1、外周T细胞淋巴瘤治疗进展,中国医学科学院肿瘤医院内科 周生余 2011.8. CCMO Beijing,Cancer Hospital of CAMS & PUMC,外周T/NK细胞淋巴瘤定义,一组源于胸腺后成熟T淋巴细胞或自然杀伤(natural killer，NK)细胞的淋巴系统恶性肿瘤，其生物学行为及临床表现具有明显异质性。,WHO成熟T/NK细胞肿瘤分类 (2008),T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative NK cell
2、s Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia Systemic EBV-positive T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type intestinal T-cell lymphoma Hepatosplenic T-cell lymphoma Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, ALK positive Anapl
3、astic large-cell lymphoma, ALK negative Peripheral T-cell lymphoma, NOS,Mycosis fungoides Szary syndrome Primary cutaneous CD30+ lymphoproliferative Primary cutaneous anaplastic large cell Lymphomatoid papulosis Borderline lesions Subcutaneous panniculitis-like T cell Primary cutaneous gamma-delta T
4、 cell Hydroa vacciniforme lymphoma Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell Primary cutaneous small/medium CD4+ T-cell lymphoma (provisional),Swerdlow SH, et al. WHO classification of tumours of the haematopoletic and lymphoid tissues. 2008.,1314例T细胞淋巴瘤，各亚型分布,Los Angeles, CA
5、.October 4, 2008,外周T细胞淋巴瘤各亚型分布,外周T细胞淋巴瘤各亚型生物学异质性,PTCL不同亚型疾病异质性,CHOP治疗PTCL不同亚型生存资料,如何改善PTCL预后？,传统治疗的探索 剂量强度与密集方案 高剂量化疗联合造血干细胞移植 新药的开发与应用 基于疾病异质性的特色治疗,PTCL生物学本质、疾病特点、以及各亚型异质性认识?!,开发应用于T细胞淋巴瘤的新药,开发应用于T细胞淋巴瘤的新药,吉西他滨治疗PTCL,CHOP-EG=CHOP-etoposide, gemcitabine; GEM-P=gemcitabine, cisplatin, methylprednisol
6、one; VGF=vinorelbine, gemcitabine, filgrastim.,Foss. 2009 ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology. 2009;480; Pro. 2009 ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology. 2009;486; Sallah. Br J Haematol. 2001;113:185; Zinzani. Ann Oncol.
7、 1998;9:1351; Arkenau. Haematologica. 2007;92:271; Spencer. Intern Med J. 2007;37:760; Kim. Cancer Chemother Pharmacol. 2006;58:35.,Phase Study of Bendamustine in Relapsed/Refractory T-Cell Lymphoma,Preliminary Results From a Multicenter, Phase II Study of Bendamustine in Refactory or Relapsed T-Cel
8、l Lymphoma The BENTLY Trial,Adapted from 11-ICAM,Phase Study of Bendamustine in Relapsed/Refractory T-Cell Lymphoma,STUDY DESIGN,BENDAMUSTINE:120 mg/m2,IV,day 1and 2 Every 3weeks for 3cycles(C1,C2,C3),CR,CRu,PR,SD,Progressive,BENDAMUSTINE C4,C5,C6,Off Study,Final Evaluation 1 month after the end of
9、treatment,Adapted from 11-ICAM,Phase Study of Bendamustine in Relapsed/Refractory T-Cell Lymphoma,RESPONSE HISTOLOGIC SUBTYPES,Adapted from 11-ICAM,Phase Study of Bendamustine in Relapsed/Refractory T-Cell Lymphoma,Adapted from 11-ICAM,Phase Study of Bendamustine in Relapsed/Refractory T-Cell Lympho
10、ma:Conclusions,Bendamustine is active in refactory and relapsed T-cell lymphoma with an acceptable toxicity High response rate in highly pretreated poor risk patients (ORR 42%;CR 23%) The median response duration time is 5.5 months. Next step: Combining Bendamustine with other drugs,Adapted from 11-
11、ICAM,普拉曲沙（Pralatrexate）治疗PTCL,High affinity for RFC-1 (an active transport mechanism for reduced folates) Effective substrate for FPGS (catalyzes the formation of polyglutamates with improved intracellular retention) Is a competitive inhibitor of DHFR (premetrexed targets TS) 15-25 fold more cytotox
