外周细胞淋巴瘤诊疗进展

1、外周细胞淋巴瘤诊疗进展第1页，共49页，2022年，5月20日，6点27分，星期四主要内容PTCL的分类PTCL的流行病学PTCL的预后因子PTCL治疗新药物第2页，共49页，2022年，5月20日，6点27分，星期四外周T淋巴瘤的分类PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomasPTCL does not refer to anatomic sites, but rather to the involvement of more mature (postthymic) T cells vs pre

2、thymic 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 NeoplasmsCutaneousExtranodalLeukemicMature T-/NK-cell neopla

3、smsNodalNK/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 lymphoma (ALK +/-)AggressiveT-

4、Lymphoblastic Leukemia/LymphomaPrimary cutaneous CD30+ T-cell disordersMFT-cell large granular lymphocytic leukemiaSzary SyndromeIndolent第3页，共49页，2022年，5月20日，6点27分，星期四International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130.1314 例PTCL 和 NKTCL 的分布25.9%18.5%10.4%9.6%6.6%5.5%4.7%12.2%2.5%

5、0.9%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 PT

6、CLOther disorders第4页，共49页，2022年，5月20日，6点27分，星期四四川省肿瘤医院淋巴瘤病区截止2014年10月总数502例淋巴瘤患者T-NHL 108例第5页，共49页，2022年，5月20日，6点27分，星期四2012.4-2014.10四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2014年10月第6页，共49页，2022年，5月20日，6点27分，星期四PTCL流行病学不同地域PTCL亚型相对发病率 1,2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;1

7、0:267-277.2. International 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-NK/TCL5.14.322.4ATLL (HTLV-1+)2.01.025.0Enteropathy-typeHepatosplenic3.02.30.

8、2Primary cutaneous ALCLSubcutaneous panniculitis-likeUnclassifiable T-cell第7页，共49页，2022年，5月20日，6点27分，星期四PTCL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

9、-follicular helper cellsPiccaluga PP, et al. Expert Rev Hematol. 2011;4:415-425.第8页，共49页，2022年，5月20日，6点27分，星期四PTCL的诊断10% PTCL诊断不正确大多数病人是III/IV期结外受累常见: 皮肤、肝脏、脾脏、骨髓、外周血PTCL的诊断：MIC （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1. Vose J, et al. J Clin Oncol. 2008;26:4124-4130. 2. Warnke RA, et al. Am J Clin P

10、athol. 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.第9页，共49页，2022年，5月20日，6点27分，星期四主要的外周T细胞淋巴瘤的临床和病理学特征第10页，共49页，2022年，5月20日，6点27分，星期四ALCL, ALK+ 97%PTCL, unspecified75%ATLL 93%Panniculi

11、tis like75%Nasal NK/T cell 92%ALCL, ALK-74%Angioimmunoblastic 81%Hepatosplenic72%Enteropathy type 79%Cutaneous ALCL66%Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.专家诊断共识第11页，共49页，2022年，5月20日，6点27分，星期四The aggressive peripheral Tcell lymphomas: 2012 update on diagnosis, risk stratification, and man

12、agementAmerican Journal of HematologyVolume 87, Issue 5, pages 511-519, 17 APR 2012 第12页，共49页，2022年，5月20日，6点27分，星期四PTCL的治疗第13页，共49页，2022年，5月20日，6点27分，星期四PTCL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;329:987-9

13、94. 2. Gallamini A, et al. Blood. 2004;103:2474-2479.International Prognostic Index All patientsAge (60 yrs vs 60 yrs)Serum LDH ( 1 x ULN vs 1x ULN)Performance 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

14、)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 ageECOG performance score (score 2)Elevated LDHBone marrow involvementThe IPI is calculated based on the sum of the number of risk factors present at

15、 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 OS)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)第14页，共49页，2022年，5月20日，6点2

16、7分，星期四PTCL的生物预后因素第15页，共49页，2022年，5月20日，6点27分，星期四PTCL SubtypesALK+ ALCLALK ALCLPTCL-NOSAITLNK/TCLATLL5-yr OS rate, %704932323214Majority of patients ( 85%) with most common disease subtypes received anthracycline-containing regimenInternational T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130

17、.OS (%)Yrs010203040506070809010002468101214161820ALCL, ALK+ALCL, ALK-All NK/T-cell lymphomasPTCL-NOSAITLAdult T-cell leukemia/lymphoma含蒽环类方案治疗PTCL的疗效有限第16页，共49页，2022年，5月20日，6点27分，星期四Treatment Guidelines for PTCL: Still CHOP BasedNCCN. Clinical practice guidelines in oncology: non-Hodgkins lymphoma.

