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Managing T-Cell Lymphoma
 
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Steven Horwitz, M.D., Assistant Attending, Lymphoma Service, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center. ...

Steven Horwitz, M.D., Assistant Attending, Lymphoma Service, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center.

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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    Managing T-Cell Lymphoma Managing T-Cell Lymphoma Presentation Transcript

    • PTCL OK, Now What? Steven M. Horwitz M.D. Assistant Attending Lymphoma ServiceMemorial Sloan-Kettering Cancer Center
    • Prognosis: Overall and Failure-free Survival 1.0 0.9 Peripheral T-cell Lymphoma-NOS 0.8Proportion 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Armitage J, et al. J Clin Oncol. 2008;26:4124–4130, International T-cell Classification Project
    • Current Problems with PTCL Current Problems  Confusing terminology/ Difficult Diagnosis  Poor Prognosis  Results with “Standard” Therapy Thinking about solutions  High-Dose therapy  New (or not so new) Drugs  Ways to move forward
    • WHO 2008 CLASSIFICATION OF MATURE T/NK-CELL NEOPLASMST-cell prolymphocytic leukemia Mycosis fungoidesT-cell large granular lymphocytic leukemia Sezary syndromeChronic lymphoproliferative NK cells Primary cutaneous CD30+ lymphoproliferativeAggressive NK-cell leukemia Primary cutaneous anaplastic large cellAdult T-cell lymphoma/leukemia Lymphomatoid papulosisSystemic EBV-positive T-cell lymphoma Borderline lesionsExtranodal NK/T-cell lymphoma, nasal type Subcutaneous panniculitis-like T-cellEnteropathy-type intestinal T-cell lymphoma Primary cutaneous gamma-delta T-cellHepatosplenic T-cell lymphoma Hydroa vacciniforme lymphomaAngioimmunoblastic T-cell lymphoma (AITL) Primary cutaneous aggressiveAnaplastic large cell lymphoma, ALK-positive epidermotropic CD8+ cytotoxic T-cellAnaplastic large cell lymphoma, ALK-negative Primary cutaneous small/medium CD4+ T-Peripheral T-cell lymphoma, NOS cell lymphoma (provisional)
    • Peripheral T-cell Lymphomas, PTCL refers to mature T-cell lymphomas (Pathology Definition) PTCL “Systemic T-cell Lymphoma” Peripheral T-cell lymphoma NOS “CTCL” Angioimmunoblastic T-cell lymphoma Mycosis Fungoides Anaplastic Large Cell-ALK-1 negative Sezary syndrome Subcutaneous panniculitis-like Anaplastic Large Cell-ALK-1 positive Primary cutaneous ALCL Enteropathy-type intestinal lymphoma Lymphomatoid papulosis Extranodal NK/T-cell lymphoma-nasal Primary cutaneous small/medium CD4+ T- Adult T-cell leukemia/lymphoma cell lymphoma Hepatosplenic T-cell lymphoma (may be derived from an Primary cutaneous aggressive immature T-cell) epidermotropic CD8+ cytotoxic T-cell lymphoma Cancers of Immature T-cells lymphoblastic lymphoma and acute lymphoblastic leukemia
    • Expert Agreement: Consensus DiagnosisALCL, ALK+ 97% PTCL, unspecified 75%ATLL 93% Panniculitis-like 75%Nasal NK/T-cell 92% ALCL, ALK- 74%Angioimmunoblastic 81% Hepatosplenic 72%Enteropathy-type 79% Cutaneous ALCL 66%Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.
    • Expert Agreement Upon Re-review Overall agreement 81% Reviewer 1 67% Reviewer 2 74% Reviewer 3 83% Reviewer 4 87% Reviewer 5 95%Data from Dennis Weisenberger, Int PTCL Project
    • International PTCL Study Major NHL Types by Region Percent NA EU FE PTCL, unspecified 34.4 34.3 22.4 Angioimmunoblastic 16.0 28.7 17.9 Anaplastic, ALK+ 16.0 6.4 3.2 Anaplastic, ALK- 7.8 9.4 2.6 NK/T-cell 5.1 4.3 22.4 ATLL 2.0 1.0 25.0Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.
    • Mature T and NK Lymphomas: FFS of Different Histologies 1.0 0.9 0.8 ALCL ALK+Proportion 0.7 0.6 0.5 0.4 0.3 ALCL ALK- 0.2 AITL PTCL 0.1 NK/T-nasal type 0.0 ATLL EATCL 0 1 2 3 4 5 6 7 8 9 10 11 12 Time . Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.
