Association between Drug-Metabolizing Enzymes Polymorphisms and Diffuse Large B-Cell Lymphoma Risk in the Middle Eastern Population.

Abstract The last four decades have seen significant increase in the incidence of non-Hodgkin’s lymphoma (NHL) as a possible result of increasing environmental carcinogens exposure. Based on the increasing evidence for the association between carcinogens exposure related cancer risk and xenobiotic gene polymorphisms. We have undertaken a case control study on xenobiotic gene polymorphisms in Saudi individuals with a diagnosis of diffuse large B-cell lymphoma (DLBCL). Polymorphisms in five genes (CYP1A1, GSTT1, GSTP1, GSTM1 and NQO1) were characterized in 187 individuals with DLBCL and 513 normal controls using polymerase chain reaction (PCR) based method. We chose the Saudi population as our study population because of its high consanguinity and its relative genetic homogeneity. The CYP1A1*2C, GSTT1 null and GSTP1 TT genotype were all found to be significant predictors of DLBCL risk (odds ratio 6.62, 11.94 and 3.42 respectively). None of the other alleles tested for proved to be significant indicators of DLBCL risk. These results suggest that the risk of DLBCL may indeed be associated with xenobiotics - metabolism and thus with environmental exposures. Table 1 Distribution of polymorphisms in healthy population and lymphoma patients. Polymorphism Genotype Control group Lymphoma patients p OR CYP1A1 −/− 384(76.5%) 104(78.8%) *2A −/2A 105(20.9%) 24(18.18%) 0.543 0.844 2A/2A 13(2.6%) 3(2.27%) 1.000 0.852 2A allele 13% 11.36% 0.659 0.839 CYP1A1 −/− 443(88.2%) 121(91.66%) *2B −/2B 50(10%) 10(7.58%) 0.505 0.732 2B/2B 9(1.8%) 1(0.76%) 0.697 0.407 2B allele 6.8% 4.55% 0.424 0.646 CYP1A1 −/− 497(99%) 125(94.7%) *2C −/2C 5(1%) 4(3.03%) 0.090 3.181 2C/2C 0 3(2.27%) 0.008 ND 2C allele 0.5% 3.8% 0.011 6.627 NQO1 C609T CC 295 (58.5%) 94 (62.7%) CT 177 (35.1%) 37 (24.7%) 0.051 0.656 TT 32 (6.4%) 19 (8.7%) 0.059 1.863 CT+TT 209 (41.5%) 56 (37.3%) 0.395 0.841 GSTP1 2293 CC 389 (76.3%) 113 (77.9%) CT 113 (22.2%) 24 (16.6%) 0.240 0.731 TT 8 (1.5%) 8 (5.5%) 0.017 3.422 CT+TT 121 (23.7%) 32 (22%) 0.739 0.910 GSTP1 A1578G AA 170 (33.5%) 56 (35%) AG 271 (53.5%) 96 (60%) 0.772 1.075 GG 66 (13%) 8 (5%) 0.013 0.368 AG+GG 337 (66.5%) 104 (65%) 0.774 0.937 GSTT1 P 385 (75%) 36 (20.1%) D 128 (25%) 143 (79.9%) <0.001 11.948 GSTM1 P 233 (45.4%) 91 (50%) D 280 (54.6%) 91 (50%) 0.300 0.832 Table 2 Distribution of combined GSTT1 and GSTM1 polymorphisms in case and control group. Genotype Control Case p OR Null: Complete deletion of GSTT1 and GSTM1 allele Present 423 (82.8%) 109 (60.9%) Double Null 88 (17.2%) 70 (39.1%) <0.001 3.087

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Interaction between BCL2 and Interleukin-10 Gene Polymorphisms Alter Outcomes of Diffuse Large B-Cell Lymphoma following Rituximab Plus CHOP Chemotherapy

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-08-1588 ◽

2009 ◽

Vol 15 (6) ◽

pp. 2107-2115 ◽

Cited By ~ 19

Author(s):

Yeon Hee Park ◽

Sang Kyun Sohn ◽

Jong Gwang Kim ◽

Myung-Hoon Lee ◽

Hong Suk Song ◽

...

