1、霍奇金淋巴瘤治疗进展霍奇金淋巴瘤治疗进展Hodgkins Lymphoma by Era n=2167Overall Survival(y)403020100Cum Survival1.0.8.6.4.20.01960s1970s1980s1990s10 yJoe Connors霍奇金淋巴瘤治疗进展2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,I
2、IA,B with risk factors93%进展期进展期 CS III IV,Selected CS IIB with ABVD (North America)65-80%(intermediate)霍奇金淋巴瘤治疗进展3霍奇金淋巴瘤治疗进展4Causes 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 3
3、53.8%Trauma/Suicide161.7%Other/Unknown9610.3%Total930100.%Stanford,R.Hoppe霍奇金淋巴瘤治疗进展5Did we learn from our mistakesover 40 years?霍奇金淋巴瘤治疗进展6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？霍奇金淋巴瘤治疗进展7霍奇金淋巴瘤治疗进展8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ESR3
4、0u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霍奇金淋巴瘤治疗进展9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霍奇金淋巴瘤治疗进展10 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霍奇金淋巴瘤治疗进展11CS III without risk factorsABVDABVD30 Gy IFABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30 Gy IF20 Gy IF20 Gy I
5、F早期预后良好组:GHSG:HD10-Trial 霍奇金淋巴瘤治疗进展12HD10,4th 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%
6、2xABVD:96%;94%;98%霍奇金淋巴瘤治疗进展13HD10,4th 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
7、.91.0012243648607284OS rates and 95%CI at 5 years:30Gy:97%;95%;98%20Gy:96%;94%;98%霍奇金淋巴瘤治疗进展14HD10结论 2ABVD is non-inferior to 4ABVD 20Gy IF-RT is non-inferior to 30Gy IF-RT 霍奇金淋巴瘤治疗进展151)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?霍奇金淋巴瘤治疗进展16霍奇金淋巴瘤治疗进展17413FFTF38826917084413O
8、S408314219114Pts.at RiskTime monthsKaplan-Meier-AnalysenGesamt Survival und FFTFFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.006121824FFTF at 18 months91%,95%CI 88,94OS at 18 months 100%,95%CI 99,100Overall Survival and FFTF Median observation time:18 months霍奇金淋巴瘤治疗进展18 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
9、够?霍奇金淋巴瘤治疗进展19CS I/II without RF*霍奇金淋巴瘤治疗进展20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霍奇金淋巴瘤治疗进展21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霍奇金淋巴瘤治疗进展22霍奇金淋巴瘤治疗进展23Hodgkin LymphomaIntermediate StagesFact:Combined chemo-and radiothe
10、rapy islargely considered as standard:4 ABVD+30 Gy IF-RTResult:90%tumorfree survival after 5 years 93%overall survival after 5 years霍奇金淋巴瘤治疗进展241)Better Results with intensified chemotherapy?霍奇金淋巴瘤治疗进展251450 pats recruited since 2003霍奇金淋巴瘤治疗进展26447FFTF427361233111449OS444397290150Pts.at RiskTime mon
11、thsFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.006121824At 18 monthsFFTF:93%95%CI:90;96 OS:100%95%CI:99;100 GHSG 04/2006霍奇金淋巴瘤治疗进展27EORTC 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 PET
12、Experim.ArmExperim.ArmStandard Arm 4 ABVD+30Gy IF-RT霍奇金淋巴瘤治疗进展28Hodgkin 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)霍奇金淋巴瘤治疗进展29霍奇金淋巴瘤治疗进展30Hodgkin Lymphoma
13、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)霍奇金淋巴瘤治疗进展31Advanced Stages:-ABVD-the Gold Standard?No!It is not!At least not for all risk groups!霍奇金淋巴瘤治疗进展32Long-Term Follow-upAdvanced HL:only stages IIB-LMM,III,