18、v.3.2012.First-line TherapyClinical trial (preferred)ALCL, ALK+ histologyCHOP-21CHOEP-21Other histologies (ALCL, ALK-; PTCL-NOS; AITL; EATL), regimens that can be used include:CHOEPCHOP-14CHOP-21CHOP followed by ICECHOP followed by IVE, alternating with intermediate-dose methotrexate (Newcastle regi

19、men)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 consolidative transplant if in remission第1

20、7页，共49页，2022年，5月20日，6点27分，星期四The International PTCL and NK/TCL Study: Analysis of Treatments多数PTCL 或 NK/TCL (除外 ALK+ ALCL) 用含蒽环类方案不能获得生存受益International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130.PTCLAILTYrs018246810121416010080604020OS (%)Anthracycline as part of initial treatmentYesNo

21、P = .11Yrs018246810121416010080604020OS (%)Anthracycline as part of initial treatmentYesNoP = .48传统含阿霉素的方案对PTCL无效第18页，共49页，2022年，5月20日，6点27分，星期四PTCL治疗？采用新的诱导化疗方案CTOP， EPOCH, CEOP, CHOPE novel drug combination regimen?CONSOLIDATION? Autologous transplant? Allogeneic transplant?MAINTENANCE?新药、靶向药物研发第1

22、9页，共49页，2022年，5月20日，6点27分，星期四Surface Antigens/ReceptorsCD2CD4CD25CD30Chemokine receptors . . .Microenvironmental FactorsAngiogenesisImmunomodulation Viral pathogensCellular Survival MechanismsProteasome inhibitionHDAC inhibitionDeath receptors and ligandsCell-cycle arrestSignal transduction inhibiti

23、onPTCL治疗可能的靶点第20页，共49页，2022年，5月20日，6点27分，星期四化疗方案的新尝试改良CHOP方案（含蒽环类药物）- EPOCH- HyperCVAD- CHOP/ICE;CHOP/IVE- ACVBP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 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 ASCO, abs 8050Sch

24、mitz N, et al. Blood, 2010; 116: 3418-25; Dearden CE, et al. Blood, 2011; Sep 26第21页，共49页，2022年，5月20日，6点27分，星期四年轻PTCL患者：GHGNHLSG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

25、 x CHOEP-14/21 (n=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)第22页，共49页，2022年，5月20日，6点27分，星期四P

26、ralatrexate is selective antifolate designed to preferentially 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,

27、resulting in high intracellular drug retentionInhibitionPralatrexate 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.

28、2003;44:1027-1035.新药Pralatrexate的作用机制第23页，共49页，2022年，5月20日，6点27分，星期四PROPEL研究: Phase II Pralatrexate in Relapsed/Refractory PTCL111 patients with relapsed/refractory PTCLPralatrexate 30 mg/m2 weekly for 6 wks in 7-wk cyclesVitamin B12 and folic acid given to decrease mucositisORR: 32/109 (29%); CR: 1

29、1%; PR: 18% Median PFS: 3.5 mosMedian OS: 14.5 mosGrade 3/4 toxicity Thrombocytopenia: 32%OConnor OA, et al. J Clin Oncol. 2011;29:1182-1189.第24页，共49页，2022年，5月20日，6点27分，星期四PROPEL研究: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 Ba

30、seline (%) Months0301.00.2Progression-Free Survival (probability)9121821Pralatrexate 30 mg/m2 (6/7 weeks)n = 109; 70 eventsMedian (months) 3.5; 95% CI, 1.7 to 4.8Months03010080604020Duration of Response (probability)9121824Months0301.00.2Overall survival (probability)9151824-500251

31、5246Pralatrexate 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 mg/m2 (6/7 weeks)n = 32; 16 eventsMedian (months) 10.1; 95% CI, 3.4 to NE6152121126第25页，共49页，2022年，5月20日，6点27分，星期四Romidepsin: A Novel, Potent Bicyclic

32、HDACiGene regulation1Histone acetylation/transcription induction2Protein acetylation3Activation of apoptosis4Antiangiogenesis5Cell-cycle arrest41. Peart MJ, et al. Proc Nat Acad Sci U S A. 2005;102:3697-3702. 2. Bolden JE, et al. Nat Rev Drug Discov. 2006;5:769-784. 3. Wang Y, et al. Biochem Biophys

33、 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.第26页，共49页，2022年，5月20日，6点27分，星期四Wk 4Wk 2Wk 31221581Wk 1Cycle 1Wk 1Cycle 2Schedule:4-hr infusion 14 mg/m2 on Days 1, 8, and 15 every 28 daysCoiffier B, et al. J Clin Oncol.

