1、外周外周T T细胞淋巴瘤的治疗进展细胞淋巴瘤的治疗进展四川省肿瘤医院肿瘤内科四川省肿瘤医院肿瘤内科 张智慧张智慧主要内容主要内容 PTCLPTCL的分类的分类 PTCLPTCL的流行病学的流行病学 PTCLPTCL的预后因子的预后因子 PTCLPTCL治疗新药物治疗新药物外周外周T淋巴瘤的分类淋巴瘤的分类PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomas PTCL does not refer to anatomic sites,but rather to the involvement of more
2、 mature(postthymic)T cells vs prethymic or immature T cellsAdapted from Swerdlow SH,et al.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.2008.Non-Hodgkins lymphomaT-/NK-cell neoplasmsB-cell neoplasmsT-cell prolymphocytic LeukemiaPrecursor Lymphoid NeoplasmsCutaneousExtranodalLe
3、ukemicMature T-/NK-cell neoplasmsNodalNK/TCL nasal typeAdult T-cell leukemia/lymphoma Subcutaneous panniculitis-like TCLEnteropathy-associated TCLHepatosplenic TCLAggressive NK-cell leukemiaTransformed MFPrimary cutaneous gamma/delta TCLPeripheral TCL-NOSAngioimmunoblastic TCLAnaplastic large-cell l
4、ymphoma(ALK+/-)AggressiveT-Lymphoblastic Leukemia/LymphomaPrimary cutaneous CD30+T-cell disordersMFT-cell large granular lymphocytic leukemiaSzary SyndromeIndolentInternational T-Cell Lymphoma Project.J Clin Oncol.2008;26:4124-4130.1314 例例PTCL 和和 NKTCL 的分布的分布25.9%18.5%10.4%9.6%6.6%5.5%4.7%12.2%2.5%0
5、.9%1.4%1.7%Peripheral T-cell lymphomaAngioimmunoblasticNatural killer/T-cell lymphomaAdult T-cell leukemia/lymphomaAnaplastic large-cell lymphoma,ALK+Anaplastic large-cell lymphoma,ALK-Enteropathy-type T cellPrimary cutaneous ALCLHepatosplenic T cellSubcutaneous panniculitis-likeUnclassifiable PTCLO
6、ther disorders四川省肿瘤医院淋巴瘤病区截止四川省肿瘤医院淋巴瘤病区截止20142014年年1010月月总数总数502例淋巴瘤患者例淋巴瘤患者T-NHL 108例例2012.4-2014.10四川省肿瘤医院淋巴瘤数据四川省肿瘤医院淋巴瘤病区截止四川省肿瘤医院淋巴瘤病区截止20142014年年1010月月PTCL流行病学不同地域不同地域PTCL亚型相对发病率亚型相对发病率 1,2 总的发病率亚洲和加勒比地区更高总的发病率亚洲和加勒比地区更高1.Savage KJ.Hematology Am Soc Hematol Educ Program.2005;10:267-277.2.Inte
7、rnational T-Cell Lymphoma Project.J Clin Oncol.2008;26:4124-4130.SubtypePercentage2North AmericaEuropeAsiaPTCL-NOS34.434.322.4Angioimmunoblastic16.028.717.9ALCL,ALK+16.06.43.2ALCL,ALK-7.89.42.6NK/TCL5.14.322.4ATLL(HTLV-1+)2.01.025.0Enteropathy-type5.89.11.9Hepatosplenic3.02.30.2Primary cutaneous ALC
8、L5.40.80.7Subcutaneous panniculitis-like1.30.51.3Unclassifiable T-cell2.33.32.4PTCL亚型及细胞来源亚型及细胞来源PTCL SubtypeImmune Cell of OriginNK-cell lymphomaNatural killer cells T-cell lymphoma T-cellsALCL and PTCL/NOST-helper and T-cytotoxic cellsAITL/Tth-PTCL/NOST-follicular helper cellsPiccaluga PP,et al.Ex
