대한내과학회지 : 제 71 권제 2 호 2006 종설 단클론성항체를활용한 B 세포악성림프종치료의신기원 : 리툭시맙 가톨릭대학교의과대학내과학교실, 성모병원조혈모세포이식센터 조석구 A new era of B cell lymphoma treatment by using monoclonal antibody; Rituximab (anti-cd20 antibody) Seok Goo Cho, M.D., PhD Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, Seoul, Korea 개요단클론성항체 (monoclonal antibody) 를이용한종양치료법은종양세포의표면에존재하는항원에대한특이적면역반응을통한종양세포의선택적살상을유도하기때문에통상적인화학요법과달리정상조직에대한치료관련독성이적을것으로기대된다. 종양을치료하기위한단클론성항체에관해서는오래전부터연구되었으나별다른성과를거두지못하다가최근 B세포계열의림프종에서발현되는 CD20 항원을표적으로하는단클론성항체인리툭시맙 (rituximab) 과 anti-cd20 항체에 iodine과 yttrium 등의방사선동위원소를부착한방사면역치료제등이개발되어상업화됨으로써 B 세포계열림프종의임상치료를위한패러다임에새로운변화가일어나고있다 ( 표 1). 리툭시맙의임상도입초기에는저도림프종과여포성림프종및외투막세포종등에국한하여단복요법등으로투여되었으나최근에는미만성거대 B 세포림프종에서일차관해요법혹은구출요법과병용투여됨으로써생존률이향상되고있다. 또한 anti-cd20 항체에방사선동위원소가부착 된 90 Y ibritumomomab tiuxetan (Zevalin) 과 idodine 131 I tositumomab (Bexxar) 은골수박멸용량으로투여한후 자가조혈모세포이식을시도하는단계로까지확대적용되고있다. 악성림프종영역에서 anti-cd20 단클론성항체를매개로한새로운임상치료법의개발은지금까지의고식적인화학요법과고용량화학요법으로치료받아오던림프종환자들에서치료관련부작용을경감시킴과동시에치료성적을향상시킴으로써림프종환자들의수명연장과삶의질을향상시키는데기여할수있을것으로기대되고있다 1, 2). 리툭시맙의개발배경과특징리툭시맙 (IDEC-C2B8) 은 chimeric anti-cd20 단클론성항체로서종양치료목적으로상용화되어미국 FDA 로부터최초로승인된단클론성항체치료제이다. 1980 년대초기의 CD20 항원에항체는생쥐로부터만들어진단클론성항체로서항원과의반응성은우수하지만생체반감기가짧고이종항원으로인한항원성 (HAMA, human anti-mouse antibody) 이유발되는단점이있었고항체의 Fc fragment 를통한 effector 기능이인형항체보다불리한결점들이있었다. 이러한생쥐기원항체의결점을보안하고생물학적효과를높이기위하여항원인식이이루어지는가변부위 (variable region) 는생쥐기원이고항체의불변부위 (constant region) 는사람 - 124 -
-Seok Goo Cho : A new era of B-cell lymphoma treatment by using monoclonal antibody; Rituximab (anti-cd20 antibody) - Table 1. Development in antibody therapy for Non-Hodgkin's lymphoma 1890 Transferable immunity first shown in animals 1890 idea of a magic bullet first proposed; hoped that therapy could be targeted to a particular site of disease 1895 First report of passive serum therapy in cancer 1929 First report of tumor-specific antiserum being made 1968 Passive serum therapy reported in humans 1975 Development of hybridoma technologyfor producing monoclonal antibodies 1980 First report of monoclonal Ab therapy in lymphomas 1980s Trials conducted with anti-idiotype monoclonal Abs specific for the unique idiotype expressed on B-cell lymphomas 1987 Reduction in circulating tumor cells and regression of lymphoma tumor masses reported with IF5 Ab to CD20; need for large doses of Ab