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...
Survivin is an inhibitor of apoptosis whose expression may be associated with inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated without rituximab.Caspase-3 is the final caspase of the apoptotic cascade and its pattern of expression may also be related to patients' outcome. In this study we investigated immunohistochemical expression of survivin and caspase-3 (CPP32) in 57 patients with DLBCL treated with rituximab and CHOP (R-CHOP). According to previously published criteria, we separately analyzed correlation of different types of survivin expression with patients' outcome. Nuclear survivin was expressed in only 26% of cases, cytoplasmic survivin was expressed in 81% of cases while application of immunoreactivity scoring system yielded 58% of survivin positive cases. Caspase-3 was expressed in 77% of cases. There were no significant correlations between any type of survivin expression and response to treatment or survival of the patients.The expression of caspase-3 was also not associated with patients' outcome. We conclude that survivin and caspase-3 have no significant prognostic significance in patients with DLBCL treated with R-CHOP.
Recent observations raise possibility for constitutively active, mutated JAK2 to modulate expression of RAS genes in CMPD. We analyzed the expression of AGT, renin, AT2R1 and ACE genes in normal and bone marrows of PV and ET patients with the respect to the presence of V617F JAK2 mutation. PV and ET had different expression patterns of major RAS components compared to normal BM which was primarily associated with the JAK2V617F mutation and less with PV or ET disease phenotype. However, AT2R1 was exclusively markedly upregulated only in PV, while ET showed moderate expression irrespective of the JAK2 mutational status.
The influence of the germinal-center B-cell (GCB) and the non-GCB phenotypes of diffuse large B-cell lymphoma (DLBCL) on the outcome of 92 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like chemotherapy, with or without rituximab was determined in this study. The differentiation between the GCB and non-GCB types was arrived at by immunohistochemistry using previously published criteria. Thirty-nine patients had the GCB and 53 had the non-GCB type of DLBCL. Forty-nine patients were treated with rituximab and chemotherapy; 43 were treated with chemotherapy alone. The GCB and non-GCB group did not differ in their international prognostic index factors and score, presence of bulky disease, or frequency of rituximab treatment. Median follow-up of the surviving patients was carried out for 37 months. There was no difference between the GCB and non-GCB groups in both overall response rates (67 vs. 70%, respectively) and estimated rates of 3-year event-free (46 vs. 49%, respectively) and overall (54 vs. 56%, respectively) survival. In addition, no differences of the outcomes were observed between the subgroups treated with or without rituximab. The patients of this study with immunohistochemically determined GCB-type DLBCL did not have an improved prognosis, irrespective of whether they had received rituximab or not.
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