外周細胞淋巴瘤診療進展

1、外周細胞淋巴瘤診療進展第一張，PPT共四十九頁，創(chuàng)作于2022年6月主要內容PTCL的分類PTCL的流行病學PTCL的預后因子PTCL治療新藥物第二張，PPT共四十九頁，創(chuàng)作于2022年6月外周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 involvement of more mature (postthymic) T cells vs prethymic or imma

2、ture 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 neoplasmsNodalNK/TCL

3、 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-Lymphoblastic

4、Leukemia/LymphomaPrimary cutaneous CD30+ T-cell disordersMFT-cell large granular lymphocytic leukemiaSzary SyndromeIndolent第三張，PPT共四十九頁，創(chuàng)作于2022年6月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%Periphera

5、l 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 PTCLOther disorders第四張，

6、PPT共四十九頁，創(chuàng)作于2022年6月四川省腫瘤醫(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例第五張，PPT共四十九頁，創(chuàng)作于2022年6月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月第六張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL流行病學不同地域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. Savage KJ. Hematology Am Soc Hematol Educ Program. 2005;10:267-277.2. International T-Cell Lymphoma

7、 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-typeHepatosplenic3.02.30.2Primary cutaneous ALCLSubcutaneo

8、us panniculitis-likeUnclassifiable T-cell第七張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL亞型及細胞來源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. Expe

9、rt Rev Hematol. 2011;4:415-425.第八張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL的診斷10% PTCL診斷不正確大多數(shù)病人是III/IV期結外受累常見: 皮膚、肝臟、脾臟、骨髓、外周血PTCL的診斷：MIC （形態(tài)學、免疫學和細胞遺傳學）細針穿刺活檢不能作為診斷依據(jù)，必須進行活檢切除術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. Swerdlow SH, et al. WHO Clas

10、sification of Tumours of Haematopoietic and Lymphoid Tissues. 2008. 4. Kocjan G. J Clin Pathol. 2005;58:561-567.第九張，PPT共四十九頁，創(chuàng)作于2022年6月主要的外周T細胞淋巴瘤的臨床和病理學特征第十張，PPT共四十九頁，創(chuàng)作于2022年6月ALCL, ALK+ 97%PTCL, unspecified75%ATLL 93%Panniculitis like75%Nasal NK/T cell 92%ALCL, ALK-74%Angioimmunoblastic 81%Hepato

11、splenic72%Enteropathy type 79%Cutaneous ALCL66%Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.專家診斷共識第十一張，PPT共四十九頁，創(chuàng)作于2022年6月The aggressive peripheral Tcell lymphomas: 2012 update on diagnosis, risk stratification, and managementAmerican Journal of HematologyVolume 87, Issue 5, pages 511-519, 17 APR

12、 2012 第十二張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL的治療第十三張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL的臨床預后指數(shù)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 pati

13、entsAge (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)Stage (I or II vs III or IV)Serum LDH ( 1 x ULN vs 1x ULN)Performance score (0 or 1 vs 2-4)

14、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 diagnosis:0-1 Low2 Low/intermediate3 High/intermediate4-5 HighThe PIT is based on number of

15、 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)第十四張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL的生物預后因素第十五張，PPT共四十九頁，創(chuàng)作于2022年6月PTCL SubtypesALK+ ALCLALK ALCLPTCL-NOSAITLNK/TCLATLL5-yr O

16、S 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.OS (%)Yrs010203040506070809010002468101214161820ALCL, ALK+ALCL, ALK-All NK/T-cell lymphomasPTCL-NOSAITLAd

17、ult T-cell leukemia/lymphoma含蒽環(huán)類方案治療PTCL的療效有限第十六張，PPT共四十九頁，創(chuàng)作于2022年6月Treatment Guidelines for PTCL: Still CHOP BasedNCCN. Clinical practice guidelines in oncology: non-Hodgkins lymphoma. v.3.2012.First-line TherapyClinical trial (preferred)ALCL, ALK+ histologyCHOP-21CHOEP-21Other histologies (ALCL,

18、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 regimen)HyperCVAD, alternating with high-dose methotrexate and cytarabine First-line ConsolidationAll patients except

19、 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第十七張，PPT共四十九頁，創(chuàng)作于2022年6月The International PTCL and NK/TCL Study: Analysis of Treatments多數(shù)PTCL 或 NK/TCL (除外 ALK+ ALC