9、pert Rev Hematol.2011;4:415-425.PTCLPTCL的诊断的诊断 10%PTCL10%PTCL诊断不正确诊断不正确 大多数病人是大多数病人是III/IVIII/IV期期 结外受累常见结外受累常见:皮肤、肝脏、脾脏、骨髓、外周血皮肤、肝脏、脾脏、骨髓、外周血 PTCLPTCL的诊断：的诊断：MIC MIC（形态学、免疫学和细胞遗传学）（形态学、免疫学和细胞遗传学）细针穿刺活检不能作为诊断依据，必须进行活检切除术细针穿刺活检不能作为诊断依据，必须进行活检切除术1.Vose J,et al.J Clin Oncol.2008;26:4124-4130.2.Warnke R
10、A,et al.Am J Clin Pathol.2007;127:511-527.3.Swerdlow SH,et al.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.2008.4.Kocjan G.J Clin Pathol.2005;58:561-567.主要的外周T细胞淋巴瘤的临床和病理学特征ALCL,ALK+97%PTCL,unspecified75%ATLL 93%Panniculitis like75%Nasal NK/T cell 92%ALCL,ALK-74%Angioimmunobl
11、astic 81%Hepatosplenic72%Enteropathy type 79%Cutaneous ALCL66%Vose JM,et al.J Clin Oncol.2008;26:4124-4130.专家诊断共识专家诊断共识The aggressive peripheral T cell lymphomas:2012 update on diagnosis,risk stratification,and managementAmerican Journal of HematologyVolume 87,Issue 5,pages 511-519,17 APR 2012 PTCL的
12、治疗的治疗PTCL的临床预后指数的临床预后指数The IPI for NHL is commonly used in PTCL11.International Non-Hodgkins Lymphoma Prognostic Factors Project.N Engl J Med.1993;329:987-994.2.Gallamini A,et al.Blood.2004;103:2474-2479.International Prognostic Index All patients Age(60 yrs vs 60 yrs)Serum LDH(1 x ULN vs 1x ULN)Per
13、formance score(0 or 1 vs 2-4)Stage(I or II localized vs III or IV advanced)Extranodal involvement(1 site vs 1 site)Age-adjusted index(age 60 yrs)Stage(I or II vs III or IV)Serum LDH(1 x ULN vs 1x ULN)Performance score(0 or 1 vs 2-4)The PIT is also in use2Prognostic Index for PTCL 60 yrs of age ECOG
14、performance score(score 2)Elevated LDH Bone marrow involvementThe IPI is calculated based on the sum of the number of risk factors present at diagnosis:0-1 Low2 Low/intermediate3 High/intermediate4-5 HighThe PIT is based on number of risk factors present at diagnosis:Group 1:0 risk factor (62%5-yr O
15、S)Group 2:1 risk factor (53%5-yr OS)Group 3:2 risk factors (33%5-yr OS)Group 4:3-4 risk factors(18%5-yr OS)PTCL的生物预后因素的生物预后因素PTCL SubtypesALK+ALCLALK ALCLPTCL-NOSAITLNK/TCLATLL5-yr OS rate,%704932323214Majority of patients(85%)with most common disease subtypes received anthracycline-containing regim
16、enInternational T-Cell Lymphoma Project.J Clin Oncol.2008;26:4124-4130.OS(%)Yrs010203040506070809010002468101214161820ALCL,ALK+ALCL,ALK-All NK/T-cell lymphomasPTCL-NOSAITLAdult T-cell leukemia/lymphoma含蒽环类方案治疗含蒽环类方案治疗PTCLPTCL的疗效有限的疗效有限Treatment Guidelines for PTCL:Still CHOP BasedNCCN.Clinical pract
17、ice guidelines in oncology:non-Hodgkins lymphoma.v.3.2012.First-line Therapy Clinical trial(preferred)ALCL,ALK+histologyCHOP-21CHOEP-21 Other histologies(ALCL,ALK-;PTCL-NOS;AITL;EATL),regimens that can be used include:CHOEPCHOP-14CHOP-21CHOP followed by ICECHOP followed by IVE,alternating with inter