for optimal biodistribution became apparent 1994 First published report on the chimeric monoclonal Ab to CD20 no known as Rituximab 1997 Rituximab approved by FDA 1999 First published report on Y ibritumomab tiuxetan 2002 90 Y ibritumomab tiuxetan approved by the FDA 2003 131 I tositumomab approved by the FDA Table 2. Characteristics of rituximab characteristics molecular structure Indication specific FDA approval molecular weight a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen IgG kappa immunoglobulin 1 murine light and heavy variable region sequences 2 human constant region sequences 3 two heavy chains of 451 AA 4 two light chains of 213 AA(based on DNA analysis) relapsed or refractory low-grade or follicular CD20-positive B-cell lymphoma MW ; 145 KD production mammlian cells (Chinese Hamster Ovary) purification affinity and ion exchange chromatography manufacturer Genentech, Inc (US License No. 1048) supplier Generic name Brand name Synonym availability IDEC Pharmaceuticals Corporation (US License No. 1235) under a shared manufacturing arrangement Rituximab Rituxan in USA, Canada, Japan Mabthera in other countries IDEC-C2B8 Monoclonal antibody IDEC-C2B8 Anti-CD20 monoclonal antibodies Pan-B antibodies C2B8 monoclonal antibody 100 mg (10 ml), 500 mg (50 ml) - 125 -
- 대한내과학회지 : 제 71 권제 2 호통권제 552 호 2006 - Table 3. Pharmacokinetic parameters of Rituximab (n=14) Parameter First Dose Fourth Dose Dose level (mg/m 2 ) Serum half life (hr) (range) Cmax ( μg /ml) Clearance (ml/hour) Data from Ann Oncol 1998 375 mg/m 2 x1 76.3 (31.5-152.6 h) 254.5 38.2 375 mg/m 2 x4 205.8 (83.9-407 h) 464.4 9.2 기원인키메라항체인리툭시맙이유전자재조합기술을통하여합성되었다 ( 표 2). 단클론성항체요법의표적분자로서선정된 CD20 항원은 B세포계열이세포주기 (cell-cycle entry) 에들어가거나 B세포로분화하는데관여하는것으로알려져있다. CD20 항원은세포표면으로부터쉽게탈각되거나변형혹은함입되지않는특성을지니고있어표적분자로서활용하기에적당한특징을갖고있다. CD20 항원의분포는정상세포의경우, pre-b 세포단계에서활성화된 B 세포 (activated B cell) 단계까지광범위하게분포하지만조혈모세포, 형질세포와다른계열의세포에는분포하지않으며림프종의경우는 B 세포림프종과만성림프구성백혈병의대부분과 pre-b cell 급성림프구성백혈병의 50% 에서 CD20 항원이발현되어단클론성항체를이용한종양특이적면역반응을유도하는데적절한표적이될수있다 3, 4). 리툭시맙의작용기전리툭시맙에의한암세포의살상효과의주된작용기전은보체매개성세포독성 (complement-mediated cytotoxicity) 과항체매개성세포독성 (antibody-dependent cell-mediated cytototoxicity) 이며그외세포아포토시스 (apoptosis) 등이관여하는것으로알려져있다. 사람의다양한조직과의반응성을조사한결과에의하면비장의백질 (white pulp of spleen), 편도선조직 (lymphoid follicel of tonsil), 림프절의 B 세포와장의림프조직에반응하지만상피세포, 섬유모세포, 내피세포및 neuroectodermal 세포인뇌척수조직등과는반응하지않는다. 