphamide and vincristine and also favor scavenging of doxorubicinderived reactive oxygen species (ROS) that contribute to anthracyclin cytotoxicity; 10,15 (3) ATP-binding cassette transporters, which increase efflux of doxorubicin, vincristine and prednisone from the cell cytoplasm to the extracellular compartment; 9 (4) nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits involved in ROS generation; 14 (5) glucocorticoid receptor 16 and (6) Fcg receptors involved in rituximab antibody-dependent cellular toxicity.…”