    • Baseline with CHOP/CHOP-Like: PTCL-U BCCA OS by IPI N=117 Savage et al. Annals of Oncology 2004; 15:1467–1475.
    • Current Problems with PTCL Current Problems  Confusing terminology/ Difficult Diagnosis  Poor Prognosis  Results with “Standard” Therapy Thinking about solutions  High-Dose therapy  New (or not so new) Drugs  Ways to move forward
    • Autologous stem cell transplantation as first-line therapy in PTCL: Results of a prospective multicenter study PTCL 39% N=83 AITL 33% CHOP x 4-6 ALCL 16% IF CR/PR Med age 46.5 (30-65)  mobilized with DexaBEAM or ESHAP AA-IPI L-LI 49% TBI + CY-ASCT HI-H 51% Median F/U: 33 months CR/CHOP 39% PR/CHOP 40% ASCT 66% POD 29% (22% CHOP)Reimer, P. et al et al. JCO vol 27, Jan 2009
    • Autologous stem cell transplantation as first-line therapy in PTCL: Survival 3-year survival 48% Overall OS: 3-year DFS: 53% Disease-free survival 1 10,8 0,80,6 0,60,4 0,40,2 0,2 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) time (months) time (months) Time (months) (n=83) (n=83) (n=83) (n=55) Reimer, P. et al et al. JCO vol 27, Jan 2009
    • Autologous stem cell transplantation as first-line therapy in PTCL: Survival Overall survival Overall Survival OverallSurvival Overall survival (Transplanted vs. non-transplanted) (IPI: high/intermediate high vs. low/intermediate low) Transplanted vs. non-transplanted IPI: high / interm.high vs. low / 1 1 interm.low p< 0.001 p= 0,17990,8 0,80,6 0,60,4 estimated 3-year OS: 71% vs. 11% 0,40,2 0,2 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) time (months) time (months) Time (months) non-transplanted (n=28) transplanted (n= 55) transplanted (n=55) non-transplanted (n= 28) high / interm.high (n= 42) IPI: high/intermediate high (n=42) IPI:low /intermediate low(n= 41) low / interm.low (n=41) CR vs PR p=0.22 PFS 36%-no plateau Reimer, P. et al. J Clin Oncol; 27:106-113 2009
    • CIBMTR Auto and Allo for PTCL: Outcomes excluding patients in CR1100 PFS 100 OS 100 NRM P <0.000190 90 9080 80 8070 70 70 Auto (N = 75)60 60 60 Auto (N = 75)50 50 5040 40 40 Allo (N = 108) Allo (N = 108)30 30 30 Allo (N = 108)20 20 2010 10 10 Auto (N = 75) P=NS P=NS 0 0 0 0 12 24 36 48 0 12 24 36 48 0 12 24 36 48 Months Months Months Smith et al, ASH 2010 abstract 689
    • ICE and Planned ASCT for Relapsed/Refractory T-cell Lymphoma: PFS from ICE Progress Free Survival PFS: Relapsed versus Refractory 1.0 1.0 0.8 0.8 0.6 0.6% % ALL, N=40 0.4 Rel, N=22 0.4 0.2 0.2 Ref, N=18 0.0 0.0 0 12 24 36 48 60 72 84 96 108 120 132 0 12 24 36 48 60 72 84 96 108 120 132 PFS ICE months PFS ICE monthsResponse to ICE 70% (28/40)Received ASCT 68% (27/40) Horwitz et al, ASH 2005
    • Retrospective Analysis of 77 PTCL Patients Who UnderwentAllogeneic Stem-cell Transplantation AITL (n=11) 80% PTCL (n=27) 63% 5 year OS 57% ALCL (n=27) 55% 5 year EFS 53% Other (n=12) 33% -Response to DLI 2/2 Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008
    • Retrospective Analysis of PTCL Patients Who Underwent Allogeneic Stem-cell Transplantation Societe´ Francaise De Greffe De Moelle Et De Therapie CellulaireREL/REFRHistologies N=77-ALCL-27-PTCL-NOS-27-AITL-11-NK/T-cell-5 5 year TRM 34%-HSTCL-3-T-LGL-1-EATCL-1-HTLV– 2myeloablative Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008conditioningregimen-57
    • Current Problems with PTCL Current Problems  Confusing terminology/ Difficult Diagnosis  Poor Prognosis  Results with “Standard” Therapy Thinking about solutions  High-Dose therapy  New (and not so new) Drugs  Ways to move forward