리툭시맙의허가용량과약동학 FDA approval 375 mg/m 2 weekly x 4 Maloney 등의초기 1상연구결과에의하면맙페라는 1회투여했을때투여후 10일까지도검출이가능하며여러차례투여할수록더높은농도로더오랜기간유지될수있음을보고하였다. McLaughlin 등도맙테라를 1차투여했을때보다 4차투여했을때항체반감기가더길며치료효과를보이는반응군 (responder group) 과종양부하가적은경우에혈청항체반감기가더길다고보고하였다. Phase I 임상연구의결과에의하면저도의림프종에 375 mg/m 2 의용량으로 1주마다총 4회를투여하였을때종양치료효과를관찰할수있었고, 이와관련된용량제한독성 (dose-limiting toxicities) 은관찰할수없었기때문에 1상연구의고안대로미국 FDA 승인을획득하였다 ( 표 3) 3). 리툭시맙의투여방법맙테라의부작용가운데용량을제한한만한독성은없으나약제를처음투여할때나타날수있는약물에대한과민반응과주입관련부작용 (infusion-related adverse effect) 등은조심해야한다. 맙테라는생리식염수혹은 5% 포도당용액에 1~4 mg/ml의농도로희석하여투여한다. 주입관련부작용을예방하기위하여맙테라투여 30~60분전에전처치로아세트아미노펜과 diphenhyramine을투여하며대부분은주입속도를늦추거나중단하면해결된다. 과민반응이발생하였을때 epinephrine과스테로이드를즉시투여할수있도록준비한다. 고혈압치료제는맙테라투여 12시간전에중단한다. 약제의초기주입속도는 50 mg/hr로실시하고활력징후를관찰하여특별한이상이없으면 30분마다 50 mg/hr 씩증량하여최대 400 mg/hr까지증량한다. 최초약제투여후별다른이상이없었으면다음번투여시에는 100 mg/hr로투여를시작하며처음보다는투여시간이단축된다 ( 표 4). 처음과마찬가지로 30분간격으로최대 400 mg/hr까 - 126 -
- 조석구 : 단클론성항체를활용한 B 세포악성림프종치료의신기원 : 리툭시맙 - Table 4. Infusion time in pivotal phase III trial 1st infusion 2nd infusion third infusion fourth infusion mean duration(hour) 5.2 3.5 3.3 3.3 Table 5. Adverse Events of infusion-related Effects; Occuring in 5% of Patients Treated With Rituximab (N=315) Incidence (all grades) Events Any adverse event General Number 275 Percent 87% Fever Chills Asthenia Headache Angioedema Myalgia Dizziness Throat irritation Abdominal pain Cardiovascular Hypotension Respiratory Rhinitis Bronchospasm Digestive Nausea Vomiting Dermatologic Pruritus Rash Urticaria Hematologic Leukopenia Thrombocytopenia Neutropenia 154 102 49 43 41 21 23 19 18 32 25 24 55 23 32 31 24 33 25 21 49% 32% 16% 14% 13% 7% 7% 6% 6% 10% 8% 8% 18% 7% 10% 10% 8% 11% 8% 7% 지증량한다. 백혈구의수가 75,000/μL을넘는경우에는종양용해증후군 (tumor lysis syndrome) 의발생이우려되어 25 mg/hr으로투여하는것도고려할수있다. 리툭시맙의부작용 맙테라의주된부작용은다른단클론성항체들에서와마찬가지로주입관련증상군 (infusion-related effects) 이 다. 주입관련증상들은처음치료받는사람과투여개시 2시간이내에주로문제가되며주증상은 grade I/II 의발열과오한이며 grade III와 IV 독성은각각 12% 와 3% 이었다. 그외의증상으로구역, 두통, 혈관부종으로인하여혀와목이붇는느낌, 비염, 소양감, 발진, 경미한혈압강하와호흡곤란과기관지협착등의증상이나타난다 ( 표 5). 이러한증상들은앞에서언급한것처럼맙테라주사의속도를늦추거나중단하면해결할수있으며전처치로아세트아미노펜과 diphenhyramine을투여하면약화시킬수있다. 증상이가라앉으면주입속도를절반으로줄여다시투여하고환자가편안해하면주입속도를점진적으로높인다. 대부분의경우이러한증상들이남아있는양의약제투여나다음번약제투여에다시발생하지는않는다. 혈액학적독성은대단히경미하며가역적이다. 