대한내과학회지 : 제 83 권제 6 호 2012 http://dx.doi.org/10.3904/kjm.2012.83.6.706 특집 (Special Review) - 위말트림프종 위말트림프종의항암치료 고려대학교의과대학내과학교실 박용 Role of Chemotherapy in Gastric Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) Type Yong Park Division of Hematology/Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Gastric mucosa-associated lymphoid tissue (MALT) lymphoma comprises approximately 50% of primary gastric lymphoma. Currently, Helicobacter pyroli eradication is the mainstay in the management of localized gastric MALT lymphoma. However, other treatment strategies such as radiotherapy and chemotherapy should be required in certain circumstances which include H. pyroli-negative disease, H. pyroli-positive disease unresponsive to standard eradication, and advanced disease (stage III/IV). Here, we reviewed the role of chemotherapy in the management of patients with gastric MALT lymphoma based on recent clinical trials. (Korean J Med 2012;83:706-711) Keywords: Gastric MALT lymphoma, Chemotherapy, Marginal zone B cell lymphoma 서론위말트림프종은서서히진행하고림프종관련이환율은매우낮은질환으로원발성위림프종의약 50% 를구성한다 [1]. Helicobacter pyroli (H. pyroli) 감염과이로인한만성위염이위말트림프종의발병에핵심병리기전으로알려지고 [2,3] H. pyroli 양성위말트림프종에서는 H. pyroli 제균치료로상당수의환자들에서림프종의관해를관찰됨이보고되 어 [3-6] 현재 H. pyroli 양성위말트림프종에서는 H. pyroli 제균치료가표준치료이다. 하지만 H. pyroli 양성위말트림프종이라할지라도진행된경우나제균치료에반응하지않는경우, H. pyroli 음성위말트림프종에서의제균치료의역할은제한적이며항암치료와같은다른치료전략이요구된다. 본종설에서는위말트림프종치료에있어서항암치료의적응범위와그효과에대해최근보고된자료를중심으로고찰하고자한다. Correspondence to Yong Park, M.D., Ph.D. Division of Hematology/Oncology, Department of Internal Medicine, Korea University College of Medical College, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea Tel: +82-2-920-6847, Fax: +82-2-920-5982, E-mail: paark76@hanmail.net Copyright c 2012 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 706 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Yong Park. Chemotherapy in gastric MALT lymphoma - 본론전신항암치료의적응증항암치료의대상이되는위말트림프종은림프종의분화도 (grade), 염색체이상등과같은여러요소를고려할수있으나진단시혹은재발시의임상적병기에기반한접근이가장중요하다. 위말트림프종의임상적병기는 Ann Arbor 분류를변형한 Lugano 분류법 [7] 이주로사용되므로본종설에서도위말트림프종의임상병기는 Lugano stage에기반하여분류하겠다. 현재까지나온근거와진료지침등을종합해보면, stage IIIE/IV 위말트림프종이외에국소적병변인 stage IE/IIE에서도 H. pyroli 음성위말트림프종과제균치료에반응하지않는 H. pyroli 양성질환에서는항암치료의역할이있다. 그각각의적응증에대해서자세히살펴보도록하겠다. 국소적 H.pylori 음성위말트림프종 (Lugano stage IE/IIE) H. pyroli 감염과위말트림프종발병사이에는유의한상관성이있음에도불구하고약 10-30% 의환자에서는 H. pyroli 가검출되지않는것으로보고되었다 [8,9]. H. pyroli 감염여부가 1차치료로제균치료도입여부를결정하는요소인지에대해서는현재논란이있다. 먼저 European Gastro-Intestinal Lymphoma Study (EGILS) group의 consensus report에서는 H. pyroli 음성위말트종에서도 H. pyroli 제균치료가도움이될수있다고추천하고있다 [10]. 