霍奇金淋巴瘤治疗进展课件

霍奇金淋巴瘤治疗进展霍奇金淋巴瘤治疗进展1960s1970s1980s1990s10 yJoe Connors1960s1970s1980s1990s10 yJo不同预后组的治疗疗效不同预后组的治疗疗效:Europe and North-America EuropeStage Cure Rates(GSHG and EORTC)早期预后良好组早期预后良好组 CS I,IIA,B no risk factors98%早期预后不良组早期预后不良组 CS I,IIA,B with risk factors93%进展期进展期 CS III IV,Selected CS IIB with ABVD (North America)65-80%(intermediate)不同预后组的治疗疗效:EuropeSt霍奇金淋巴瘤治疗进展课件Causes of Death among 2733 Patients with Hodgkins Disease (1960-97)Hodgkins Disease38341.2%Secondary Cancers20021.5%MDS111.2%Cardiovascular 14815.9%Pulmonary 414.4%Infection 353.8%Trauma/Suicide161.7%Other/Unknown9610.3%Total930100.%Stanford,R.HoppeCauses of Death among 2733 Did we learn from our mistakesover 40 years?Did we learn from our mistakes个体化治疗！对于早期患者如何在保证疗效的情况下尽可能减少副作用？能否进一步减少化疗疗程？减小放疗剂量？晚期患者如何进一步提高治愈率？个体化治疗！对于早期患者早期预后良好组早期预后良好组早期预后良好组早期预后良好组:CS I/II CS I/II 无不良预后因素无不良预后因素无不良预后因素无不良预后因素早期预后不良组早期预后不良组早期预后不良组早期预后不良组:CS I/II CS I/II 有不良预后因素有不良预后因素有不良预后因素有不良预后因素*进展期进展期进展期进展期:CS III/IV;CS IIB CS III/IV;CS IIB(LMM)(LMM)*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areas*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areasGHSG 临床预后分组临床预后分组早期预后良好组:CS I/II 无不良预后因素*a)预后不良(Unfavorable)早期HLu年龄年龄50岁岁u4个淋巴结区域受侵个淋巴结区域受侵u单独单独ESR50uB症状和症状和ESR30u纵隔大肿块，或肿块直径大于纵隔大肿块，或肿块直径大于10cmu2个结外部位受累个结外部位受累预后不良(Unfavorable)早期HL年龄50岁预后良好(Favorable)早期HLu不符合预后不良组条件的不符合预后不良组条件的其它其它临床临床I/II期期HL预后良好(Favorable)早期HL不符合预后不良组条件的 Hodgkin Lymphoma:早期预后不良组 Is less more?寻找高效和低毒间的最佳平衡点 Hodgkin Lymphoma:早期CS III without risk factorsABVDABVD30 Gy IFABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30 Gy IF20 Gy IF20 Gy IF2003:1375 patients recruited.2003:1375 patients recruited.Trial closed 1/2003.Trial closed 1/2003.早期预后良好组:GHSG:HD10-Trial CS III without risk factorsABHD10,4th Interim Analysis,August 20061OS(CT-Comparison)5764xABVD561534454323208925762xABVD2.56152246433820097Pts.at RiskOverall Survival months4xABVD2xABVDProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284OS rates and 95%CI at 5 years*:4xABVD:97%;95%;98%2xABVD:96%;94%;98%HD10,4th Interim Analysis,AuHD10,4th Interim Analysis,August 2006Survival curves are Kaplan-Meier estimates.Median observation time is 53 months,N=1109OS(RT-Comparison)55330Gy54551343932520610055620Gy54351145331418680Pts.at RiskOverall Survival months30Gy20GyProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284OS rates and 95%CI at 5 years:30Gy:97%;95%;98%20Gy:96%;94%;98%HD10,4th Interim Analysis,AuHD10结论2ABVD is non-inferior to 4ABVD20Gy IF-RT is non-inferior to 30Gy IF-RT HD10结论2ABVD is non-inferior HD13 Trial:早期无不良预后早期无不良预后 问题问题1)减少化疗疗程的可能性减少化疗疗程的可能性?2)Do we need bleomycin and dacarbacin in ABVD?HD13 Trial:早期无不良预后 问题减少化疗疗程的CS I/II without RF*CS I/II without RF*ABVDABVDABVDABVDABVABVABVABVAVDAVDAVDAVDAVAVAVAV30 Gy IF30 Gy IF30 Gy IF30 Gy IF30 Gy IF30 Gy IF30 Gy IF30 Gy IF*Large mediastinal mass;extranodal