Updates in T cell Lymphoma Mary Jo Lechowicz August 2014 Disclosures - PDF document

8/6/2014 Winship Cancer Institute of Emory University Updates in T cell Lymphoma Mary Jo Lechowicz August 2014 Disclosures • Consulting fees from: – Allos, Celgene, Millennium, and Seattle Genetics 1

8/6/2014 Objectives • Update current care for patients with Peripheral T cell Non Hodgkin lymphomas (PTCL) upfront treatment • Update current care for patients with relapsed/refractory PTCL • Describe the experience and treatment of Breast Implant Associated Alk positive t cell lymphoma Fig 1. Distribution of 1,314 cases by consensus diagnosis International T ‐ Cell Lymphoma Project, J Clin Oncol; 26:4124 ‐ 4130 2008 2

8/6/2014 Upfront treatment for PTCL • No Standard of Care! • Most common approach is CHOP/CHOP like • NCCN guidelines suggest – Clinical trial – CHOP ‐ 14 or 21 – CHOP followed by IVE or ICE – CHOEP – Dose adjusted EPOCH – HyperCVAD Ongoing trials in Upfront Setting Slide by S Horwitz 2014 PanPacific Lymphoma 3

8/6/2014 A Phase II Study of Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) Alternating with Pralatrexate (P) as Front Line Therapy PTCL Ranjana H. Advani, Stephen M. Ansell, Mary J. Lechowicz, Anne W. Beaven, Fausto R. Loberiza Jr, Kenneth R. Carson, Andrew M. Evens, Francine M. Foss, Steven M. Horwitz, Barbara Pro, Lauren Pinter ‐ Brown,Sonali M. Smith, Andrei R. Shustov, Kerry J. Savage and Julie M. Vose • Preliminary Results from the T ‐ Cell Consortium Trial • ASH 2013 Adapted from Advani R et al. ASH abstract 3044. Blood. 2013;122(21 suppl) Background Peripheral T ‐ cell lymphomas (PTCL) are a heterogeneous group of non ‐ Hodgkin's lymphomas (NHL) characterized by poor treatment outcomes with conventional chemotherapy, including CHOP [complete remission (CR) ~40%]. • Retrospective studies suggest that the incorporation of etoposide into chemotherapy regimens may improve outcomes compared to CHOP. • In contrast, anthracyclines appear to have a limited role in PTCL, largely attributed to p ‐ glycoprotein related resistance. Pralatrexate was the first drug approved for patients (pts) with relapsed PTCL, providing a rationale to evaluate it in the front ‐ line setting. 4

8/6/2014 Methods • Eligible histologies included, PTCL ‐ NOS, AILT, ALCL (ALK positive pts only allowed if IPI ≥ 3). • Cycle A: CEOP ‐ Cyclophosphamide 750 mg/m2 IV d1 ‐ Etoposide 100 mg/m2 IV d1 ‐ 3 ‐ Vincristine 2 mg IV day 1 ‐ Prednisone 100 mg/day X 5 • Alternating Cycle B: Pralatrexate (P) ‐ 30 mg/m2 IV d 15, 22 and 29 (with vitamin B12 and folate supplementation) • Growth factors were used to support both cycles of therapy. 5

8/6/2014 Conclusions CR rate at end of therapy suggests the regimen is useful per study design. • Primary statistical aim of improving CR from 40 ‐ 60% not met. • Estimated 1 and 2 year PFS are 50% and 34% respectively. ‐ Age < 60 y, a low IPI score, achieving a CR and consolidation with ASCT were statistically significant for better PFS. • Estimated 1 and 2 year OS is 64%. ‐ Lack of B symptoms, low IPI score, achieving a CR and consolidation with ASCT were factors statistically significant for OS • Longer follow up is needed to assess the impact on the secondary objectives of EFS and OS with this regimen. • 15 pts received ASCT with a younger median age (59 versus 68y) than those who did not. • Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. 6

8/6/2014 Objectives • Update current care for patients with Peripheral T cell Non Hodgkin lymphomas (PTCL) upfront treatment • Update current care for patients with relapsed/refractory PTCL • Describe the experience and treatment of Breast Implant Associated Alk positive t cell lymphoma FDA approves Belinostat to treat rare, aggressive form of non ‐ Hodgkin lymphoma • The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy • July 2014 from treatment of 129 patients study • The Belief trials O’Connor OA et al. ASCO 2013;Abstract 8507 7

