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Peripheral T-Cell Lymphomas: How I Manage PTCL in the Frontline Setting Owen A. O’Connor, M.D., Ph.D. owenoconnor@columbia.edu Professor of Medicine and.

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Presentation on theme: "Peripheral T-Cell Lymphomas: How I Manage PTCL in the Frontline Setting Owen A. O’Connor, M.D., Ph.D. owenoconnor@columbia.edu Professor of Medicine and."— Presentation transcript:

1 Peripheral T-Cell Lymphomas: How I Manage PTCL in the Frontline Setting
Owen A. O’Connor, M.D., Ph.D. Professor of Medicine and Experimental Therapeutics Director, Center for Lymphoid Malignancies Columbia University Medical Center – College of Physicians and Surgeons The New York Presbyterian Hospital New York, N.Y. Center for Lymphoid Malignancies

2 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
Putting The T-cell Lymphomas in Context What Are the Optimal Upfront Treatment Considerations Bridging Patients with Relapsed or Refractory Disease with Novel Drugs Conclusion 2 2

3 Most Common PTCL Subtypes
PTCL-NOS is the most common subtype Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic lymphoma are also common subtypes Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Adult T-cell leukemia/lymphoma Anaplastic large cell lymphoma, ALK+ Anaplastic large cell lymphoma, ALK- Enteropathy-associated T-cell lymphoma Primary cutaneous anaplastic large cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Unclassifiable peripheral T-cell lymphoma Other disorders A survey of 1,314 PTCL and NKTCL cases from 22 sites around the world evaluated the histopathology of previously untreated patients consecutively diagnosed between 1990 and PTCL-NOS was the most common subtype at 25.9%.1 Anaplastic large cell lymphoma (ALCL) ALK+/-, angioimmunoblastic lymphoma, adult t-cell leukemia/lymphoma and natural killer/t-cell lymphoma were also common subtypes.1 Reference: 1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130. Source: Adapted from Armitage J, et al. J Clin Oncol. 2008;26:p4125. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. 1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130. 3 3

4 Classification of Peripheral T-cell Lymphoma (PTCL)
PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomas1 PTCL does not refer to anatomic sites, but rather to the involvement of more mature (post-thymic) T cells vs pre-thymic or immature T cells1 Non-Hodgkins Lymphoma B-cell Neoplasms T-/NK-cell Neoplasms NHL Neoplasm Grouping Precursor Lymphoid Neoplasms Mature T-/NK-cell Neoplasms Cutaneous Extranodal Nodal Leukemic PTCL refers to a heterogeneous group of aggressive T- and NK-cell lymphomas, characterized by the involvement of mature (post-thymic) T or NK cells. The term “peripheral” in PTCL does not refer to anatomic sites. T- and NK-cell lymphomas may be characterized as cutaneous, nodal, extranodal, or leukemic disseminated. References: 1. Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. 2. Adapted from Rodriguez J, et al. Crit Rev Oncol Hematol 3. Adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues T-Lymphoblastic Leukemia/Lymphoma Mycosis Fungoides (MF) NK/TCL Nasal Type Peripheral TCL-NOS Adult T-cell Leukemia/ Lymphoma Transformed MF Enteropathy- associated TCL Anaplastic Large Cell Lymphoma (ALK +/-) Aggressive NK-Cell Leukemia 2008 WHO Classification of Major Subtypes2,3 Sézary Syndrome Hepatosplenic TCL Angioimmunoblastic TCL T-cell Prolymphocytic Leukemia Primary Cutaneous CD30+ T-cell Disorders Subcutaneous Panniculitis-like TCL T-cell Large Granular Lymphocytic Leukemia Primary Cutaneous Gamma/Delta TCL Aggressive 1. Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. 2. Adapted from Rodriguez J, et al. Crit Rev Oncol Hematol 3. Adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4 4

5 No Improvements in Survival
Source: International T-Cell Lymphoma Project. J Clin Oncol. 2008;26: and courtesy of the T-Cell Project Executive Committee, unpublished data.

6 PTCL Prognosis Most PTCL subtypes have a worse prognosis than aggressive B-cell NHL Median overall survival for most subtypes of PTCL is 1–3 years1,2 5-year overall survival is approximately 26%3 ALK+ ALCL is an exception, with a 5-year survival of 65–90%2 The majority of PTCL subtypes have poorer prognoses than aggressive B-cell NHL. For most PTCL subtypes, the course of disease is fairly aggressive with limited overall survival.1,3 ALK+ ALCL is the notable exception, with the most favorable response to treatment and a 5-year OS in the range of 65–90%.2 References: 1. Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. 2. Savage KJ. Blood Rev. 2007;21:201–216. 3. Rüdiger T, et al. Ann Oncol. 2002;13:140–149. Armitage JO, et al. Towards understanding the peripheral T-cell lymphomas. Ann Oncol. 2004;15:1447–1449. by permission of Oxford University Press. 1. Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. 2. Savage KJ. Blood Rev. 2007;21:201–216. 3. Rüdiger T, et al. Ann Oncol. 2002;13:140–149. 6

