国内美罗华联合CHOP治疗NHL疗效和安全性的meta分析
摘要
目的：综合评价国内美罗华联合CHOP方案对非霍奇金淋巴瘤的疗效和安全性。
方法：计算机检索Pubmed(1999-2010),Elsevier(1990-2010),中国学术期刊全文数据库(CNKI)(1994-2010),中文科技期刊数据库(1989-2009),万方数据库(1982-2010)和中国生物医学文献服务系统(1980-2010),并手工检索所有纳入文献的参考文献,纳入国内美罗华联合CHOP方案治疗非霍奇金淋巴瘤的随机对照试验(RCT)和临床对照试验。评价纳入研究的方法学质量并进行资料提取后,采用RevMan 4.2软件进行Meta分析。
结果：共纳入13个研究,包括684例患者。Meta分析结果显示,美罗华联合CHOP方案与单用CHOP方案相比：①总有效率[OR=3.10,95%CI(2.10,4.56)]、完全缓解率[OR=2.44,95%CI(1.78,3.35)]明显提高,差异均有统计学意义(P均<0.00001)；②部分缓解率[OR=0.90,95%CI(0.63,1.28)]无明显改善(P=0.55)；③1年总生存率[OR=2.03,95%CI(1.05,3.90)]、2年总生存率[OR=2.30,95%CI(1.24,4.26)]、3年总生存率[OR=3.02,95%CI(1.38,6.60)]均明显提高,差异均有统计学意义(P值分别为0.03、0.008、0.006)；④两组白细胞减少[OR=0.97,95%CI(0.60,1.55)],贫血[OR=1.02,95%CI(0.56,1.88)],恶心、呕吐[OR=0.88,95%CI(0.58,1.33)],脱发[OR=0.88,95%CI(0.50,1.56)]及肝功能损害[OR=0.77,95%CI(0.41,1.42)]等各不良反应发生率差异无统计学意义(P值分别为0.88、0.94、0.53、0.66、0.40)。
结论：目前国内的有限证据表明,与单用CHOP方案相比,美罗华联合CHOP方案能明显增加非霍奇金淋巴瘤治疗的总有效率和完全缓解率,延长患者的生存期,并不增加毒副作用,但由于纳入研究样本量小且质量较低,上述结论尚需要高质量、大样本的随机双盲对照试验加以证实。
Objective:To assess the efficacy and safety of rituximab combined CHOP for treating Non-Hodgkin's Lymphoma in China.
Methods:Randomized controlled trials(RCTs) and clinical trials of rituximab combined CHOP for treating Non-Hodgkin's Lymphoma in China were collected from Pubmed (1999-2010), Elsevier (1990-2010), CNKI (1994-2010), VIP (1989-2009), WanFang Data (1982-2010), and CBM (1980-2010) databases. Other relevant journals were also handsearched. The methodological quality of the included studies was evaluated, and data analyses were performed using the Cochrane Collaboration's software RevMan 4.2.
Results:A total of 13 trials involving 684 patients were included.
①As for the total effective rate and complete remission rate, significant differences were found between rituximab+CHOP vs CHOP alone[OR=3.10,95 % CI (2.10,4.56);OR=2.44,95 % CI (1.78,3.35)];
②As for the partial remission rate, differences between rituximab+CHOP vs CHOP alone did not reach significant(P=0.55)[OR=0.90,95 % CI(0.63,1.28)];
③As for the overall survival rate of 1 year,2 years, and 3 years, significant differences were found between rituximab+CHOP vs CHOP alone [OR=2.03,95 % CI (1.05,3.90);OR=2.30,95 % CI (1.24,4.26);OR=3.02,95 % CI (1.38,6.60)];
④As for the adverse effect rate of leukopenia, anemia, nausea and vomiting, alopecia, and liver damage, differences between rituximab+ CHOP vs CHOP alone did not reach significant [OR=0.97,95 % CI (0.60,1.55); OR=1.02,95 % CI(0.56,1.88);OR=0.88,95 % CI(0.58,1.33);OR=0.88,95 % CI (0.50,1.56);OR=0.77,95 % CI (0.41,1.42)].
Conclusion:According to the domestic evidence, treatment for NHL with R-CHOP can significantly improve the total effective rate and the complete remission rate, extend the survival without more adverse effect rate. However, more high-quality, large-sample, randomized, double-blind, controlled trials are required.