    • Is there an “R-CHOP” for TCL? Alemtuzumab- anti-CD52 antibody  N=14, Rel/Refr-Phase II, standard dosing (30 mg iv 3x/week)1  10 PTCL, nos, RR 36% (3CR/2PR)  5 deaths-closed early (TB, zoster, aspergillus)  N=10, Phase II -10 mg x 12 doses (4 weeks) 2  PTCL nos 6, CTCL 4  Response 50% in PTCL, CR2/PR1  Less toxic Denileukin diftitox-fusion protein-IL2-diphtheria toxin  N=27, (PTCL 19) Phase II, standard dosing3  48%RR , not myelosuppressive1. Enblad et al. Blood. 2004;103:2920-2924.2. Zinzani et al Haematologica. 2005;90:702-703.3. Dang et al British Journ Haematol 136:439-447, 2007
    • Alemtuzumab and CHOP chemotherapy as first-line treatment of PTCL: results of a GITIL prospective multicenter trial A-30 mg + CHOP Q 4 weeks x 8 N=24 (PTCL/AITL 20) 2 year FFS 48% IPI 0-1 33% 2-3 58% 4-5 8% CR ALL 70.8% PTCL 50% 2 year OS 53% AITL 100%Gallamini et al, Blood 110:2316-2323; 2007
    • Issues with Alemtuzumab + CHOP Toxicity – Gallamini et al – Grade 4 Infection-17% – Sepsis, Aspergillosis, JC virus, PCP – Kim et al – Toxicity-Grade 3-4 • Neutropenia 90%, Lymphopenia 95%, Febrile neutropenia 55% • Infectious deaths 10% • Study halted early due to SAE Heterogeneity of CD52 expression – Series of PTCL 35-40%* – Down-regulated in PTCL? – Varies by technique Flow vs Immunohistochemistry *Piccaluga et al Haematologica 2007 92:566-567, Rodig et al. Clin Cancer Res 2006;12:7174
    • Denileukin Diftitox (DD) + CHOP in First-Line PTCL (CONCEPT Trial)  Multicenter phase II study of patients with aggressive T-cell NHL  Treatment: DD 18 μg/kg/d on Days 1-2, CHOP on Day 3, G-CSF or filgrastim on Day 4  N=49 (80% PTCL/AITL/ALCL)  7 patients completed only 1 cycle of therapy – 3 deaths after cycle 1 (2 cardiac, 1 rhabdomyolysis) – 4 discontinued due to toxicity  Efficacy – ORR overall: 68%; 57% CR – ORR (≥2 cycles): 86%; 73% CR – Median PFS 12 mos; estimated 2-year OS 60%Foss FM, et al. ASCO 2010. Abstract 8045.
    • Treatment and Prognosis of Mature T-cell andNK-cell Lymphoma: an analysis of patients with T-celllymphoma treated in studies of the German High-GradeNon-Hodgkin’s Lymphoma Study Group (DSHNHL)•7 trials: German High-Grade Non-Hodgkin’s Lymphoma Study Group•343 patients•Most received 6-8 courses of CHOP or CHOEP (Hi-CHOEP, orMegaCHOEP)•56% ALCL, 8% AITL Histology N 3 yr EFS 3 yr OS ALCL ALK+ 78 75.8% 89.8% ALCL, ALK- 113 45.7% 62.1% PTCLU 70 41.1% 53.9% AITL 28 50.0% 67.5% Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
    • Treatment and Prognosis of Mature T-cell andNK-cell Lymphoma: Event-free survivalYounger patients treated on the NHL-B1 trial EFS Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
    • Treatment and Prognosis of Mature T-cell andNK-cell Lymphoma: Event-free survivalYounger patients treated on NHL-B1/Hi-CHOEP trial EFS EFS ALCL, ALK+ Other subtypes Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
    • Current Problems with PTCL Current Problems  Confusing terminology/ Difficult Diagnosis  Poor Prognosis  Results with “Standard” Therapy Thinking about solutions  High-Dose therapy  New (and not so new) Drugs  Ways to move forward
    • Pralatrexate cMOAT/ MRP RFC-1 Plasma membrane ATPase ATP PDX PDX PDX FPGS PDX(G)n(& Natural ATP + MgCl2 Folates) Lysosome ADP Gn PDX(G)n PDX FPGH + SH cysteine cysteine ? cysteine TMTX cysteine Compared to MTX PDX more efficiently enters tumor cells (RFC-1) and is more readily polyglutamylated (FPGS)
    • PROPEL Pivotal Trial: Pralatrexate in Relapsed/Refractory PTCL Primary endpoint N=115 • Response rate • Single-arm Pralatexate 30 mg/m² IV Secondary endpoints • Phase II x 6 weeks in 7 week • Duration of response • Relapsed or cycles* • Overall survival refractory PTCL • Progression-free survival*No pre-medications were required and patients also received vitamin B12 every 8-10 weeks,and 1 mg of oral folic acid daily.O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
