1. Update on T-cell Non-Hodgkin Lymphoma in China Huaqing Wang, M.D. Cancer Hospital and Institute of Tianjin Medical University

2. International Variation http://www-dep.iarc.fr/Males Females

3. 发病率 (Incidence)  亚洲国家的发病率较西方国家高，在非霍奇金淋巴瘤中的比例 15-20%  一项国际性回顾研究评估了北美、欧洲和亚洲 22 个地区 1314 例 T 细胞淋巴瘤 * * Arimitage.International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes. J Clin Onco2008; 26(25):4124-30

4. International PTCL Study Major NHL Types by Region PercentNAEUAsia PTCL, unspecified33.722.1 Angioimmunoblastic15.730.817.6 Anaplastic, ALK+16.0 9.1 3.6 Anaplastic, ALK- 7.711.6 2.5 NK/T-cell 5.0 5.422.1 ATLL 2.0 1.424.6

5. Trends in incidence of PTCL by subtype from 1992 to 2005, 13 SEER registries PTCL incidence increased by 280%. Abouyabis et al., Leuk & Lymphoma 2008;49:2099

6. T-cell Lymphoma Classification: WHO Predominantly leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic NK/T-cell leukemia/lymphoma Adult T-cell leukemia/lymphoma Predominantly nodal Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma Peripheral T-cell lymphoma (Unspecified) Predominantly Extranodal Mycosis Fungoides Sezary syndrome Primary cutaneous CD30+ disorders Anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell NK/T-cell lymphoma-nasal Enteropathy-type intestinal lymphoma Hepatosplenic T-cell lymphoma Precursor T/NK Neoplasms Precursor T lymphoblastic leukemia/lymphoma Blastic NK lymphoma Peripheral T/NK Neoplasms

7. 天津地区 20 年恶性淋巴瘤的发病率 天津医科大学肿瘤医院回顾性了分析 1986~2005 年天津地区 20 年恶性淋巴瘤的发病情况： 外周 T 细胞占非霍奇金淋巴瘤的比例高达 34% ， 外周 T 细胞非特指型为 10.8% ， NK/T 细胞淋巴瘤为 14.9% ， 皮肤 T 细胞淋巴瘤为 2.0% ， 肠病型 T 细胞淋巴瘤为 0.5% 。

8. Known Risk Factors Immune modulation –Congenital immunodeficiencies –Immunosuppression –HIV –Autoimmune disorders Infectious organisms –Human T-cell lymphotrophic virus (HTLV-1) - ATLL –Epstein-Barr virus (NK/T-cell, AITL?) –H Pylori Familial aggregation

9. …. the Remaining Cases of NHL Environmental factors (e.g., pesticides, solvents, PCBs) Lifestyle factors –Obesity –Diet –Alcohol –UV light Genetic factors

10. IIL GOL GITIL GISL/NHLCSG GIMURELL GR. TOSCANO GR. RO/BO HOST IEO Samsung Medical Center Seoul Queen Mary Hospital Programa Nacional de Cancer del Adulto Chile (PANDA) Santiago de Chile – Hospital del Salvador (GATLA) Grupo Argentino de Tratamiento de la Leucemia Aguda Buenos Aires – FUNDALEU La Plata – Hospital San Martin Nebraska University Cleveland Clinic Memorial Sloan Kettering CC Stanford University NCI MD Anderson Yale-New Haven CC Utah University Nashville-Vanderbilt UMC CALGB Columbus-Ohio St. Bartholomew’s Hospital, London Guy's and St Thomas, London Newcastle University Christie Hospital, Manchester Southampton University Royal Wolverhampton Hospitals NHS Trust SAKK Czech Lymphoma Study Group National Oncological Institution (NOU) GELCAB Tel Hashmer Sheba Medical Center Tel Aviv Sourasky Medical Center Beilinson Medical Center Rambam Medical Center Shaare Zedek Medical Center Moscow-Cancer Research Center of RAMN Uruguayan Society of Hematology (SHU) Montevideo-Hospital Maciel GEMOH Brazil University of Campinas Sao Paulo-Santa Casa Medical School