方法：计算机检索Pubmed(1999-2010),Elsevier(1990-2010),中国学术期刊全文数据库(CNKI)(1994-2010),中文科技期刊数据库(1989-2009),万方数据库(1982-2010)和中国生物医学文献服务系统(1980-2010),并手工检索所有纳入文献的参考文献,纳入国内美罗华联合CHOP方案治疗非霍奇金淋巴瘤的随机对照试验(RCT)和临床对照试验。评价纳入研究的方法学质量并进行资料提取后,采用RevMan 4.2软件进行Meta分析。
结果：共纳入13个研究,包括684例患者。Meta分析结果显示,美罗华联合CHOP方案与单用CHOP方案相比：①总有效率[OR=3.10,95%CI(2.10,4.56)]、完全缓解率[OR=2.44,95%CI(1.78,3.35)]明显提高,差异均有统计学意义(P均<0.00001)；②部分缓解率[OR=0.90,95%CI(0.63,1.28)]无明显改善(P=0.55)；③1年总生存率[OR=2.03,95%CI(1.05,3.90)]、2年总生存率[OR=2.30,95%CI(1.24,4.26)]、3年总生存率[OR=3.02,95%CI(1.38,6.60)]均明显提高,差异均有统计学意义(P值分别为0.03、0.008、0.006)；④两组白细胞减少[OR=0.97,95%CI(0.60,1.55)],贫血[OR=1.02,95%CI(0.56,1.88)],恶心、呕吐[OR=0.88,95%CI(0.58,1.33)],脱发[OR=0.88,95%CI(0.50,1.56)]及肝功能损害[OR=0.77,95%CI(0.41,1.42)]等各不良反应发生率差异无统计学意义(P值分别为0.88、0.94、0.53、0.66、0.40)。
结论：目前国内的有限证据表明,与单用CHOP方案相比,美罗华联合CHOP方案能明显增加非霍奇金淋巴瘤治疗的总有效率和完全缓解率,延长患者的生存期,并不增加毒副作用,但由于纳入研究样本量小且质量较低,上述结论尚需要高质量、大样本的随机双盲对照试验加以证实。
Objective:To assess the efficacy and safety of rituximab combined CHOP for treating Non-Hodgkin's Lymphoma in China.
Methods:Randomized controlled trials(RCTs) and clinical trials of rituximab combined CHOP for treating Non-Hodgkin's Lymphoma in China were collected from Pubmed (1999-2010), Elsevier (1990-2010), CNKI (1994-2010), VIP (1989-2009), WanFang Data (1982-2010), and CBM (1980-2010) databases. Other relevant journals were also handsearched. The methodological quality of the included studies was evaluated, and data analyses were performed using the Cochrane Collaboration's software RevMan 4.2.
Results:A total of 13 trials involving 684 patients were included.
①As for the total effective rate and complete remission rate, significant differences were found between rituximab+CHOP vs CHOP alone[OR=3.10,95 % CI (2.10,4.56);OR=2.44,95 % CI (1.78,3.35)];
②As for the partial remission rate, differences between rituximab+CHOP vs CHOP alone did not reach significant(P=0.55)[OR=0.90,95 % CI(0.63,1.28)];
③As for the overall survival rate of 1 year,2 years, and 3 years, significant differences were found between rituximab+CHOP vs CHOP alone [OR=2.03,95 % CI (1.05,3.90);OR=2.30,95 % CI (1.24,4.26);OR=3.02,95 % CI (1.38,6.60)];
④As for the adverse effect rate of leukopenia, anemia, nausea and vomiting, alopecia, and liver damage, differences between rituximab+ CHOP vs CHOP alone did not reach significant [OR=0.97,95 % CI (0.60,1.55); OR=1.02,95 % CI(0.56,1.88);OR=0.88,95 % CI(0.58,1.33);OR=0.88,95 % CI (0.50,1.56);OR=0.77,95 % CI (0.41,1.42)].
Conclusion:According to the domestic evidence, treatment for NHL with R-CHOP can significantly improve the total effective rate and the complete remission rate, extend the survival without more adverse effect rate. However, more high-quality, large-sample, randomized, double-blind, controlled trials are required.
引文
[1]Landis SH, Murray T, Bolden S, et al. Cancer statistics,1999. CA Cancer J Clin,1999,49(1):8-31.
[2]Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen(CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med,1993,328(14): 1002-1006.
[3]Marcus R. Current treatment options in aggressive lymphoma. Leuk Lymphoma,2003,44 (Suppl 4):S15-S27.
[4]Webb MS, Saltman DL, Connors JM, et al.A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma,2002,43(5):975-982.
[5]Tedder TF, Engel P. CD20:a regulator of cell-cycle progression of B lymphocytes. Immunol Today,1994,15(9):450-454.
[6]Plosker GL, Figgitt DP. Rituximab:a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs, 2003,63 (8):803-843.