Keyword(s):

B Cell ◽

Gene Polymorphisms ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Interleukin 10 ◽

Chop Chemotherapy ◽

Large B Cell Lymphoma ◽

Large B Cell

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FcγRIIIa Gene Polymorphisms May Correlate with Response to Frontline R-CHOP Therapy for Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.2457.2457 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2457-2457

Author(s):

Dong Hwan Kim ◽

Hee Du Jung ◽

Sang Kyun Sohn ◽

Je-Jung Lee ◽

Deok-Hwan Yang ◽

...

Keyword(s):

B Cell ◽

Gene Polymorphisms ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Effector Cells ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell ◽

Chop Therapy

Abstract Background: The precise mechanism of rituximab (R) plus CHOP (R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Besides overcoming bcl-2 mediated chemoresistance, antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via IgG fragment C receptors (FcR), was also proposed as a mechanism of Rituximab. The current study evaluated the impact of FcR polymorphism on the response to R-CHOP therapy for DLBCL with the basis that FcR polymorphism can affect R’s affinity for ADCC effector cells. Patients and Methods: The FcγRIIIa and FcγRIIa gene polymorphisms were determined in DLBCL patients receiving R-CHOP (n=113) comparing to CHOP therapy (n=85). Results: The FcγRIIIa valine (V) allele was significantly correlated with higher complete response rate to R-CHOP compared to phenylalalnine (F) allele (88% in V/V versus 79% in V/F versus 50% in F/F, p=0.002), while no difference was found between FcγRIIa polymorphism. In addition, V/V allele was associated with faster achievement of response than other alleles. The impact of FcγRIIIa gene polymorphism on response rate was not noted in CHOP group. In terms of overall or event-free survival, no difference was found according to FcγRIIIa or FcγRIIa alleles. Conclusion: The FcγRIIIa SNP is predictive of response to R-CHOP, but does not correlate with survival in DLBCL patients.

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Role of nuclear factor-κB regulators TNFAIP3 and CARD11 in Middle Eastern diffuse large B-cell lymphoma

Leukemia & Lymphoma ◽

10.3109/10428194.2012.668286 ◽

2012 ◽

Vol 53 (10) ◽

pp. 1971-1977 ◽

Cited By ~ 8

Author(s):

Rong Bu ◽

Prashant Bavi ◽

Jehad Abubaker ◽

Zeenath Jehan ◽

Wael Al-Haqawi ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Middle Eastern ◽

B Cell Lymphoma ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Large B Cell Lymphoma ◽

Large B Cell

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Lymphotoxin alfa and receptor-interacting protein kinase 1 gene polymorphisms may correlate with prognosis in patients with diffuse large B cell lymphoma treated with R-CHOP

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-009-1066-x ◽

2009 ◽

Vol 65 (3) ◽

pp. 571-577 ◽

Cited By ~ 8

Author(s):

Yee Soo Chae ◽

Jong Gwang Kim ◽

Sang Kyun Sohn ◽

Joon Ho Moon ◽

Shi Nae Kim ◽

...

Keyword(s):

Protein Kinase ◽

B Cell ◽

Gene Polymorphisms ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Interacting Protein ◽

Large B Cell Lymphoma ◽

Large B Cell

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Does Rituximab Influence the Prognostic Effect of Germinal Centre Phenotype in Diffuse Large B-Cell Lymphoma?.

Blood ◽

10.1182/blood.v108.11.2743.2743 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2743-2743 ◽

Cited By ~ 1

Author(s):

Heidi Nyman ◽

Marja-Liisa Karjalainen-Lindsberg ◽

Minna Taskinen ◽

Mattias Berglund ◽

Magdalena Adde ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Positive Impact ◽

