managing t-cell lymphoma
Post on 19-Oct-2014
1.277 views
DESCRIPTION
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/CMETRANSCRIPT
![Page 1: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/1.jpg)
PTCLOK, Now What?
Steven M. Horwitz M.D.Assistant AttendingLymphoma Service
Memorial Sloan-Kettering Cancer Center
![Page 2: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/2.jpg)
Peripheral T-cell Lymphoma-NOS
Prop
ortio
n
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Prognosis: Overall and Failure-free Survival
Armitage J, et al. J Clin Oncol. 2008;26:4124–4130, International T-cell Classification Project
![Page 3: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/3.jpg)
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
![Page 4: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/4.jpg)
WHO 2008 CLASSIFICATION OF MATURE T/NK-CELL NEOPLASMS
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative NK cells
Aggressive NK-cell leukemia
Adult T-cell lymphoma/leukemia
Systemic EBV-positive T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type intestinal T-cell lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AITL)
Anaplastic large cell lymphoma, ALK-positive
Anaplastic large cell lymphoma, ALK-negative
Peripheral T-cell lymphoma, NOS
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30+ lymphoproliferative
Primary cutaneous anaplastic large cell
Lymphomatoid papulosis
Borderline lesions
Subcutaneous panniculitis-like T-cell
Primary cutaneous gamma-delta T-cell
Hydroa vacciniforme lymphoma
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell
Primary cutaneous small/medium CD4+ T-cell lymphoma (provisional)
![Page 5: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/5.jpg)
“Systemic T-cell Lymphoma”Peripheral T-cell lymphoma NOS
Angioimmunoblastic T-cell lymphoma
Anaplastic Large Cell-ALK-1 negative
Anaplastic Large Cell-ALK-1 positive
Enteropathy-type intestinal lymphoma
Extranodal NK/T-cell lymphoma-nasal
Adult T-cell leukemia/lymphoma
Hepatosplenic T-cell lymphoma (may be derived from an immature T-cell)
Peripheral T-cell Lymphomas, PTCL refers to mature T-cell lymphomas (Pathology Definition)
“CTCL”Mycosis FungoidesSezary syndrome
Subcutaneous panniculitis-like Primary cutaneous ALCLLymphomatoid papulosis
Primary cutaneous small/medium CD4+ T-cell lymphoma
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell
lymphoma
Cancers of Immature T-cells lymphoblastic lymphoma and acute
lymphoblastic leukemia
PTCL
![Page 6: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/6.jpg)
Expert Agreement: Consensus Diagnosis
ALCL, 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.
![Page 7: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/7.jpg)
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
![Page 8: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/8.jpg)
International PTCL StudyMajor 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 25.0
Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.
![Page 9: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/9.jpg)
Time
Prop
ortio
nMature T and NK Lymphomas:
FFS of Different Histologies
.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12
PTCL
ATLL
AITLALCL ALK-
EATCLNK/T-nasal type
Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.
ALCL ALK+
![Page 10: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/10.jpg)
Savage et al. Annals of Oncology 2004; 15:1467–1475.
Baseline with CHOP/CHOP-Like: PTCL-U BCCA
OS by IPI
N=117
![Page 11: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/11.jpg)
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
![Page 12: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/12.jpg)
Autologous stem cell transplantation as first-line therapy in PTCL: Results of a prospective
multicenter study
N=83 CHOP x 4-6 IF CR/PR
mobilized with DexaBEAM or ESHAP
TBI + CY-ASCT Median F/U: 33 months
PTCL 39%AITL 33%ALCL 16%Med age 46.5 (30-65)
AA-IPI L-LI 49%HI-H 51%
CR/CHOP 39%PR/CHOP 40%ASCT 66%POD 29% (22% CHOP)
Reimer, P. et al et al. JCO vol 27, Jan 2009
![Page 13: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/13.jpg)
Overall survival
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60
Time (months)
(n=83)
3-year OS: 48%
time (months) (n=83)
Disease-free survival
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60
Time (months)
(n=55)
3-year DFS: 53%
time (months) (n=83)
Autologous stem cell transplantation as first-line therapy in PTCL: Survival
Reimer, P. et al et al. JCO vol 27, Jan 2009
![Page 14: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/14.jpg)
Overall Survival(IPI: high/intermediate high vs. low/intermediate low)
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60
Time (months)
IPI: high/intermediate high (n=42) IPI: low /intermediate low (n=41)
p= 0,1799
Overall survivalIPI: high / interm.high vs. low /
interm.low
time (months)