이는위말트림프종진단시 H. pyroli 감염이간과될수있고또드물긴하지만 H. pyroli 이외의다른 Helicobacter도위말트림프종의원인이될수있다는것을근거로삼고있다. 하지만미국의 National Cancer Center Network (NCCN) 지침에서는 stage IE ( 위에만국한 )/IIE ( 국소림프절까지진행 ) 의 H. pyroli 음성위말트림프종에서는방사선치료내지는항암치료를 1차치료로권고하고있다 [11]. H. pyroli 음성위말트종환자에서 H. pyroli 제균치료로림프종의관해를관찰한보고가있으나 [12] 소수의환자들을대상을한연구이며상반된결과를보고한연구도있어 [13,14] 아직까지모든 H. pyroli 음성위말트종에서 H. pyroli 제균치료를우선시도하는것은현재로서근거가부족하다고생각된다. H. pylori 음성환자에서불량한예후인자인 t (11;18), t (1;10), t (14;18) 염색체이상이높은빈도로관찰되며위말트림프종의진행 / 재발과연관성이있다는연구결과 [12] 에기반하여 H. pylori 음성환자에서염색체이상유무에의해제 균치료가아닌다른치료전략을고려할수있음이제시되었으나추가적인검증이필요하다 [12,15]. 따라서신뢰할만한생물학적표지자가발굴되어있지않는현시점에서 H. pyroli 음성위말트림프종환자들에게제균치료를 1차로적용시림프종의진행을방임할수있는위험이있기때문에항암치료를포함한다른치료전략을우선해야될것으로사료된다. Stage IE/IIE 위말트림프종의경우방사선치료의성적이매우우수하여침범된림프절병변까지포함되는 involve field ratiotherpay 가우선시되나방사선치료가불가능한경우에는 CD20 단클론항체 rituximab 단독투여가고려될수도있다. H. pyroli 음성혹은 H. pyroli 제균치료에반응하지않는위말트종환자 (n = 27, 81% 가 stage IE/IIE) 를대상으로표준용량의 rituximab을투여한전향적연구에서 rituximab 단독치료는 77% 의반응률 ( 완전관해 46%) 과관찰기간 ( 중앙값 28개월 ) 내에모든환자가생존해있는 (54% 는재발없이생존 ) 우수한결과를보고하였다 [16]. NCCN 진료지침에서 rituximab 단독투여가본환자들에게추천되고있으나 (category 2A) 현시점에서국내에서는 rituximab 단독요법의허가사항에국소적 H. pyroli 음성위말트종이포함되지않아임상시험을제외한실제진료현장에서 rituximab 단독투여는현실적으로불가능하다. H. pylori 제균치료에반응하지않는국소적 H. pylori 양성위말트림프종 (Lugano stage IE/IIE) H. pylori 제균치료후반응유무는신중히평가되어야한다. H. pyroli 가소실후림프종이소실되기까지는상당한시간이요구되기때문에 EGILS consensus report와 NCCN 진료지침에서는제균치료후증상이악화되지않는한최소 3개월후에내시경적평가를진행할것을권장하고있다 [10,11]. 재평가시에림프종이잔존해있는경우라도 H. pyroli 가제거되지않았다면 2차약제로제균치료를다시시도해볼수있다. H. pyroli 가제거된상태에서림프종이잔존해있는경우에는환자의증상에기초하여무증상인경우 3개월을더기다려볼수있다. 따라서요약한다면진단시국소적 (stage IE/IIE) H. pyroli 양성위말트림프종에서제균치료후 H. pyroli 는소실된상태에서림프종이지속될때관련증상이있거나증상이없어도 6개월이상지속되는경우를제균치료에반응하지않는경우로분류할수있다. 이런환자들에게는 involved field radiotherapy 가우수한효 - 707 -
- 대한내과학회지 : 제 83 권제 6 호통권제 628 호 2012 - 과를보이는것으로보고되었기때문에방사선치료가우선적으로고려된다. 방사선치료에도반응을보이지않을경우에는전신항암치료가고려될수있다. 전신항암치료의종류및효과에대해서는추후에기술하겠다. 진행성병변 (Lugano stage IIIE/IV) 위말트림프종은대부분진단시국소질환이며 stage III 이상의진행성질환으로발견되는경우는드물다. Stage IIIE/IV 의진행성 / 전신성질환에서는전신항암치료의적응이되나위말트림프종은서서히진행하면서예후가양호하고질환관련이환율이매우낮음을감안할때항암치료의이득과손해를평가하여치료를하지않고기다리는것도고려할수있다 (watch and wait). 하지만림프종관련증상, 말초장기기능의이상, 림프종으로인한말초혈구감소증, 매우큰병변, 진행성 / 재발의경우에는치료의적응이된다. 이상황에서방사선치료는증상의완화를위한목적으로전신항암치료와함께사용될수있다. 전신항암치료의종류와효과에대해서는아래에기술하겠다. 전신항암치료의종류와효과항암화학요법으로는과거 cyclophosphamide나 chlorambucil 의단독요법부터최근 CD20 단클론항체인 rituximab 까지포함된다양한약제들이위말트림프종치료를위해사용된다. 위말트림프종환자들을대상으로시행된대부분의임상시험은 stage IE/IIE의국소질환을포함하고있고다른장기의말트림프종을포함하고있어해석에주의가요구되나그럼에도불구하고현재까지보고된결과에서경한독성을보이는약제로도우수한치료효과및장기생존을기대할수있을것으로사료된다. 주요임상시험결과는표 1에요약하였다. 