7 NCCN- 2011 PTCL PRACTICE GUIDELINES FIRST LINE THERAPY
Clinical Trial Preferred CHOP appropriate for ALCL alk+ CHOEP, CHOP followed by ICE, CHOP followed by IVE HyperCVAD FIRST-LINE Consolidation All patients, except low risk IPI consider consolidation with high dose therapy and stem cell rescue (ALCL ALK Positive is a subtype with good prognosis and dose not need consolidative transplant if in remission NCCN Practice Guidelines in Oncology v

8 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
Putting The T-cell Lymphomas in Context What Are the Optimal Upfront Treatment Considerations Bridging Patients with Relapsed or Refractory Disease with Novel Drugs Conclusion 8 8

9 Overall Survival By Initial Treatment
PTCL-NOS Cases by Anthracycline Initial Treatment 1.0 0.9 0.8 0.7 0.6 0.5 Proportion 0.4 Test: p=0.14 0.3 0.2 0.1 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Anthracycline as part of initial tx CENSOR FAIL TOTAL MEDIAN yes 98 173 271 2.1 no 14 34 48 1.57 International T-cell Non-Hodgkin’s lymphoma Study Group, ASH 2005 9

10 Baseline with CHOP/CHOP-Like Therapy: PTCL-By IPI: Is there Favorable Risk Disease?
1.0 0.8 0, 1 (n = 36) 0.6 Cumulative Survival CR: 64% PFS: 24% 0.4 2, 3 (n = 54) BCCA, BC Cancer Agency; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; IPI, International Prognostic Index; OS, overall survival; PFS, progression-free survival; PTCL-U, peripheral T-cell lymphoma unconfirmed. There are Vancouver data showing patient long‑term results with CHOP treatment. What the graph demonstrates is that with CHOP or CHOP‑like therapy, approximately 64% of patients had a complete response, but in the long‑term only 24% of patients were progression free, and many of those patients came from the low‑risk group comprising patients with 0-1 risk factors. 0.2 4, 5 (n = 27) 2 4 6 8 10 12 14 16 OS (Yrs) Courtesy British Columbia Cancer Agency

11 Are Etoposide Containing Regimens Better?
Breakdown by Subtype of T-Cell Lymphoma PTCL subtype N pts ALCL alk+ 78 ALCL alk- 113 PTCL-NOS 70 AITL 28 Other 31 Total 320 Blood 2010;116:

12 Collective T-Cell Lymphoma Experience
Overall Survival as Function of Histological Subtypes (n=295) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Proportion 10 20 30 40 50 60 70 80 90 100 110 Months 3-years OS-rate: ALK+: 88.8% (95% CI: 80.8%-96.8%) ALK-: 63.3% (95% CI: 53.9%-72.7%) PTCL: 52.9% (95% CI: 40.2%-65.6%) AILT: 65.9% (95% CI: 47.7%-84.1%) T/NK: 48.9% (95% CI: 25.4%-72.4%) p-values 1 < < <0.001 1: ALK+ (n= 73) 2: ALK- (n= 108) 3: PTCL (n= 68) 4: AILT (n= 28) 5: T/NK (n= 18) Schmitz et al., Blood 2010;116(18):3418

13 Event Free Survival of 320 Patients with T-cell Lymphoma
According to Histologic Subtype Event Free Survivial % 10 20 30 40 50 60 70 80 90 100 Months 110 ALCL/ALK+ (n=78) ALCL/ALK- (n=113) PTCLU (n=70) AITL (n=28) Other (n=31) Schmitz et al., Blood 2010;116(18):3418

14 GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
Patients with other major subtypes (Patients with ALK+ or ALCL exlcuded) 100 90 80 70 60 Etoposide (n=69) % 50 40 non Etoposide (n=29) 30 20 p=0.057 10 10 20 30 40 50 60 70 80 90 100 110 Months EFS of younger patients (18-60 years, LDH<=UNV) treated on the NHL-B1 or Hi-CHOEP Phase II/III trials Schmitz et al., Blood 2010;116(18):3418

15 NLG-T-01: 2001-2007 Design and schedule CR, PR SD,PD CR, PR SD,PD
Nordic PTCL project NLG-T-01: Design and schedule Excluded: Alk pos ALCL T/0 CTCL Leukemic T-NHL CHOEP-14d x 3 CR, PR SD,PD CHOEP-14d x 3 (stem cell collection) CR, PR SD,PD Prompted by the activity in the NLG mantle cell group starting a program to analyze the impact of upfront ASCT in MCL, the first reports from the German bi-weekly CHOP/CHOEP regimens and litterature data pointing at a prognostic relevance of alk.fusion protein expression, we decided to launch a PTCL-specific phase II study testing a dose-intensified induction schedule (CHOEP-14) followed by ASCT with BEAM as conditioning regimen. Alk+ positive ALCL, primary cutaneous and primary leukemic cases were excluded. HDT (BEAM) Follow-up d’Amore et al EHA 2009: abs.#53 15

