What is the best approach to the initial therapy of PTCL? standards of treatment? Should all

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1 What is the best approach to the initial therapy of PTCL? standards of treatment? hould all Jia Ruan, M.D., Ph.D. Center for Lymphoma and Myeloma Weill Cornell Medical College New York Presbyterian Hospital 10/24/2015

2 PTCL: uncommon and heterogenous 5-10% of all NHL in Western countries Most common: PTCL-nos, angioimmunoblastic, and ALCL Higher incidence, 15-20% of all lymphomas, in Asia Most common: PTCL-nos, NK/TCL, and ATLL J Clin Oncol 2008;26:

3 PTCL: outcome varies by subtypes and IPI 5-yr O Diagnosis % IPI 0/1 IPI 4/5 PTCL-NO 32% 50% 11% AITL 32% 56% 25% ALCL, ALK+ 70% 90% 33% ALCL, ALK- 49% 74% 13% ATLL 14% 28% 7% NKTCL, nasal 42% 57% 0 NKTCL, extranasal 9% 17% 0 Enteropathy-type 20% 29% 14% Hepatosplenic 7% 0 0 ubcutaneous panniculitis-like 64% 60% 0 J Clin Oncol 2008;26:

4 Initial Treatment of PTCL NCCN Guidelines 2015 Clinical trial ALK+ ALCL CHOP-21 CHOEP-21 Other PTCL histologies CHOEP CHOP 14 or 21 Dose adjusted EPOCH CHOP followed by IVE or ICE HyperCVAD Consider consolidation with CT Other than ALK + ALCL, no standard of care for most.

5 PTCL: Can we do better than CHOP? ORR %, CR % Durable remissions <20-30% Adding to the CHOP backbone CHOP + alemtuzumab CHOP + denileukin diftitox CHOP + bortezomib CHOP + etoposide Alternative intensive regimens Upfront CT consolidation Novel strategies

6 DHNHL tudies: CHOP vs CHOEP Analysis of Younger Patients with Normal LDH 7 trials: DHNHL ( ) 320 patients CHOP or CHOEP 56% ALCL 21% PTCL 9% AITL 3-yr EF ALCL, ALK+ 3-yr EF Other subtypes 91.2% vs 57.1% 60.7% vs 48.3% chmitz et al., Blood 2010;116:

7 Improving on CHOP Upfront ACT for PTCL: NLG-T-01 Phase 2 study by the Nordic Lymphoma Group (NLG) N=160, 156 evaluable Induction regimen with dose dense biweekly CHOEP ORR 82%, CR 51%, transplant rate 72% 5-yr O 51%, 5-yr PF 44% D Amore et al J Clin Oncol 30:

8 U Multicenter Retrospective tudy 341 newly PTCL patients from 2000 to 2011 in 10 centers PTCL-NO (31%), ALCL (26%), AITL (23%), NK/T-cell lymphoma (7%), ATLL (6%), and other (7%) Frontline therapy CHOP-like regimens (70%) hypercvad/ma (6%) Other chemo (18%) Palliation (7%) Consolidation XRT (21%) Consolidation CT (10%, 26 auto, 7 allo) ORR 73%, CR 61% (ORR 69%, CR 58% with CHOP-like) Abramson et al, Annals of Oncology 25: , 2014

9 U Multicenter Retrospective tudy All patients Inferior survival compared to DLBCL Patients w CT CT urvival benefit disappeared in MVA adjusting to treatment response Abramson et al, Annals of Oncology 25: , 2014

10 wedish Lymphoma Registry tudy 755 newly PTCL patients from 2000 to 2009, 7.4% NHL PTCL-NO (34%), ALCL (29%), AITL (14%), EATL (9%), NK/T-cell lymphoma (4%), and other (10%) Frontline therapy (n=594, 78%) CHOP-like regimens (n=499) Other intensive chemo (n=43) Response rate 70% (n=570) CHOP: ORR 65% (n=343) CHOEP: ORR 75% (n=156) Consolidation CT AutoCT: 104 (18%) AlloCT: 5 (1%) Ellin et al, Blood :