18、mediate-dose methotrexate(Newcastle regimen)HyperCVAD,alternating with high-dose methotrexate and cytarabine First-line ConsolidationAll patients except low risk(aaIPI)should be considered for high-dose therapy and stem cell rescue;ALCL,ALK+is a subtype with good prognosis and does not need consolid
19、ative transplant if in remissionThe International PTCL and NK/TCL Study:Analysis of Treatments多数多数PTCL PTCL 或或 NK/TCL(NK/TCL(除外除外 ALK+ALCL)ALK+ALCL)用含蒽环类方案不能获得生存用含蒽环类方案不能获得生存受益受益International T-Cell Lymphoma Project.J Clin Oncol.2008;26:4124-4130.PTCLAILTYrs018246810 12 14 16010080604020OS(%)Anthrac
20、ycline as part of initial treatmentYesNoP=.11Yrs018246810 12 14 16010080604020OS(%)Anthracycline as part of initial treatmentYesNoP=.48传统含阿霉素的方案对传统含阿霉素的方案对PTCLPTCL无效无效PTCLPTCL治疗？治疗？采用新的诱导化疗方案采用新的诱导化疗方案CTOP，EPOCH,CEOP,CHOPE novel drug combination regimen?CONSOLIDATION?Autologous transplant?Allogeneic
21、 transplant?MAINTENANCE?新药、靶向药物研发新药、靶向药物研发Surface Antigens/ReceptorsCD2CD4CD25CD30Chemokine receptors.Microenvironmental FactorsAngiogenesisImmunomodulation Viral pathogensCellular Survival MechanismsProteasome inhibitionHDAC inhibitionDeath receptors and ligandsCell-cycle arrestSignal transduction
22、inhibitionPTCLPTCL治疗可能的靶点治疗可能的靶点化疗方案的新尝试化疗方案的新尝试改良改良CHOPCHOP方案（含蒽环类药物）方案（含蒽环类药物）-EPOCH-HyperCVAD-CHOP/ICE;CHOP/IVE-ACVBP新组合化疗方案新组合化疗方案 -门冬酰胺酶为主方案联合放疗（NK/T细胞淋巴瘤鼻型）-IFO/VP-16/铂类/吉西他滨/MTX/Ara-C等 新药的使用新药的使用 -分子靶向药物 -单克隆抗体、小分子TKI -信号传导 -免疫调节剂 Vose JM,et al.JCO,2008;26:4124-30;NCCN guideline(2012);2012 AS
23、CO,abs 8050Schmitz N,et al.Blood,2010;116:3418-25;Dearden CE,et al.Blood,2011;Sep 26年轻年轻PTCLPTCL患者：患者：GHGNHLSGGHGNHLSG的研究的研究Schmitz N,et al.Blood.2010;116:3418-3425.18-60 yrs of age,LDH UNVOther Major SubtypesALCL,ALK+/-Months020010080604020EFS(%)p=0.0034060801006 x CHOP-14/21(n=41)6 x CHOEP-14/21(n
24、=42)Months020010080604020EFS(%)p=0.012406080100non Etoposide(n=12)Etoposide(n=32)Months020010080604020EFS(%)p=0.004406080100non Etoposide(n=41)Etoposide(n=103)Months020010080604020EFS(%)p=0.057406080100non Etoposide(n=29)Etoposide(n=69)Pralatrexate is selective antifolate designed to preferentially
25、accumulate in cancer cellsEntryPralatrexate is selective for cells that express RFC-1,which is overexpressed on some cancer cells relative to normal cellsAccumulationOnce taken up by cancer cells,pralatrexate becomes polyglutamylated,resulting in high intracellular drug retentionInhibitionPralatrexa