high / interm.high (n= 42) low / interm.low (n= 41)
Overall Survival(Transplanted vs. non-transplanted)
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60
Time (months)
non-transplanted (n=28) transplanted (n=55)
p< 0.001
Overall survivalTransplanted vs. non-transplanted
time (months)
transplanted (n= 55) non-transplanted (n= 28)
estimated 3-year OS: 71% vs. 11%
Autologous stem cell transplantation as first-line therapy in PTCL: Survival
CR vs PR p=0.22PFS 36%-no plateau
Reimer, P. et al. J Clin Oncol; 27:106-113 2009
![Page 15: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/15.jpg)
100
0
20
40
60
80
90
10
30
50
70
Months0 12 24 4836
100
0
20
40
60
80
90
10
30
50
70
Months0 12 24 4836
100
0
20
40
60
80
90
10
30
50
70
Months0 12 24 4836
CIBMTR Auto and Allo for PTCL: Outcomes excluding patients in CR1PFS OS NRM
Auto (N = 75)
Allo (N = 108)
Auto (N = 75)
Allo (N = 108)
Auto (N = 75)
Allo (N = 108)
P=NS
P <0.0001
P=NS
Smith et al, ASH 2010 abstract 689
![Page 16: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/16.jpg)
ICE and Planned ASCT for Relapsed/Refractory T-cell Lymphoma: PFS from ICE
ALL, N=40Rel, N=22
Ref, N=18
Horwitz et al, ASH 2005
Response to ICE 70% (28/40)
Received ASCT 68% (27/40)
0 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
0 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
![Page 17: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/17.jpg)
Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008
-Response to DLI 2/2
Retrospective Analysis of 77 PTCL Patients Who Underwent Allogeneic Stem-cell Transplantation
5 year EFS 53%
5 year OS 57%
AITL (n=11) 80%
PTCL (n=27) 63%
ALCL (n=27) 55%
Other (n=12) 33%
![Page 18: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/18.jpg)
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 Cellulaire
REL/REFRHistologies-ALCL-27-PTCL-NOS-27-AITL-11-NK/T-cell-5 -HSTCL-3-T-LGL-1-EATCL-1-HTLV– 2
myeloablative conditioning regimen-57
5 year TRM 34%
N=77
![Page 19: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/19.jpg)
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
![Page 20: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/20.jpg)
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 myelosuppressive
Is there an “R-CHOP” for TCL?
1. 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
![Page 21: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/21.jpg)
Alemtuzumab and CHOP chemotherapy as first-line treatment of PTCL: results of a GITIL prospective
multicenter trial
2 year FFS 48%
2 year OS 53%
Gallamini et al, Blood 110:2316-2323; 2007
A-30 mg + CHOP Q 4 weeks x 8N=24 (PTCL/AITL 20)
IPI 0-1 33%2-3 58%4-5 8%
CR ALL 70.8%PTCL 50%AITL 100%
![Page 22: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/22.jpg)
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
![Page 23: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/23.jpg)
Foss FM, et al. ASCO 2010. Abstract 8045.
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%
Denileukin Diftitox (DD) + CHOP in First-Line PTCL (CONCEPT Trial)
![Page 24: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/24.jpg)
Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL)
Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
•7 trials: German High-Grade Non-Hodgkin’s Lymphoma Study Group•343 patients•Most received 6-8 courses of CHOP or CHOEP (Hi-CHOEP, or MegaCHOEP)•56% ALCL, 8% AITL
Histology N 3 yr EFS 3 yr OSALCL 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%
![Page 25: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/25.jpg)
Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: Event-free survival Younger patients treated on the NHL-B1 trial
Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
EFS
![Page 26: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/26.jpg)
Treatment and Prognosis of Mature T-cell and NK-cell Lymphoma: Event-free survival Younger patients treated on NHL-B1/Hi-CHOEP trial
Schmitz et al., Blood First Edition Paper, prepublished online July 21, 2010
EFS ALCL, ALK+
EFS Other subtypes
![Page 27: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/27.jpg)
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
![Page 28: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/28.jpg)
Plasma membrane
Lysosome
cysteine cysteine cysteine
cysteine
PDXPDX(& Natural
Folates)
PDXFPGSATP + MgCl2
PDX(G)n
PDX FPGH+ SH
Gn
?
ATP
ADP
Pralatrexate
RFC-1
cMOAT/MRP
ATPase
PDX(G)n
TMTX
Compared to MTXPDX more efficiently enters tumor cells
(RFC-1) and is more readily polyglutamylated (FPGS)
![Page 29: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/29.jpg)
PROPEL Pivotal Trial: Pralatrexate in Relapsed/Refractory PTCL
Pralatexate 30 mg/m² IV x 6 weeks in 7 week cycles*
N=115• Single-arm• Phase II• Relapsed or refractory PTCL
Primary endpoint• Response rateSecondary endpoints• Duration of response• Overall survival• 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.
