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P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE PTCL IN THE F RONTLINE S ETTING Professor of Medicine and Experimental Therapeutics Director, Center for.

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Presentation on theme: "P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE PTCL IN THE F RONTLINE S ETTING Professor of Medicine and Experimental Therapeutics Director, Center for."— Presentation transcript:

1 P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE PTCL IN THE F RONTLINE S ETTING 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. Owen A. O’Connor, M.D., Ph.D. Center for Lymphoid Malignancies

2 P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE F RONTLINE D ISEASE  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

3 M OST C OMMON PTCL S UBTYPES  PTCL-NOS is the most common subtype  Anaplastic large cell lymphoma (ALCL) ALK +/- and angioimmunoblastic lymphoma are also common subtypes 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. 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

4 C LASSIFICATION OF P ERIPHERAL T- CELL L YMPHOMA (PTCL)  PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomas 1 –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 cells 1 1. Armitage JO, et al. Ann Oncol. 2004;15:1447 – Adapted from Rodriguez J, et al. Crit Rev Oncol Hematol Adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Non-Hodgkins Lymphoma Precursor Lymphoid Neoplasms T-Lymphoblastic Leukemia/Lymphoma Cutaneous Primary Cutaneous CD30+ T-cell Disorders Mycosis Fungoides (MF) T-/NK-cell Neoplasms B-cell Neoplasms Extranodal NK/TCL Nasal Type Adult T-cell Leukemia/ Lymphoma T-cell Large Granular Lymphocytic Leukemia Subcutaneous Panniculitis-like TCL Leukemic Enteropathy- associated TCL Hepatosplenic TCL Aggressive NK-Cell Leukemia T-cell Prolymphocytic Leukemia Transformed MF Mature T-/NK-cell Neoplasms Primary Cutaneous Gamma/Delta TCL S é zary Syndrome Peripheral TCL-NOS Nodal Angioimmunoblastic TCL Anaplastic Large Cell Lymphoma (ALK +/-) 2008 WHO Classification of Major Subtypes 2,3 NHL Neoplasm Grouping Aggressive

5 N O I MPROVEMENTS IN S URVIVAL Source: International T-Cell Lymphoma Project. J Clin Oncol. 2008;26: and courtesy of the T-Cell Project Executive Committee, unpublished data.

6 PTCL P ROGNOSIS  Most PTCL subtypes have a worse prognosis than aggressive B-cell NHL – Median overall survival for most subtypes of PTCL is 1–3 years 1,2 – 5-year overall survival is approximately 26% 3 – ALK+ ALCL is an exception, with a 5-year survival of 65–90% 2 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– Savage KJ. Blood Rev. 2007;21:201– Rüdiger T, et al. Ann Oncol. 2002;13:140–149.

7 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 NCCN PTCL PRACTICE GUIDELINES FIRST LINE THERAPY

8 P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE F RONTLINE D ISEASE  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

9 Time Proportion Anthracycline as part of initial txCENSORFAILTOTALMEDIAN yes no Test: p= PTCL-NOS Cases by Anthracycline Initial Treatment International T-cell Non-Hodgkin’s lymphoma Study Group, ASH 2005 O VERALL S URVIVAL B Y I NITIAL T REATMENT

10 Baseline with CHOP/CHOP-Like Therapy: PTCL-By IPI: Is there Favorable Risk Disease? OS (Yrs) Cumulative Survival CR: 64% PFS: 24% 0, 1 (n = 36) 2, 3 (n = 54) 4, 5 (n = 27) Courtesy British Columbia Cancer Agency

11 A RE E TOPOSIDE C ONTAINING R EGIMENS B ETTER ? Blood 2010;116: PTCL subtype N pts ALCL alk+78 ALCL alk-113 PTCL- NOS 70 AITL28 Other31 Total320 Breakdown by Subtype of T-Cell Lymphoma

12 C OLLECTIVE T-C ELL L YMPHOMA E XPERIENCE O VERALL S URVIVAL AS F UNCTION OF H ISTOLOGICAL S UBTYPES ( N =295) Proportion Months 1: ALK+ (n= 73) 2: ALK- (n= 108) 3: PTCL (n= 68) 4: AILT (n= 28) 5: T/NK (n= 18) p-values <0.001 < < 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%) 3-years OS-rate: Schmitz et al., Blood 2010;116(18):3418