16 NLG-T-01 Intention-to-treat Population Only 50% of patients in CR 3
months post ASCT Higher fraction than expected made it to ASCT d’Amore et al EHA 2009: abs.#53

17 NLG Study: Autologous BMT in First Remission (Median F/U: 45 Mos)
PTCL-NOS AILT ALCL, ALK- EATL PTCL-NOS AILT ALCL, ALK- EATL 10 10 80 80 60 60 OS (%) PFS (%) 40 40 20 20 Log-rank test P = .21 Log-rank test P = .26 12 24 36 48 60 72 12 24 36 48 60 72 Mos Mos AIL, angioimmunoblastic lymphoma; ALCL, anaplastic large cell lylmphoma; BMT, bone marrow transplantation; F/U, follow-up; OS, overall survival; PFS, progression-free survival; PTCL-NOS, peripheral T-cell lymphoma unspecified. Subtype, % OS PFS 3 Yrs 5 Yrs PTCL-U (n = 62) 51 47 43 38 AILT (n = 30) 57 52 54 49 ALCL, ALK- (n = 31) 77 70 64 61 Enteropathy (n = 21) 48 d’Amore F, et al. European Hematology Association Abstract 53. d’Amore F, et al. J Clin Oncol. 2012;30:

18 Collection of stem cells
Autologous Stem Cell Transplantation (AutoSCT) as First-Line Therapy in Peripheral T-Cell Lymphomas (PTCL): Results of a Prospective Multicenter Study Study Design Collection of stem cells PTCL DexaBEAM / ESHAP DexaBEAM / ESHAP AutoSCT Cyc 120mg / kg + TBI CHOP-21 CHOP-21 CHOP-21 CHOP-21 CHOP-21 CHOP-21 PR/CR PR/CR PR/CR Reimer et al., 2009

19 Autologous Stem Cell Transplantation (AutoSCT) as First-Line Therapy in Peripheral T-Cell Lymphomas (PTCL): Outcome n= 83 N = 24 progressive disease N = 2 patient request N = 2 other PTCL n= 28 n= 55 No autoSCT AutoSCT Overall survival curve for all pts enrolled is shown on this slide with a median follow-up of 12 months Due to this the data has to be regarded with caution n= 3 n= 2 n= 23 n= 32 n= 6 n= 17 Complete Remission Alive with Disease Complete Remission Alive with Disease Dead Dead Reimer et al., 2009, JCO 27(1):

20 German Prospective Study: OS After ASCT in First Remission
PleXus Communications German Prospective Study: OS After ASCT in First Remission 4/14/2017 Nontransplanted patients did poorly N = 83 CHOP x 4-6 If ≥ PR, dexaBEAM or ESHAP dexaBEAM or ESHAP ± TBI Median follow-up: 33 mos 1.0 Transplanted (n = 55) 0.8 0.6 Proportion Achieving OS 0.4 Nontransplanted (n = 28) 0.2 P < .001 Poor-risk patients did poorly 1.0 12 24 36 48 60 ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; dexaBEAM, dexamethasone, carmustine, melphalan, etoposide, cytarabine; ESHAP, etoposide, methylprednisone, cytarabine, cisplatin; OS, overall survival; PIT, Prognostic Index for PTCL; PR, partial response; TBI, total body irradiation. Mos 0.8 PIT group 1 (n = 25) PIT group 2 (n = 34) PIT group 1: 0 risk factors PIT group 2: 1 risk factor PIT group 3: 2 risk factors PIT group 4: 3-4 risk factors 0.6 Proportion Achieving OS 0.4 PIT group 4 (n = 3) 0.2 PIT group 3 (n = 21) P = .0414 12 24 36 48 60 Reimer P, et al. J Clin Oncol. 2009;27: Mos

21 + DexaBEAM (mobilizing)
ASCT 1st line in PTCL OS + PFS in the two largest PTCL-restricted ASCT trials NLG-T = Etoposide in Induction vs Reimer = No Etoposide in Induction OS NLG-T-01 (EHA 09) Reimer et al (JCO 09) 3-yrs 57% 48% 5-yrs 50% 40% PFS NLG-T-01 (EHA 09) Reimer et al (JCO 09) 3-yrs 49% 36% 5-yrs 43% n.d. Differences in treatment schedule Induction Conditioning regimen Nordic trial CHOEP-14 x6 BEAM German trial CHOP-21 x4-6 + DexaBEAM (mobilizing) HdCy+TBI