34、2012;30: 631-636.Romidepsin in Relapsed/Refractory PTCL: Treatment ScheduleRomidepsinRomidepsinRomidepsinRomidepsinA Phase II, Multicenter, Open-Label Trial 第27页，共49页，2022年，5月20日，6点27分，星期四Romidepsin in Rel/Ref PTCL: ORRsBest Response Category, n (%)IRC (N = 130)Investigators(N = 130)Objective respon

35、se (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. 第28页，共49页，202

36、2年，5月20日，6点27分，星期四Romidepsin in Rel/Ref PTCL: DOR and SafetyMedian DOR: 17 mosOf 19 patients in CR/Cru, 17 (89%) had not progressed at a median follow-up of 13.4 mosGrade 3 toxicitiesThrombocytopenia: 24%Neutropenia: 20%Coiffier B, et al. J Clin Oncol. 2012;30:631-636.第29页，共49页，2022年，5月20日，6点27分，星期四

37、Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma:(A Phase II, Multicenter, Open-Label Trial )Coiffier B, et al. J Clin Oncol. 2012;30:631-636.第30页，共49页，2022年，5月20日，6点27分，星期四Anti-CD30 ADC: Brentuximab Vedotin (SGN-35)ADC: 3 partsChimeric antibody SGN-30Synthetic analogue

38、 (MMAE) of the antitubulin agent dolastatin 10Stable drug linkerProposed mechanism of actionBinds to CD30Internalized into the tumor cellMMAE 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. Bloo

39、d. 2003;102:1458-1465.第31页，共49页，2022年，5月20日，6点27分，星期四Brentuximab Vedotin + 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 cycles1.8 mg/kg brentuximab vedotin + CHP q3w for up to 6 cyclesDetermine optimal dose of b

40、rentuximab vedotin to be used in combination with CHP in third armResponders receive additional cycles of brentuximab vedotin monotherapyORR: 100% (26/26); CR: 88% (23/26)Brentuximab vedotin MTD not exceeded at 1.8 mg/kg1 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

41、发(38%) Fanale MA, et al. ASH 2012. Abstract 60.第32页，共49页，2022年，5月20日，6点27分，星期四Pro B, et al. J Clin Oncol. 2012;30:2190-2196.Brentuximab Vedotin in Rel/Ref Systemic ALCL: Maximum Tumor Reduction (IRC)Tumor Size (% changefrom baseline)-100 -50 050 100Individual Patients (n = 57)Best clinical responseC

42、omplete remissionPartial remissionStable diseaseProgressive diseaseHistologically ineligible第33页，共49页，2022年，5月20日，6点27分，星期四Dueck G, et al. Cancer. 2010;116:4541-4548.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、皮疹第34页，共49

43、页，2022年，5月20日，6点27分，星期四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 PO qd on Days 1-21 of a 28day cycleThe primary endpoint ；ORR The secondary endpoints: OS, PFS, and safety. open-label, single-

44、arm, multicenter Canadian phase 2 clinical trial September 2006 to November 2008, Cancer Volume116.Issue 19. pages 45414548,1 October 2010PD or Intolerable 第35页，共49页，2022年，5月20日，6点27分，星期四Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma Cancer Volume116.Issue

45、 19. pages 45414548,1 October 2010第36页，共49页，2022年，5月20日，6点27分，星期四Alisertib: Investigational Aurora A Kinase InhibitorResults in mitotic defectsAbnormal spindlesUnseparated centrosomesDelayed mitotic progressionApoptosis or senescence UntreatedTreatedTreatedNCIOFNNHNOOHOFriedberg J, et al. ASH 2011.

46、Abstract 95.第37页，共49页，2022年，5月20日，6点27分，星期四Friedberg J, et al. ASH 2011. Abstract 95.Alisertib (MLN8237): An Aurora A Kinase InhibitorII 期进展期B-cell 和T-cell NHLN = 48ORR: 32%CR: 12%病理学诊断PTCL: 57%DLBCL: 20%; MCL: 23%; 转化 FL: 40%副作用: 中性粒细胞减少, 血小板减少, 胃炎第38页，共49页，2022年，5月20日，6点27分，星期四Alisertib的随机临床开放III

47、期临床试验：复发难治 PTCLPrimary 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*ClinicalT. NCT01482962.第39页，共49页，2022年，5月20日，6点27分，星期四Pohlman B, et al. ASH 2009. Abstract 920.Belinostat (PXD101): A Pan-Histone Deacetylase InhibitorPhase II trial in PTCLN = 20ORR: 25%CR: 2PR: 3DOR: 5 mosAEs: pruritus, edema, rash第40页，共49页，2022年，5月20日，6点27分，星期四Damaj G, et al. J Clin Oncol. 2012;E