항암화학요법에사용되는약제의종류와관계없이위말트림프종치료중출혈과천공의위험을줄이기위한 proton pump inhibitor와추가적림프종유발인자를없애기위해 H. pyroli 양성질환에서는제균치료가병행되어야한다. Alkylating agents Hammel 등이최초로 cyclophosphamide (100 mg/day) 또는 chloambucil (6 mg/m 2 /day) 을지속적으로경구투여하는방법으로 75% 의완전관해, 28% 의재발 ( 추적기간중앙값 14개월 ) 및경한독성을보고하여 [17] 효능과안전성을증명하였다. 이후시행된연구에서 t (11;18) 이있는환자에서 Alkylating agents의효과가크게감소된다는보고이후에이제제의단독투여선택은매우감소하였는데이는제균요법에실패한환자들중상당수가 t (11;18) 를가지기때문이다 [18]. 더욱이 H. pyroli 양성환자들에서제균치료후재발을예방하기위한목적으로 chloambucil 보조요법이연구되었으나관찰군과비교하여재발률이나병의진행을통계적으로유의미하게감소시키는데실패하여 [19] 현재알킬화제제단독요법은다른복합항암요법을투여받기어려운환자에서염색체변이가동반되지않은경우우선적으로고려될수있다. Cladribine 위말트림프종의발달과유지에 H. pyroli 특이 T 세포의역할이중요함이알려지면서 [20,21] T 세포억제에효능이뛰어난 nucleoside 유사체인 cladribine 을이용한전향적임상연구가시행되었다. 19명의위말트림프종환자를포함한 26 명의말트림프종환자를대상으로 100% 의완전관해율과 78.5% 의무병생존율 ( 추적기간중앙값 80개월 ) 의우수한성적을보고하였다 [22,23]. 하지만국내에서는아직식약청허가사항에포함되지않아임상시험이아닌진료현장에서사용은불가능하다. Mitoxantrone, chlorambucil, prednisone (MCP) 5명의위말트림프종환자가포함된 19명의말트림프종환자를대상으로한후향적분석에서 mitoxantrone, chlorambucil, prednisone의복합항암화학요법 [mitoxantrone 8 mg/m 2 (days 1 and 2), chlorambucil 3 3 mg/m 2 (days 1-5) and prednisone 25 mg (days 1-5) every 4 weeks] 은 5명의위말트림프종환자에서 4명의완전관해와 1명의부분관해를보이며추적기간 ( 중앙값 16개월 ) 동안재발이관찰되지않는우수한효과를나타냈다 [24]. 이요법은내약성이우수하였고대부분의독성은처치가능한혈액학적독성이었다. Rituximab 위말트림프종은 B세포에서유래하기때문에 B세포항원인 CD20에대한단클론항체 rituximab 에대한연구가최근에많이보고되었다. Rixutimab (R) 단독투여시객관적반응율은 55-70% 로기존항암제와유사하거나다소감소된반응이관찰되었다. 기존항암요법과의상승작용을기대하여기존의 CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) 혹은 CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisolone) 요법과의병합연구가재발성말트림프종환자 - 708 -
- 박용. 위말트림프종의항암치료 - Table 1. Review of literature about chemotherapy of gastric MALT lymphoma First author, year Hammel, et al. 1995 [17] Levy, et al. 2005 [18] Wöhrer, et al. 2005 [24] Jäger, et al. 2002/2006 [22,23] Martinelli, et al. 2005 [16] Raderer, et al. 2006 [25] Salar, et al. 2009 [27] Lévy, et al. 2010 [26] Kang, et al. 2012 [28] No. of Stage I/II vs patitens III/IV Modified from Sathis A et al. [32]. 24 71%/29% Cylophosphamide or Chlorambucil 21 81%/19% Cylophosphamide or chlorambucil 5 100%/0% Mitoxantrone, chlorambucil, prednisone (MCP) Treatment Response Outcome Comment 75% CR 28% relapse (median FU 14 mo) 89% CR [t (11;18) negative] 42% CR [t (11;18) positive] 11% relapse [t (11;18) negative] 92% relapse [t (11;18) negative], median FU 7 yr 80% CR, 20% PR No relapse observed (median FU 16 mo) 19 100%/0% cladribine 100% CR 78.5% DFS (median FU 80 mo) 26 86%/14% Rituximab 46% CR, 31% PR 90% DFS (median FU 33months) Patients with H.pyoli-negative disease or unresponsive to eradication 15 MALT lymphoma (5 gastric) positive disease positive disease 7 57%/43% R-CHOP/R-CNOPP 100% CR Median FU 18 mo 26 MALT lymphoma (7 gastric) 10 73%/27% Rituximab+fludarabin 100% CR No relapse observed (median FU 24 mo) 13 705/30% Rituximab+clorambucil 100% CR No relapse observed (median FU 24 mo) 5 R-CVP 60% CR, 40% PR positive disease positive disease. 