13 E VENT F REE S URVIVAL OF 320 P ATIENTS WITH T- CELL L YMPHOMA A CCORDING TO H ISTOLOGIC S UBTYPE Event Free Survivial % Months 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 % Months p=0.057 non Etoposide (n=29) Etoposide (n=69) P ATIENTS WITH OTHER MAJOR SUBTYPES (P ATIENTS WITH ALK+ OR ALCL EXLCUDED ) GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) EFS OF YOUNGER PATIENTS (18-60 YEARS, LDH<=UNV) TREATED ON THE NHL-B1 OR H I -CHOEP P HASE II/III TRIALS Schmitz et al., Blood 2010;116(18):3418

15 CHOEP-14d x 3 CR, PRSD,PD CHOEP-14d x 3 (stem cell collection) NLG-T-01: Design and schedule HDT (BEAM) CR, PRSD,PD Follow-up Excluded: 1)Alk pos ALCL T/0 2)CTCL 3)Leukemic T- NHL Nordic PTCL project d’Amore et al EHA 2009: abs.#53

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 Subtype, % OSPFS 3 Yrs5 Yrs3 Yrs5 Yrs PTCL-U (n = 62) AILT (n = 30) ALCL, ALK- (n = 31) Enteropathy (n = 21) d’Amore F, et al. European Hematology Association Abstract 53. d’Amore F, et al. J Clin Oncol. 2012;30: NLG S TUDY : A UTOLOGOUS BMT IN F IRST R EMISSION (M EDIAN F/U: 45 M OS ) Mos OS (%) PTCL-NOS AILT ALCL, ALK- EATL Log-rank test P =.21 Mos PFS (%) PTCL-NOS AILT ALCL, ALK- EATL Log-rank test P =.26

18 A UTOLOGOUS S TEM C ELL T RANSPLANTATION (A UTO SCT) AS F IRST - L INE T HERAPY IN P ERIPHERAL T-C ELL L YMPHOMAS (PTCL): R ESULTS OF A P ROSPECTIVE M ULTICENTER S TUDY S TUDY D ESIGN PTCL Collection of stem cells Cyc 120mg / kg + TBI AutoSCT CHOP-21 DexaBEAM / ESHAP PR/CR Reimer et al., 2009

19 PTCL n= 83 Dead Complete Remission Alive with Disease n= 17n= 6n= 32 No autoSCT n= 28 A UTOLOGOUS S TEM C ELL T RANSPLANTATION (A UTO SCT) AS F IRST - L INE T HERAPY IN P ERIPHERAL T-C ELL L YMPHOMAS (PTCL): O UTCOME AutoSCT n= 55 Dead Complete Remission Alive with Disease n= 23n= 2n= 3 N = 24 progressive disease N = 2 patient request N = 2 other Reimer et al., 2009, JCO 27(1):

20 G ERMAN P ROSPECTIVE S TUDY : OS A FTER ASCT IN F IRST R EMISSION 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 N = 83 CHOP x 4-6 If ≥ PR, dexaBEAM or ESHAP dexaBEAM or ESHAP ± TBI Median follow-up: 33 mos Reimer P, et al. J Clin Oncol. 2009;27: Nontransplanted patients did poorly Poor-risk patients did poorly Proportion Achieving OS Mos P <.001 Transplanted (n = 55) Nontransplanted (n = 28) Proportion Achieving OS Mos P =.0414 PIT group 2 (n = 34) PIT group 4 (n = 3) PIT group 3 (n = 21) PIT group 1 (n = 25)

21 ASCT 1st line in PTCL OS + PFS in the two largest PTCL-restricted ASCT trials OS NLG-T-01 (EHA 09) Reimer et al (JCO 09) 3-yrs57%48% 5-yrs50%40% PFS NLG-T-01 (EHA 09) Reimer et al (JCO 09) 3-yrs49%36% 5-yrs43%n.d. Induction Conditioning regimen Nordic trialCHOEP-14 x6BEAM German trial CHOP-21 x4-6 + DexaBEAM (mobilizing) HdCy+TBI Differences in treatment schedule NLG-T = Etoposide in Induction vs Reimer = No Etoposide in Induction