말초혈액의혈소판이 25,000/μL 미만, 호중구수가 500/μL 미만, 혈색소가 8.0 g/dl 미만으로감소하는빈도는각각 1% 미만, 1.3% 미만, 2.6% 이었다. 종양용해증후군 (tumor lysis syndrome) 은 166명을대상으로한 pivotal study 에서는발생하지않았다. 백혈병상태가아닌 indolent lymphoma에서는발생하기어렵고드물게말초혈액에서 B 세포의수가많은환자들에서보고된바있어주의할필요는있다 ( 표 6). 임상적상황에따른리툭시맙의치료효과 1. 개요악성림프종의치료변천사를살펴보면 1976년 CHOP 복합화학요법이임상에도입된이후새로운관해유도요법을개발하기위한다양한시도가있었다 5). 그러나, 1993년발표된 SWOG의보고에의하면 1세대요법인 CHOP 과 3세대다제화학요법들 (ProMACE- CytaBOM, m-bacod, MACOP-B) 과의대규모비교연구결과새로운 3세대요법들이 CHOP에비하여유의한생존률의향상을얻을수없었고오히려치료관련독성만더높았다 6). 한편, 1995년 Parma group의연구결과에의하면 - 127 -
-The Korean Journal of Medicine : Vol. 71, No. 2, 2006 - Table 6. Specific consideration of side effect of rituximab Cardiac condition Bronchospasm Hematologic Tumor lysis Sx arrhythmia, angina less frequently during rituximab therpay bronchospasm 8%, requirement of bronchodilator 2% mild and reversible 1 PLT < 25,000/μL ; < 1% 2 WBC nadirs of < 500/μL ; < 1.3% 3 hemoglobin < 8.0 g/dl ; 2.6% not observed in 166 patients Table 7. Development in front-line therapy for Non-Hodgkin's lymphoma 1975 1976 1985 1993 1993 1994 1995 1997 2002 C-MOPP by De Vita Introduction of CHOP regimen in lymphoma field (SWOG) MACOP-B regimen of Vancouver study (Canadian NCI) Result of Phase III comparison study; CHOP vs MACOP-B, ProMACE-CytaBOM, m-bacod (SWOG) 13 Introduction of International prognostic index (IPI score) (SWOG) First published report on the chimeric monoclonal Ab to CD20 Role of high dose therapy in sensitive relapse group (Parma Trial) FDA approval of rituximab Survival benefit of Rituximab + CHOP vs CHOP 9 Figure 1. Event-free survival of 399 patients (R-CHOP vs CHOP). Figure 2. Overall survival of 399 patients (R-CHOP vs CHOP). 재발성림프종환자들가운에구출요법에반응을보이는감수성재발군 (sensitive relapse) 에서고용량화학요법과자가말초혈액조혈모세포이식이구출요법만을시행한군에비하여생존율이유의하게향상이되었다 7). 결론적으로통상적인관해유도요법으로치유가능한군을일차선별하고그이후재발된환자들가운데감수성재발군을고용량화학요법으로이차선별하여치료하는 전략이보편화되었고, 최근에는국제예후인자가높은경우진단초기관해유도요법과고용량화학요법을연속으로시행하는프로토콜등이활성화되고있어새로운일차관해유도요법을개발하는것은사실상매우어려운상황에직면하게되었다. 그러나리툭시맙이 B 세포계열의저도림프종은물론최근에는 CD20 항원이양성인 B 세포림프종전체로확대되면서 B 세포림프종의치 - 128 -