22 Autologous Stem Cell Transplant in First Remission – Prospective Data
Study Author (Yr) n Regimen Transplanted, % Outcomes, % Corradini (2006) 62 Mitoxantrone/ melphalan or BEAM 73 12-yr EFS: 30 12-yr OS: 34 Rodriguez (2007) 26 MegaCHOP ± IFE 3-yr PFS: 56 3-yr OS: 84 Mercadal (2008) 41 High-dose CHOP/ESHAP 4-yr PFS: 30 4-yr OS: 39 Reimer (2009) 83 dexaBEAM or ESHAP ± TBI 66 3-yr PFS: 36 3-yr OS: 48 d’Amore (2011) 160 CHO(E)P-14 x 6 ± BEAM/BEAC 71 5-yr OS: 51 5-yr PFS: 44 BEAC, carmustine, etoposide, cytarabine, cyclophosphamide; BEAM, carmustine, etoposide, cytarabine, melphalan; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CHO(E)P, cyclophosphamide, doxorubicin, vincristine, prednisone, with or without etoposide; dexaBEAM, dexamethasone, carmustine, etoposide, cytarabine, melphalan; EFS, event-free survival; ESHAP, etoposide, methylprednisone, high-dose cytarabine, cisplatin; IFE, ifosfamide, etoposide; NCCN, National Comprehensive Cancer Network; OS, overall survival; PFS, progression-free survival; TBI, total body irradiation. Corrandini P, et al. Leukemia. 2006;20: Rodriguez J, et al. Eur J Haematol. 2007;79:32-38. Mercadal S, et al. Ann Oncol. 2008;19: Reimer P, et al. J Clin Oncol. 2009;27: d’Amore F, et al. ASH Abstract 331.

23 ICE and Planned ASCT for Relapsed/Refractory T-cell Lymphoma: PFS from ICE
12 24 36 48 60 72 84 96 108 120 132 PFS ICE months 0.0 0.2 0.4 0.6 0.8 1.0 % Progress Free Survival 12 24 36 48 60 72 84 96 108 120 132 PFS ICE months 0.0 0.2 0.4 0.6 0.8 1.0 % PFS: Relapsed versus Refractory ALL, N=40 Rel, N=22 Ref, N=18 Response to ICE 70% (28/40) Received ASCT 68% (27/40) PTCL is Not DLBCL Horwitz et al, ASH 2005

24 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
Putting The T-cell Lymphomas in Context What Are the Optimal Upfront Treatment Considerations Bridging Patients with Relapsed or Refractory Disease with Novel Drugs Conclusion 24 24

25 PROPEL Summary of Response 70% of responders did so in Cycle 1
Central Review (N=109) Investigator Assessment n Percent Best Response CR+CRu+PR 32 29% 43 39% CR 11 10% 17 16% CRu 1 1% 3 3% PR 20 18% 23 21% SD 21 19% 22 PD 40 37% UE 2 2% 0% ND: off-treatment in Cycle 1 14 13% 5 5% O. A. O’Connor et al., JCO, 2011; 29(9):

26 Case Matching Procedures Using 4 Databases From 3 Continents
Historical control N Pralatrexate N 868 - 390 109 280 75 92 66 Very Closely Matched Patients Populations MSK UNMC GELA SMC Total Timeframe N Patients with:  Relapsed/refractory PTCL  Appropriate histology  No pralatrexate Matched by: (1) Histology (2) No. therapies (3) Age ranges (4) Gender Medical review 1:1 match MSK UNMC GELA SMC Courtesy Charlie Morris

27 Significant Improvement in OS versus Matched Controls
Hazard Ration = (95% CI: 0.259, 0.600) Pralatrexate Matched Controls Courtesy Charlie Morris

28 PROPEL: As 2nd line therapy after CHOP failure
15/109 had previously received CHOP as their first-line therapy 11/15 had a prior response to CHOP (7 CR, 4 PR) 2/15 remained on treatment at the time of data cut-off (12.9 and 18.5 months) 2 patients proceeded to SCT after response to pralatrexate (censored at 2.3 and 3.3 months) Remain in CR and disease free at publication (20.1 and 21.7 months) Shustov, et al, Blood (ASH Annual Meeting Abstracts) : Abstract 4882

29 Central Review Assessment (n=15), % Investigator Assessment (n=15), %
PROPEL: Summary of Efficacy as Second-line Treatment Following CHOP Failure Efficacy Assessments Central Review Assessment (n=15), % Investigator Assessment (n=15), % Tumour Response ORR (CR+CRu+PR) 7 (47) 6 (40) CR 3 (20) 4 (27) CRu 0 (0) 1 (7) PR SD PD 4(27) Not Evaluable Median DoR ND* 12.5 mths Median by PFS** 8.1 mths 7.4 mths Median OS *ND- not determined, as there were insufficient events at the time of last follow-up; **per a Kaplan-Meier estimate CR=complete response; CRu=complete response unconfirmed; PR=partial response; SD=stable disease; PD=progressive disease; DoR=duration of response; PFS=progression-free survival; OS=overall survival. Shustov, et al, Blood (ASH Annual Meeting Abstracts) : Abstract 4882