20、L) 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.PTCLAILTYrs018246810121416010080604020OS (%)Anthracycline as part of initial treatmentYesNoP = .11Yrs018246810121416010080604020OS (%)Anthracycline as part of initial treatmentYesNoP = .48傳統(tǒng)含阿霉素的方案對PTCL無效第十八張，PP

21、T共四十九頁，創(chuàng)作于2022年6月PTCL治療？采用新的誘導化療方案CTOP， EPOCH, CEOP, CHOPE novel drug combination regimen?CONSOLIDATION? Autologous transplant? Allogeneic transplant?MAINTENANCE?新藥、靶向藥物研發(fā)第十九張，PPT共四十九頁，創(chuàng)作于2022年6月Surface Antigens/ReceptorsCD2CD4CD25CD30Chemokine receptors . . .Microenvironmental FactorsAngiogenesisIm

22、munomodulation Viral pathogensCellular Survival MechanismsProteasome inhibitionHDAC inhibitionDeath receptors and ligandsCell-cycle arrestSignal transduction inhibitionPTCL治療可能的靶點第二十張，PPT共四十九頁，創(chuàng)作于2022年6月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 - 門冬酰胺酶為主方案聯(lián)合放療（NK/T細

23、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 免疫調節(jié)劑 Vose JM, et al. JCO, 2008; 26: 4124-30; NCCN guideline(2012); 2012 ASCO, abs 8050Schmitz N, et al. Blood, 2010; 116: 3418-25; Dearden CE, et al. Blood, 2011; Sep 26第二十一張，PPT共四十九頁，創(chuàng)作于2022年6月年輕PTCL患者：GHGNHLSG的研究Schmitz N, et al

24、. 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=42)Months020010080604020EFS (%)p = 0.012406080100non Etoposide (n=12)Etoposide (n=32)Months020010080604020EFS (%)p = 0.0044060801

25、00non Etoposide (n=41)Etoposide (n=103)Months020010080604020EFS (%)p = 0.057406080100non Etoposide (n=29)Etoposide (n=69)第二十二張，PPT共四十九頁，創(chuàng)作于2022年6月Pralatrexate is selective antifolate designed to preferentially accumulate in cancer cellsEntryPralatrexate is selective for cells that express RFC-1, whi

26、ch is overexpressed on some cancer cells relative to normal cellsAccumulationOnce taken up by cancer cells, pralatrexate becomes polyglutamylated, resulting in high intracellular drug retentionInhibitionPralatrexate acts on folate pathway to interfere with DNA synthesis and elicit cancer cell death

27、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.新藥Pralatrexate的作用機制第二十三張，PPT共四十九頁，創(chuàng)作于2022年6月PROPEL研究: Phase II Pralatrexate in Relapsed/Refractory PTCL111 patients with relapsed/refra

28、ctory PTCLPralatrexate 30 mg/m2 weekly for 6 wks in 7-wk cyclesVitamin B12 and folic acid given to decrease mucositisORR: 32/109 (29%); CR: 11%; 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.第二十四張，PPT共四十九頁，創(chuàng)作于

29、2022年6月PROPEL研究:腫瘤體積、有效時間和生存OConnor OA, et al. J Clin Oncol. 2011;29:1182-1189.Patients-1001007550-25-75Change in Tumor Volumne From Baseline (%) Months0301.00.2Progression-Free Survival (probability)9121821Pralatrexate 30 mg/m2 (6/7 weeks)n = 109; 70 eventsMedian (months) 3.5; 95% CI, 1.7

30、to 4.8Months03010080604020Duration of Response (probability)9121824Months0301.00.2Overall 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 mg/m2 (6/7 weeks

31、)n = 32; 16 eventsMedian (months) 10.1; 95% CI, 3.4 to NE6152121126第二十五張，PPT共四十九頁，創(chuàng)作于2022年6月Romidepsin: A Novel, Potent Bicyclic HDACiGene regulation1Histone acetylation/transcription induction2Protein acetylation3Activation of apoptosis4Antiangiogenesis5Cell-cycle arrest41. Peart MJ, et al. Proc Na

32、t 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 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.第二十六張，PPT共四十九頁，創(chuàng)作于2022年6月Wk 4Wk 2Wk 312215