26、te acts on folate pathway to interfere with DNA synthesis and elicit cancer cell death Sirotnak FM,et al.Cancer Chemother Pharmacol.1998;42:313-318.Krug LM,et al.Clin Cancer Res.2000;6:3493-3498.Wang ES,et al.Leuk Lymphoma.2003;44:1027-1035.新药新药Pralatrexate的作用机制的作用机制PROPEL研究研究:Phase II Pralatrexate
27、in Relapsed/Refractory PTCL 111 patients with relapsed/refractory PTCL Pralatrexate 30 mg/m2 weekly for 6 wks in 7-wk cycles Vitamin B12 and folic acid given to decrease mucositis ORR:32/109(29%);CR:11%;PR:18%Median PFS:3.5 mos Median OS:14.5 mos Grade 3/4 toxicity Thrombocytopenia:32%OConnor OA,et
28、al.J Clin Oncol.2011;29:1182-1189.PROPELPROPEL研究研究:肿瘤体积、有效时间和生存肿瘤体积、有效时间和生存OConnor OA,et al.J Clin Oncol.2011;29:1182-1189.Patients-1001007550-25-75Change in Tumor Volumne From Baseline(%)Months0301.00.80.60.40.2Progression-Free Survival(probability)91218 21Pralatrexate 30 mg/m2(6/7 weeks)n=109;70 e
29、ventsMedian(months)3.5;95%CI,1.7 to 4.8Months03010080604020Duration of Response(probability)9121824Months0301.00.80.60.40.2Overall survival(probability)9151824-5002515246Pralatrexate 30 mg/m2(6/7 weeks)n=109;62 eventsMedian(months)14.5;95%CI,10.6 to 22.56-month,75%;95%CI,65.7%to 82.1%Pralatrexate 30
30、 mg/m2(6/7 weeks)n=32;16 eventsMedian(months)10.1;95%CI,3.4 to NE6152121126Romidepsin:A Novel,Potent Bicyclic HDACi Gene regulation1 Histone acetylation/transcription induction2 Protein acetylation3 Activation of apoptosis4 Antiangiogenesis5 Cell-cycle arrest41.Peart MJ,et al.Proc Nat Acad Sci U S A
31、.2005;102:3697-3702.2.Bolden JE,et al.Nat Rev Drug Discov.2006;5:769-784.3.Wang Y,et al.Biochem Biophys Res Commun.2007;356:998-1003.4.Sato N,et al.Int J Oncol.2004;24:679-685.5.Kwon HJ,et al.Int J Cancer.2002;97:290-296.Wk 4Wk 2Wk 31221581Wk 1Cycle 1Wk 1Cycle 2Schedule:4-hr infusion 14 mg/m2 on Day
32、s 1,8,and 15 every 28 daysCoiffier B,et al.J Clin Oncol.2012;30:631-636.Romidepsin in Relapsed/Refractory PTCL:Treatment ScheduleRomidepsinRomidepsinRomidepsinRomidepsinA Phase II,Multicenter,Open-Label Trial Romidepsin in Rel/Ref PTCL:ORRsBest Response Category,n(%)IRC(N=130)Investigators(N=130)Obj
33、ective response(CR/CRu+PR)33(25)38(29)Complete response(CR/CRu)19(15)21(16)CR13(10)19(15)CRu6(5)2(2)PR14(11)17(13)SD33(25)22(17)PD/not evaluable*64(49)70(54)Coiffier B,et al.J Clin Oncol.2012;30:631-636.*Insufficient efficacy data to determine response due to early termination.Romidepsin in Rel/Ref