30 Committee Analysis (n = 130)
Single-Agent Romidepsin in Relapsed Peripheral T-Cell Lymphoma: Efficacy Response Independent Review Committee Analysis (n = 130) Overall Response Rate 34 (26%) Complete response 10 (8%) Unconfirmed complete response 7 (5%) Duration of Response Median (Range) Overall 12 (< ) months Complete response/unconfirmed complete response Not reached (< ) months) Responses reported in PTCL (not otherwise specified) (29%), angioimmunoblastic TCL (33%), and ALK1– ALCL (24%) Similar response rates in patient subgroups according to number of prior therapies (< 3 vs. ≥ 3), prior SCT (yes vs. no), and refractory to most recent therapy (yes vs. no) Coiffier et al. JCO, 2012; Jan. 23 (epub ahead of print)

31 International PTCL Study
Subtype (n) CD30 Expression (%) 0-5% 6-49% 50-80% >80% PTCL-NOS (168) 54 32 7 AITL (167) 55 42 2 1 EATL (27) 74 11 4 ATLL (120) 50 37 8 5 Nasal NK/T (73) 53 34 6 Extranasal NK/T (30) 27 23 Courtesy Dennis Weisberger, University of Nebraska

32 Reduced-Intensity Allogeneic BMT in Relapsed PTCL: Retrospective Data
PleXus Communications Reduced-Intensity Allogeneic BMT in Relapsed PTCL: Retrospective Data 4/14/2017 100 PTCL-NOS AILD ALCL Others OS PFS 100 75 50% 75 Survival (%) 50 OS (%) 50 25 40% 25 P = NS 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 Yrs After Transplantation Yrs After Transplantation 100 Sensitive Refractory 100 ≤ 2 previous regimens > 2 previous regimens 75 75 51% 54% PFS (%) 50 PFS (%) 50 AILD, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; BMT, bone marrow transplantation; DLI, donor lymphocyte infusion; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified. 25 16% 8% 25 P < .0001 P < .0026 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 Yrs After Transplantation Yrs After Transplantation 52 patients; 12 had DLI for relapse Chemosensitive patients (n = 39) did better Patients who had > 2 previous regimens (n = 13) had inferior outcomes Dodero A, et al. Leukemia. 2012;26:

33 An Algorithm for the Management of PTCL-NOS Upfront
Confirm Hematopathology : CD30, CD52 Expression Baseline CT/PET and Bone Marrow Biopsy, full skin exam with punch biopsy of suspicious lesions; HLA Typing, viral studies including HTLV-1, HIV Combination Chemotherapy: EPOCH / CHOEP x 6 – 8 cycles Complete Remission Partial Remission or Worse Complete Remission Autologous Stem Cell Transplant Pralatrexate Romidepsin Brentuximab Gemcitabine Relapse Partial Remission or Worse Consider Allogeneic Stem Cell Transplant Palliative Care 33 33

34 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
CHOP clearly inferior, but is a regulatory standard. Integrating etoposide may provide advantage? Caution removal of doxorubicin based upon the T-cell Lymphoma Project Consolidation with ASCT probably beneficial, and more so then in the relapsed or refractory setting Allogeneic stem cell transplant should be considered in eligible patients with R/R disease USE NEWER FDA APPROVED DRUGS earlier in the natural history of the disease. Many new studies emerging as CHOP additions (Pralatrexate, Romidepsin, Brentuximab vedotin, Belinostat)

35 THANK YOU

36 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
Putting The T-cell Lymphomas in Context Defining ‘Standards of Care’ for Upfront Treatment (won’t take long) Newly Emerging Options for Advanced (R/R) Disease: Is combination the right way to go? - Pralatrexate in Relapsed/Refractory PTCL - Targeting the Epigenome in PTCL - Targeting CD30+ T-cell Malignancies Conclusion 36 36

37 13_Disease_Background_(DB)
4/14/ :25 PM NCCN Guidelines for Relapsed or Refractory PTCLsa Clinical Trial is Recommended First! Relapsed/ refractory disease Additional therapy Response #2 Consolidation/ additional therapy Relapse #2 or greater Complete response -or- Partial response Clinical trial -or- Auto- or allo- SCT Clinical trial Clinical trial preferred -or- Second-line therapyb Candidate for high-dose therapy Clinical trial -or- Best supportive care Palliative RT Relapsed/ Refractory disease No response Clinical trial preferred -or- Second-line therapyb Palliative RT Non-candidate for high-dose therapy Clinical trial preferred for 1st and 2nd relapse; no therapies other than clinical trial described for 2nd relapse a Reproduced from NCCN Practice Guidelines in Oncology – v b See suggested regimens (TCEL-B). WORKING DRAFT

38 01_Introduction_(CI)01_Introduction_(CI)
4/14/ :25 PM 4/14/ :25 PM Mechanism of Action and Biomarker Discovery RFC-1; FPGS; DHFR; GARPH; Other? Pralatrexate >> > Methotrexate Cell membrane RFC-1 RFC-1 Extracellular Folate Pralatrexate DNA FPGS Cytosol dTMP DHF TS DHFR Pralatrexate-Glu(n) THF dUMP AMP RNA DNA 5.10- methenyl THF IMP GMP AICARFT GARFT 10- formyl THF PRPP WORKING DRAFT WORKING DRAFT DRAFTWORKING DRAFT 38 38