    • Pralatrexate in Relapsed/Refractory PTCL  Median number prior systemic therapies: 3 (range, 1-12) Outcome Patients (N=109 evaluable) ORR 29% • CR 11% • PR 18% Median duration of response 10.1 months Median PFS 3.5 months Median OS 14.5 monthsO’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
    • PROPEL: Response Analysis by Subsets Number of Proportion of Factor Patients Patients ORR Age • < 65 years 70 64% 27% • ≥ 65 years 39 36% 33% Number prior systemic regimens • 1 23 21% 35% • 2 29 27% 24% •≥3 57 52% 30% Prior transplant • Yes 18 17% 33% • No 91 83% 29% Histology • PTCL-NOS 59 54% 32% • AILT 13 12% 8% • ALCL 17 16% 35% • Transformed MF 12 11% 25% • Other 8 7% 38%O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
    • PROPELAdverse Events ≥ Gr 3 Occurring in ≥ 3% of Patients (n=111) Any Grade Grade 3 Grade 4 Mucosal inflammation* 70% 17% 4% Thrombocytopenia** 41% 14% 19%1 Nausea 40% 4% 0% Fatigue 36% 5% 2% Anemia** 34% 16% 2% Neutropenia** 24% 13% 7% Dyspnea 19% 7% 0% Hypokalemia** 15% 4% 1% Abnormal LFTs* 13% 5% 0% Abdominal pain 11% 4% 0% Leukopenia** 11% 3% 4% Febrile Neutropenia 5% 5% 0% Sepsis 5% 3% 2% Hypotension 5% 3% 1% *includes 6 MedDRA preferred terms **includes 2 MedDRA preferred terms ***includes 3 MedDRA preferred terms 1- Only 5 patients had platelet count < 10,000 μL O’Connor OA, et al JCO Jan 18 2011
    • Pralatrexate for CTCL: Efficacy ResultsCohort Pralatrexate Dose mg/m2 Response Response Schedule Rate Type 1 30- 3/4 weeks 100% (2/2) 2 PR 2 20- 3/4 weeks 67% (2/3) 2 PR 3 20- 2/3 weeks 57% (4/7) 1 CR/3 PR 4 15- 3/4 weeks 50% (3/6) 3 PR 5 15- 2/3 weeks 0 (0/3) --- 6 10- 3/4 weeks 10% (1/10) 1 CR Overall 39% (12/31) 2 CR/10 PR Doses >15 mg/m2, 3/4 weeks 61% (11/18) “Optimal” dose 15 mg/m2, 3/4 weeks 10/22 (45%) Horwitz SM, Kim Y, Foss F, et al, ASH Annual Meeting., 2010;
    • Response by CTCL Subtype and Stage (N = 54)CTCL Subtype (per Stage Rate at Optimal Response Rate Overall Investigator) Dose/Sched at ≥ 15 mg/m2 Response % (n/N) 3/4 weeks Rate % (n/N) % (n/N)MF IB 60% (3/5) 63% (5/8) 50% (5/10) IIB 67% (4/6) 67% (8/12) 53% (9/17) III 50% (1/2) 50% (1/2) 50% (1/2) IVA 60% (3/5) 60% (3/5) 50% (3/6) IVB 0% (0/1) 0% (0/1) 0% (0/1)Sézary IIB 0% (0/1) 0% (0/1) 0% (0/1) III 33% (1/3) 25% (1/4) 25% (1/4) IVA 33% (1/3) 33% (1/3) 13% (1/8) IVB 0% (0/1) 50% (1/2) 50% (1/2)PC-ALCL IIB ------- 100% (1/1) 100% (1/1)All patients 45% (13/29) 51% (21/41) 41% (22/54) Horwitz SM, Kim Y, Foss F, et al, ASH Annual Meeting., 2010;
    • Romidepsin in PTCL A pan-histone deacetylase (HDAC) inhibitor FDA-approved in 2009 for use in patients with CTCL who have received ≥ 1 prior systemic therapy Pivotal trial in PTCL presented at ASH 2010
    • Pivotal Trial of Romidepsin in Relapsed/Refractory PTCL Primary endpoint N=131 • CR rate by independent • Single-arm review Romidepsin 14 mg/m2 IV • Phase II Secondary endpoints on Days 1,8,15 every 28 • PCTL failing ≥1 • CR rate by investigator days prior systemic assessment therapy • ORR • Systemic disease • Duration of response • Time to first responseT-cell lymphoma subtypes (n): • Time to progression• PTCL-NOS (53) • Safety, tolerability• AITL (21)• ALCL (ALK-1-neg) (16)  Median age: 61 years (range, 20-83)• Other (10)  Median of 2 prior regimens (range, 1-6)  62% refractory to frontline therapyCoiffier B, et al. ASH 2010. Abstract 114.
