外周t細(xì)胞淋巴瘤診療進(jìn)展張智慧

1、外周T細(xì)胞淋巴瘤的治療進(jìn)展,四川省腫瘤醫(yī)院腫瘤內(nèi)科 張智慧,主要內(nèi)容,PTCL的分類PTCL的流行病學(xué)PTCL的預(yù)后因子PTCL治療新藥物,,,,,,外周T淋巴瘤的分類,PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomasPTCL does not refer to anatomic sites, but rather to the i

2、nvolvement of more mature (postthymic) T cells vs prethymic or immature T cells,Adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008.,,,,,Non-Hodgkin’s lymphoma,T-ce

3、ll prolymphocytic Leukemia,Aggressive,,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%,0.9%,1.4%,1.7%,Peripheral T-cell lym

4、phomaAngioimmunoblasticNatural killer/T-cell lymphomaAdult T-cell leukemia/lymphomaAnaplastic large-cell lymphoma, ALK+Anaplastic large-cell lymphoma, ALK-Enteropathy-type T cellPrimary cutaneous ALCLHepatospleni

5、c T cellSubcutaneous panniculitis-likeUnclassifiable PTCLOther disorders,四川省腫瘤醫(yī)院淋巴瘤病區(qū)截止2014年10月,總數(shù)502例淋巴瘤患者,T-NHL 108例,2012.4-2014.10四川省腫瘤醫(yī)院淋巴瘤數(shù)據(jù),四川省腫瘤醫(yī)院淋巴瘤病區(qū)截止2014年10月,PTCL流行病學(xué),不同地域PTCL亞型相對發(fā)病率 [1,2]總的發(fā)病率亞洲和加勒比地區(qū)更高,1

6、. Savage KJ. Hematology Am Soc Hematol Educ Program. 2005;10:267-277.2. International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130.,,,PTCL亞型及細(xì)胞來源,Piccaluga PP, et al. Expert Rev Hematol. 2011;4:415-425.,PTCL

7、的診斷,10% PTCL診斷不正確大多數(shù)病人是III/IV期結(jié)外受累常見: 皮膚、肝臟、脾臟、骨髓、外周血PTCL的診斷：MIC （形態(tài)學(xué)、免疫學(xué)和細(xì)胞遺傳學(xué)）細(xì)針穿刺活檢不能作為診斷依據(jù)，必須進(jìn)行活檢切除術(shù),1. Vose J, et al. J Clin Oncol. 2008;26:4124-4130. 2. Warnke RA, et al. Am J Clin Pathol. 2007;127:511-527. 3.

8、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細(xì)胞淋巴瘤的臨床和病理學(xué)特征,Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.,專家診斷共識,T

9、he aggressive peripheral T‐cell lymphomas: 2012 update on diagnosis, risk stratification, and management,American Journal of HematologyVolume 87, Issue 5, pages 511-519, 17 APR 2012,PTCL的治療,PTCL的臨床預(yù)后指數(shù),The IPI for NHL i

10、s commonly used in PTCL[1],1. International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994. 2. Gallamini A, et al. Blood. 2004;103:2474-2479.,The PIT is also in use[2],The IPI is c

11、alculated based on the sum of the number of risk factors present at diagnosis:0-1 Low2 Low/intermediate3 High/intermediate4-5 High,The PIT is based on number of risk factors present at diagnosis:Group

12、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),PTCL的生物預(yù)后因素,,Majority of patients (> 85%) with most commo

13、n disease subtypes received anthracycline-containing regimen,International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130.,OS (%),Yrs,,,,,,,,,,,,,0,10,20,30,40,50,60,70,80,90,100,,,,,,,,,,,,0,2,4,6,8,10,12,14,1

14、6,18,,20,,,,,,,ALCL, ALK+ALCL, ALK-All NK/T-cell lymphomasPTCL-NOSAITLAdult T-cell leukemia/lymphoma,含蒽環(huán)類方案治療PTCL的療效有限,Treatment Guidelines for PTCL: Still CHOP Based,,NCCN. Clinical practice guidelines in oncology

15、: non-Hodgkin’s lymphoma. v.3.2012.,,The International PTCL and NK/TCL Study: Analysis of Treatments,多數(shù)PTCL 或 NK/TCL (除外 ALK+ ALCL) 用含蒽環(huán)類方案不能獲得生存受益,International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130.,