[7]Vose JM, Link BK, Grossbard ML, et al. Phase Ⅱ study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol,2001,19: 389-397.
[8]Coffier B, L epage E, B rier J, et a 1. 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.
[9]Feugier P, Van-Hoof A, Sebban C, 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
[10]王彦华,蔡华,翁香勤,等.CHOP方案单用或联合美罗华治疗48例弥漫大B细胞淋巴瘤的随机对照临床研究.中国综合临床,2006,22(11)：1030-1032.
[11]林桐榆,张红雨,黄岩,等.R-CHOP与CHOP方案治疗初治弥漫大B细胞型淋巴瘤在中国的多中心随机对照研究.癌症,2005,24(12)：1421-1426.
[12]李虎生,张华,陶晓明.利妥昔单抗联合CHOP方案治疗26例B细胞性淋巴瘤的临床分析.华夏医学,2009,22(3)：432-433.
[13]郭俊煜,石浩强,张芬琴.利妥昔单抗联合CHOP方案治疗NHL的临床疗效评价.中国药房,2007,18(26)：2042-2043.
[14]李岭,李志铭.利妥昔单抗联合CHOP治疗弥漫大B细胞性非霍奇金淋巴瘤的临床观察.肿瘤基础与临床,2009,22(1)：36-37.
[15]吴宏菊,张清媛,陈德发,等.美罗华联合CHOP方案与CHOP方案治疗初治弥漫性大B细胞淋巴瘤的临床对比研究.癌症,2005,24(12)：1498-1502.
[16]戴朝霞,乌左翔,徐丽叶,等.美罗华联合CHOP方案与CHOP方案治疗侵袭性B细胞性淋巴瘤的临床对比研究.大连医科大学学报,2009,31(3)：299-301.
[17]双跃荣,叶大茜,陈建祥,等.美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤45例临床疗效观察.中国肿瘤临床,2007,34(24)：1414-1417.
[18]徐志巧,刘培杰,高岭,等.美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤的临床研究.中华肿瘤防治杂志,2007,14(20)：1589-1590.
[19]黄小兵,符成杰,刘骅,等.美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤的临床研究.白求恩军医学院学报,2009,7(5)：288-289.
[20]徐才刚,吴俣,陈心传,等.美罗华治疗32例弥漫型大B细胞性非何杰金氏淋巴瘤.华西药学杂志,2004,19(2)：147-149.
[21]韩晓凤,黄洪晖,钟璐,等.美罗华治疗B细胞性非霍奇金淋巴瘤的临床观察.临床血液学杂志,2007,20(6)：326-328.
[22]徐卫,李建勇,张智弘,等.R-CHOP方案与CHOP方案治疗初治弥漫性大B细胞淋巴瘤的临床研究..中国实验血液学杂志,2008,16(4)：933-937.
[23]Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood,1994,83(2): 435-445.
[24]Demidem A, Lam T, Alas S, et al. Chimeric anti-CD20(IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm,1997,12(3): 177-186.
[1]San Miguel JF, Garcia-Sanz R. Prognostic features of multiple myeloma. Best Practice &Research Clinical Haematology,2005,18(4):569-583.
[2]陈仲武,陈益光,李跃明.多发性骨髓瘤的临床及影像分析.中国临床医学影像杂志,2004,15(1)：35-37.
[3]Johnson RJ, Feehally J.Comprehensive clinical nephrology.2nd ed.Mosby:Edinburgh,2003,235-240.
[4]邓敏茹,卢建沛.28例多发性骨髓瘤的实验室分析.河北医学,2007,13(6)：721-723.
[5]孙江飞,楼燕茹,牧启田,等.多发性骨髓瘤T细胞亚群及免疫表型分析.现代实用医学,2005,17(1)：17-19.
[6]秦燕,丁润生,陆伟,等.多参数流式细胞术在多发性骨髓瘤诊断中的价值.交通医学,2009,23(2)：137-138,140.
[7]陈世伦.多发性骨髓瘤.北京：人民卫生出版社,2004：213.
[8]Yeh HS, Berenson JR. Myeloma bone disease and treatment options.Eur J Cancer,2006,42 (11):1554-1563.
[9]Grogan TM, Spier CM. The B cell immunoproliferative disorders including multiple myeloma and amyloidosis. In:Knowles DM, editor. Neoplastic haematopathology.2nd ed. Philadelphia: Lippincott Williams and Wilkins,2001,1557-1587.
[10]全昌斌,贾树林,孙德清.典型及不典型多发性骨髓瘤40例X线分析.中国医学影像技术,1999,15(6)：429.