    • Romidepsin in Relapsed/Refractory PTCL  ORR (by IRC): 26% (34/130)  CR: 13%  Median duration of response: 12 months  Median duration of CR: not reached (<1 to 26.3+ months)  Median time to progression: 6 months  Safety profile consistent with CTCL studies – Most common grade ≥3 AEs: thrombocytopenia (24%); neutropenia (20%)Coiffier B, et al. ASH 2010. Abstract 114.
    • Treatment-Related Adverse Events in ≥ 20% of Patients (N = 131) At least one TEAE Nausea Infection Fatigue Vomiting Thrombocytopenia Diarrhea Pyrexia Neutropenia Constipation Anorexia Overall Anemia ≥ Grade 3 DysgeusiaEvents with a missing toxicity grade are included.
    • Hematologic Toxicities ≥ 5% (N = 131) Grade ≥ 3; Drug- All Grade ≥ 3 Drug- D/C Related RelatedThrombocytopenia* 38% 24% 37% 23% 2%Neutropenia† 30% 20% 29% 18% 1%Anemia 24% 10% 20% 5% 0Leukopenia 12% 6% 12% 6% 1%*9 patients (7%) had a bleeding event [3 pts ≥ Grade 3]. 6/9 related to thrombocytopenia† Febrile neutropenia reported as AE in 5 patients (4%). Growth factors used in 13% of patientsD/C, events leading to discontinuation. 39
    • Brentuximab Vedotin (SGN-35) in ALCL  3 components: – Chimeric antibody SGN-30 – Synthetic analog (MMAE) of the antitubulin agent dolastatin 10 – Stable drug linker  Proposed mechanism of action – Binds to CD30 – Internalized into the tumor cell – MMAE is released G2/M cell cycle – Tumor cell undergoes G2/M arrest and apoptosis phase cell cycle arrest and apoptosis  Preclinical activity observed both in vitro and in vivoADC=antibody-drug conjugate; MMAE= monomethylauristatin E.Reproduced with permission from Seattle Genetics, Inc.; Pro. 2009 ASCO Educational Book.Alexandria, VA: American Society of Clinical Oncology. 2009;486; Younes. EHA. 2009 (abstr 0503).
    • Brentuximab Vedotin in Relapsed/ Refractory Systemic ALCL N=58 Primary endpoint • Single-arm • ORR by independent • Phase II Brentuximab vedotin 1.8 review • Relapsed or mg/kg IV every 21 days Secondary endpoints refractory • CR rate systemic ALCL • Duration of response • PFS • OS  Median age: 52 years (range, 14-76)  Median of 2 prior regimens (range, 1-6)  62% refractory to frontline therapyShustov AR, et al. ASH 2010. Abstract 961.