disease;high ERS;3 or more areas involved*Large mediastinal mass;extranodal disease;high ERS;3 or more areas involvedHD13 Trial for patients with early favourable stage DesignCS I/II without RF*ABVDABVAVDAFFTF at 18 months91%,95%CI 88,94OS at 18 months 100%,95%CI 99,100Overall Survival and FFTF Median observation time:18 monthsFFTF at 18 months91%,95%CIHD16 Trial:早期预后良好组早期预后良好组 Questions 对于反应良好者化疗是否足够对于反应良好者化疗是否足够?HD16 Trial:早期预后良好组 QuestionsCS I/II without RF*2 x ABVD2 x ABVDPET-PET-30 Gy IF30 Gy IF2 x ABVD2 x ABVDPET+PET+2 x ABVD2 x ABVDPET(+/-)PET(+/-)Follow upFollow up30 Gy IF30 Gy IFStandardStandardArmArmExperimental Experimental ArmsArms*a)large mediastinal mass;b)extranodal disease;c)high ERS;d)3 or more areas*a)large mediastinal mass;b)extranodal disease;c)high ERS;d)3 or more areasHD16 Trial for patients with early favourable stage Planned Design with PETCS I/II without RF*2 x ABVD30 早期患者联合治疗VS 单化疗联合ABVDTotal2673（9 trials）330（3 trials）EFS8099%（84%）89.5，86，87%OS8899%（94%）90,96,96早期患者联合治疗VS 单化疗联合ABVDTotal2673早期预后良好患者2ABVD+20 Gy IF-RT是标准治疗！是标准治疗！单化疗、减药化疗+放疗尚待随机研究结果早期预后良好患者2ABVD+20 Gy IF-RT是标准治Early favourable stages:Early favourable stages:CS I/II without risik factor*CS I/II without risik factor*Early unfavourable stages:Early unfavourable stages:CS I/II with risik factor*CS I/II with risik factor*Advanced stages:Advanced stages:CS III/IV;CS IIB CS III/IV;CS IIB(LMM)(LMM)*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areas*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areasGHSG Clinical Risk GroupsEarly favourable stages:CSHodgkin LymphomaIntermediate StagesFact:Combined chemo-and radiotherapy islargely considered as standard:4 ABVD+30 Gy IF-RTResult:90%tumorfree survival after 5 years 93%overall survival after 5 yearsHodgkin LymphomaIntermediate HD14 Trial for patients with early unfavourable stage Questions1)Better Results with intensified chemotherapy?HD14 Trial for patients with eHD14 Trial for patients with early unfavourable stage DesignStages I,IIA with RF a-d;IIB with RF c,d Stages I,IIA with RF a-d;IIB with RF c,d BEACOPP escalatedBEACOPP escalatedBEACOPP escalatedBEACOPP escalated ABVDABVDABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30 Gy IF30 Gy IF30 Gy IF30 Gy IF*a)bulk;b)extranodal disease;c)high ERS;d)3 or more areas*a)bulk;b)extranodal disease;c)high ERS;d)3 or more areas1450 pats recruited since 2003HD14 Trial for patients with eHD14 Trial for patients with early unfavourable stage FFTF and OS At 18 monthsFFTF:93%95%CI:90;96 OS:100%95%CI:99;100 GHSG 04/2006HD14 Trial for patients with eEORTC Trials:H10+H11Standard Arm:3 ABVD+30Gy IF-RTNeg 1 ABVD no RTPos 2 BEACOPP esc+RTEarly Favorable:H102 ABVD PETNeg +2 ABVD no RTEarly Unfavorable:H112 ABVD PETExperim.ArmExperim.ArmStandard Arm 4 ABVD+30Gy IF-RTEORTC Trials:H10+H11StandarHodgkin LymphomaEarly and Intermediate