Updates in T cell Lymphoma

Transcription

1 Winship Cancer Institute of Emory University Updates in T cell Lymphoma Mary Jo Lechowicz August 2014

2 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

3 Fig 1. Distribution of 1,314 cases by consensus diagnosis International T-Cell Lymphoma Project, J Clin Oncol; 26:

4 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

5 Ongoing trials in Upfront Setting Slide by S Horwitz 2014 PanPacific Lymphoma

6 A phase 1 multicenter clinical trial of alemtuzumab and CHOP chemotherapy for peripheral T-cell lymphomas MTD with highest trough levels would define the recommended phase II/III dose Eligibility: > age 18, untreated CD52+ PTCL, stage 2-4, measurable disease and adequate organ function Alemtuzumab was given subcutaneously in 1 of 4 schedules using a 3+3 design with CHOP chemotherapy: 1) 10 mg day 1 2) 10 mg weekly days 1, 8, 15 3) 30 mg day 1 4) 60 mg day 1 J Clin Oncol 32:5s, 2014 (suppl; abstr 8551)

7 A phase 1 multicenter clinical trial of alemtuzumab and CHOP chemotherapy for peripheral T-cell lymphomas Results: 20 pts were enrolled; histology: AILD (n=7), PTCL NOS (n=6), ALK 1 ALCL (n=3), subpanniculitic (n=2), hepatosplenic (n=1) and enteropathy associated (n=1) DLT s necessitated dose expansion of dose level 2 (fatal TB reactivation) and 4 (grade 4 thrombocytopenia). MTD was not reached Hematologic toxicities: lymphopenia (65% grade 3-4), neutropenia (55% grade 3-4) and febrile neutropenia (25%) Ten (50%) pts asymptomatic CMV reactivations at a median of 39 days (range 4-99) treated with valganciclovir and two pts developed fungal pneumonias J Clin Oncol 32:5s, 2014 (suppl; abstr 8551)

8 A phase 1 multicenter clinical trial of alemtuzumab and CHOP chemotherapy for peripheral T-cell lymphomas 18 evaluable, ORR 65% (CR/Cru (n=7), PR (n=6)) Median f/u 28m (range ), 10 pts (52%) relapsed or progressed and 4 (21%) died Median OS not reached and median PFS is 23 months. Peripheral blood CD3+ T cells declined by % from baseline and recovered in 55% of patients at a median time of 15 mos Conclusions: Weekly SC alemtuzumab 10 mg achieves trough levels comparable with 60 mg q21d when given with CHOP. J Clin Oncol 32:5s, 2014 (suppl; abstr 8551)

9 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 Blood. 2013;122(21 suppl)

10 Background PTCL are characterized by poor treatment outcomes with conventional chemotherapy, including CHOP(CR) ~40% Retrospective studies suggest incorporation of etoposide 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.

11 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.

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14 Conclusions CR rate at end of therapy suggests the regimen is useful per study design. Primary statistical aim of improving CR from 40 to 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.

15 Conclusions 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 needed to assess the impact on the secondary objectives of EFS and OS 15 pts received ASCT a younger median age (59 versus 68y) Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

16 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

17 Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma 51 pts between relapsed (n=31, 61%) or primary refractory (n=20, 39%) PTCL with the following histologic subtypes: PTCL-NOS, n=17 (33%) ALCL, n=16 (31%) [ALK-positive, n=4 (8%) ALK-negative, ALCL n=10 (20%) ALK status unknown, n=2 (4%)] AILT, n=13 (25%); NK/T cell nasal type, n=4 (8%); hepatosplenic, n=1 (2%); subcutaneous panniculitis-like, n=2 (4%). November 15, 2013; Blood: 122 (21) Abstract 4345 Parkin et al

18 Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma CHOP-like regimen in (n=48) pts and one NK/TCL received SMILE Two pts with NK/TCL received radiation alone The median time to progression or relapse after initial diagnosis was 7.4 m (range ) At relapse, median age 56 years (range 17-86) November 15, 2013; Blood: 122 (21) Abstract 4345 Parkin et al

19 Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma GDP: gemcitabine 1,000 mg/m2 days 1 and 8 dexamethasone 40 mg days 1 4 cisplatin 75 mg/m2 day 1 November 15, 2013; Blood: 122 (21) Abstract 4345 Parkin et al