22 A UTOLOGOUS S TEM C ELL T RANSPLANT IN F IRST R EMISSION – P ROSPECTIVE D ATA Study Author (Yr) nRegimenTransplanted, %Outcomes, % Corradini (2006) 62 Mitoxantrone/ melphalan or BEAM yr EFS: yr OS: 34 Rodriguez (2007) 26MegaCHOP ± IFE73 3-yr PFS: 56 3-yr OS: 84 Mercadal (2008) 41 High-dose CHOP/ESHAP 41 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 Corrandini P, et al. Leukemia. 2006;20: Rodriguez J, et al. Eur J Haematol. 2007;79: 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 ALL, N=40 Rel, N=22 Ref, N=18 Horwitz et al, ASH 2005 Response to ICE 70% (28/40) Received ASCT 68% (27/40) PFS ICE months % Progress Free Survival PFS ICE months % PFS: Relapsed versus Refractory PTCL is Not DLBCL

24 P ERIPHERAL T-C ELL L YMPHOMAS : H OW I M ANAGE F RONTLINE D ISEASE  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

25 70% of responders did so in Cycle 1 Central Review (N=109) Investigator Assessment (N=109) nPercentn Best Response CR+CRu+PR 3229%4339% CR 1110%1716% CRu 11%33% PR 2018%2321% SD 2119%2219% PD 4037%4037% UE 22%00% ND: off-treatment in Cycle %55% S UMMARY OF R ESPONSE PROPEL O. A. O’Connor et al., JCO, 2011; 29(9):

26 C ASE M ATCHING P ROCEDURES U SING 4 D ATABASES F ROM 3 C ONTINENTS MSKUNMCGELASMCTotal 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 Historical control N Pralatrexate N MSKUNMCGELASMC Very Closely Matched Patients Populations Courtesy Charlie Morris

27 S IGNIFICANT I MPROVEMENT IN OS VERSUS M ATCHED C ONTROLS Pralatrexate Matched Controls Hazard Ration = (95% CI: 0.259, 0.600) Courtesy Charlie Morris

28 PROPEL: A S 2 ND 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 PROPEL: S UMMARY OF E FFICACY AS S ECOND - LINE T REATMENT F OLLOWING CHOP F AILURE * 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 Efficacy AssessmentsCentral Review Assessment (n=15), % Investigator Assessment (n=15), % Tumour Response ORR (CR+CRu+PR)7 (47)6 (40) CR3 (20)4 (27) CRu0 (0)1 (7) PR4 (27)1 (7) SD4 (27) PD4(27) Not Evaluable0 (0)1 (7) Median DoRND*12.5 mths Median by PFS**8.1 mths7.4 mths Median OSND*

30 S INGLE -A GENT R OMIDEPSIN IN R ELAPSED P ERIPHERAL T-C ELL L YMPHOMA : E FFICACY 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) Response Independent Review Committee Analysis (n = 130) Overall Response Rate34 (26%) Complete response10 (8%) Unconfirmed complete response7 (5%) Duration of ResponseMedian (Range) Overall12 (< ) months Complete response/unconfirmed complete response Not reached (< ) months)

31 International PTCL Study Subtype (n)CD30 Expression (%) 0-5% 6-49%50-80%>80% PTCL-NOS (168) AITL (167) EATL (27) ATLL (120) Nasal NK/T (73) Extranasal NK/T (30) Courtesy Dennis Weisberger, University of Nebraska

32 R EDUCED -I NTENSITY A LLOGENEIC BMT IN R ELAPSED PTCL: R ETROSPECTIVE D ATA 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: Survival (%) Yrs After Transplantation % 40% OS PFS PFS (%) Yrs After Transplantation % 8% Sensitive Refractory P < PFS (%) Yrs After Transplantation % 16% ≤ 2 previous regimens > 2 previous regimens P < OS (%) Yrs After Transplantation PTCL-NOS AILD ALCL Others P = NS