[11]Horger M, Kanz L, Denecke B, et al.The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow up and therapy response monitoring in patients with multiple myeloma. Cancer,2007,109:1617-1626.
[12]叶香华,吴湖炳,王全师,等.18F-FDG PET／CT诊断多发性骨髓瘤.中国医学影像技术,2009,25(5)：897-900.
[13]孙龙,吴华,官永松,等.PET／CT在放射性粒子组织间种植治疗恶性实体肿瘤.中国介入影像与治疗学,2006,3(3)：231-234.
[14]Baur-Melnyk A, Buhmann S, Durr HR, et al. Role of MRI for the diagnosis and prognosis of multiple myeloma. Eur J Radiol,2005,55:56-63.
[15]张华,潘自来,江浩,等.多发性骨髓瘤的MRI表现.中国医学影像技术, 1999,15 (7):563-565.
[16]龙莉玲,宋英儒,黄仲奎.多发性骨髓瘤的MRI和X线诊断价值.临床放射学杂志,2001,20(9)：696-698.
[17]Collins CD. Multiple myeloma. Cancer Imaging,2004,4:S47-S53.
[18]Chiu ML, kronauge JF, Piwnica Worms D. Effect of mitochondfial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile)technetium in cultured mouse fibroblasts.J Nucl Med,1990,31:1646-1653.
[19]Fonti R,Del Vecchio S,Zannetti A, et al.Bone marrow uptake of 99mTc-MIBI in patients with multiple myeloma. Eur J Nucl Med, 2001,28(2):214-220.
[20]白砚霞,杨芳,陆敏秋,等.99mTc-MDP骨显像监测多发性骨髓瘤骨质破坏.中国医学影像技术,2008,24(7)：1106-1109.
[21]LeCouvet FE, Malghem J, Michaux L, et al. Skeletal survey in advanced multiple myeloma:radiographic versus MR imaging survey. Br J Haematol, 1999,106(1):35-9.
[22]徐文坚,徐爱德.骨髓弥漫性病变MRI应用的现状与展望.中华放射学杂志,2001,35(6)：422-425.
[23]Vacca A,Ribatti D,Roncali L, et al.Bong marrow angiogenesis and progression in multiple myeloma. Br J Haematol,1994,87:503-508.
[24]Singhal S, Mehta J, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med,1999,341 (21):1565-1571.
[25]Rajkumar SV, Kyle RA. Angiogenesis in multiple myeloma. Semin Oncol, 2001,28:560-564.
[26]Barlogie B, Yricot G, Anaissie E.Thalidomide in the management of multiple myeloma. Semin Oncol,2001,28:577-582.
[27]王明林,刘曰芬,李英刚,等.酞咪哌啶酮治疗多发性骨髓瘤疗效与机制.中华血液学杂志,2002,23：514-516.
[28]周言新,张莉,刘楠,等.反应停联合化疗治疗难治及复发性多发性骨髓瘤疗效观察及治疗前后VEGF变化.中国现代医学杂志,2005,15(24)：3815-3817.
[29]孙卫红,尹礼烘,刘娟.沙利度胺联合改良VAD方案治疗多发性骨髓瘤临床观察.中国现代医药杂志,2009,11(4)：15-16.
[30]曲东霞.沙利度胺联合小剂量MP方案化疗治疗老年多发性骨髓瘤的临床观察.大连医科大学学报,2007,29(3)：249-251.
[31]Burger AM, Sethak. The Ubiquitin-media protein degradation pathway in cancer:therapeutic implications. Eur J Cancer,2004,40(9):2217.
[32]Jaqannath S, Tomthon W, Jackjons,et al. Bortezomib therapy alone and in combination with dexamethansone for previously untreated symptomatic multiple myeloma. Br J Haematol,2005,129(6):776-783.
[33]Richardson P, Barlogie B, Berenson J, et al.A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med,2003, 348(26):2609-2617.
[34]Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms cediating antimyeloma activity of proteasome inhibitor PS-341. Blood,2003,101:1530-1534.
[35]Oakervee H, Popat R, Curry N, et al.PAD combination therapy(PS-341 /bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol,2005,129(6):755-762.
[36]张永清,陈协群,白庆咸,等.硼替佐米联合阿霉素地塞米松治疗伴髓外浸润难治性多发性骨髓瘤4例疗效观察.中国实用内科杂志,2008,28(10)：882-883.
[37]Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoielic cell. Nature,2005,313(1):103-109.
[38]Baud V, Karin M. Is NF-kappaB a good target for cancer therapy. Nat Rev Drug Discov,2008,8(1):31-40.
