1. Advances in the treatment of T cell lymphomas Yok-Lam Kwong Department of Medicine Queen Mary Hospital

2. Mature T and NK cell malignancies T-cell prolymphocytic leukaemia T-cell large granular lymphocyte leukaemia Chonic lymphoproliferative disroder of NK cells Aggressive NK cell leukaemias Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood Adult T-cell leukaemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis like T-cell lymphoma Mycosis fungoides Sezary syndrome Primary cutaneous CD30 positive T-cell lymphoproliferative disorders Primary cutaneous peripheral T-cell lymphomas Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative

3. 393 cases of lymphomas in 5 hospitals in Hong Kong in 2006

4. Overview of the management of TCL 1. All TCL are not the same 2. Different subtypes of TCL may need different treatment strategies 3. There may be intrinsic differences in some types of TCL in different patient populations 4. Owing to relative rarity of these lymphomas, large controlled trials have not been conducted to evaluate the efficacy of different treatment protocols

5. Specific subtypes of TCL that may require different treatment strategies 1. Adult T cell lymphoma / leukaemia 2. Enteropathy associated T cell lymphoma 3. Hepatosplenic T cell lymphoma 4. Subcutaneous panniculitis-like T cell lymphoma 5. Mycosis fungoides 6. Primary cutaneous T cell lymphomas

6. The three most common subtypes of T- cell lymphomas 1. Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) 2. Angioimmunoblastic T cell lymphoma (AITL) 3. Anaplastic large cell lymphoma (ALCL)

7. Problems of treatment of TCL 1.CHOP designed for conventional aggressive B-cell lymphoma still used 2. Response is suboptimal, and remissions are often short-lived 3. Dose dense or escalation on a CHOP backbone has not been shown to be beneficial 4. High dose chemotherapy + autologous hematopoietic stem cell transplantation (HSCT) may improve outcome. However, many patients do not actually make it to HSCT because of disease progression

8. Bendamustine

9. Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in Refractory or Relapsed T-Cell Lymphomas: The BENTLY Trial Damaj et al. Histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma Disease progression afterone or more lines of prior chemotherapy Bendamustine: 120 mg/m 2 per day on days 1, 2 every 3 weeks for six cycles. Primary end point: overall response rate (ORR) Secondary end points: duration of response (DOR), progression-free-survival (PFS), and overall survival (OS).

10. Results 60 patients, 27 (45%) of whom were refractory to their last prior chemotherapy Histology: PTCL-NOS and AITL, advanced stage in 87% of patients. Median number of previous chemotherapy: 1 (1 – 3) ORR: 50% CR: 17 patients (28%) PR: 13 patients (22%) DoR: 3.5 months PFS: 3.6 months OS: 6.2 months Grade III/IV adverse effects Neutropenia:30%; thrombocytopenia: 24%; Infections: 20%

11. Autologous HSCT

12. Schetelig et al Haematologica 2003;88:1272-1278 EBMT-based survey 29 patients with AITL in 16 transplant centers Median age at HSCT: 53 years. Upfront: N=14 (48%) 2nd / 3rd-line therapy: N=15 (52%) Conditioning regimens: BEAM: 16 patients ICE: 7 patients Others: 6 patients TRM: 1 patient Outcome CR increased from 45% before HSCT to 76% afterwards Median observation time: 5 years (range 2.5 to 10 years) 14 patients have died (13 from progressive disease) 15 patients are alive 5-year overall survival: 44% (95% CI, 22% to 66%) 5-year event-free survival was 37% (95% CI, 17% to 57%) AITL

13. Kyriakou et al J Clin Oncol 2008;26:218-24. Retrospective, EBMT multicenter study of 146 patients with AITL undergoing autologous HSCT PBHSC: 143 patients; BM: 3 patients Conditioning: BEAM in most cases Median follow-up of 31 months (range, 3 to 174 months) 95 patients (65%) remained alive 51 patients (35%) died (disease progression: 42, TRM: 9) Non-relapse mortality at 1 yr: 5% and at 2 yr: 7% Actuarial overall survival (OS): 67% at 2 yr and 59% at 4 yr Cumulative incidence of relapse: 40% at 2 yr and 51% at 4 yr Progressive free survival according to status CR: 70% at 2 yr and 56% at 4 yr Chemotherapy sensitive disease: 42% at 2 yr and 30% at 4 yr Chemotherapy refractor disease: 23% at 2 yr and 23% at 4 yr 1.HSCT offers the possibility of long-term disease-free survival to patients with AITL. 2.Early transplantation is necessary to achieve optimal results.