20 Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma ORR for all 51 pts was 80% (CR 47%) and with a median follow-up of 10.4 m 2 y PFS was 25% and 2 y OS was 43% with no differences amongst the histologic subtypes Pts planned for transplant, the ORR was 83% (CR 58%) 2 y PFS and OS for this group intended for transplant were 30% and 50%, respectively, and those with relapsed disease (n=22) had a superior outcome to those with primary refractory disease (n=14) (2 y PFS 42.5% vs 9%, p=.0027) The 2 y post-transplant OS was 53% and no difference between relapsed and refractory pts ultimately transplanted (p=.23). November 15, 2013; Blood: 122 (21) Abstract 4345 Parkin et al

21 Gemcitabine, Dexamethasone, and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory Peripheral T-Cell Lymphoma 36 pts (71%) were planned for HDC/SCT, based on age and lack of significant comorbidities, following a response to GDP Those were more likely to be younger (< 60 y) (p=.050) with a good PS (0-1) at relapse (p=0.049) but similar sipi risk distribution (p=0.195) 26 underwent HDC/SCT (transplant rate 72%; auto, n=15; allo, n=11 [non-myeloablative n=2]) AlloSCT pts (vs autosct) were more likely to have disease refractory to primary therapy (p=.045) November 15, 2013; Blood: 122 (21) Abstract 4345 Parkin et al

22 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

23 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.

24 Phase II BELIEF Trial Design Eligibility (n = 129) Relapsed or refractory PTCL* 1 prior systemic therapy Platelet counts 50,000/uL No prior HDACi therapy No relapse within 100 days of autologous or allogeneic bone marrow transplant Belinostat 1,000 mg/m 2 (IV), d1-5 q3wk * 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.

25 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.

26 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.

27 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.

28 Clinical Outcomes Outcome All patients (n = 120) Baseline platelet counts 100,000/uL (n = 100) <100,000/uL (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.

29 Select Grade 3 Adverse Events Event All patients (n = 129) Baseline platelet counts 100,000/uL (n = 105) <100,000/uL (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.

30 46 pts over 4 yr prospectively Mixture of upfront (24) and relapsed (22)pts Included NK/T cell histologies along with PTCL histologies CHOP plus thalidomide at increasing dose every week Toxicity not significant CR 50 versus 34% in thalidomide versus control arm(p<0.05) ORR 79.2 versus 63.6 did not reach significance

31 U.S. Intergroup phase II trial (SWOG 1108) of alisertib, an investigational aurora A kinase (AAK) inhibitor, in patients with peripheral T-cell lymphoma AAK is a serine/threonine kinase that regulates the G2-M transition and centrosome separation during mitosis Pts received alisertib 50mg BID for 7d on 21d cycles 42 pts accrued, 37 eligible pts had a median age of 62 (range 22-86) Median of 3 (range 1-18) prior therapies, 3 pts had undergone a prior stem cell transplant and 20 were refractory to prior therapy. J Clin Oncol 32:5s, 2014 (suppl; abstr 8523)

32 U.S. Intergroup phase II trial (SWOG 1108) of alisertib, an investigational aurora A kinase (AAK) inhibitor, in patients with peripheral T-cell lymphoma Grade 3 and 4 AEs in 5% of pts included neutropenia (30%), anemia (27%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%) and rash (5%) 6 pts d/c therapy and 9 were dose reduced due to AEs Treatment was discontinued most commonly for PTCL progression 2 CRs and 7 PRs with ORR of 24% (95%CI: 12-41%) Among the most common subtypes, (PTCL NOS, AITL and ALCL), the ORR was 33% (95%CI: 16-55%) International randomized Phase III trial is ongoing J Clin Oncol 32:5s, 2014 (suppl; abstr 8523)

33 Current Trials in Relapsed Setting Lenalidomide, Vorinostat and Dexamethasone Bortezomib and Panobinostat (completed) Romidepsin Plus ICE Gemcitabine Plus Romidepsin (GEMRO Regimen) Lenalidomide (Revlimid) and Romidepsin (Istodax) Pralatrexate + Romidepsin Alisertib in Combination With Vorinostat Peg-L-Asparaganase + Dexamethasone Alisertib (MLN8237) vs. Investigator's Choice Brentuximab Vedotin Phase 1 Study of SP-02L (Darinaparsin) Ipilimumab Ruxolitinib Phosphate (Oral JAK Inhibitor INCB18424) Carfilzomib Open currently at Emory

34 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

35 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?

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39 Therapy Chosen

40 Thirty-nine (93%) of 42 pts with disease confined by the fibrous capsule achieved complete remission Pts with tumor mass presentation with CR in 13 (72%) of 18 pts Pts with breast mass worse OS and PFS P = and P =0.03, respectively OS or PFS were similar between pts who received and did not receive chemotherapy (P= 0.44 and P =0.28, respectively).

41 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

42 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

43 Questions?