[39]Cokrell AS, Kafrit. Gene delivery by lentivirus vectors. Molbiotechnol, 2007,36 (3):101-105.
[40]Brown J, Wilson W. Exploiting tumor hypoxia in cancertreatment. Nat Rev Cancer,2005,4(6):217-238.
[41]黑秀明,谢东霞,高立超,等.拓扑替康治疗多发性骨髓瘤的实验研究.中国现代医生,2009,47(27)：21-22.
[42]韩红,张克俭,左学兰,等.以THP为主的联合化疗方案治疗多发性骨髓瘤及非霍奇金淋巴瘤103例临床分析.临床血液学杂志,2008,21(11)：593-596.
[43]Velichko MG, Petushole VG,Gorbach IV,et al.Lactate level in the tissues of animals with a tumor administered oxythiamine and the properties of lactate dehychrog-enase. Vopr med khim,1981,27(5): 594-600.
[44]Alesandrakis MG, Passam FH,Ganotakis ES, et al.The clinical and prognostic significance of erythrocyte sedimentation rate(ESR), serum interleukin-6(IL-6) and acute phase protein levels in multiple myeloma. Clin Lab Haematol,2003,25(1):41-46.
[45]沈志祥,欧阳仁荣.血液肿瘤学[M].北京：人民卫生出版社,1999：438,429.
[46]Astrom M, Bodin L, Nilsson I, et al. Treatment Long term outcome and prognostic variable in 214 unselected Aml patients in Sweden. Br Jeancer,2000,82(8):1387-1392.
[47]葛祥花,隋金财,刘景玲,等.多发性骨髓瘤血清β2-MG及LDH检测的临床意义.白血病·淋巴瘤,2006,15(2)：124-125.
[48]Nguyena AN, Stebbinsa EG, Hensona M, et al. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. Experimental Cell Research,2006,312:1909.
[49]Monika Engelhardt, Roland Mertelsmann.160 years of multiple myeloma: Progress and challenges. European J Cancer,2006,42:1507.
[50]Klein B, Tarte K, Jourdan M, eI al. Survival and proliferation factors of normal and malignant plasma cells.Int J Hematol,2003,78(2): 106-113.
[51]董丽华,申建凯,张广森,等.多发性骨髓瘤患者血清白细胞介素-6含量与临
床骨病关系的研究.临床血液学杂志,2005,18(4)：218-220.
[52]Terpos E, Politou M, Viniou N, et al. Significance of macrophage inflammatory protein-1 alpha(MIP-1 alpha)in multiple myeloma. Leuk Lymphoma,2005,46(12):1699-1707.
[53]Moller C, Stromberg T, Juremam M,et al.Expression and function of chemokine receptors in human multiple myeloma. Leuke,2003,17(1): 203-210.
[54]刘竹珍,赵春亭,李广伦,等.不同治疗方案对多发性骨髓瘤患者血清IL-6、TNF-α水平的影响.山东医药,2009,49(13)：36-38.
[55]杨云,张王刚,陈银霞,等.沙利度胺对多发性骨髓瘤患者细胞因子影响的临床研究.临床血液学杂志,2007,20(5)：272-274.
[56]Sezer O, Jakob C, Eucker J, et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor(VEGF)and hepatocyte growth factor(HGF)in multiple myeloma. Eur J Haematol,2001,66(2):83-88.
[57]王金湖,倪红兵,王旭东,等.多发性骨髓瘤患者B淋巴细胞刺激因子及其受体的表达水平.现代检验医学杂志,2009,24(2)：39-41.
[58]Hashimoto T, Abe M, Oshima T, et al. Ability of myeloma cells to secrete macrophage inflammatory protein(MIP)-lalpha and MIP-lbeta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol,2004,125(1):38-41.
[59]王晓桃,罗绍凯,莫东华,等.巨噬细胞炎症蛋白-1α对多发性骨髓瘤细胞增殖与迁移能力的影响.中华血液学杂志,2005,26(11)：692-693.
[60]王晓桃,罗绍凯,莫汉有.噬细胞炎症蛋白-1α在多发性骨髓瘤中的表达及临床意义.中山大学学报(医学科学版),2007,28(2)：152-154.
[61]王晓桃,林文远,陈蓓莉,等.多发性骨髓瘤骨髓单个核细胞CCR1和CCR5的表达及临床意义.临床肿瘤学杂志,2009,14(6)：520-523.
[2]Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen(CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med,1993,328(14): 1002-1006.
[3]Marcus R. Current treatment options in aggressive lymphoma. Leuk Lymphoma,2003,44 (Suppl 4):S15-S27.
[4]Webb MS, Saltman DL, Connors JM, et al.A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma,2002,43(5):975-982.