39 03_Efficacy-Safety_(CE)03_Efficacy-Safety_(CE)
02_Disease_Background_(CD) 4/14/ :25 PM 4/14/ :25 PM PROPEL Eligible Histologies T-/NK-cell neoplasms Mature T-/NK-cell neoplasms Precursor lymphoid neoplasms Cutaneous Extranodal Nodal Leukemic Blastic NK lymphoma Precursor T/NK neoplasms Mycosis fungoides (MF) Transformed MF Sézary Syndrome Primary cutaneous CD30+ disorders: ALCL and lymphomatoid papulosis T/NK-cell lymphoma – nasal Enteropathy-type intestinal lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis T-cell lymphoma Peripheral T/NK-cell lymphoma unspecified PTCL – unspecified Anaplastic large-cell lymphoma, primary systemic type Angioimmuno-blastic T-cell lymphoma Adult T-cell lymphoma/ leukemia (HTLV1+) T/NK-cell leukemia/ lymphoma T-cell prolymphocytic leukemia (T-PLL) T-cell large granular lymphocytic leukemia Adapted from Jaffe et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues DRAFTWORKING DRAFT WORKING DRAFT 39 39 39

40 PROPEL Number of Prior Systemic Regimens
Number of Regimens n Percent 1 23 21% 2 30 27% 3 4 14 13% ≥ 5 21 19% Median (range) 3.0 (1-12) 53% of patients had no evidence of response to the most recent line of prior therapy 25% of patients had no evidence of response to any prior therapy O. A. O’Connor et al., JCO, 2011; 29(9):

41 03_Efficacy-Safety_(CE)03_Efficacy-Safety_(CE)
Core - Efficacy (CE) 03_Efficacy-Safety_(CE)03_Efficacy-Safety_(CE) 4/14/ :25 PM 4/14/ :25 PM PROPEL Response by Key Subsets Parameter Category IWC Response Rate 95% CI Region North America Europe 27 / 85 (32%) 5 / 24 (21%) (22%, 43%) (7%, 42%) Histology PTCL NOS Anaplastic LC Angioimmunoblastic Transformed MF Other 19 / 59 (32%) 6 / 17 (35%) 1 / 13 (8%) 3 / 12 (25%) 3 / 8 (25%) (21%, 46%) (14%, 62%) (0%, 36%) (5%, 57%) (9%, 76%) Prior transplant Yes No 6 / 18 (33%) 26 / 91 (20%) (13%, 59%) (20%, 39%) OO. A. O’Connor et al., JCO, 2011; 29(9): WORKING DRAFT DRAFTWORKING DRAFT WORKING DRAFT 41

42 Response by Prior Treatment
PROPEL Response by Prior Treatment Parameter Category Response Rate 95% CI Prior systemic therapy 1 regimen 2 regimens > 2 regimens 8 / 23 (30%) 7 / 29 (24%) 17 / 57 (30%) (16%, 57%) (10%, 44%) (18%, 43%) Best Response to Any Prior Therapy CR / PR SD / PD / Unknown 25 / 83 (30%) 5 / 26 (19%) (21%, 41%) (7%, 39%) Response to Most Recent Therapy SD / PD Unknown 13 / 40 (32%) 14 / 57 (25%) 3 / 12 (25%) (19%, 49%) (14%, 38%) (5%, 57%) Prior Methotrexate Yes No 5 / 21 (24%) 25 / 88 (28%) (8%, 47%) (19%, 39%) O. A. O’Connor et al., JCO, 2011; 29(9):

43 Duration of Response by Central Review
PROPEL Duration of Response by Central Review SCT 1.00 Number of Responders = 30 Median duration = 10.1 months SCT Updated Permanently censored (eg, transplant) (n = 8) 0.75 SCT SCT Continue in follow-up for response (n=7) Proportion 0.50 Follow-up exceeds 6 months for all patients who continue in follow-up for response 0.25 3 6 9 12 15 18 Months O. A. O’Connor et al., JCO, 2011; 29(9):

44 Romidepsin Ongoing Studies in PTCL
NCI Trial (NCI 1312) Romidepsin 14 mg/m2 days 1,8,15 of a 28 day cycle O B J E C T I V Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior “chemotherapy” GPI Registration Trial Romidepsin 14 mg/m2 days 1,8,15 of a 28 day cycle O B J E C T I V Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior systemic therapy 44

45 Phase 2 Romidepsin in PTCL Response Rates
4/14/2017 Phase 2 Romidepsin in PTCL Response Rates Overall Response Rates All Pts N=48 Pts ≥ 2 cycles** N=34 ORR (CR+PR), n (%) 15 (31%) 15 (44%) CR*, n (%) 4 (8%) 4 (12%) PR, n (%) 11 (23%) 11 (32%) SD, n(%) 7 (15%) 7 (21%) File is the Piekarz 2008 ASH Poster deconstructed into slides s Piekarz et al., Blood, 2011; 117(2):