34、PTCL:DOR and Safety Median DOR:17 mos Of 19 patients in CR/Cru,17(89%)had not progressed at a median follow-up of 13.4 mos Grade 3 toxicities Thrombocytopenia:24%Neutropenia:20%Coiffier B,et al.J Clin Oncol.2012;30:631-636.Romidepsin for the treatment of Romidepsin for the treatment of relapsed/refr
35、actory peripheral T-cell lymphoma:relapsed/refractory peripheral T-cell lymphoma:(A Phase II,Multicenter,Open-Label Trial)Coiffier B,et al.J Clin Oncol.2012;30:631-636.Anti-CD30 ADC:Brentuximab Vedotin(SGN-35)ADC:3 parts Chimeric antibody SGN-30 Synthetic analogue(MMAE)of the antitubulin agent dolas
36、tatin 10 Stable drug linkerProposed mechanism of action Binds to CD30 Internalized into the tumor cell MMAE is released Tumor cell undergoes G2/M phase cell-cycle arrest and apoptosisPreclinical activity observed both in in vitro and in vivoFrancisco JA,et al.Blood.2003;102:1458-1465.Brentuximab Ved
37、otin+化疗一线治疗化疗一线治疗ALCL I 期临床试验:39 pts 高危ALCL(IPI 2)or CD30+成熟T-cell/NK-细胞淋巴瘤随机分为3组 1.8 mg/kg brentuximab vedotin q3w X 2 cycles,then CHOP x 6 cycles 1.8 mg/kg brentuximab vedotin+CHP q3w for up to 6 cycles Determine optimal dose of brentuximab vedotin to be used in combination with CHP in third armRe
38、sponders receive additional cycles of brentuximab vedotin monotherapyORR:100%(26/26);CR:88%(23/26)Brentuximab vedotin MTD not exceeded at 1.8 mg/kg 1 DLT:grade 3 rash in 6 pts治疗相关并发症:恶心(58%),疲乏(50%),腹泻(50%),周围神经病变(38%),脱发(38%)Fanale MA,et al.ASH 2012.Abstract 60.Pro B,et al.J Clin Oncol.2012;30:2190
39、-2196.Brentuximab Vedotin in Rel/Ref Systemic ALCL:Maximum Tumor Reduction(IRC)Tumor Size(%changefrom baseline)-100-50 050 100Individual Patients(n=57)Best clinical responseComplete remissionPartial remissionStable diseaseProgressive diseaseHistologically ineligibleDueck G,et al.Cancer.2010;116:4541
40、-4548.来啦度胺来啦度胺 II 期临床试验：24 PTCL Pts.（N=24）ORR:30%(7/23)All PRs 所有亚型都有效 Median PFS:96 days Median OS:241 days AEs:中性粒细胞减少、疼痛、血小板减少、皮疹中性粒细胞减少、疼痛、血小板减少、皮疹Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma Relapsed/refractory PTCLECOG PS 0-2(N=24)Lenalidomide25mg
41、PO qd on Days 1-21 of a 28day cycleThe primary endpoint；ORR The secondary endpoints:OS,PFS,and safety.open-label,single-arm,multicenter Canadian phase 2 clinical trial September 2006 to November 2008,Cancer Volume116.Issue 19.pages 45414548,1 October 2010PD or Intolerable Interim report of a phase 2