14. Yang et al Biol Blood Marrow Transplant 2009;15:118-25 Retrospective analysis of autologous HSCT 64 patients Median age 44 years (range: 15-63 years) Risk categorization a-IPI: 8 patients (12.5%) at high risk PIT: 16 patients (26.6%) at 2 – 3 Median follow-up of 29.7 months 3-year overall survival (OS): 53% 3-year progression-free survival (PFS) 44.3% Risk factors on univariate analysis for OS poor performance status, high lactate dehydrogenase (LDH) levels, high a-IPI score, high PIT classes, failure to achieve complete response (CR) at transplantation, and nonfrontline transplantation Risk factors on multivariate analysis for OS Non-CR at transplantation (hazard ratio [HR] 2.23; 95% CI 1.78-7.93) 2-3 PIT factors (HR 3.76; 95% CI 1.02-5.42) PTCL-NOS

15. Mercadal et al Ann Oncol 2008;19:958-63. Forty-one patients (men: 30; women: 11) Median age: 47 years Mega-CHOP, responders received autologous HSCT 28 patients (68%) received planned treatment CR: 20 patients (50%), PR: 4 patients (10%) HSCT in 17 patients Median follow-up of 3.2 years for the whole cohort 4 yr progression free survival: 30% 4-yr overall survival: 39% Prognostic factor: International Prognostic Index Survivals were not different between patients receiving and not receiving autologous HSCT PTCL-NOS

16. Reimer et al J Clin Oncol 2009;27:106-13 Prospective multicenter study CHOP (4–6 cycles) CR and PR patients are eligible for autologous HSCT Conditioning regimen: Cy – TBI 83 patients were enrolled (PTCL-NOS: 32; AITL: 27) 55 / 83 patients (66%) received autologous HSCT progressive disease was the main reason for no HSCT Overall response rate after HSCT: 66% (56% CR and 8% PR). Median follow-up time of 33 months, 43 patients were alive 3-year overall survival for CR patients: 48% 3-year overall survival for HSCT patients: 71% 3-year overall survival for non-HSCT patients: 11% 1.Substantial impact on outcome for upfront autologous HSCT 2.Treatment needs to be improved so that more patients can receive HSCT PTCL-NOS, AITL

17. Reimer P et al. JCO 2009;27:106-113

18. Sieniawski et al Blood 2010;115:3664-3670 26 patients EATL 5-year PFS: 52% 5-year OS: 60% Significantly better than conventional CHOP treatment alone

19. Rodriguez et al Ann Oncol 2007;18:652-7 Retrospective analysis of T-cell lymphoma transplanted at CR1 74 patients at a median age o f46 years. Stage III / IV: 88% B sympotms: 53% Increased LDH: 52% IPI (2–3 risk factors): 65% PIT (> 2 risk factors): 14% Median follow-up of 67 months 5-year overall survival (OS): 68% 5-year progression free survival (PFS): 63%. Significant risk factor for OS and PFS on multivariate analysis PIT > 2 risk factors 1.High risk patients benefited from autologous HSCT 2.Patients with unfavorable PIT scores did not appear to benefit from autologous HSCT, and might be considered for other innovative therapies T-cell lymphoma

20. Numata et al Bone Marrow Tranplant 2010;45:311-316 Retrospective analysis 39 patients with T-cell lymphoma AITL: 11 ALCL: 9 NK/T: 7 PTCL-NOS: 12 Condition at HSCT: CR: 17; Non-CR: 12 Median follow up of 78 months 5-year OS: 62.1% CR patients - 5-year OS: 71.4% Non-CR patients - 5-year OS: 27.3% P=0.046 T-cell lymphoma