11 wedish Lymphoma Registry tudy Multivariate urvival Analysis in 252 Patients Up to Age 70 Treated with CHOP/CHOEP AutoCT uperior O and PF 5-yr O 51%, 5-yr PF 44% PF benefit w adding etoposide in patients 60 Ellin et al, Blood :

12 Incorporating novel agents in frontline therapies in PTCL

13 Novel Agents with Indications in TCL Drugs Class Indications Pralatrexate Antifolate FDA:PTCL (2009) Romidepsin HDAC inhibitor FDA: CTCL (2009), PTCL (2011) Brentuximab vedotin Anti-CD30 ADC FDA: ALCL (2011) Belinostat HDAC inhibitor FDA: PTCL (2014) Mogamulizumab (KW-0761) Anti-CCR4 mab Japan: CCR4 ATLL (2012) Chidamide HDAC inhibitor China: PTCL (2014)

14 Antifolate: Pralatrexate Antifolate 30 mg/m2 IV push 6 weeks 109 people treated, many types of T-cell lymphoma On average 3 prior treatment regimens Cycle 1 Cycle 2 Cycle 3 Cycle 4 Weeks ORR 29%, CR 11%, median DOR 10 months Common A/E: mucositis, thrombocytopenia, and fatigue FDA approval for relapsed / refractory PTCL in 2009 O Connor et al J Clin Oncol 2011;29:

15 Phase 2 tudy of CEOP + Pralatrexate University of Nebraska / NCI: NCT Newly Diagnosed PTCL Part A: CEOP D1-5 Part B: Pralatrexate D15, D22, D29 q42d, 6 cycles A E * *: Consolidative ACT permitted per investigator discretion.

16 Phase 2 tudy of CEOP + Pralatrexate 33 evaluable patients, median age 62 years Median 4 cycles of treatment ORR 70% with CR 52% 15 patients (45%) went on to ACT A/Es included cytopenias, mucositis, sepsis 1-yr PF: 50% 2-yr PF: 34% 1-yr O: 64% 2-yr O: 64% Advani et al, AH2013 abstract 3044

17 Antibody-Drug Conjugates: Brentuximab Vedotin

18 Brentuximab Vedotin: Phase II study in salcl 58 patients with relapsed systemic ALCL Brentuximab vedotin 1.8 mg/kg IV over 30 min every 21 days Maximum 16 cycles A/E: peripheral neuropathy, neutropenia, and thrombocytopenia FDA approval for salcl in 2011 Responses Overall response rate (95% CI) 86% (75, 94) Complete remission 57% Partial remission 29% J Clin Oncol Jun 20;30(18):2190-6

19 Brentuximab Vedotin: Phase II study in CD30 + TCL NCT patients with PTCL enrolled: AITL (13) and PTCL-NO (22) Median age 64 CD30 expression ranged from 5-100% Brentuximab vedotin 1.8 mg/kg IV over 30 min every 21 days 34 evaluable: ORR 41% (8 CR, 6 PR) ubset in AITL: ORR 54% (5 CR, 2 PR), median PF 6.7 mon afety data consistent with profile of BV No correlation of response to CD30 expression level Blood2014;123:

20 Phase 1: Brentuximab Vedotin in Frontline Therapy for CD30+ PTCL I II BV 2 cycles BV + CHP 6 cycles CHOP 6 cycles A E CR PR BV 8 cycles BV 10 cycles Group I: equential Therapy, n=13 (salcl) Group II: Combination Therapy, n=26 (salcl 19, non-salcl 7) Fanale et al. J Clin Oncol 32:

21 Phase 1: Brentuximab Vedotin in Frontline Therapy for CD30+ PTCL Combination Therapy (n=26) ORR: 100%; CR 88% Median PF: NR 1-yr PF 71%;1-yr O 88% equential Therapy (n=13) ORR: 85%; CR 62% Median PF: 22.1 months 1-yr PF 77%; 1-yr O 85% Fanale et al. J Clin Oncol 32:

22 Phase 3 tudy of Brentuximab Vedotin + CHP vs CHOP ECHELON -2 tudy (NCT ) Newly Diagnosed CD30+ PTCL R A N D O M I Z E BV + CHP 6-8 cycles CHOP 6-8 cycles A E * * Consolidative ACT permitted per investigator discretion 1 o objective: PF 2 o objective: Response rates; O; safety Estimated enrollment: 450