33 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 Autologous Stem Cell Transplant Partial Remission or Worse Pralatrexate Romidepsin Brentuximab Gemcitabine Partial Remission or Worse Consider Allogeneic Stem Cell Transplant Palliative Care A N A LGORITHM FOR THE M ANAGEMENT OF PTCL-NOS U PFRONT Relapse Complete Remission

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

37 NCCN G UIDELINES FOR R ELAPSED OR R EFRACTORY PTCL S A C LINICAL T RIAL IS R ECOMMENDED F IRST ! a Reproduced from NCCN Practice Guidelines in Oncology – v b See suggested regimens (TCEL-B). Clinical trial preferred for 1st and 2nd relapse; no therapies other than clinical trial described for 2nd relapse Relapsed/ refractory disease Relapsed/ Refractory disease Clinical trial preferred -or- Second-line therapy b Clinical trial preferred -or- Second-line therapy b -or- Palliative RT Complete response -or- Partial response No response Clinical trial -or- Auto- or allo- SCT Clinical trial -or- Best supportive care -or- Palliative RT Candidate for high-dose therapy Non-candidate for high-dose therapy Relapse #2 or greater Consolidation/ additional therapy Response #2 Additional therapy

38 M ECHANISM OF A CTION AND B IOMARKER D ISCOVERY RFC-1; FPGS; DHFR; GARPH; O THER ? RFC-1 Cell membrane Extracellular Cytosol Pralatrexate >> > Methotrexate DNA 10- formyl THF methenyl THF Pralatrexate THF Folate DHF PRPP GARFT Pralatrexate-Glu (n) IMP AICARFT AMP GMP dUMP dTMP DHFR RNA DNA TS FPGS RFC-1

39 Adapted from Jaffe et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues T-/NK-cell neoplasms ExtranodalLeukemic Mature T-/NK-cell neoplasms NodalCutaneous Precursor lymphoid neoplasms  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 E LIGIBLE H ISTOLOGIES PROPEL

40 N=111 Number of Regimens nPercent 12321% 23027% 32321% 41413% ≥ 52119% 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 N UMBER OF P RIOR S YSTEMIC R EGIMENS O. A. O’Connor et al., JCO, 2011; 29(9):

41 PROPEL ParameterCategory 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%) R ESPONSE BY K EY S UBSETS OO. A. O’Connor et al., JCO, 2011; 29(9):

42 R ESPONSE BY P RIOR T REATMENT PROPEL ParameterCategoryResponse Rate95% 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 CR / PR 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 D URATION OF R ESPONSE BY C ENTRAL R EVIEW PROPEL Months Proportion Number of Responders = 30 Median duration = 10.1 months Permanently censored (eg, transplant) (n = 8) Continue in follow-up for response (n=7) Follow-up exceeds 6 months for all patients who continue in follow-up for response SCT O. A. O’Connor et al., JCO, 2011; 29(9): Updated

44 GPI Registration Trial Romidepsin 14 mg/m 2 days 1,8,15 of a 28 day cycle OBJECTIVEOBJECTIVE Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior systemic therapy NCI Trial ( NCI 1312) Romidepsin 14 mg/m 2 days 1,8,15 of a 28 day cycle OBJECTIVEOBJECTIVE Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior “chemotherapy” R OMIDEPSIN O NGOING S TUDIES IN PTCL

45 P HASE 2 R OMIDEPSIN IN PTCL R ESPONSE R ATES 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%) s Piekarz et al., Blood, 2011; 117(2): Overall Response Rates

46 P HASE 2 R OMIDEPSIN IN PTCL R ESPONSE D ATA Duration of Response (DOR) &Time to Disease Progression (TTP) Median time to first response was 1.8 (1-6) months PopulationN* Median (range) DOR in months Median (range) TTP in months ORR (CR & PR) 159 (2 – 61+)12 (4 – 63+) CR434 (3 – 61+)NR (14 – 63+) PR118 (2 – 41+)10 (4 – 42+) SD7–9 (3 – 26+) PD19 – 1.4 (.2– 4) *7 patients were not evaluable; NR, median not yet reached; + denotes continuing response Piekarz et al., Blood, 2011; 117(2):