12、ic than MTX in a variety of human tumor cell lines,PROPEL Trial: Pralatrexate in Relapsed/Refractory PTCL,OConnor OA, et al. ASH 2008. Abstract 261.,Romidepsin治疗复发难治PTCL pivotal phase II study,Schedule: 4-hour infusion 14 mg/m2 on days 1, 8, & 15 every 28 days,Coiffier B, Pro B, Prince HM, et al. 52
13、nd ASH Abstract 114.,Romidepsin治疗复发难治PTCL pivotal phase II study,Coiffier B, Pro B, Prince HM, et al. 52nd ASH Abstract 114.,Romidepsin治疗复发难治PTCL pivotal phase II study,Conclusions:romidepsin should be further investigated in combination with chemotherapy in the frontline setting,Most common grade 3
14、 adverse events, observed in 10% Thrombocytopenia ,Neutropenia ,Infection ,Anemia,Coiffier B, Pro B, Prince HM, et al. 52nd ASH Abstract 114.,单抗类药物治疗PTCL,“Alemtuzumab + CHOP” in PTCL,1.Enblad G, et al. Blood. 2004;103:2920-2924. 2. Kim JG, et al. Cancer Chemother Pharmacol. 2007;60:129-134.,3. Galla
15、min Ai, et al. Blood. 2007;110:2316-2323. 4. Weidmann E, et al. Leuk Lymphoma. 2010;51:447-455,Phase CHOP+/-A in PTCL,Phase II Study of Denileukin Diftitox + CHOP in PTCL: “CONCEPT” Trial,DD18mg/kg/day on days 1 and 2，CHOP starting day 3，G-CSF day 4 Every 21 days, for 6-8 cycles N = 49 (ITT)，Median
16、age, 52 years (range, 23-80 years) PTCL, NOS, n = 19；AITL, n = 10；ALCL, n = 8,Foss. Clin Adv Hematol Oncol. 2009;7(suppl 18):12.,1. Bartlett N, et al. Blood. 2008;111:1848-1854. 2. Forero-Torres, et al. Br J Haematol. 2009;146:171-179. 3. Ansell S, et al. J Clin Oncol. 2007;25:2764-2769.,第一代抗CD30单抗：
17、毒性小，疗效有限,MOA of Brentuximab Vedotin (SGN-35),Reproduced with permission from Seattle Genetics, Inc.; Younes. EHA. 2009 (abstr 0503).,ADC=antibody-drug conjugate; MMAE= monomethylauristatin E.,Phase I Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory CD30+ Lymphoma,Dose cohorts: 0.1, 0.2, 0.
18、4, 0.6, 0.8, 1.2, 1.8, 2.7, and 3.6 mg/kg Tumor types (N) HL (42) Systemic ALCL (2) AITL (1) Study objectives: safety and MTD,Younes. EHA. 2009 (abstr 0503).,Relapsed/refractory CD30+ lymphoma ECOG PS 2(N=45),SGN-35 IV q21d for 2 cycles Restage after cycle 2; SD or better may receive additional cycl
19、es,1.2 mg/kg Median PFS=2.2 mos,Phase I Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory CD30+ Lymphoma: Results,MTD=1.8 mg/kg ORR=41% DOR=7.3 mo,Adapted with permission from Younes. EHA. 2009 (abstr 0503).,18,24,30,36,42,48,54,60,66,72,78,84,12,6,0,0,10,20,30,40,50,60,70,80,90,100,Time (W
20、eeks),Patients Without Disease Progression (%),1.2 mg/kg Median PFS=6.3 mos,1.2 mg/kg (N=16),1.2 mg/kg (N=29),All Doses,Phase Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory ALCL,Demographics and Baseline Characteristics,Adapted from 11-ICAM,Phase Study: Brentuximab Vedotin (SGN-35) in Re
21、lapsed/Refractory ALCL,Key Response Results Summary,Adapted from 11-ICAM,Phase Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory ALCL,PFS in Patients with CR by Subsequent Transplant,Adapted from 11-ICAM,Phase Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory ALCL,Adapted from 11-I