23 Histone Deacetylase (HDAC) Inhibitors Agents Romidepsin Belinostat Drug class Class I HDACi Class I&II HDACi Dosing 14 mg/m2 IV 4h, weekly 3 of 4 wks JCO 2012;30: ACO2013, abstract 8507; ICML2013, abstract mg/m2 IV 30min, daily x 5, every 3 wks PTCL subtypes PTCL PTCL AITL Pt number ORR 25% 26% 45% CR 15% 10% 18% TTR 1.8 months 5.6 wk DOR 28 months 8.3 months 7.5 months PF 4 months N/A 5.8 months O 11.3 months N/A 9.2 months Thrombocytopenia (gr 3/4) Neutropenia (gr 3/4) Anemia (gr 3/4) 24% 20% 11% 13% 13% 10%

24 Phase Ib/II tudy of Romidepsin(Ro)-CHOP The Lymphoma Academic Research Organisation (LYARC) NCT Newly Diagnosed PTCL Ph1b N=18 Ph2 N=19 CHOP D1 Ro (8-14) mg/m² IV, D1, 8 8 cycles CHOP D1 Ro 12 mg/m² IV, D1, 8 8 cycles A E

25 Phase Ib/II tudy of Romidepsin(Ro)-CHOP afety 25 (68%) of 37 patients had AEs Common grade 3-4 A/Es: febrile neutropenia (14%), physical deterioration (14%), lung infection (11%), and vomiting (8%), neutropenia (89%), and thrombocytopenia (78%). Efficacy ORR 68%: CR 51%, PR17% 18-month PF 57%; 18-month O 76.5% Dupuis et al. Lancet Haematol 2015;2:e160

26 Phase 3 tudy of Romidepsin(Ro)-CHOP vs CHOP The Lymphoma Academic Research Organisation (LYARC) NCT Newly Diagnosed PTCL R A N D O M I Z E Ro + CHOP Ro 12 mg/m² IV, D1, 8 6 cycles CHOP 6 cycles A E 1 o objective: PF Estimated enrollment: 420

27 Phase 2 tudy of Romidepsin Maintenance Following AutoCT NCT MKCC, U Washington, Weill Cornell Newly Diagnosed PTCL CHOP-based + AutoCT A E CR1 PR1 Romidepsin Maintenance 1 o objective: 2-yr PF post-transplant 2 o objective: safety, 2-yr O Estimated enrollment: 33

28 Phase 1 Dose Finding tudy of Belinostat (Bel)-CHOP NCT Newly Diagnosed PTCL CHOP D1 Belinostat dose escalation q21d, 6 cycles A E * *: 3+3 design to assess MTD of belinostat in combination with CHOP. Estimated enrollment: 28

29 Phase I/II tudy of Romidepsin and Lenalidomide tudy Design: NCT Lenalidomide, D1-21 Romidepsin Romidepsin Romidepsin D1 D8 D15 D22 Week 1 Cycle 1 Week 2 Week 3 Week 4 Week 1 Cycle 2 Results in 21 R/R TCL patients MTD: romidepsin 14 mg/m2 and lenalidomide 25 mg Median dose: romidepsin 8 mg/m2 and lenalidomide 15 mg ORR 53% (10/19; CR 2, PR 8) Common A/E: cytopenias and fatigue Mehta-hah et al, Lugano 2015, abstract 016

30 Phase II Upfront tudy of Romidepsin and Lenalidomide NCT Newly Diagnosed PTCL Romidepsin D1, 8, 15 Lenalidomide D1-21 q28d, up to 1 year A E * *: 1 o objective: efficacy 2 o objective: safety; delay to cytotoxic chemotherapy Estimated enrollment: 35

31 Potential Molecular Therapeutic Insights CCR2014;20:

32 ummary Management for T-cell lymphoma is challenging Rare incidence and heterogenous biology tandard of care should be clinical trial when possible CHOP is inadequate as initial therapy for most Addition of etoposide and consolidation CT for fit patients Novel agents alone / in combination are promising HD consolidation vs maintenance strategies Concerted efforts in research to improve diagnostic precision and identify diseasespecific therapeutic targets.

33 Thank you! Center for Lymphoma and Myeloma Meyer Cancer Center