에서수행되었다. 포함된위말트림프종환자모두에서완전관해를획득하였고, 이는 t (11;18) 이동반된환자에서도관찰되었다 [25]. Rituximab 과 chlorambucil을병용하는요법에서도 100% 의완전관해와장기간의무병생존율이관찰되었고 [26] Rituximab 과 fludarabine의병용요법에서도위말트림프종환자에서 100% 의완전관해율과 100% 의 2년무병생존율을관찰하였다 [27]. 최근국내에서 stage III/IV의변연림프종환자 (5명의위말트림프종포함 ) 를대상으로시행된 R-CVP 병합요법에서도위말트림프종환자에서는 60% 의완전관해와 40% 의부분반응을보여효용이있음을나타냈다 [28]. Bortezomib 말트림프종의약 30% 에서 monoclonal immunoglobulin이생산되며조직내에 plasmacytic differentiation이관찰되고 nuclear factor kappa B (NF-kB) 의활성이증가되어있어 [29,30] 이의활성을억제하는 proteasome inhibitor 인 bortezomib이항림프종효과가있을것으로기대되어왔다. 총 16명의환자중위말트종환자가 4명포함된 pilot study에서전반적반응율은 80% 로위말트림프종환자는모두완전관해를유지하였다 [31]. 향후전향적임상을통한효용성과안정성규명이필요하다. NCCN 진료지침고찰 NCCN 진료지침은앞에서기술한환자군을전신항암치료의대상으로추천하고있으며선택할수있는항암치료요법은저분화도 (grade 1-2) 의여포성림프종에준할것을권장하고있다. 이는위말트림프종만을대상으로시행된임상시험이거의없고저분화도의여포성림프종은위말트림프종 - 709 -
- The Korean Journal of Medicine: Vol. 83, No. 6, 2012 - 과유사한임상경과를보이기때문으로사료된다. NCCN 진료지침에기반하여위말트림프종의 1차항암치료로사용할수있는약제는 R-bendamustine, R-CHOP, R-CVP (cyclophosphamide, vincristine, prednisolone), R-FND (fludarabine, mitoxantrone, dexamethasone), radioimmunotherapeutics, R monotherapy 등이해당되며고령혹은전신상태가불량한환자들에게는 radioimmunotherapeutics, R monotherapy, alkylating agent ± R 등을추천하고있다. 즉, 위말트림프종의일차치료제로서 rituximab 의역할이매우강조되고있다. 이는 rituximab 은독성이경해내약성이우수하고 B세포기원림프종에서의항림프종효과가매우뛰어나기존의세포독성항암제들과상승작용이있기때문이다. 하지만현재우리나라의식약청허가사항과보험기준을참조한다면 NCCN 진료지침에서 1차약제로추전되고있는 rituximab 은현실적으로사용이불가능하며일부의기관에서만다학제적위원회의승인을전제로 stageiiie/iv 위말트림프종에서만 R-CVP 요법이사용가능하다. 위말트림프종과같이유병률이낮고그경과가양호하여진행을억제하는것만으로도환자의삶의질과생존율향상을도모할수있는질환에서는어느정도의효용만기대할수있다면임상의의선택가능한범위를넓게허용하는것이필요하다고생각된다. 결론 H. pylori 제균치료또는국소방사선치료에실패하거나재발한위말트림프종또는증상을동반한 stage IIIE/IV의진행성 / 전신성위말트림프종에서는전신항암화학치료를고려할수있겠다. 가능한약제는기존에효용을보였던세포독성항암제에 rituximab 을추가한것이가장적절할것으로생각되나서서히진행하고장기간생존이가능한위말트림프종의특성을고려하여환자개개인의전신상태와동반된질환등을고려하여가급적독성이적은용법을시행하는것이추천된다. 아울러위말트림프종과관련된임상연구결과는대부분소규모연구이며위이외에서발생한말트림프종을포함하는경우가많아해석에주의를요한다. 따라서가능할경우임상시험에등록하여치료하는것을적극적으로고려해야된다. 중심단어 : 위말트종 ; 항암치료 ; 변연부B세포림프종 REFERENCES 1. Neubauer A, Zucca E. Gastrointestinal tract lymphomas. In: Cavali F, Stein H, Zucca E, eds. Extranodal Lymphomas Pathology and Management. London: Informa Health Care, 2008:233-243. 2. Du MQ, Isaccson PG. Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol 2002;3:97-104. 