Homozygous A polymorphism of the complement C1qA276 correlates with prolonged overall survival in patients with diffuse large B cell lymphoma treated with R-CHOP

Journal of Hematology & Oncology

Jun Zhu³  Yuqin Song³  Zhiying Fu³  Ning Ding³  Huirong Ding²  Xuan Jin¹ 

[1] Department of Internal Medicine Oncology, Peking University First Hospital, Beijing, 100034, China;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, 100142, China;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, 100142, China

关键词: C1qA;    DLBCL;    Rituximab;    Polymorphism;    Complement;   

Others  :  822205
DOI  :  10.1186/1756-8722-5-51

 received in 2012-06-13, accepted in 2012-07-12,  发布年份 2012

【 摘 要 】

Background

The precise mechanism of action for rituximab (R) is not fully elucidated. Besides antibody-dependent cellular cytotoxicity (ADCC), complements may also play an important role in the clinical response to rituximab-based therapy in diffuse large B cell lymphoma (DLBCL). The purpose of this study was to explore the relationship between C1qA_[276] polymorphism and the clinical response to standard frontline treatment with R-CHOP in DLBCL patients.

Methods

Genotyping for C1qA_[276A/G] was done in 164 patients with DLBCL. 129 patients treated with R-CHOP as frontline therapy (R ≥ 4 cycles) were assessable for the efficacy.

Results

Patients with homozygous A were found to have a higher overall response rate than those with heterozygous or homozygous G alleles (97.3% vs. 83.7%,P = 0.068). The complete response rate in patients with homozygous A was statistically higher than that in AG and GG allele carriers (89.2% vs. 51.1%,P = 0.0001). The overall survival of patients with homozygous A was longer than that of the G allele carriers (676 days vs. 497 days, P = 0.023). Multivariate Cox regression analysis showed that C1qA A/A allele was an independent favorable prognostic factor for DLBCL patients treated with R-CHOP as first-line therapy.

Conclusion

These results suggest that C1qA polymorphism may be a biomarker to predict response to R-CHOP as frontline therapy for DLBCL patients.

【 授权许可】

   
2012 Jin et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Plosker GL, Figgitt DP: Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs 2003, 63:803-843.
• [2]Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002, 346:235-242.
• [3]Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, et al.: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005, 23:4117-4126.
• [4]Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, et al.: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006, 24:3121-3127.
• [5]Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006, 7:379-391.
• [6]Tan J, Cang S, Ma Y, Petrillo RL, Liu D: Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 2010, 3:5. BioMed Central Full Text
• [7]Wang J, Ke XY: The four types of Tregs in malignant lymphomas. J Hematol Oncol 2011, 4:50. BioMed Central Full Text
• [8]Wu ZL, Song YQ, Shi YF, Zhu J: High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J Hematol Oncol 2011, 4:31. BioMed Central Full Text
• [9]Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR: Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol 2011, 4:16. BioMed Central Full Text
• [10]Elbaz H, Stueckle T, Tse W, Rojanasakul Y, Dinu C: Digitoxin and its analogs as novel cancer therapeutics. Experimental Hematology & Oncology 2012, 1:4. BioMed Central Full Text
• [11]Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, et al.: Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 2003, 101:4279-4284.
• [12]Ansell SM, Witzig TE, Kurtin PJ, Sloan JA, Jelinek DF, et al.: Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood 2002, 99:67-74.
• [13]Byrd JC, Kitada S, Flinn IW, Aron JL, Pearson M, et al.: The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood 2002, 99:1038-1043.
• [14]Shan D, Ledbetter JA, Press OW: Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol Immunother 2000, 48:673-683.
• [15]Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, et al.: Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000, 95:3900-3908.
• [16]Harjunpaa A, Junnikkala S, Meri S: Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol 2000, 51:634-641.
• [17]Idusogie EE, Presta LG, Gazzano-Santoro H, Totpal K, Wong PY, et al.: Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol 2000, 164:4178-4184.
• [18]Cragg MS, Glennie MJ: Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 2004, 103:2738-2743.
• [19]Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, et al.: Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 2003, 171:1581-1587.
• [20]Racila E, Link BK, Weng WK, Witzig TE, Ansell S, et al.: A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clin Cancer Res 2008, 14:6697-6703.
• [21]Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999, 17:1244.
• [22]Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, et al.: Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003, 12:205-216.
• [23]Carlini DB, Chen Y, Stephan W: The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr. Genetics 2001, 159:623-633.
• [24]Pike SE, Yao L, Jones KD, Cherney B, Appella E, et al.: Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J Exp Med 1998, 188:2349-2356.
• [25]Stuart GR, Lynch NJ, Lu J, Geick A, Moffatt BE, et al.: Localisation of the C1q binding site within C1q receptor/calreticulin. FEBS Lett 1996, 397:245-249.