16、PTCL,AILT,Yrs,0,18,2,4,6,8,10,12,14,16,0,100,80,60,40,20,OS (%),Anthracycline as part of initial treatment,YesNo,P = .11,Yrs,0,18,2,4,6,8,10,12,14,16,0,100,80,60,40,20,OS (%),Anthracycline as part of initial treatment

17、,YesNo,P = .48,傳統(tǒng)含阿霉素的方案對PTCL無效,PTCL治療？,新藥、靶向藥物研發(fā),Surface Antigens/ReceptorsCD2CD4CD25CD30Chemokine receptors . . .,Microenvironmental FactorsAngiogenesisImmunomodulation Viral pathogens,Cellular Survival Mechan

18、ismsProteasome inhibitionHDAC inhibitionDeath receptors and ligandsCell-cycle arrestSignal transduction inhibition,PTCL治療可能的靶點,化療方案的新嘗試,改良CHOP方案（含蒽環(huán)類藥物）-- EPOCH-- HyperCVAD-- CHOP/ICE;CHOP/IVE-- ACVBP新組合化療方案

19、 -- 門冬酰胺酶為主方案聯(lián)合放療（NK/T細(xì)胞淋巴瘤鼻型）-- IFO/VP-16/鉑類/吉西他濱/MTX/Ara-C等 新藥的使用 ---分子靶向藥物 ---單克隆抗體、小分子TKI ----信號傳導(dǎo) ----免疫調(diào)節(jié)劑,Vose JM, et al. JCO, 2008; 26: 4124-30; NCCN guideline(2012); 2012 ASCO, abs 8

20、050Schmitz N, et al. Blood, 2010; 116: 3418-25; Dearden CE, et al. Blood, 2011; Sep 26,,年輕PTCL患者：GHGNHLSG的研究,Schmitz N, et al. Blood. 2010;116:3418-3425.,18-60 yrs of age, LDH ≤ UNV,Other Major Subtypes,ALCL, ALK+/-,Mon

21、ths,0,20,0,100,80,60,40,20,EFS (%),p = 0.003,40,60,80,100,6 x CHOP-14/21 (n=41),6 x CHOEP-14/21 (n=42),Months,0,20,0,100,80,60,40,20,EFS (%),p = 0.012,40,60,80,100,non Etoposide (n=12),Etoposide (n=32),Months,0,20,0,100,

22、80,60,40,20,EFS (%),p = 0.004,40,60,80,100,non Etoposide (n=41),Etoposide (n=103),Months,0,20,0,100,80,60,40,20,EFS (%),p = 0.057,40,60,80,100,non Etoposide (n=29),Etoposide (n=69),,,,,,,,,Pralatrexate is selective antif

23、olate designed to preferentially accumulate in cancer cells,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-

24、1035.,新藥Pralatrexate的作用機(jī)制,PROPEL研究: Phase II Pralatrexate in Relapsed/Refractory PTCL,111 patients with relapsed/refractory PTCLPralatrexate 30 mg/m2 weekly for 6 wks in 7-wk cyclesVitamin B12 and folic acid given to

25、decrease mucositisORR: 32/109 (29%); CR: 11%; PR: 18% Median PFS: 3.5 mosMedian OS: 14.5 mosGrade 3/4 toxicity Thrombocytopenia: 32%,O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189.,,PROPEL研究:腫瘤體積、有效時間和生存,O’Conn

26、or OA, et al. J Clin Oncol. 2011;29:1182-1189.,Patients,-100,100,75,50,-25,-75,Change in Tumor Volumne From Baseline (%),Months,0,3,0,1.0,0.8,0.6,0.4,0.2,Progression-Free Survival (probability),9,12,18,21,Pralatrexate 30

27、 mg/m2 (6/7 weeks)n = 109; 70 eventsMedian (months) 3.5; 95% CI, 1.7 to 4.8,Months,0,3,0,100,80,60,40,20,Duration of Response (probability),9,12,18,24,Months,0,3,0,1.0,0.8,0.6,0.4,0.2,Overall survival (probability),9,

28、15,18,24,-50,0,25,15,24,6,Pralatrexate 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 (m