-Seok Goo Cho : A new era of B-cell lymphoma treatment by using monoclonal antibody; Rituximab (anti-cd20 antibody) - 료영역에새로운변화를예고하였다 ( 표 7) 8). 2. 관해유도에서리툭시맙의역할미만성거대 B 세포림프종 (diffuse large B cell lymphoma, DLBCL) 에서표준요법인 CHOP 요법과리툭시맙 (375 mg/m 2 on D1 of each cycle) 이 CHOP과병용투여된 R-CHOP 요법과간의 3상연구결과들이보고되고있다. 추적기간중앙값이 4년이상인 GELA group의연구결과를보면완전관해율 (60% vs 76%, p=0.005), event-free survival (EFS, 29% vs 51%, p= 0.00001) 및 overall survival (OS, 7% vs 59%, p=0.01) 은 R-CHOP 군에서유의하게높았다 ( 그림 1, 2) 9). 60~ 80세의고령의환자를대상으로 R-CHOP 을 8주기시행한 GELA 연구와달리 18~60까지의비교적젊은연령의환자를대상으로리툭시맙과 CHOP 혹은 CHOP 유사요법을병용하여 6주기시행한 MinT study 에서도리툭시맙병용군이 3년무병생존율 (79% vs. 59%, p<0.0001) 과 3년전체생존율 (93% vs 84% p= 0.0001) 에서각각유의하게향상되었다 10). 1993년 SWOG의 DLBCL에서 3세대요법들과 CHOP 요법의 3상비교연구결과를상기할때리툭시맙의임상적유용성은매우높다고사료되며향후이와유사한연구결과들이국외는물론국내에서도추가적으로발표될것으로사료된다. R-CHOP의임상성적들가운데특이할만한보고로는 DLCBL에서 bcl-2 음성환자군의경우에는 R-CHOP과 CHOP 요법간에생존율의차이가없고 (60% vs 40%, p=0.13) bcl-2 양성환자군에서 R-CHOP이유의하게높은생존율을보였다 (EFS 58% vs 32%, p<0.001). 이러한결과는리툭시맙이 bcl-2 과다발현으로인한 CHOP 요법의실패요인을예방할수있음을시사하는것이다 11). 서구에비하여발생빈도가낮은여포성림프종의경우도관해유도치료시리툭시맙을활용한 3상비교연구에서 R-CVP군이 CVP군에비하여치료성적과생존율이우수하다는것이최근에보고되었다 12). 이러한결과들을토대로우리나라에서도미만성 B세포림프종에서 R-CHOP 요법과여포성림프종에서 R-CVP 요법이보험급여가되고있다. 3. 재발성혹은불응성림프종에서리툭시맙의활용재발성혹은불응성미만성거대 B 세포림프종의생존율은자가조혈모세포이식전에시행하는구출요법에 대한반응율에의하여결정된다. 구출요법으로흔히사용되는 ICE (ifosfamide, carboplatinm etoposide) 요법에리툭시맙을첨가한 R-ICE 요법을시행한 Memorial Sloan-Kettering Cancer Center는 36명을대상으로 CR 과 PR이각각 53% 와 25% 로보고하였다. R-ICE 요법후자가이식을시행한환자들의치료성적이 ICE 요법후자가이식을시행한역사적대조군에비하여우수한경향은보였지만통계적으로유의한성적향상은없었다고보고하였다. R-ICE 요법이구출요법이자가이식후의궁극적인생존율을향상시키지는못하였지만반응율은높일수있었다 13). 통상적으로많이사용되는재발성혹은불응성 DLBCL의구출요법에리툭시맙을첨가하는것은아직 3상연구결과가발표되지는않았으나문헌상의성적에비하여반응은우수한경향을보이나생존율의현저한향상은뚜렷하지않으며향후림프종의구출요법에서리툭시맙의역할에관한활발한 3상연구들이필요할것으로사료된다. 4. 기타임상적상황에서리툭시맙의활용여포성림프종 (follicular lymphoma) 혹은외투막세포종 (mantle cell lymphoma) 과같이골수침습이빈번하게일어나는아형의경우고용량화학요법과자가조혈모세포이식의치료성적은종양세포가오염되지않은이식편 (graft) 의확보에좌우된다 14). Magni와 Gianni 등은 4단계고용량화학요법의중간에리툭시맙 ( 총 6회투여 ) 을투여하는생체내골수정화요법 (in vivo purging) 으로 100% PCR-음성이식편을얻을수있었다고보고하였다 15). 골수정화요법은개발초기에는실험실내정화법 (in vitro graft purging) 이시행되었으나기술적번잡성과낮은정화율이문제로지적되고있는상황에서리툭시맙또는방사선동위원소가부착된 CD20 항체등을이용한생체내방법이더효과적이라는방법으로자리잡아가고있다 16). 리툭시맙을활용한유지요법은미만성 B 세포림프종에서는효과가입증되지않았고일차관해유도요법으로 CHOP을시행한군에한하여일부효과가인정되고있다 17). 그러나현재 R-CHOP 요법이표준요법으로활용되고있는의료현실을감안할때이러한임상적이득은도움이되지않는다고생각된다. 그러나스위스연구그룹 (SAKK, Swiss Group for Clinical Cancer Research) 은일차치료에반응을보인여포성림프종환 - 129 -