33、81Wk 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. 2012;30: 631-636.Romidepsin in Relapsed/Refractory PTCL: Treatment ScheduleRomidepsinRomidepsinRomidepsinRomidepsinA Phase II, Multicenter, Open-Label Trial 第二十七張，PPT共四十九頁，創(chuàng)作于20

34、22年6月Romidepsin in Rel/Ref PTCL: ORRsBest Response Category, n (%)IRC (N = 130)Investigators(N = 130)Objective 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

35、Clin Oncol. 2012;30:631-636.*Insufficient efficacy data to determine response due to early termination. 第二十八張，PPT共四十九頁，創(chuàng)作于2022年6月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 toxicitiesThromb

36、ocytopenia: 24%Neutropenia: 20%Coiffier B, et al. J Clin Oncol. 2012;30:631-636.第二十九張，PPT共四十九頁，創(chuàng)作于2022年6月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.第三十張，PPT共四十九頁，創(chuàng)作于2022年6

37、月Anti-CD30 ADC: Brentuximab Vedotin (SGN-35)ADC: 3 partsChimeric antibody SGN-30Synthetic analogue (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 arres

38、t and apoptosisPreclinical activity observed both in in vitro and in vivoFrancisco JA, et al. Blood. 2003;102:1458-1465.第三十一張，PPT共四十九頁，創(chuàng)作于2022年6月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-細胞淋巴瘤隨機分為3組1.8 mg/kg brentuximab vedotin q3w X 2 cycles, then CHOP x 6

39、 cycles1.8 mg/kg brentuximab 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% (26/26); CR: 88% (23/26)Brentuximab vedotin MTD not exceeded

40、at 1.8 mg/kg1 DLT: grade 3 rash in 6 pts治療相關并發(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.第三十二張，PPT共四十九頁，創(chuàng)作于2022年6月Pro B, et al. J Clin Oncol. 2012;30:2190-2196.Brentuximab Vedotin in Rel/Ref Systemic ALCL: Maximum Tumor Reduction (IRC)Tumor Size (% c

41、hangefrom baseline)-100 -50 050 100Individual Patients (n = 57)Best clinical responseComplete remissionPartial remissionStable diseaseProgressive diseaseHistologically ineligible第三十三張，PPT共四十九頁，創(chuàng)作于2022年6月Dueck G, et al. Cancer. 2010;116:4541-4548.來啦度胺II 期臨床試驗：24 PTCL Pts.（ N = 24）ORR: 30% (7/23)All P

42、Rs所有亞型都有效Median PFS: 96 days Median OS: 241 days AEs:中性粒細胞減少、疼痛、血小板減少、皮疹第三十四張，PPT共四十九頁，創(chuàng)作于2022年6月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 endpo

43、int ；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 第三十五張，PPT共四十九頁，創(chuàng)作于2022年6月Interim report of a phase 2 clinical trial of

44、 lenalidomide for T-cell non-Hodgkin lymphoma Cancer Volume116.Issue 19. pages 45414548,1 October 2010第三十六張，PPT共四十九頁，創(chuàng)作于2022年6月Alisertib: Investigational Aurora A Kinase InhibitorResults in mitotic defectsAbnormal spindlesUnseparated centrosomesDelayed mitotic progressionApoptosis or senescence Untr

45、eatedTreatedTreatedNCIOFNNHNOOHOFriedberg J, et al. ASH 2011. Abstract 95.第三十七張，PPT共四十九頁，創(chuàng)作于2022年6月Friedberg J, et al. ASH 2011. Abstract 95.Alisertib (MLN8237): An Aurora A Kinase InhibitorII 期進展期B-cell 和T-cell NHLN = 48ORR: 32%CR: 12%病理學診斷PTCL: 57%DLBCL: 20%; MCL: 23%; 轉化 FL: 40%副作用: 中性粒細胞減少, 血小板減

46、少, 胃炎第三十八張，PPT共四十九頁，創(chuàng)作于2022年6月Alisertib的隨機臨床開放III 期臨床試驗：復發(fā)難治 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.第三十九張，PPT共四十九頁，創(chuàng)作于2022年6月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第四十張，PPT共四十九頁，創(chuàng)作于2022年6月Damaj G, et a