29、onths) 10.1; 95% CI, 3.4 to NE,6,15,21,,,21,12,6,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Romidepsin: A Novel, Potent Bicyclic HDACi,Gene regulation[1]Histone acetylation/

30、transcription induction[2]Protein acetylation[3]Activation of apoptosis[4]Antiangiogenesis[5]Cell-cycle arrest[4],1. Peart MJ, et al. Proc Nat Acad Sci U S A. 2005;102:3697-3702. 2. Bolden JE, et al. Nat Rev Drug Dis

31、cov. 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 4,Wk 2,Wk 3,1,22,15,8,1,,,,,,,,,

32、,,,,,,,,,,,,,,,,,,,,,,,,,Wk 1Cycle 1,Wk 1Cycle 2,,,,Schedule:4-hr infusion 14 mg/m2 on Days 1, 8, and 15 every 28 days,,,,,,,,,,,Coiffier B, et al. J Clin Oncol. 2012;30: 631-636.,Romidepsin in Relapsed/Refractory PTC

33、L: Treatment Schedule,Romidepsin,Romidepsin,Romidepsin,Romidepsin,A Phase II, Multicenter, Open-Label Trial,Romidepsin in Rel/Ref PTCL: ORRs,Coiffier B, et al. J Clin Oncol. 2012;30:631-636.,*Insufficient efficacy data t

34、o determine response due to early termination.,Romidepsin in Rel/Ref PTCL: DOR and Safety,Median DOR: 17 mosOf 19 patients in CR/Cru, 17 (89%) had not progressed at a median follow-up of 13.4 mosGrade ≥ 3 toxicitiesTh

35、rombocytopenia: 24%Neutropenia: 20%,Coiffier B, et al. J Clin Oncol. 2012;30:631-636.,Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma:,(A Phase II, Multicenter, Open-Label Trial ),Coiffier

36、 B, et al. J Clin Oncol. 2012;30:631-636.,Anti-CD30 ADC: Brentuximab Vedotin (SGN-35),ADC: 3 partsChimeric antibody SGN-30Synthetic analogue (MMAE) of the antitubulin agent dolastatin 10Stable drug linkerProposed mec

37、hanism 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 vivo,Francisco JA, e

38、t al. Blood. 2003;102:1458-1465.,Brentuximab Vedotin + 化療一線治療ALCL,I 期臨床試驗: 39 pts 高危ALCL (IPI ≥ 2) or CD30+ 成熟T-cell/NK-細(xì)胞淋巴瘤隨機(jī)分為3組1.8 mg/kg brentuximab vedotin q3w X 2 cycles, then CHOP x 6 cycles1.8 mg/kg brentuxim

39、ab vedotin + CHP q3w for up to 6 cyclesDetermine optimal dose of brentuximab vedotin to be used in combination with CHP in third armResponders receive additional cycles of brentuximab vedotin monotherapyORR: 100% (26/

40、26); CR: 88% (23/26)Brentuximab vedotin MTD not exceeded at 1.8 mg/kg1 DLT: grade 3 rash in 6 pts治療相關(guān)并發(fā)癥: 惡心(58%), 疲乏 (50%), 腹瀉(50%), 周圍神經(jīng)病變 (38%), 脫發(fā)(38%),Fanale MA, et al. ASH 2012. Abstract 60.,Pro B, et al. J Clin

41、 Oncol. 2012;30:2190-2196.,Brentuximab Vedotin in Rel/Ref Systemic ALCL: Maximum Tumor Reduction (IRC),,,,,,,Tumor Size (% changefrom baseline),-100,-50,0,50,100,Individual Patients (n = 57),Best clinical response,Compl

42、ete remissionPartial remissionStable diseaseProgressive diseaseHistologically ineligible,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Dueck G, et al. Cancer. 2010;116:4541-4548.,來啦度胺,II 期臨床試驗：24 PTC

43、L Pts.（ N = 24）ORR: 30% (7/23)All PRs所有亞型都有效Median PFS: 96 days Median OS: 241 days AEs:中性粒細(xì)胞減少、疼痛、血小板減少、皮疹,Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma,Relapsed/re

44、fractory PTCLECOG PS 0-2(N = 24),Lenalidomide25mg PO qd on Days 1-21 of a 28day cycle,The primary endpoint ；ORR  The secondary endpoints: OS, PFS, and safety.,open-label, single-arm, multicenter Canadian phase