8/6/2014 Background  Study objective: To assess the safety and efficacy of single-agent belinostat for patients with relapsed or refractory PTCL.  Currently approved therapies for relapsed or refractory PTCL have overall response rates of 25% to 29% ( JCO 2011;29(9):1182-9; JCO 2012;30(6):631-6).  Previously, a Phase II CLN-6 trial demonstrated that belinostat monotherapy yielded an overall response rate of 25% in relapsed/refractory PTCL ( Proc ASH 2009;Abstract 920). – Belinostat was well tolerated, with the most common toxicities being Grade 1/2 gastrointestinal and constitutional side effects. O’Connor OA et al. Proc ASCO 2013;Abstract 8507. Phase II BELIEF Trial Design Eligibility (n = 129) Relapsed or refractory PTCL* ≥ 1 prior systemic therapy Belinostat Platelet counts ≥ 50,000/uL 1,000 mg/m 2 (IV), d1-5 q3wk No prior HDACi therapy No relapse within 100 days of autologous or allogeneic bone marrow transplant * Confirmed by central pathology review (CPRG) • Primary endpoint: Objective response rate (ORR) • Secondary endpoints include: Safety, time to response, progression-free and overall survival and duration of response • Exploratory analyses were conducted to determine response by PTCL subtypes O’Connor OA et al. Proc ASCO 2013;Abstract 8507. 8

8/6/2014 Response by Central Review Response rate n = 120 ORR 26% Complete response (CR) 11% Partial response (PR) 15% Stable disease 15% Progressive disease 40% Not evaluable* 19% * Prior to first radiologic assessment due to death (n = 7); clinical progression (n = 10); patient withdrawal (n = 5); lost to follow-up (n = 1) O’Connor OA et al. Proc ASCO 2013;Abstract 8507. Response Rates According to Disease Characteristics Characteristic Response rate Bone marrow involvement (n = 120) No (n = 65) 31% Yes (n = 35) 23% Indeterminate (n = 8) 25% Not assessed (n = 12) 8% Platelet counts (n = 120) ≥ 100,000/uL (n = 100) 28% <100,000/uL (n = 20) 15% O’Connor OA et al. Proc ASCO 2013;Abstract 8507. 9

8/6/2014 Response Rates by CPRG Lymphoma Diagnosis Diagnosis ORR PTCL-NOS (n = 77) 23% AITL (n = 22) 46% ALCL, ALK-negative (n = 13) 15% ALCL, ALK-positive (n = 2) 0% Enteropathy-associated TCL (n = 2) 0% Extranodal NK/TCL, nasal type (n = 2) 50% Hepatosplenic TCL (n = 2) 0% PTCL-NOS = PTCL-not otherwise specified; ALCL = angioimmunoblastic T-cell lymphoma; TCL = T-cell lymphoma O’Connor OA et al. Proc ASCO 2013;Abstract 8507. Clinical Outcomes Baseline platelet counts All patients ≥ 100,000/uL <100,000/uL Outcome (n = 120) (n = 100) (n = 20) ORR by CPRG 25.8% 28.0% 15.0% Median DoR 13.6 months 13.6 months 4.1 months Median PFS 1.6 months 1.8 months 1.3 months Median OS 7.9 months 9.2 months 4.3 months Median TTR 5.6 weeks 5.6 weeks 6.4 weeks DoR = duration of response; PFS = progression-free survival; OS = overall survival; TTR = time to response O’Connor OA et al. Proc ASCO 2013;Abstract 8507. 10

8/6/2014 Select Grade ≥ 3 Adverse Events Baseline platelet counts All patients ≥ 100,000/uL <100,000/uL Event (n = 129) (n = 105) (n = 24) Thrombocytopenia 15% 6% 54% Neutropenia 13% 10% 25% Leukopenia 13% 9% 29% Anemia 12% 8% 29% Dyspnea 6% Not reported Pneumonia 6% Not reported Febrile neutropenia 5% Not reported Fatigue 5% Not reported Hypokalemia 4% Not reported O’Connor OA et al. Proc ASCO 2013;Abstract 8507. Objectives • Update current care for patients with Peripheral T cell Non Hodgkin lymphomas (PTCL) upfront treatment • Update current care for patients with relapsed/refractory PTCL • Describe the experience and treatment of Breast Implant Associated Alk positive t cell lymphoma 11

8/6/2014 Breast Implant Associated Anaplastic Large Cell Lymphoma • First Case 1997 Keech and Creech • FDA following these cases • One lymphoma that surgical treatment alone may be indicated? 12

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8/6/2014 Conclusions • Ongoing research and monitoring needed • Most confined to fibrous capsule and have good prognosis • Proper management may be capsulectomy and implant removal • Patient presentation with a mass justifies more aggressive therapy in addition to implant removal Acknowledgements • The patients and their families • The Organizers • The Lymphoma Team at Winship Cancer Institute at Emory University • All my co-T cell lymphoma colleagues for all their guidance and support 15

8/6/2014 Questions? 16