47 P HASE II T RIAL OF R OMIDEPSIN IN R ELAPSED OR P ROGRESSIVE P ERIPHERAL T-C ELL L YMPHOMA F OLLOWING P RIOR S YSTEMIC T HERAPY Patient population: –131 enrolled –130 with confirmed PTCL –Failed ≥ 1 prior systemic therapy Treatment regimen: romidepsin 14 mg/m 2, 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

49 CD30 Expression in in Non-Lymphoma Tumors  Acute Myeloid Leukemia/Granulocytic Sarcoma –M Fickers 1996, J Clin Pathol 49: ; 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:  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+ Stein et al., % (2/45) 0% (0/45) Norton et al., % (3/28) 7% (2/28) Hall et al., % (6/60) 2% (1/60) Schwarting et al., % (35/121) 9% (11/121)* Miettinen, % (14/37) 11% (4/37) Noorduyn et al., % (36/91) 23% (21/91) Eow et al., % (3/67) 0% (0/67) Total22% (99/449) 9% (39/449) Courtesy Dennis Weisberger, University of Nebraska

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

52 B RENTUXIMAB V EDOTIN M ECHANISM OF A CTION Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antimicrotubule agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 MMAE disrupts microtubule network ADC-CD30 complex traffics to lysosome MMAE is released Apoptosis G2/M cell cycle arrest

53 D EMOGRAPHICS AND B ASELINE C HARACTERISTICS N=58 Age* 52 yr (14  76) Gender33 M / 25 F ECOG status 033% 166% 22% ALCL confirmed by central pathology97% ALK-negative72% Refractory to frontline therapy62% Refractory to most recent treatment50% No response to any prior treatment22% Prior chemotherapy regimens* 2 (1  6) Prior radiation45% Prior ASCT26% * Median (range) R. Advani, ASH Abstract 443, 2011

54 K EY R ESPONSE R ESULTS S UMMARY 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 OSNot reached R. Advani, ASH Abstract 443, 2011

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

56 PFS by Disease Response Median PFS (months) CR 14.6 PR 4.2 SD 2.7 PD 1.2 HI*  Time (months) % Patients Free of PD or Death * Histologically ineligible R. Advani, ASH Abstract 443, 2011

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

58 S TRATEGIES TO I MPROVE U PFRONT T HERAPY 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 A UTOLOGOUS S TEM C ELL T RANSPLANTATION (A UTO SCT) AS F IRST - L INE T HERAPY IN P ERIPHERAL T-C ELL L YMPHOMAS (PTCL): I MPROVED O VERALL S URVIVAL 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< Overall survival 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 Time Carbo/Cisplatin as part of initial txCENSORFAILTOTALMEDIAN yes no Test: p= PTCL-NOS cases by Carbo/Cisplatin Initial Treatment Proportion International T-cell non-Hodgkin's Lymphoma Study Group O VERALL S URVIVAL B Y I NITIAL T REATMENT

62 NLG-T-01: OS + PFS (Med follow-up 45 mos) Subtype Analysis analysis time rhistdia = ptcl, nosrhistdia = aild rhistdia = alcl, alk neg OS : ALCL, AIL, PTCL-NOS analysis time rhistdia = ptcl, nosrhistdia = aild rhistdia = alcl, alk neg PFS : ALCL, AIL, PTCL-NOS OSPFS Subtype3-yr5-yr3-yr5-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%47%40% d’Amore et al EHA 2009: abs.#53

63 PROPEL: PRIOR ICE  20/109 had previously received ICE-based regimen 2 nd 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 PROPEL: PRIOR ICE ( N =20) ORR (CR + PR): 40% CR: 25% by Investigator Assessment Median Duration of Response: 16.2 months by Investigator Assessment Efficacy Assessments Central Review Assessment (n=20), % Investigator Assessment (n=20), % Tumor Response ORR (CR+PR)8 (40) CR5 (25)3 (15) PR3 (15)5 (25) SD5 (25)2 (10) PD6 (30)4 (20) Not Evaluable1 (5)6 (30) Median DoR16.2 mths13.1 mths Goy A, et al, Blood (ASH Annual Meeting Abstracts) : Abstract 1753


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