11. International T-cell NHL Study: Sites (N = 1314) North America –Vancouver, Bethesda (NCI), Nebraska, Massachusetts (MGH), California (USC), Arizona Europe –Barcelona, Norway, Wuerzburg, London, Lyon, Leeds, Madrid, Bologna, Modena Asia –Bangkok, Hong Kong, Singapore, Tokyo, Nagoya, Okayama, Fukuoka, Seoul

12. CENSORFAILTOTALMEDIAN FFS 72 261 3330.91 OAS 112 221 3332.01 PTCL-NOS Cases Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time 0123456789101112131415161718 Overall and Failure-free Survival

13. Proportion Time IPICENSORFAILTOTALMEDIAN 0/1 36 47 835.03 2 36 67 103 2.1 3 20 53 731.41 4/5 9 38 470.68 Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112131415161718 Overall Survival PTCL-NOS Cases by IPI

14. Time Proportion Anthracycline as part of initial txCENSORFAILTOTALMEDIAN yes 98 173 271 2.1 no 14 34 481.57 Test: p=0.14 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112131415161718 Overall Survival PTCL-NOS Cases by Anthracycline Initial Tx

15. Time Proportion Transplant reasonCENSORFAILTOTALMEDIAN inital tx 8 15 231.46 0 24 0.71 Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234567891011 subseq. to recur. Failure-free Survival PTCL-NOS Cases by Transplant Reason

16. CENSORFAILTOTALMEDIAN 45 32 7710.4 56 21 77. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234567891011121314 Survival FFS OAS Time Proportion Overall and Failure-free Survival Anaplastic large cell lymphoma, ALK+

17. Time Proportion Overall and Failure-free Survival Anaplastic large cell lymphoma, ALK- CENSORFAILTOTALMEDIAN 30 39 691.33 36 33 694.49 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112131415 Survival FFS OAS

18. Time Proportion CENSORFAILTOTALMEDIAN 4 30 340.29 5 29 340.36 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234567 Survival FFS OAS Overall and Failure-free Survival NK/T-cell lymphoma, nasal type

19. Phase II study of Bevacizumab and CHOP (A-CHOP) for patients with PTCL or NK Cell Neoplasms ECOG 2404

20. O.A. O’Connor, B. Pro, L. Pinter-Brown, L. Popplewell, N. Bartlett, A. Shustov, M.J. Lechowicz, K. Savage, B. Coiffier, E. Jacobsen, P.L. Zinzani, A. Goy, J. Zain, S. Wilroy, M. Patterson, A. Boyd, M. Saunders, P. Cagnoni, S. Horwitz PROPEL: A Multi-center Phase 2 Open-label Study of Pralatrexate with Vitamin B 12 and Folic Acid Supplementation in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL) Blood 112: 261a, 2008

21. Design Phase 2 single arm, open label, multi-center, non- randomized, international Target PopulationAdult patients with relapsed or refractory PTCL Number of Patients Minimum of 100 evaluable patients Treatment Pralatrexate 30 mg/m 2 IV x 6 weeks followed by 1 week rest (7 week cycle) in combination with vitamin supplementation Primary EndpointResponse rate by IWC (CR + CRu + PR) Secondary Endpoints Duration of response Progression-free survival Overall survival PROPEL Study IWC: International Workshop Criteria

22. Histopathology Per Independent Central Review (N=111) n Percent Per Investigator (N=111) n Percent PTCL-unspecified 59 53% 51 46% Anaplastic large cell lymphoma, primary systemic type 17 15% Angioimmunoblastic T-cell lymphoma 13 12% 18 16% Transformed mycosis fungoides 12 11% 13 12% Blastic NK lymphoma (with skin, lymph node, or visceral involvement) 4 4% T/NK-cell lymphoma-nasal 2 2% 1 <1% Extranodal peripheral T/NK-cell lymphoma unspecified 1 <1% 2 2% Adult T-cell leukemia/lymphoma (HTLV 1+) 1 <1% 2 2% T/NK-cell leukemia/lymphoma 0 0% 1 <1% Mycosis fungoides (not transformed)* 1 <1% 0 0% Inconsistent with T-cell lymphoma* 1 <1% 0 0% Aggressive T-cell lymphoma 0 0% 1 <1% Aggressive large cell T-cell lymphoma 0 0% 1 <1% *Two treated patients excluded from efficacy analysis PROPEL Histology