Stages Summary The GHSG experience Standard outside clinical trials:Early favorable:2ABVD+20 Gy IF-RT Early unfavorable:4 ABVD+20-30 Gy IF-RT (intermediate)Hodgkin LymphomaEarly and IntEarly favourable stages:Early favourable stages:CS I/II without risik factor*CS I/II without risik factor*Early unfavourable stages:Early unfavourable stages:CS I/II with risik factor*CS I/II with risik factor*Advanced stages:Advanced stages:CS III/IV;CS IIB CS III/IV;CS IIB(LMM)(LMM)*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areas*a)bulk;b)E-lesion;c)high ESR;d)=3 involved areasGHSG Clinical Risk GroupsEarly favourable stages:CSHodgkin Lymphoma Advanced Stages Current PracticeIntensive Chemotherapy CR:no RT PR:30 Gy IF-RT Chemotherapy:IF-RT6-8 ABVD (45%RT)Or 6-8 BEACOPP (15%RT)Hodgkin Lymphoma Advanced StaAdvanced Stages:-ABVD-the Gold Standard?No!It is not!At least not for all risk groups!Advanced Stages:-ABVD-the Long-Term Follow-upAdvanced HL:only stages IIB-LMM,III,IV!Failure-free survivalOverall survivalYears after study entryCanellos et al.NEJM,2002Long-Term Follow-upFailure-freFourth Generation Regimens:are they superior to ABVD?1.Stanford V 2.ClVP/EVA 3.MEC(Gobbi:10 drug regimen!)(JCO 2005)4.BEACOPPFourth Generation Regimens:arGobbi PG,et al.J Clin Oncol.2005;23(36):9198-9207.Epub 2005 September 19.MOPP-EBV-CAD:Meclorethamine,CCNU,Vindesine,Alkeran,Prednisone,Epidoxorubicin,Vincristine,Procarbazine,Vinblastine,Bleomycin355 patients,RT bulk+residual disease.ABVD vs Stanford V vs MECLog rank 27.48P0.0001Log rank 3.05P=0.22FFS(%)OS(%)FFS(%)Time,MonthsTime,MonthsMECABVDStanford VGobbi PG,et al.J Clin Oncol.Italian StudyAdvanced Hodgkin LymphomaABVD vs 4 BEACOPP-esc+4 BEACOPP-base vs MEC(Italian 10 drug regimen)Italian StudyAdvanced Hodgkin ChemotherapyRadiotherapyCT-Intensity ABVDBEAescStanfordVAdvanced HL(5-10%)(45%)(90%)RT IntensityNeed for RT:ChemotherapyRadiothB BleomycinE EtoposideA AdriamycinC Cyclophos.O VincristinP ProcarbazinP PrednisonBasismg/m210100256501,410040The BEACOPP-schedule Escalatedmg/m2102003512501,410040G-CSF sc1 2 3 4 5 6 7 8 9 10 11 12 13 14 1522 restartB BleomycinBasisThe BEACOPP-CS IIB-IIIA with risk factorsCS IIIB-IVArm A4 COPP+ABVD RTArm B8 BEACOPP baseline RTArm C8 BEACOPP escalated*RTRT to initial bulk and residual tumorGHSG:HD9 Trial Design(1992-96)*with G-CSFRandomisationDiehl et al,NEJM,2003CS IIB-IIIA with risk factorsAHD9-10 ys FFTF by treatment armLog-rank tests:A v B v C p0.0001A v Bp=0.040B v Cp0.0001A v Cp0.0001 BEA escC/ABVD82%64%HD9-10 ys FFTF by treatment aGHSG 2007 HD9HD9-10 ys-OS by treatment armLog-rank tests:A v B v C p=0.0005A v Bp=0.19B v Cp=0.0053A v Cp45 yearsSexMaleTumorStage IVLaboratory VariablesAnemiaHgb 10.5 g/dLAlbumin15,000/mm3Lymphopenia600/mm3 or8%of leukocytesHasenclever D,Diehl V.N Engl J Med.1998;339(21):1506-1514.Prognostic Factors in