[5]Tedder TF, Engel P. CD20:a regulator of cell-cycle progression of B lymphocytes. Immunol Today,1994,15(9):450-454.
[6]Plosker GL, Figgitt DP. Rituximab:a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs, 2003,63 (8):803-843.
[7]Vose JM, Link BK, Grossbard ML, et al. Phase Ⅱ study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol,2001,19: 389-397.
[8]Coffier B, L epage E, B rier J, et a 1. 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.
[9]Feugier P, Van-Hoof A, Sebban C, 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
[10]王彦华,蔡华,翁香勤,等.CHOP方案单用或联合美罗华治疗48例弥漫大B细胞淋巴瘤的随机对照临床研究.中国综合临床,2006,22(11)：1030-1032.
[11]林桐榆,张红雨,黄岩,等.R-CHOP与CHOP方案治疗初治弥漫大B细胞型淋巴瘤在中国的多中心随机对照研究.癌症,2005,24(12)：1421-1426.
[12]李虎生,张华,陶晓明.利妥昔单抗联合CHOP方案治疗26例B细胞性淋巴瘤的临床分析.华夏医学,2009,22(3)：432-433.
[13]郭俊煜,石浩强,张芬琴.利妥昔单抗联合CHOP方案治疗NHL的临床疗效评价.中国药房,2007,18(26)：2042-2043.
[14]李岭,李志铭.利妥昔单抗联合CHOP治疗弥漫大B细胞性非霍奇金淋巴瘤的临床观察.肿瘤基础与临床,2009,22(1)：36-37.
[15]吴宏菊,张清媛,陈德发,等.美罗华联合CHOP方案与CHOP方案治疗初治弥漫性大B细胞淋巴瘤的临床对比研究.癌症,2005,24(12)：1498-1502.
[16]戴朝霞,乌左翔,徐丽叶,等.美罗华联合CHOP方案与CHOP方案治疗侵袭性B细胞性淋巴瘤的临床对比研究.大连医科大学学报,2009,31(3)：299-301.
[17]双跃荣,叶大茜,陈建祥,等.美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤45例临床疗效观察.中国肿瘤临床,2007,34(24)：1414-1417.
[18]徐志巧,刘培杰,高岭,等.美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤的临床研究.中华肿瘤防治杂志,2007,14(20)：1589-1590.
[19]黄小兵,符成杰,刘骅,等.美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤的临床研究.白求恩军医学院学报,2009,7(5)：288-289.
[20]徐才刚,吴俣,陈心传,等.美罗华治疗32例弥漫型大B细胞性非何杰金氏淋巴瘤.华西药学杂志,2004,19(2)：147-149.
[21]韩晓凤,黄洪晖,钟璐,等.美罗华治疗B细胞性非霍奇金淋巴瘤的临床观察.临床血液学杂志,2007,20(6)：326-328.
[22]徐卫,李建勇,张智弘,等.R-CHOP方案与CHOP方案治疗初治弥漫性大B细胞淋巴瘤的临床研究..中国实验血液学杂志,2008,16(4)：933-937.
[23]Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood,1994,83(2): 435-445.
[24]Demidem A, Lam T, Alas S, et al. Chimeric anti-CD20(IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm,1997,12(3): 177-186.
[1]San Miguel JF, Garcia-Sanz R. Prognostic features of multiple myeloma. Best Practice &Research Clinical Haematology,2005,18(4):569-583.
[2]陈仲武,陈益光,李跃明.多发性骨髓瘤的临床及影像分析.中国临床医学影像杂志,2004,15(1)：35-37.
[3]Johnson RJ, Feehally J.Comprehensive clinical nephrology.2nd ed.Mosby:Edinburgh,2003,235-240.
[4]邓敏茹,卢建沛.28例多发性骨髓瘤的实验室分析.河北医学,2007,13(6)：721-723.
[5]孙江飞,楼燕茹,牧启田,等.多发性骨髓瘤T细胞亚群及免疫表型分析.现代实用医学,2005,17(1)：17-19.
[6]秦燕,丁润生,陆伟,等.多参数流式细胞术在多发性骨髓瘤诊断中的价值.交通医学,2009,23(2)：137-138,140.
[7]陈世伦.多发性骨髓瘤.北京：人民卫生出版社,2004：213.
[8]Yeh HS, Berenson JR. Myeloma bone disease and treatment options.Eur J Cancer,2006,42 (11):1554-1563.
[9]Grogan TM, Spier CM. The B cell immunoproliferative disorders including multiple myeloma and amyloidosis. In:Knowles DM, editor. Neoplastic haematopathology.2nd ed. Philadelphia: Lippincott Williams and Wilkins,2001,1557-1587.