3. Zucca E, Bertoni F, Roggero E, Cavalli F. The gastric marginal zone B-cell lymphoma of MALT type. Blood 2000;96:410-419. 4. Fischbach W, Goebeler ME, Ruskone-Fourmestraux A, et al. Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series. Gut 2007;56:1685-1687. 5. Stathis A, Chini C, Bertoni F, et al. Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann Oncol 2009;20: 1086-1093. 6. Wündisch T, Thiede C, Morgner A, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 2005;23:8018-8024. 7. Rohatiner A, d'amore F, Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994;5:397-400. 8. Nakamura S, Yao T, Aoyagi K, Iida M, Fujishima M, Tsuneyoshi M. Helicobacter pylori and primary gastric lymphoma: a histopathologic and immunohistochemical analysis of 237 patients. Cancer 1997;79:3-11. 9. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 1991;338:1175-1176. 10. Ruskoné-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus report: gastric extranodal marginal zone B-cell lymphoma of MALT. Gut 2011;60:747-758. 11. National Comprehensive Cancer Network. National Comprehensive Cancer Network Guidelines V.3.2012-Non- Hodgkin's lymphomas [Internet]. Fort Washington (PA): National Comprehensive Cancer Network, c2012. Available from: http://www.nccn.org/index.asp. 12. Nakamura S, Matsumoto T, Ye H, et al. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a clinicopathologic and molecular study with reference to antibiotic treatment. Cancer 2006;107:2770-2778. 13. Ruskoné-Fourmestraux A, Lavergne A, Aegerter PH, et al. Predictive factors for regression of gastric MALT lym- - 710 -
- Yong Park. Chemotherapy in gastric MALT lymphoma - phoma after anti-helicobacter pylori treatment. Gut 2001; 48:297-303. 14. Steinbach G, Ford R, Glober G, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: an uncontrolled trial. Ann Intern Med 1999;131:88-95. 15. Raderer M, Streubel B, Wöhrer S, Häfner M, Chott A. Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas. Gut 2006;55:616-618. 16. Martinelli G, Laszlo D, Ferreri AJ, et al. Clinical activity of rituximab in gastric marginal zone non-hodgkin's lymphoma resistant to or not eligible for anti-helicobacter pylori therapy. J Clin Oncol 2005;23:1979-1983. 17. Hammel P, Haioun C, Chaumette MT, et al. Efficacy of single-agent chemotherapy in low-grade B-cell mucosaassociated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol 1995;13:2524-2529. 18. Lévy M, Copie-Bergman C, Gameiro C, et al. Prognostic value of translocation t(11;18) in tumoral response of low-grade gastric lymphoma of mucosa-associated lymphoid tissue type to oral chemotherapy. J Clin Oncol 2005;23: 5061-5066. 