14、IV!Failure-free survivalOverall survivalYears after study entryCanellos et al.NEJM,2002霍奇金淋巴瘤治疗进展33Fourth Generation Regimens:are they superior to ABVD?1.Stanford V 2.ClVP/EVA 3.MEC(Gobbi:10 drug regimen!)(JCO 2005)4.BEACOPP霍奇金淋巴瘤治疗进展34Gobbi PG,et al.J Clin Oncol.2005;23(36):9198-9207.Epub 2005 Sept
15、ember 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 V霍奇金淋巴瘤治疗进
16、展35Italian StudyAdvanced Hodgkin LymphomaABVD vs 4 BEACOPP-esc+4 BEACOPP-base vs MEC(Italian 10 drug regimen)霍奇金淋巴瘤治疗进展36 ChemotherapyRadiotherapyCT-Intensity ABVDBEAescStanfordVAdvanced HL(5-10%)(45%)(90%)RT IntensityNeed for RT:霍奇金淋巴瘤治疗进展37B BleomycinE EtoposideA AdriamycinC Cyclophos.O Vincristin
17、P 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 restart霍奇金淋巴瘤治疗进展38CS IIB-IIIA with risk factorsCS IIIB-IVArm A4 COPP+ABVD RTArm B8 BEACOPP baseline RTArm C8 BEACOPP escalated*RTRT to initial bulk
18、 and residual tumorGHSG:HD9 Trial Design(1992-96)*with G-CSFRandomisationDiehl et al,NEJM,2003霍奇金淋巴瘤治疗进展39261A19417314611075190469B378332282222106260466C41238432123492140p=.001Pts.at RiskyearsABCProbability0.00.10.20.30.40.50.60.70.80.91.00123456789101112131415HD9-10 ys FFTF by treatment armLog-rank
19、 tests:A v B v C p0.0001A v Bp=0.040B v Cp0.0001A v Cp0.0001 BEA escC/ABVD82%64%霍奇金淋巴瘤治疗进展40GHSG 2007 HD9261A238218196147107300469B436392344272134360466C441412357270113180p=.001Pts.at RiskyearsABCProbability0.00.10.20.30.40.50.60.70.80.91.00123456789101112131415HD9-10 ys-OS by treatment armLog-rank
20、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.霍奇金淋巴瘤治疗进展47Survival rates according to IPS at 10 ysFFTF OS (%,10 y)
21、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 AVD霍奇金淋巴瘤治疗进展53 Early or Late Intensification?How can we
22、 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 霍奇金淋巴瘤治疗进展54The early intensification in advancedHL2-4 BEACOPP escProg/Relapse 5-10%6-8 ABVDProgr/Relapse 30-40%(IPS:3)
23、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 base霍奇金淋巴瘤治疗进展55HD15: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
24、upNoPET-studyPET negative:follow upPET positive:RT 30 Gy15%of all pats!Yes霍奇金淋巴瘤治疗进展56Median observation time:21 months21-month OS:95%(95%CI:93%-97%)21-month FFTF:86%(95%CI:83%-89%)559FFTF515437283133370560OS541492336185581Pts.at RiskTime monthsFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.006121
25、8243036霍奇金淋巴瘤治疗进展57HD 15 Trial8 vs 6 BEAesc vs 8 BEA-14(550 pats)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 霍奇金淋巴瘤治疗进展582x BEACOPP esc.PET positivePET negative2x BEACOPP esc.2 BEA esc
26、.-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 Rituximab霍奇金淋巴瘤治疗进展59NFkB(p50/RelA)IKKa/b/gp50/RelAProteasomal degradation(e.g.Bortezomib;MG-132)26S proteasomeIkB-a/Selective Ikk-b inhibitors(e.g.S
27、PC-839;BMS-345541)HDAC inhibitor(e.g.depsipeptide;SAHA)Proproliferative and antiapoptotic phenotype InflammationTargeted Therapies霍奇金淋巴瘤治疗进展60Therapy with the anti-CD30 MoAk 5F11Before Therapy6 Weeks after TherapyBorchmann et al.,2004霍奇金淋巴瘤治疗进展61Future Strategies:1.Response adapted intensity:(clinom
28、ics“)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“)霍奇金淋巴瘤治疗进展62Thomas 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 attention霍奇金淋巴瘤治疗进展63霍奇金淋巴瘤治疗进展64