Survival Rates ◽

B Cell Lymphoma ◽

Risk Groups ◽

Germinal Centre ◽

Control Group ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract PURPOSE: Germinal centre (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL), and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. Our aim was to determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome. METHODS: 95 DLBCL patients treated with rituximab in combination with CHOP or CHOEP regimen (immunochemotherapy) were included in the study. The median follow-up time was 27 months. 107 patients previously treated with chemotherapy served as a historical control group. BCL-6, CD10, and MUM1 expression was analyzed immunohistochemically by means of identifying GC and non-GC phenotypes. In addition, BCL-2 expression was determined. Expression data was correlated with survival parameters. RESULTS: Consistent with previous studies, chemotherapy-treated patients with GC phenotype displayed a significantly better overall survival (OS) than the non-GC group (70% vs 47% p=0.012). In contrast, GC-phenotype did not predict outcome in immunochemotherapy-treated patients. The OS for GC-group was 82% compared with 80% for those with non-GC phenotype (p=ns). Conversely, the relapse free survival (RFS) for patients with GC and non-GC phenotypes were 74% and 65% (p=ns), respectively. When the patients were grouped according to BCL-2 expression, survival rates among the group of BCL-2 negative patients tended to be better than in BCL-2 positive patients (OS, 94% vs 77%, p=0.097; RFS, 94% vs 66%, p=0.029). CONCLUSIONS: Rituximab in combination with chemotherapy seems to interfere with the prognostic value of GC- and non-GC phenotypes in DLBCL. However, rituximab may have a positive impact on outcome among the patients with BCL-2 negativity.

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R-CHOP with Etoposide Substituted for Doxorubicin (R-CEOP): Excellent Outcome in Diffuse Large B Cell Lymphoma for Patients with a Contraindication to Anthracyclines.

Blood ◽

10.1182/blood.v114.22.408.408 ◽

2009 ◽

Vol 114 (22) ◽

pp. 408-408 ◽

Cited By ~ 21

Author(s):

Alden A. Moccia ◽

Kimberly Schaff ◽

Paul Hoskins ◽

Richard Klasa ◽

Kerry J. Savage ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Control Group ◽

Advanced Stage ◽

Anthracycline Therapy ◽

Limited Stage ◽

Large B Cell Lymphoma ◽

Stage Disease ◽

Large B Cell

Abstract Abstract 408 Introduction: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) is the current standard of care for the treatment of diffuse large B cell lymphoma (DLBCL). Doxorubicin has an integral role but is associated with significant toxicity. The omission of doxorubicin in patients who are frail, have poor baseline cardiac function or who have previously received anthracycline therapy may compromise outcome. However, the recent introduction of rituximab may allow for improved outcomes without the use of doxorubicin. We assessed the efficacy of substituting etoposide for doxorubicin for patients with a contraindication to anthracyclines. Patients and Methods: Treatment guidelines in British Columbia (BC) recommend the substitution of etoposide for doxorubicin in standard dose R-CHOP for patients with DLBCL who have a contraindication to anthracyclines (R-CEOP). Etoposide is administered at a dose of 50 mg/m2 IV on day 1 and 100 mg/m2 PO on days 2 and 3 of each cycle. Patients with limited stage disease receive 3-4 cycles of chemotherapy with or without radiation therapy; patients with advanced stage disease receive 6 cycles of chemotherapy. We performed a retrospective population-based analysis using the BC Cancer Agency Lymphoid Cancer and pharmacy databases and included all patients with newly diagnosed DLBCL who were treated with curative intent with R-CEOP from December 2000 to March 2009. Patients who began treatment with R-CHOP but then switched to R-CEOP (due to intolerance or because a maximum threshold of anthracycline dosing was reached) were also included in the analysis if R-CEOP was administered for more than 50% of cycles delivered. Outcome of this population was compared with a 2:1 control group treated with R-CHOP in the same time period and matched for age, clinical stage and International Prognostic Index (IPI). End points were time to progression (TTP) and overall survival (OS). Results: We identified 81 patients treated with R-CEOP who met the stated inclusion criteria. Clinical characteristics were as follows: median age 73 y (range 34-93), 55 (68%) male, 15 (18%) limited stage and 66 (82%) advanced stage. Adverse prognostic factors according to the IPI were as follows: 85% age > 60 y, 58% stage III/IV, 31% PS > 1, 43% elevated LDH, and 12% > 1 extranodal site. IPI score: 19 (23%) low risk, 33 (41%) low-intermediate, 18 (22%) high-intermediate, and 11 (14%) high risk. Reasons for etoposide substitution were: 71 (88%) cardiac contraindication, 7 (9%) prior exposure to anthracyclines and 3 (4%) other co-morbidities. 72 (89%) patients received rituximab as part of the treatment, 25 (31%) received partial treatment with R-CHOP and then switched to R-CEOP and 56 (69%) received no anthracycline therapy. The control group included 162 randomly chosen patients matched for age, stage and IPI score and treated with R-CHOP. At a median follow-up of 28 months (range 3-86), 33/81 (41%) R-CEOP patients had died (23 with lymphoma, 3 treatment toxicity, 7 unrelated causes). The 5-year TTP was similar for patients treated with R-CEOP compared to patients in the R-CHOP control group, 57% versus 62%, respectively (p=0.21). (Fig. 1) The 5-y OS was lower for patients receiving R-CEOP compared with the R-CHOP control group (49% versus 64%, p=0.02), reflecting the underlying co-morbidities and frailty of this population. Interestingly, the 5-y TTP and 5-y OS rates were similar for patients in the R-CEOP cohort who had received partial treatment with an anthracycline and those who had received no anthracycline treatment (p=0.49 and p=0.77, respectively). Conclusions: A significant proportion of patients with DLBCL who are unable to receive anthracycline-based therapy can be cured with the etoposide-substituted regimen R-CEOP. R-CEOP is well tolerated even by patients with numerous co-morbidities. Moreover, the outcome of these patients does not appear to be significantly different compared to a similar population treated with standard R-CHOP. Disclosures: No relevant conflicts of interest to declare.