42、 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma Cancer Volume116.Issue 19.pages 45414548,1 October 2010Alisertib:Investigational Aurora A Kinase Inhibitor Results in mitotic defects Abnormal spindles Unseparated centrosomes Delayed mitotic progression Apoptosis or senescence Untreate
43、dTreatedTreatedNCIOFNNHNOOHOFriedberg J,et al.ASH 2011.Abstract 95.Friedberg J,et al.ASH 2011.Abstract 95.Alisertib(MLN8237):An Aurora A Kinase Inhibitor II 期进展期期进展期B-cell 和和T-cell NHL N=48 ORR:32%CR:12%病理学诊断病理学诊断 PTCL:57%DLBCL:20%;MCL:23%;转化转化 FL:40%副作用副作用:中性粒细胞减少中性粒细胞减少,血小板减少血小板减少,胃炎胃炎AlisertibAli
44、sertib的随机临床开放的随机临床开放III III 期临床试验：期临床试验：复发难治复发难治 PTCLPTCLPrimary endpoint:ORR,PFSSecondary endpoints:safety,CR,OS,TTPRelapsed/refractory PTCLECOG PS 0-2(N=354)*Choices:PralatrexateRomidepsinGemcitabineAlisertib5 x 10 mg PO BID on Days 1-7 of a 21-day cycleInvestigators choice*ClinicalTrials.gov.NCT0
45、1482962.Pohlman B,et al.ASH 2009.Abstract 920.Belinostat(PXD101):A Pan-Histone Deacetylase Inhibitor Phase II trial in PTCL N=20 ORR:25%CR:2 PR:3 DOR:5 mos AEs:pruritus,edema,rashDamaj G,et al.J Clin Oncol.2012;Epub ahead of print.苯达莫司丁苯达莫司丁 复发耐药复发耐药PTCL的多中心的多中心II期临床试验期临床试验(BENTLY)：N=60(23 pts PTCL-
46、U)方案方案:120 mg/m2 D1、2 q3w ORR:50%28%CR/CRu Median PFS:3.6 mos Median OS:6.2 mos 最常见最常见3/4 AEs:中性粒细胞减少、感染、血小板减少中性粒细胞减少、感染、血小板减少Ishida T,et al.J Clin Oncol.2012;30:837-842.Mogamulizumab(KW-0761):Mogamulizumab(KW-0761):抗抗-CCR4-CCR4（趋化因子受体（趋化因子受体4 4）单克隆抗体）单克隆抗体 II II 期临床试验：入组期临床试验：入组ATLLATLL患者患者N=28N=28
47、ORR:50%(13/26)ORR:50%(13/26)CR:8/26CR:8/26Median PFS:5.2 mosMedian PFS:5.2 mosMedian OS:13.7 mosMedian OS:13.7 mosAEs:AEs:输注反应输注反应 (89%),(89%),皮疹皮疹 (63%)(63%)Select Ongoing Clinical Trials of First-line Therapy for PTCLPhase III CHOP alemtuzumab CHOP followed by pralatrexatePhase II CEOP/pralatrexat
48、e CHOP+everolimus CHOP vs GEM-P CHOP+romidepsin CHOP+lenalidomide CHOP+alemtuzumab CHOP+denileukin diftitox CHP+brentuximab vedotinClinicalTrials.gov.NCT00725231.NCT01420679.NCT01336933.NCT01198665.NCT01719835.NCT01280526 NCT00453427.目前已批准和正在进行的临床试验目前已批准和正在进行的临床试验造血干细胞移植在造血干细胞移植在PTCLPTCL的疗效的疗效目前造血干细
49、胞的共识目前造血干细胞的共识 首次复发、化疗有效患者行首次复发、化疗有效患者行ASCT：Yes！结论肯定，EFS提高15-40%存在问题：如何提高CR率；是否维持治疗？首次首次CR后行后行ASCT作为巩固治疗：作为巩固治疗：Maybe！NCCN推荐部分争议！低危患者；ALK+的高危间变大T细胞淋巴瘤 鼻咽局部NK/T细胞淋巴瘤；血管免疫母T细胞淋巴瘤Mak V,et al.Blood,2011;118:abstract 96 目前造血干细胞的共识目前造血干细胞的共识 异基因造血干细胞移植（异基因造血干细胞移植（Allo-SCT）：不休的争论！）：不休的争论！有限的回顾性研究数据，无前瞻性研究数据有限的回顾性研究数据，无前瞻性研究数据 何时做？何时做？PR，Auto-SCT的效果极差的效果极差 PR，Allo-SCT的效果极差的效果极差 如何做？如何做？清髓（清髓（MAC）vs.非清髓非清髓(RIC)移植相关死亡率移植相关死亡率 vs.复发率复发率Mak V,et al.Blood,2011;118:abstract 96