46 Phase 2 Romidepsin in PTCL Response Data
4/14/2017 Phase 2 Romidepsin in PTCL Response Data Duration of Response (DOR) &Time to Disease Progression (TTP) Median time to first response was 1.8 (1-6) months Population N* Median (range) DOR in months Median (range) TTP in months ORR (CR & PR) 15 9 (2 – 61+) 12 (4 – 63+) CR 4 34 (3 – 61+) NR (14 – 63+) PR 11 8 (2 – 41+) 10 (4 – 42+) SD 7 9 (3 – 26+) PD 19 1.4 (.2– 4) File is the Piekarz 2008 ASH Poster deconstructed into slides *7 patients were not evaluable; NR, median not yet reached; + denotes continuing response Piekarz et al., Blood, 2011; 117(2): 46

47 Phase II Trial of Romidepsin in Relapsed or Progressive Peripheral T-Cell Lymphoma Following Prior Systemic Therapy Patient population: 131 enrolled 130 with confirmed PTCL Failed ≥ 1 prior systemic therapy Treatment regimen: romidepsin 14 mg/m2, days 1, 8, and 15 q 28 days × 6 cycles; continued beyond 6 cycles in responding patients at investigator and patient discretion Primary endpoint: CR/CRu by independent review Secondary endpoints including: ORR, duration of response, TTP, tolerability, and safety Coiffier et al. JCO, 2012; Jan. 23 (epub ahead of print)

48 Peripheral T-Cell Lymphomas: How I Manage Frontline Disease
Putting The T-cell Lymphomas in Context Defining ‘Standards of Care’ for Upfront Treatment (won’t take long) Newly Emerging Options for Advanced (R/R) Disease: Is combination the right way to go? - Pralatrexate in Relapsed/Refractory PTCL - Targeting the Epigenome in PTCL - Targeting CD30+ T-cell Malignancies Conclusion 48 48

49 CD30 Expression in in Non-Lymphoma Tumors
Acute Myeloid Leukemia/Granulocytic Sarcoma M Fickers 1996, J Clin Pathol 49: 762-3; R Horie 1999, Am J of Path. 155: ALL and AML Gattei 1997, Blood 89: Bone sarcomas G Mechtersheimer 1990, Cancer 66: Lung (Adenocarcinoma) M Garcia-Prats 1998, Histopathology 32: Mastocytosis Sotlar 2010, Modern Pathology, 1-11 Mesothelioma M Garcia-Prats 1998, Histopathology 32: ; C Dunphy 2000, Arch Pathol Lab Med 124: Melanoma Internal data on file Nasopharyngeal carcinoma Kneile 2006, Histopathology 48: Testicular embryonal carcinoma J Ferreiro 1994, Hum. Pathol. 25: ; K Iczkowski 2008, Hum. Pathol. 39: Thyroid Carcinoma (Medullary, Papillary) M Trovato 2001, Thyroid 11: 621-8 Cervical, Head and Neck SCC (Viral-associated cancers), Lung, Breast, Endometrial, Ovarian,Prostate, & Melanoma Human protein atlas (http://www.proteinatlas.org/ENSG /cancer)

50 CD30 Expression in DLBCL Citation CD30+ High CD30+ Total 22% (99/449)
Stein et al., 1985 4% (2/45) 0% (0/45) Norton et al., 1987 11% (3/28) 7% (2/28) Hall et al., 1988 10% (6/60) 2% (1/60) Schwarting et al., 1989 29% (35/121) 9% (11/121)* Miettinen, 1992 38% (14/37) 11% (4/37) Noorduyn et al., 1994 40% (36/91) 23% (21/91) Eow et al., 2006 4% (3/67) 0% (0/67) Total 22% (99/449) 9% (39/449) Courtesy Dennis Weisberger, University of Nebraska

51 Anaplastic Large cell Lymphoma: A Unique Entity Among PTCL
Overall Survival After Failure of Primary Therapy2 sALCL is a CD30-positive aggressive subtype of peripheral T-cell lymphoma 4065% of patients develop recurrent disease after initial multiagent chemotherapy1 To improve OS, durable responses must be attained – few therapies available for this unmet need Median = 3.3 months N = 61 Survival Time (years) 1 Savage et al, 2008 2 Data provided by J. Connors, BC Cancer Agency

52 Brentuximab Vedotin Mechanism of Action
Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antimicrotubule agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released G2/M cell cycle arrest MMAE disrupts microtubule network Apoptosis

53 Demographics and Baseline Characteristics
Age* 52 yr (1476) Gender 33 M / 25 F ECOG status 33% 1 66% 2 2% ALCL confirmed by central pathology 97% ALK-negative 72% Refractory to frontline therapy 62% Refractory to most recent treatment 50% No response to any prior treatment 22% Prior chemotherapy regimens* 2 (16) Prior radiation 45% Prior ASCT 26% * Median (range) R. Advani, ASH Abstract 443, 2011