22、CAM,Phase Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory ALCL,Adapted from 11-ICAM,Phase Study: Brentuximab Vedotin (SGN-35) in Relapsed/Refractory ALCL: Conclusions,Durable complete remissions achieved with brentuximab vedotin in highly refactory systemic ALCL patients,Adverse events we
23、re manageable, including peripheral neuropathy,Based on these encouranging trial resulte,a frontline study in sALCL is underway (ClinicalTrials.gov #NCT01309789),Adapted from 11-ICAM,Targets CCR4 (CC Chemokine receptor type 4) Expressed on sub-population of Treg cells (Th2 CD4+ T cells) 88% of patie
24、nts with ATLL 38% of patients with PTCL Phase I/II Study 16 patients received antibody q week x 4 with escalating doses; 1 patient off study early secondary to treatment related side effects No MTD noted; recommended dose going forward 1 mg/kg RR 31%, 2CR 3PR Grade 3/4 toxicities included lymphopeni
25、a (10), neutropenia (3), leukopenia (2), zoster (1),Anti-CCR4（ KW0761 ）治疗复发CCR4+ ATLL or PTCL,Anti-CCR4（ KW0761 ）治疗复发CCR4+ ATLL，Phase 2 Trial,Adapted from 11-ICML,Anti-CCR4（ KW0761 ）治疗复发CCR4+ ATLL，Phase 2 Trial,Adapted from 11-ICML,Anti-CCR4（ KW0761 ）治疗复发CCR4+ ATLL，Phase 2 Trial,Adapted from 11-ICML
26、,Summery of Phase II Study of KW-0761,Adapted from 11-ICML,Most common AEs:infusion reaction and rash as well as hematologic ones such as lymphopenia, thrombocytopenia and neutropenia Grade 3 rash: Observed in 5pts,But,they disappeared or improved by steroid treatmengs ORR : 50%(13/26;95%Cl.30-70%)
27、Median PFS ,5.2 months; median OS,13.7months,Conclusion: KW-0761 is an effective agent with acceptable toxicity profiles for pts with relapsed ATL, in which no standard therapy exists. Further investigation are warranted,基于疾病异质性的特色治疗,CD30+ T-cell lymphomas: ALCL, PTCL-nos,初步研究显示，第一代抗CD30单克隆抗体治疗相关毒性小
28、、临床耐受性良好。 SGN-35是第二代或改进型抗CD30单抗，其治疗复发耐药ALCL的期临床研究获得了高CR率和持续性的缓解期。 SGN-35与化疗联合的一线治疗值得期待。,CCR4+ T-cell lymphomas: ATLL，PTCL,Angioimmunoblastic T-cell lymphoma (AILT),Surface Antigens/Receptors CD4 CD25 CD52 CD20,Microenvironmental Factors Angiogenesis Immunomodulation Viral Pathogens,Cellular Survival
29、 Mechanisms Proteasome Inhibition HDAC inhibition Death Receptors & Ligands Cell Cycle Arrest Signal Transduction Inhibition,50%75%病例 EBER（+） 滤泡辅助T细胞活化 VEGF-A在AITL肿瘤细胞中表达增高 CD20+ B免疫母细胞增生 恶性T细胞高表达CD52 免疫缺陷、免疫调控异常,环孢霉素A：强免疫调节药物，可显著抑制T细胞活化。 沙利度胺/贝伐单抗：VEGF-A在AITL肿瘤细胞中表达增高 利妥昔单抗：CD20+ B免疫母细胞增生与疾病进展、IgH克
30、隆性重排密切相关 阿仑单抗（Alemtuzumab）：恶性T细胞高表达CD52，因此抗CD52抗体可能有效； Zanolimumab（HuMax-CD4）：人源化抗CD4单克隆抗体； 地尼白介素一毒素连接物(denileukin difiitox)：与T细胞的IL-2受体结合诱导凋亡； Lenalidomide：抑制VEGF抑制肿瘤血管生成，也可直接抑制肿瘤细胞增生。,AITL的靶向免疫治疗,AITL的靶向免疫治疗,Clinical Advances in Hematology 899-908.,HSCT治疗高危/不良PTCL,AHSCT,Allo-SCT,Journal of Clinical Oncology,2008;(26):2264-2271.,Reimer P, et al. J Clin Oncol. 2009;27:106113.,PTCL治疗进展总结,正确诊断和认识是合理治疗PTCL根本所在； CHOP作为经典方案有其现实性的局限性； 新药治疗研究方兴未艾、值得期待； 基于疾病异质性的特色治疗，是近年来对PTCL治疗策略的重大发展，也是其必然发展趋势。,More time, More development, We hope.,谢谢！,