45、2 clinical trial,,September 2006 to November 2008,,Cancer Volume116.Issue 19. pages 4541–4548, 1 October 2010,PD or Intolerable,,Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin

46、 lymphoma,Cancer Volume116.Issue 19. pages 4541–4548, 1 October 2010,Alisertib: Investigational Aurora A Kinase Inhibitor,Results in mitotic defectsAbnormal spindlesUnseparated centrosomesDelayed mitotic progre

47、ssionApoptosis or senescence,Untreated,Treated,Treated,N,CI,O,F,N,N,HN,O,OH,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,O,Friedberg J, et al. ASH 2011. Abstract 95.,Friedberg J, et al. ASH 2011. Abstract 95.,

48、Alisertib (MLN8237): An Aurora A Kinase Inhibitor,II 期進(jìn)展期B-cell 和T-cell NHLN = 48ORR: 32%CR: 12%病理學(xué)診斷PTCL: 57%DLBCL: 20%; MCL: 23%; 轉(zhuǎn)化 FL: 40%副作用: 中性粒細(xì)胞減少, 血小板減少, 胃炎,Alisertib的隨機(jī)臨床開放III 期臨床試驗：復(fù)發(fā)難治 PTCL,Primary end

49、point: ORR, PFSSecondary endpoints: safety, CR, OS, TTP,Relapsed/refractory PTCLECOG PS 0-2(N = 354),*Choices:PralatrexateRomidepsinGemcitabine,Alisertib5 x 10 mg PO BID on Days 1-7 of a 21-day cycle,Investigator

50、’s choice*,,,ClinicalTrials.gov. NCT01482962.,Pohlman B, et al. ASH 2009. Abstract 920.,Belinostat (PXD101): A Pan-Histone Deacetylase Inhibitor,Phase II trial in PTCLN = 20ORR: 25%CR: 2PR: 3DOR: 5 mosAEs: pruritus

51、, edema, rash,Damaj G, et al. J Clin Oncol. 2012;[Epub ahead of print].,苯達(dá)莫司丁,復(fù)發(fā)耐藥PTCL的多中心II期臨床試驗 (BENTLY)：N = 60 (23 pts PTCL-U)方案: 120 mg/m2 D1、2 q3wORR: 50%28% CR/CRuMedian PFS: 3.6 mosMedian OS: 6.2 mos最常見3/4

52、AEs: 中性粒細(xì)胞減少、感染、血小板減少,Ishida T, et al. J Clin Oncol. 2012; 30:837-842.,Mogamulizumab (KW-0761): 抗-CCR4（趨化因子受體4）單克隆抗體,II 期臨床試驗：入組ATLL患者N = 28ORR: 50% (13/26)CR: 8/26Median PFS: 5.2 mosMedian OS: 13.7 mosAEs: 輸注反應(yīng) (8

53、9%), 皮疹 (63%),Select Ongoing Clinical Trials of First-line Therapy for PTCL,Phase IIICHOP ± alemtuzumabCHOP followed by ± pralatrexate,Phase IICEOP/pralatrexateCHOP + everolimusCHOP vs GEM-PCHOP + romidep

54、sinCHOP + lenalidomideCHOP + alemtuzumabCHOP + denileukin diftitoxCHP + brentuximab vedotin,ClinicalTrials.gov. NCT00725231. NCT01420679. NCT01336933. NCT01198665. NCT01719835. NCT01280526 NCT00453427.,目前已批準(zhǔn)和正在進(jìn)行的臨床試

55、驗,造血干細(xì)胞移植在PTCL的療效,目前造血干細(xì)胞的共識,首次復(fù)發(fā)、化療有效患者行ASCT：Yes！結(jié)論肯定，EFS提高15-40%存在問題：如何提高CR率；是否維持治療？ 首次CR后行ASCT作為鞏固治療：Maybe！NCCN推薦部分爭議！ 低危患者；ALK+的高危間變大T細(xì)胞淋巴瘤 鼻咽局部NK/T細(xì)胞淋巴瘤；血管免疫母T細(xì)胞淋巴瘤,Mak V, et al. Blood, 2011;118: abstract