54 Key Response Results Summary
N=58 Objective response rate (95% CI) 86% (75, 94) Median duration of OR (95% CI) 12.6 mo (5.7, ) CR rate (95% CI) 57% (43, 70) Median duration of response in patients with CR (95% CI) 13.2 mo (10.8, ) Median PFS (95% CI) 13.3 mo (6.9, ) Median OS Not reached R. Advani, ASH Abstract 443, 2011 54

55 Maximum Tumor Reduction
Complete remission 97% of patients achieved tumor reduction Tumor Size (% Change from Baseline) Individual Patients (n=57) R. Advani, ASH Abstract 443, 2011

56 PFS by Disease Response
Time (months) % Patients Free of PD or Death * Histologically ineligible Median PFS (months) CR PR SD PD HI*  R. Advani, ASH Abstract 443, 2011

57 PFS: Brentuximab Vedotin vs. Last Prior Therapy
PFS brentuximab vedotin*; median = 14.3 months PFS last prior therapy; median = 5.9 months HR=0.48 (p=0.001) % Patients Free of PD or Death Time (months) 91% of the most recent prior therapies were multiagent chemotherapy or ASCT * Investigator-assessed R. Advani, ASH Abstract 443, 2011

58 Strategies to Improve Upfront Therapy for PTCL
CHOP based + Etoposide- CHOEP, EPOCH + Alemtuzumab + Pralatrexate + anti CD4 + anti CXC4 + lenalidomide + Brentuximab vendotin Novel combinations PEGS (cisplatin, etoposide, gemcitabine, methylprednisolone) Pralatrexate + Bortez + SAHA Pralatrexate + Romidepsin Novel targeted agents + monoclonal antibodies

59 Thank You

60 Autologous Stem Cell Transplantation (AutoSCT) as First-Line Therapy in Peripheral T-Cell Lymphomas (PTCL): Improved Overall Survival with ASCT p= 0,1799 Overall survival IPI: high / interm.high vs. low / interm.low high / interm.high (n= 42) low / interm.low (n= 41) p< 0.001 Transplanted vs. non-transplanted time (months) transplanted (n= 55) non-transplanted (n= 28) estimated 3-year OS: 71% vs. 11% Reimer et al., 2009, JCO 27(1):

61 Overall Survival By Initial Treatment
PTCL-NOS cases by Carbo/Cisplatin Initial Treatment 1.0 0.9 0.8 0.7 0.6 0.5 Proportion 0.4 Test: p=0.46 0.3 0.2 0.1 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Carbo/Cisplatin as part of initial tx CENSOR FAIL TOTAL MEDIAN yes 2 6 8 2.01 no 110 200 310 2.1 International T-cell non-Hodgkin's Lymphoma Study Group 61

62 NLG-T-01: OS + PFS (Med follow-up 45 mos)
Subtype Analysis 0.00 0.20 0.40 0.60 0.80 1.00 12 24 36 48 60 72 analysis time rhistdia = ptcl, nos rhistdia = aild rhistdia = alcl, alk neg OS : ALCL, AIL, PTCL-NOS 0.00 0.20 0.40 0.60 0.80 1.00 12 24 36 48 60 72 analysis time rhistdia = ptcl, nos rhistdia = aild rhistdia = alcl, alk neg PFS : ALCL, AIL, PTCL-NOS Another important part of our data analysis, was the subtype-specific outcome. Given the large size of this trial, there certainly is a potential of generating a more solid statement for each histological subtype in the very heterogeneous context of PTCL Here is the OS for the 3 main subtypes with ALCL showing a very favourable course with a 5 yr OS of over 70% at what seems to be a plateau level of the curve OS PFS Subtype 3-yr 5-yr PTCLu (n=62) 51% 45% 43% 34% AIL (n=30) 57% 50% 54% 47% ALCL alk-neg (n=31) 77% 73% 64% Enteropathy (n=21) 52% 44% 40% d’Amore et al EHA 2009: abs.#53 62

63 PROPEL: prior ICE 20/109 had previously received ICE-based regimen 2nd line ORR to ICE-based regimens was 25% (3 CR, 2 PR) Median duration on treatment for responders was <1 month 9/20 received an ICE-based regimen immediately before pralatrexate Of those 9, 2 did not respond to the ICE-based regimen, but did respond to pralatrexate (1 CR, 1 PR) Goy A, et al, Blood (ASH Annual Meeting Abstracts) : Abstract 1753

64 Central Review Assessment (n=20), % Investigator Assessment (n=20), %
PROPEL: prior ICE (n=20) Efficacy Assessments Central Review Assessment (n=20), % Investigator Assessment (n=20), % Tumor Response ORR (CR+PR) 8 (40) CR 5 (25) 3 (15) PR SD 2 (10) PD 6 (30) 4 (20) Not Evaluable 1 (5) Median DoR 16.2 mths 13.1 mths ORR (CR + PR): 40% CR: 25% by Investigator Assessment Median Duration of Response: months by Investigator Assessment Goy A, et al, Blood (ASH Annual Meeting Abstracts) : Abstract 1753


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