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Exploratory Study on the Relationship Between FcγRIIIa Gene Polymorphisms and the Efficacy and Toxicity of Rituximab in the Treatment of Stage I/II Diffuse Large B-Cell Lymphoma

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2035 ◽

2019 ◽

Vol 9 (5) ◽

pp. 615-622

Author(s):

Zhijun Wuxiao ◽

Hua Wang ◽

Qunhao Su ◽

Haiyan Zhou ◽

Min Hu ◽

...

Keyword(s):

B Cell ◽

Gene Polymorphisms ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Stage I ◽

Term Survival ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

The Relationship ◽

Large B Cell

Rituximab is an IgG1 monoclonal antibody approved for the treatment of diffuse large B-cell lymphoma (DLBCL); however, its efficacy is poor in some patients. Previous studies indicate that the difference in efficacy may be due to antibody-dependent cell-mediated cytotoxicity (ADCC). The effect of ADCC is closely related to Fcγ receptor IIIA (FcγRIIIa) receptor gene polymorphisms, but no study has investigated this gene in patients with DLBCL in China. In this study, we explored FcγRIIIa gene polymorphisms in patients with DLBCL in China and the ethnic differences in the FcγRIIIa gene. Moreover, we determined the relationship between FcγRIIIa gene polymorphisms and the effect and toxicity of rituximab treatment. Peripheral blood samples of 60 patients with newly diagnosed stage I/II DLBCL who received standard treatment with rituximab were collected, and DNA samples were extracted and normalized. Among the FcγRIIIa gene polymorphisms, there was a homozygous mutation, a heterozygous mutation, and a wild-type genotype at the site of 161514542 (rs396991). The proportion of these genotypes was significantly different from those found in previous studies for European and American populations and healthy Chinese populations. Moreover, we found that individuals with the homozygous (158-V/V) or heterozygous (V/F) mutation possessed better near-term effectiveness of the standard chemotherapeutic treatment, although there was no significant difference in long-term survival. However, patients with one of these genotypes usually suffer from a more severe hematological toxicity in response to the rituximab treatment. In conclusion, knowledge of a patient's FcγRIIIa gene polymorphism may be of value for the individualized treatment of DLBCL, which is worthy of follow-up research.

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Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy

Blood ◽

10.1182/blood-2006-09-047068 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4930-4935 ◽

Cited By ~ 207

Author(s):

Heidi Nyman ◽

Magdalena Adde ◽

Marja-Liisa Karjalainen-Lindsberg ◽

Minna Taskinen ◽

Mattias Berglund ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Risk Groups ◽

Control Group ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

AbstractGerminal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.

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