[10]全昌斌,贾树林,孙德清.典型及不典型多发性骨髓瘤40例X线分析.中国医学影像技术,1999,15(6)：429.
[11]Horger M, Kanz L, Denecke B, et al.The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow up and therapy response monitoring in patients with multiple myeloma. Cancer,2007,109:1617-1626.
[12]叶香华,吴湖炳,王全师,等.18F-FDG PET／CT诊断多发性骨髓瘤.中国医学影像技术,2009,25(5)：897-900.
[13]孙龙,吴华,官永松,等.PET／CT在放射性粒子组织间种植治疗恶性实体肿瘤.中国介入影像与治疗学,2006,3(3)：231-234.
[14]Baur-Melnyk A, Buhmann S, Durr HR, et al. Role of MRI for the diagnosis and prognosis of multiple myeloma. Eur J Radiol,2005,55:56-63.
[15]张华,潘自来,江浩,等.多发性骨髓瘤的MRI表现.中国医学影像技术, 1999,15 (7):563-565.
[16]龙莉玲,宋英儒,黄仲奎.多发性骨髓瘤的MRI和X线诊断价值.临床放射学杂志,2001,20(9)：696-698.
[17]Collins CD. Multiple myeloma. Cancer Imaging,2004,4:S47-S53.
[18]Chiu ML, kronauge JF, Piwnica Worms D. Effect of mitochondfial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile)technetium in cultured mouse fibroblasts.J Nucl Med,1990,31:1646-1653.
[19]Fonti R,Del Vecchio S,Zannetti A, et al.Bone marrow uptake of 99mTc-MIBI in patients with multiple myeloma. Eur J Nucl Med, 2001,28(2):214-220.
[20]白砚霞,杨芳,陆敏秋,等.99mTc-MDP骨显像监测多发性骨髓瘤骨质破坏.中国医学影像技术,2008,24(7)：1106-1109.
[21]LeCouvet FE, Malghem J, Michaux L, et al. Skeletal survey in advanced multiple myeloma:radiographic versus MR imaging survey. Br J Haematol, 1999,106(1):35-9.
[22]徐文坚,徐爱德.骨髓弥漫性病变MRI应用的现状与展望.中华放射学杂志,2001,35(6)：422-425.
[23]Vacca A,Ribatti D,Roncali L, et al.Bong marrow angiogenesis and progression in multiple myeloma. Br J Haematol,1994,87:503-508.
[24]Singhal S, Mehta J, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med,1999,341 (21):1565-1571.
[25]Rajkumar SV, Kyle RA. Angiogenesis in multiple myeloma. Semin Oncol, 2001,28:560-564.
[26]Barlogie B, Yricot G, Anaissie E.Thalidomide in the management of multiple myeloma. Semin Oncol,2001,28:577-582.
[27]王明林,刘曰芬,李英刚,等.酞咪哌啶酮治疗多发性骨髓瘤疗效与机制.中华血液学杂志,2002,23：514-516.
[28]周言新,张莉,刘楠,等.反应停联合化疗治疗难治及复发性多发性骨髓瘤疗效观察及治疗前后VEGF变化.中国现代医学杂志,2005,15(24)：3815-3817.
[29]孙卫红,尹礼烘,刘娟.沙利度胺联合改良VAD方案治疗多发性骨髓瘤临床观察.中国现代医药杂志,2009,11(4)：15-16.
[30]曲东霞.沙利度胺联合小剂量MP方案化疗治疗老年多发性骨髓瘤的临床观察.大连医科大学学报,2007,29(3)：249-251.
[31]Burger AM, Sethak. The Ubiquitin-media protein degradation pathway in cancer:therapeutic implications. Eur J Cancer,2004,40(9):2217.
[32]Jaqannath S, Tomthon W, Jackjons,et al. Bortezomib therapy alone and in combination with dexamethansone for previously untreated symptomatic multiple myeloma. Br J Haematol,2005,129(6):776-783.
[33]Richardson P, Barlogie B, Berenson J, et al.A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med,2003, 348(26):2609-2617.
[34]Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms cediating antimyeloma activity of proteasome inhibitor PS-341. Blood,2003,101:1530-1534.
[35]Oakervee H, Popat R, Curry N, et al.PAD combination therapy(PS-341 /bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol,2005,129(6):755-762.
[36]张永清,陈协群,白庆咸,等.硼替佐米联合阿霉素地塞米松治疗伴髓外浸润难治性多发性骨髓瘤4例疗效观察.中国实用内科杂志,2008,28(10)：882-883.