23. PROPEL Summary of Response by Central Review: IWC Pralatrexate (N=109) nPercent95% CI Best Response CR+CRu+PR2927%19-36 CR109% CRu1<1% PR1817% SD2321% PD4037% UE33% ND: off-treatment in C11413% 69% of responders did so after Cycle 1 C1: Cycle 1

24. Youn H. Kim, Sunil ReddyStanford Cancer Center, Stanford, CA Sean WhittakerSt. Thomas’ Hospital, London, UK Mariefrance Demierre, Adam LernerBoston Medical Center, Boston, MA Ellen J. Kim, Alain H. RookHospital of the Univ. of Penn, Philadelphia, PA Madeleine DuvicM D. Anderson Cancer Center, Houston, TX Tadeusz RobakMedical University, Lódz, Poland Jürgen C. BeckerUniveritätsklinikum, Würzburg, Germany Alexey SamtsovAKademika Lebedeva, Saint-Petersburg, Russia William McCullochGloucester Pharmaceuticals, Cambridge, MA Archibald G. Prentice Royal Free Hospital, London, UK On Behalf of All Investigators Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study ASH 12/2008, Abstract# 263

25. Romidepsin Novel bicyclic peptide Potent pan-histone deacetylase (HDAC) inhibitor Greatest activity against: −Class I (HDACs 1, 2, 8) −Class II (HDACs 4, 5, 6) −Class IV (HDAC 11) In vitro efficacy −HUT-78 (TCL cell line) IC 50 = 1.4 x 10 -9 M Romidepsin CH 3 HN H H3CH3CH3CH3C H O NH O S HN S HN O O H O O H Molecular Weight 540.71

26. HDAC Inhibitors: Multifunctional Anticancer Agents Acetylation of Histone and Non-Histone Proteins Altered Gene Expression And Protein Function Angiogenesis VEGF, VEGFR, MMPs, Activin A, Ang2, eNOS Cellular Transformation C-myc, Ras, Raf, Bcl-6, p53 Cell Cycle Arrest p21, p27, Cyclin A & D Apoptosis Hsp90, Bcl-2, Bcl-XL, Bax, Fas, Caspase-3 & 9 Cellular Differentiation MDR-1, Na-I Symporter, CD25, CAR (Adenovirus Receptor), RARα & β

27. Patient Characteristics As-Treated Population (N=96) Age (yrs), median (range)57 (21 – 89) Sex (n, %) Men 59 (61.5%) Women 37 (38.5%) Clinical Stage (n, %) IB 15 (15.6%) IIA13 (13.5%) IIB 21 (21.9%) III 23 (24.0%) IVA 24 (25.0%) ECOG Status 0 49 (51.0%) 1 47 (49.0%) Prior Systemic CTCL Therapies, median (range) 3 (1-11) Pruritus at Study Entry, n (%) Moderate 23/52 (44.2%) Severe 29/52 (55.8%) 71% with advanced stage (≥IIB)

28. Response by CTCL Clinical Stage Evaluable Population (N=72) Clinical StageN=72ORRCR/CCRPR IB-IIA247 (29%)1 ( 4%)6 (25%) IIB169 (56%)2 (13%)7 (44%) III188 (44%)1 ( 6%)7 (39%) IVA146 (43%)2 (14%)4 (29%) Responses in advanced disease (stages IIB-IVA) 48% ORR for ≥ IIB 8 patients with Sézary syndrome, 4 (50%) had a PR

29. Conclusions Single agent romidepsin is active in CTCL with an overall response rate (ORR) of 42% in evaluable patients including 6 CRs In advanced stage disease (IIB-IVA) the ORR is 48% –ORR in stage IIB 56%, SS 50% Pruritus relief in 63% of patients with mod-severe pruritus at baseline despite the exclusion of the use of steroids and antihistamines Most AEs associated with romidepsin were mild (grades 1-2) and manageable Romidepsin does not have a significant effect on the QT Interval

30. Agents In Development for T-Cell NHL HDAC inhibitors –Vorinostat –Romidepsin –LBH 589 Folate antagonists –Pralatrexate Lenalidamide Syk inhibitor – R788 Proteosome inhibitors Purine analogues Gemcitabine Platinum agents Bevacizimab Campath Ontak Endostar Tranditional Chinese herbs