21. Chen et al Biol Blood Marrow Transplant 2006;14:741-7 Retrospective review 55 patients ALCL: 18; PTCL-NOS: 17; AITL:9; NK/T: 7; Hepatosplenic: 2; ATLL: 1 CR1 / PR1: 15 CR2 / PR2+: 32 Primary refractory: 11 Median follow up: 5 years (range: 1.0 – 11.5 years) 5-year progression free survival (PFS): 25% 5-year overall survival: 48% CR1/PR1CR2/PR2+Refractory 5-yr PFS51%12%0% 5-yr OS76%40%30% T-cell lymphoma

22. Conclusions 1. Autologous HSCT improves outcome of patients with T-cell lymphomas 2. The improvement, however, is seen mainly in patients who attain a complete remission, or who have chemotherapy sensitive disease in an up-front setting 3. The challenge therefore is to get the majority of patients with T-cell lymphoma into a remission with optimal chemotherapy 4. Patients with PIT of 2 or more risk factors do not appear to benefit, and may be considered candidates for experimental therapy

23. Allogeneic HSCT

24. Kyriakou et al J Clin Oncol 2009;27:3951-8 EBMT 45 patients undergoing allogeneic HSCT Median age 48 years (range, 23 to 68 years) Risk categories 34 patients had received ≥ 2 chemotherapies 11 patients had failed a previous autologous HSCT Myeloablative conditioning: 25 Reduced intensity conditioning: 20 Sibling donors: 26 None-sibling donors: 19 Chemotherapy-sensitive disease: 27 Chemotherapy-refractory: 18 Non-relapse mortality (NRM): 18% (3m), 22% (6m), and 25% (12m) NRM significantly correlated with poor performance status Relapse rate: 16% (2 yr), 20% (3 yr) Progressive free surival: 62% (1 yr), 53% (3 yr) Overall survival: 66% (1 yr) and 64% (3 yr) AITL

25. Molina et al J Clin Oncol 2005;23:6163-71 8 patients Failed a median of 7 (5 – 12) regimens Marrow involvement confirmed by TCR rearrangement: 6 patients Conditioning: Cy-TBI (N=3); BuCy (N=1); Flud/Mel (N=4) Sibling donor (N=4); MUD (N=4) CR: 8/8 (100%) TRM: 2/8 (25%) (GVHD and RSV pneumonia) Median follow up of 56 months 6 patients were alive and without evidence of lymphoma Allogeneic HSCT may induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma refractory to standard therapies Mycosis fungoides and Sezary syndrome

26. Duarte et al J Clin Oncol 2010;28:4492-9 EBMT 60 patients (men: 37, women: 23) Median age: 46.5 years (range 22 – 66 years) MF (n = 36); SS (n = 24) Risk categories 44 had TMN stage IV disease 40 patients had advanced disease Sibling donor (N=45); MUD (N=15) Myeloablative: 16; Reduced intensity conditioning: 44 T cell depletion: 25 Overall survival: 66% (1 yr) and 54% (3 yr) RIC gave higher OS (RIC decreased NRM, without increaseing relapse) Advanced-phase disease gave lower PFS and OS (by increasing relapses) Sibling better than MUD for PFS and OS T-cell depletion increased relapses DLI might be effective in relapses Mycosis fungoides and Sezary syndrome

27. Jacobsen et al Ann Oncol 2011;22:1608-13 Retrospective analysis 52 patients Median age: 46 (24 – 72) years Myeloablative: 31, Reduced intensity conditioning: 21 Nodal (AITL, PTCL-NOS, ALCL): 31 Extranodal (NK/T, EATL, HSTCL, SPTCL, MF): 21 Median follow-up of 49 months Non-relapse mortality: 27% (3 yr) Relapse: 43% (3 yr) 3-year progression-free survival was 30% 3-yr PFS: 45% for nodal 3-yr PFS: 6% for extranodal Overall survival: 41% (3 year) Allogeneic HSCT can produce long-term remissions in nodal T-cel;l lymphomas T-cell lymphomas

28. Conclusions 1. Allogeneic HSCT improves outcome of patients with nodal T-cell lymphomas 2. Non relapse mortality is increased in patients with poor performance status 3.In CTCL, HSCT from a sibling donor with reduced intensity conditioning and performed early in the disease cause leads to the best outcome 4.Efforts should continue for the definition of an optimal primary chemotherapy