AdvancedSurvival rates according to IPS at 10 ysFFTF OS (%,10 y)C/ABVDn=261BEAbasen=469BEAescn=466log-rank p(A vs.C)IPS 0-1n=3077888798591940.0150.27IPS 2-3n=4645973718483872.5cm(involved node)IPS 0 7randomizeCT3 AN=1,100 ptsFollow-up(no radiation)6 cycles BEACOPP-14Transatlantic Study4 cycles ABVD4 cycles AVD2 cycles ABVDPET negativePET p Early or Late Intensification?How can we avoid 30%failures?Is High-dose therapy+Stem Cell Supportthe only solution for failures?Or-should we aim to avoid themalready from start of therapy?This means:early intensification Early or Late IntensifThe early intensification in advancedHL2-4 BEACOPP escProg/Relapse 5-10%6-8 ABVDProgr/Relapse 30-40%(IPS:3)HDCT/SCT2nd hit“in 30-40%1st hit“1st hit“2nd hit“in 5-10%HDCT/SCT0.9%AML/MDS!5-10%AML/MDS4 BEA baseThe early intensification in HD15:study Ongoing Study:1530 patsDose density and reduction of toxicityABC8 x BEACOPP 14(baseline)6 x BEACOPP escalated8 x BEACOPP escalatedRandomizationResidual tumor mass?(2.5 cm)follow upNoPET-studyPET negative:follow upPET positive:RT 30 Gy15%of all pats!YesHD15:study ABC8 x BEACOPP 146HD15 Trial for patients with advanced stage FFTF and OSMedian observation time:21 months21-month OS:95%(95%CI:93%-97%)21-month FFTF:86%(95%CI:83%-89%)559FFTF515437283133370560OS541492336185581Pts.at RiskTime monthsFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.0061218243036HD15 Trial for patients with aHD 15 Trial8vs6BEAescvs8BEA-14(550pats)PET after end of chemotherapy for 2,5cm rests:Patients with rests 2,5 cm:245 (78,8%)PET neg:no RT:244 4,1%relapses 311 66 (21,2%)PET pos:IF-RT:62 15,3%relapses HD 15 Trial8 vs 6 BEAesc vs2x BEACOPP esc.PET positivePET negative2x BEACOPP esc.2 BEA esc.-4 baseABCRT PET+Rests 2,5cm(involved node-technique)No RT No RTFuture GHSG Study:HD18 Advanced HL IPS 0-72 BEA esc-4 base+Rituximab2BEA esc-4 base 0 Rituximab2x BEACOPP esc.PET positivePETNFkB(p50/RelA)IKKa/b/gp50/RelAProteasomal degradation(e.g.Bortezomib;MG-132)26S proteasomeIkB-a/Selective Ikk-b inhibitors(e.g.SPC-839;BMS-345541)HDAC inhibitor(e.g.depsipeptide;SAHA)Proproliferative and antiapoptotic phenotype InflammationTargeted TherapiesNFkB(p50/RelA)IKKa/b/gp50/RelTherapy with the anti-CD30 MoAk 5F11Before Therapy6 Weeks after TherapyBorchmann et al.,2004Therapy with the anti-CD30 MoAFuture Strategies:1.Response adapted intensity:(clinomics“)2.-PET:as predictor of early response and prognosticator“2.Risk adapted strategy:(genomics“)3.-using gene-expression profiles for risk groups4.-IPS5.3.Targeted/molecule-directed therapy(proteomics“)4.Global Cooperative Trials(globolics“)Future Strategies:Response adaThomas Hodgkin 1832Dorothy Reed 1902 Thanks to -the GHSG-team-the participating doctors/nurses -the thousands of patients -the Deutsche Krebshilfe“for support -you for your attentionThomas Hodgkin 1832Dorothy Ree霍奇金淋巴瘤治疗进展课件