- 대한내과학회지 : 제 71 권제 2 호통권제 552 호 2006 - 자를대상으로리툭시맙을일주일간격으로총 4회유지요법을실시한결과무병생존기간이유의하게연장되었다 ( 유지요법군 36개월 vs 관찰군 16개월, p=0.004) 18). 리툭시맙은 B세포악성림프종이외에도다양한유사질환에서효과적을활용될수있다. 장기이식후엡스타인바바이러스 (Epstein-Barr virus, EBV) 와연관되어발생하는장기이식후림프증식성질환 (post-transplantation lymphoproliferative disese, PTLD) 의새로운치료법으로활용되고있으며 19) 그외에Waldenstrom's macroglobuinemia, 특발성혈소판감소성자반증 (ITP), 캐슬만씨병 (multicentric Castleman's disease) 20, 21), 류마티양관절염 22, 23), 자가면역성용혈성빈혈 22), 혈전성혈소판감소성자반증 24) 등의질환에서새로운치료법의활용되고있다. 결론 유전자재조합기술의발달과함께등장한리툭시맙은종양특이적항원인 CD20 항원을보유한 B세포림프종의치료에서괄목할만한치료성적의향상을가져왔다 9, 10). 리툭시맙은앞으로미만성 B 세포림프종과여포성림프종은물론모든아형의 B세포림프종의치료를위한복합화학요법과병용투여함으써치료성적을향상시킬수있을것으로전망된다. 리툭시맙이임상에도입되기전에확립된모든치료전략과개념이새롭게재검증혹은재수립되어야할것으로생각된다. Key Words : Rituximab, B cell lymphoma 중심단어 : 리툭시맙, B 세포림프종 REFERENCES 1) Forero A, Lobuglio AF. History of antibody therapy for non-hodgkin's lymphoma. Semin Oncol, 30:1-5, 2003 2) Cheson BD. Radioimmunotherapy of non-hodgkin lymphomas. Blood, 101:391-398, 2003 3) Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (Rituximab) anti-cd20 monoclonal antibody therapy in patients with relapsed lowgrade non-hodgkin's lymphoma. Blood, 90:2188-2195, 1997 4) McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence- Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol, 16:2825-2833, 1998 5) McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, Lane M, Gamble JF, Jones SE, Grozea PN, Gutterman J, Coltman C, Moon TE. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer, 38:1484-1493, 1976 6) Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr., Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-hodgkin's lymphoma. N Engl J Med, 328:1002-1006, 1993 7) Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non- Hodgkin's lymphoma. N Engl J Med, 333:1540-1545, 1995 8) Foran JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M, Coiffier B, Johnson PW, Gisselbrecht C, Reyes F, Radford JA, Bessell EM, Souleau B, Benzohra A, Lister TA. European phase II study of rituximab (chimeric anti- CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol, 18:317-324, 2000 9) Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large- B-cell lymphoma. N Engl J Med, 346:235-242, 2002 10) Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, Lopez-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with goodprognosis diffuse large-b-cell lymphoma: a randomised controlled trial by the MabThera International - 130 -
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