[37]Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoielic cell. Nature,2005,313(1):103-109.
[38]Baud V, Karin M. Is NF-kappaB a good target for cancer therapy. Nat Rev Drug Discov,2008,8(1):31-40.
[39]Cokrell AS, Kafrit. Gene delivery by lentivirus vectors. Molbiotechnol, 2007,36 (3):101-105.
[40]Brown J, Wilson W. Exploiting tumor hypoxia in cancertreatment. Nat Rev Cancer,2005,4(6):217-238.
[41]黑秀明,谢东霞,高立超,等.拓扑替康治疗多发性骨髓瘤的实验研究.中国现代医生,2009,47(27)：21-22.
[42]韩红,张克俭,左学兰,等.以THP为主的联合化疗方案治疗多发性骨髓瘤及非霍奇金淋巴瘤103例临床分析.临床血液学杂志,2008,21(11)：593-596.
[43]Velichko MG, Petushole VG,Gorbach IV,et al.Lactate level in the tissues of animals with a tumor administered oxythiamine and the properties of lactate dehychrog-enase. Vopr med khim,1981,27(5): 594-600.
[44]Alesandrakis MG, Passam FH,Ganotakis ES, et al.The clinical and prognostic significance of erythrocyte sedimentation rate(ESR), serum interleukin-6(IL-6) and acute phase protein levels in multiple myeloma. Clin Lab Haematol,2003,25(1):41-46.
[45]沈志祥,欧阳仁荣.血液肿瘤学[M].北京：人民卫生出版社,1999：438,429.
[46]Astrom M, Bodin L, Nilsson I, et al. Treatment Long term outcome and prognostic variable in 214 unselected Aml patients in Sweden. Br Jeancer,2000,82(8):1387-1392.
[47]葛祥花,隋金财,刘景玲,等.多发性骨髓瘤血清β2-MG及LDH检测的临床意义.白血病·淋巴瘤,2006,15(2)：124-125.
[48]Nguyena AN, Stebbinsa EG, Hensona M, et al. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. Experimental Cell Research,2006,312:1909.
[49]Monika Engelhardt, Roland Mertelsmann.160 years of multiple myeloma: Progress and challenges. European J Cancer,2006,42:1507.
[50]Klein B, Tarte K, Jourdan M, eI al. Survival and proliferation factors of normal and malignant plasma cells.Int J Hematol,2003,78(2): 106-113.
[51]董丽华,申建凯,张广森,等.多发性骨髓瘤患者血清白细胞介素-6含量与临
床骨病关系的研究.临床血液学杂志,2005,18(4)：218-220.
[52]Terpos E, Politou M, Viniou N, et al. Significance of macrophage inflammatory protein-1 alpha(MIP-1 alpha)in multiple myeloma. Leuk Lymphoma,2005,46(12):1699-1707.
[53]Moller C, Stromberg T, Juremam M,et al.Expression and function of chemokine receptors in human multiple myeloma. Leuke,2003,17(1): 203-210.
[54]刘竹珍,赵春亭,李广伦,等.不同治疗方案对多发性骨髓瘤患者血清IL-6、TNF-α水平的影响.山东医药,2009,49(13)：36-38.
[55]杨云,张王刚,陈银霞,等.沙利度胺对多发性骨髓瘤患者细胞因子影响的临床研究.临床血液学杂志,2007,20(5)：272-274.
[56]Sezer O, Jakob C, Eucker J, et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor(VEGF)and hepatocyte growth factor(HGF)in multiple myeloma. Eur J Haematol,2001,66(2):83-88.
[57]王金湖,倪红兵,王旭东,等.多发性骨髓瘤患者B淋巴细胞刺激因子及其受体的表达水平.现代检验医学杂志,2009,24(2)：39-41.
[58]Hashimoto T, Abe M, Oshima T, et al. Ability of myeloma cells to secrete macrophage inflammatory protein(MIP)-lalpha and MIP-lbeta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol,2004,125(1):38-41.
[59]王晓桃,罗绍凯,莫东华,等.巨噬细胞炎症蛋白-1α对多发性骨髓瘤细胞增殖与迁移能力的影响.中华血液学杂志,2005,26(11)：692-693.
[60]王晓桃,罗绍凯,莫汉有.噬细胞炎症蛋白-1α在多发性骨髓瘤中的表达及临床意义.中山大学学报(医学科学版),2007,28(2)：152-154.
[61]王晓桃,林文远,陈蓓莉,等.多发性骨髓瘤骨髓单个核细胞CCR1和CCR5的表达及临床意义.临床肿瘤学杂志,2009,14(6)：520-523.