    • Brentuximab Vedotin: Key Response ResultsN=58 IRF InvestigatorOverall response rate (95% CI) 86% (75, 94) 81% (69, 90) Complete remission 53% 59% Partial remission 33% 22%Stable disease 3% 9%Progressive disease 5% 3%Histologically ineligible 3% 3%Not evaluable 2% 3%OutcomesMedian duration of OR (95% CI) Not reached (36, −) 36 weeks (31, −)Median duration of CR (95% CI) Not reached (36, −) Not reached (35, −)Median PFS (95% CI) Not reached 41 weeks (23, −)Median OS Not reached
    • Common Adverse Events*Preferred Term All GradesNausea 38%Peripheral sensory neuropathy 38%Fatigue 34%Pyrexia 33%Diarrhea 29%Neutropenia 21%Rash 21%* Events of any relationship occurring in ≥20% of patients, N=58
    • 1.0 Primary Cutaneous 0.9 ALCL 0.8 0.7Proportion 0.6 0.5 ALCL, ALK+ 0.4 0.3 ALCL, ALK- 0.2 0.1 Transformed MF PTCL-NOS 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time PTCL, if CD30+ in > 80% of cells-worse prognosis HTLV-1/ATLL may be CD30+ . MF with large cell transformation will be CD30+ Vose, Weisenburger, et al, International T-cell Classification Project
    • Bendamustine in T-cell lymphoma (BENTLY Trial) N=60 • Multicenter, single-arm, Bendamustine 120 If no PD: phase II study mg/m2 IV on Days 1,2 Additional 3 cycles • Relapsed or every 3 weeks for 3 bendamustine refractory T- cycles cell lymphoma • ≤ 3 prior lines chemotherapy Primary endpoint • ORR (IWC 1999 criteria) T-cell lymphoma subtypes (n):  AILT (24) Secondary endpoints  PTCL-NOS (17) • Safety, tolerability  ALCL (4) • Duration of response  EATL (1) • PFS  MF (1) • OSDamaj G, et al. 11th ICML; Lugano 2011. Abstract 126.
    • Bendamustine in Relapsed/ Refractory T-cell Lymphoma  ORR: 42%; CR: 23%  Median DOR: 5.5 months – Median duration of CR: 11.9 months  Most common grade 3/4 adverse events: – Neutropenia (49%) – Thrombocytopenia (36%) – Infections (34%)Damaj G, et al. 11th ICML; Lugano 2011. Abstract 126.
    • Phase II Trial: Lenalidomide in Relapsed/Refractory TCLN=24 Lenalidomide 25 mg PO Primary endpoint• T-cell lymphoma QD on days 1-21 of each • ORR (other than MF) 28-day cycle Secondary endpoints• WHO PS ≤3 Until disease • PFS• Previously treated or progression, death, or • OS untreated but not unacceptable toxicity • Safety suitable for standard therapy MF=mycosis fungoides.Dueck G, et al. Cancer. 2010;116:4541-4548.
    • Lenalidomide in Relapsed/Refractory TCL ORR=30% (7/23) Median PFS = 96 days Median OS = 241 days (range, 8-696+ days) Common AEs – Grade 4: thrombocytopenia (33%) – Grade 3: neutropenia (20.8%), febrile neutropenia (16.7%), pain NOS (16.7%) Histology No. CR PR ORR, % ALCL 5 0 2 40 AITL 7 0 2 29 EATCL 1 0 0 0 HSTCL 1 0 0 0 PTCL 9 0 3 33Dueck G, et al. Cancer. 2010;116:4541-4548.
    • Phase II Study of SMILE Chemotherapy in Extranodal NK/T-cell Lymphoma, Nasal Type • SMILE = Steroid (dexamethasone), Methotrexate, Ifosfamide, L-asparaginase, Etoposide • Patients with newly diagnosed stage IV or relapsed/refractory ENKL (N=39)  ORR 74%; CR 38%  Highly myelosuppressive: – Grade 3/4 neutropenia: 8%/92% – Grade 3/4 leukopenia: 28%/72% – Grade 3/4 infection: 41%/13% – Lymphocyte count ≥ 500/mm3 added to eligibility criteria after first 2 patients died from infection Yamaguchi M, et al. ASCO 2010. Abstract 8044.
    • Current Problems with PTCL Current Problems  Confusing terminology/ Difficult Diagnosis  Poor Prognosis  Results with “Standard” Therapy Thinking about solutions  High-Dose therapy  New (and not so new) Drugs  Ways to move forward
    • Can we move new therapies upfront to change standard treatment paradigms?•Incorporating new therapies•Adding to existing regimens may be limited (very active single agent)•Otherwise novel approaches •Novel ways to incorporate new drugs-can be done now •Completely novel regimens-will take time CHOP SGN-35 or similarNew Drug New Drug New Drug Etc. Combination Alternating or Maintenance
    • A Multi-center, Randomized, Phase 3 Study of Sequential Pralatrexate Versus Observation in Patients PTCL Who Have Not Progressed Following Initial Treatment with CHOP-based Chemotherapy R R Pralatrexate A E MaintenancePTCL-see eligibility N “CHOP” S DNo prior therapy (1 x 6 cycles T Ocycle CHOP-like CR, PRallowed) A MAppropriate for CHOP G Ibased treatment I observation Z N E G 2:1 At progression- Co-Primary Endpoint OS/PFS PD not eligible treat as physician discretion, including PDX