29. Novel, potent, bi-cyclic class 1 selective histone deacetylase inhibitor Approved in 2009 by US FDA for patients with cutaneous T-cell lymphoma who received at least one prior systemic therapy and in 2011 for patients with PTCL who received at least one prior therapy Approval in PTCL was primarily based on results from a phase 2, single-arm, open-label study in relapsed/refractory PTCL, GPI-06- 0002 1 29 Romidepsin

30. Romidepsin for PTCL – phase II studies

31. Phase II Trial of Romidepsin in patients with T-Cell Lymphomas Piekarz et al. Relapsed/refractory mature T-cell lymphoma Romidepsin: 14 mg/m 2 per day on days 1, 8 and 15 every 4 weeks. Primary end point: overall response rate (ORR) Secondary end points: duration of response (DOR), toxicity profile

32. Results 45 patients; median age 59 Histology: PTCL-NOS (57%) and AITL (15%) Stage IV: 72% Median number of prior chemotherapies: 2 (1 – 6) Prior HSCT: 38% ORR: 38% CR: 8 patients (18%) PR: 9 patients (20%) Overall median DoR: 8.9 months (2-27) [for CR pt – 29.7 months] Most common non-haematological adverse effects Nausea(51%); fatigue (40%) Grade III/IV Haematological toxicities Neutropenia:26%; thrombocytopenia: 15% Infections:2%

33. Phase II Study of Romidepsin in Relapsed/Refractory T- Cell Lymphomas Coiffier et al. Relapsed/refractory mature T-cell lymphoma Romidepsin: 14 mg/m 2 per day on days 1, 8 and 15 every 4 weeks. Primary end point: overall response rate (ORR) Secondary end points: duration of response (DOR), toxicity profile

34. Results 130 patients; median age 61 Histology: PTCL-NOS (53%); AITL (21%); ALK1-ve ALCL (16%) Stage III/IV: 70% Median number of prior chemotherapies: 2 (1 – 8) Prior HSCT: 16% ORR: 25% CR: 19 patients (15%) PR: 14 patients (11%) Overall median DoR: 17 months Median PFS: 4 months [18 months for CR patients] Most common non-haematological adverse effects Nausea(59%); fatigue (55%) Grade III/IV Haematological toxicities Neutropenia:18%; thrombocytopenia: 23% Infections:6%

35. Durable responses in patients with the more common subtypes of relapsed/refractory PTCL –Rate of CR/CRu similar across 3 subtypes 14% in PTCL-NOS to 19% in AITL and ALK-1 negative ALCL –Nearly half (46%) of patients experienced disease control –Median DOR of 17 months, with responses ongoing up to 34 months Thrombocytopenia (25%), neutropenia (18%), and any infection (15%) were the most common ≥ grade 3 adverse events –Only infections, thrombocytopenia, dyspnea, and fatigue led treatment discontinuations in >1 patient. Conclusions FDA approval of Romidepsin in R/R T-cell lymphoma

36. Pralatrexate (RS)-10-propargyl-10-deazamminopterin Anti-folate Similar structure to methotrexate Improved intracellular transport via reduced folate carrier Undergo greater polyglutamation, hence increased intracelluar half-life of pralatrexate

38. Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: PROPEL Study O’Connor et al. Relapsed/refractory mature T-cell lymphoma Pralatrexate: 30 mg/m 2 per week for 6 weeks in 7-week cycle Primary end point: overall response rate (ORR) Secondary end points: duration of response (DOR), toxicity profile

39. Results 111 patients; median age 58 Histology: PTCL-NOS (53%); ALK1-ve ALCL (15%); AITL (12%); transformed MF (11%) Median number of prior chemotherapies: 3 (1 – 12) Prior HSCT: 16% ORR: 29% CR: 12 patients (11%) PR: 20 patients (18%) Overall median DoR: 10.1 months Median PFS: 3.5 months Median OS: 14.5 months Most common non-haematological adverse effects Mucositis(71%, Gr3/4:22%); fatigue (36%); oedema(34%) Grade III/IV Haematological toxicities Neutropenia:22%; thrombocytopenia: 33% Sepsis:5%