19. Hancock BW, Qian W, Linch D, et al. Chlorambucil versus observation after anti-helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial. Br J Haematol 2009;144:367-375. 20. Hussell T, Isaacson PG, Crabtree JE, Spencer J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 1996;178:122-127. 21. Hussell T, Isaacson PG, Spencer J. Proliferation and differentiation of tumour cells from B-cell lymphoma of mucosa-associated lymphoid tissue in vitro. J Pathol 1993; 169:221-227. 22. Jäger G, Neumeister P, Brezinschek R, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol 2002;20:3872-3877. 23. Jäger G, Neumeister P, Quehenberger F, Wöhrer S, Linkesch W, Raderer M. Prolonged clinical remission in patients with extranodal marginal zone B-cell lymphoma of the mucosaassociated lymphoid tissue type treated with cladribine: 6 year follow-up of a phase II trial. Ann Oncol 2006;17: 1722-1723. 24. Wöhrer S, Raderer M, Kaufmann H, et al. Effective treatment of indolent non-hodgkin's lymphomas with mitoxantrone, chlorambucil and prednisone. Onkologie 2005; 28:73-78. 25. Raderer M, Wohrer S, Streubel B, et al. Activity of rituximab plus cyclophosphamide, doxorubicin/mitoxantrone, vincristine and prednisone in patients with relapsed MALT lymphoma. Oncology 2006;70:411-417. 26. Lévy M, Copie-Bergman C, Molinier-Frenkel V, et al. Treatment of t(11;18)-positive gastric mucosa-associated lymphoid tissue lymphoma with rituximab and chlorambucil: clinical, histological, and molecular follow-up. Leuk Lymphoma 2010;51:284-290. 27. Salar A, Domingo-Domenech E, Estany C, et al. Combination therapy with rituximab and intravenous or oral fludarabine in the first-line, systemic treatment of patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type. Cancer 2009; 115:5210-5217. 28. Kang HJ, Kim WS, Kim SJ, et al. Phase II trial of rituximab plus CVP combination chemotherapy for advanced stage marginal zone lymphoma as a first-line therapy: Consortium for Improving Survival of Lymphoma (CISL) Study. Ann Hematol 2012;91:543-551. 29. Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005;23:6370-6378. 30. Isaacson PG, Du MQ. MALT lymphoma: from morphology to molecules. Nat Rev Cancer 2004;4:644-653. 31. Troch M, Jonak C, Müllauer L, et al. A phase II study of bortezomib in patients with MALT lymphoma. Haematologica 2009;94:738-742. 32. Stathis A, Bertoni F, Zucca E. Treatment of gastric marginal zone lymphoma of MALT type. Expert Opin Pharmacother 2010;11:2141-2152. - 711 -