![Page 30: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/30.jpg)
Pralatrexate in Relapsed/Refractory PTCL
Median number prior systemic therapies: 3 (range, 1-12)
O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
Outcome Patients (N=109 evaluable)ORR 29%• CR 11%• PR 18%Median duration of response 10.1 monthsMedian PFS 3.5 monthsMedian OS 14.5 months
![Page 31: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/31.jpg)
PROPEL: Response Analysis by Subsets
O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
FactorNumber of Patients
Proportion of Patients ORR
Age• < 65 years• ≥ 65 years
7039
64%36%
27%33%
Number prior systemic regimens• 1• 2• ≥ 3
232957
21%27%52%
35%24%30%
Prior transplant• Yes• No
1891
17%83%
33%29%
Histology• PTCL-NOS• AILT• ALCL• Transformed MF• Other
591317128
54%12%16%11%7%
32%8%
35%25%38%
![Page 32: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/32.jpg)
*includes 6 MedDRA preferred terms **includes 2 MedDRA preferred terms ***includes 3 MedDRA preferred terms1- Only 5 patients had platelet count < 10,000 μL
PROPELAdverse Events ≥ Gr 3 Occurring in ≥ 3% of Patients (n=111)
Any Grade Grade 3 Grade 4Mucosal 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%
O’Connor OA, et al JCO Jan 18 2011
![Page 33: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/33.jpg)
Pralatrexate for CTCL: Efficacy Results
Cohort Pralatrexate Dose mg/m2
ScheduleResponse
RateResponse
Type1 30- 3/4 weeks 100% (2/2) 2 PR2 20- 3/4 weeks 67% (2/3) 2 PR3 20- 2/3 weeks 57% (4/7) 1 CR/3 PR4 15- 3/4 weeks 50% (3/6) 3 PR5 15- 2/3 weeks 0 (0/3) ---6 10- 3/4 weeks 10% (1/10) 1 CR
Overall 39% (12/31) 2 CR/10 PRDoses >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;
![Page 34: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/34.jpg)
Response by CTCL Subtype and Stage (N = 54)
CTCL Subtype (perInvestigator)
Stage Rate at OptimalDose/Sched
% (n/N)
Response Rateat ≥ 15 mg/m2
3/4 weeks% (n/N)
OverallResponse
Rate% (n/N)
MF IBIIBIII
IVAIVB
60% (3/5)67% (4/6)50% (1/2)60% (3/5)0% (0/1)
63% (5/8)67% (8/12)50% (1/2)60% (3/5)0% (0/1)
50% (5/10)53% (9/17)50% (1/2)50% (3/6)0% (0/1)
Sézary IIBIII
IVAIVB
0% (0/1)33% (1/3)33% (1/3)0% (0/1)
0% (0/1)25% (1/4)33% (1/3)50% (1/2)
0% (0/1)25% (1/4)13% (1/8)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;
![Page 35: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/35.jpg)
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
![Page 36: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/36.jpg)
Pivotal Trial of Romidepsin in Relapsed/Refractory PTCL
Median age: 61 years (range, 20-83) Median of 2 prior regimens (range, 1-6) 62% refractory to frontline therapy
Romidepsin 14 mg/m2 IV on Days 1,8,15 every 28 days
N=131• Single-arm• Phase II• PCTL failing ≥1 prior systemic therapy
• Systemic disease
Primary endpoint• CR rate by independent review
Secondary endpoints• CR rate by investigator assessment
• ORR• Duration of response• Time to first response• Time to progression• Safety, tolerability
T-cell lymphoma subtypes (n):• PTCL-NOS (53)• AITL (21)• ALCL (ALK-1-neg) (16)• Other (10)
Coiffier B, et al. ASH 2010. Abstract 114.
![Page 37: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/37.jpg)
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.
![Page 38: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/38.jpg)
Events with a missing toxicity grade are included.
At least one TEAE
Nausea
Fatigue
Vomiting
Thrombocytopenia
Diarrhea
Pyrexia
Neutropenia
Constipation
Anorexia
Anemia
Dysgeusia
Overall
≥ Grade 3
Infection
Treatment-Related Adverse Events in ≥ 20% of Patients (N = 131)
![Page 39: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/39.jpg)
Hematologic Toxicities ≥ 5% (N = 131)
All Grade ≥ 3 Drug-Related
Grade ≥ 3;Drug-
RelatedD/C
Thrombocytopenia* 38% 24% 37% 23% 2%
Neutropenia† 30% 20% 29% 18% 1%
Anemia 24% 10% 20% 5% 0
Leukopenia 12% 6% 12% 6% 1%
39
*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 patients
D/C, events leading to discontinuation.
![Page 40: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/40.jpg)
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 – Tumor cell undergoes G2/M
phase cell cycle arrest and apoptosis
Preclinical activity observed both in vitro and in vivo
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).
ADC=antibody-drug conjugate; MMAE= monomethylauristatin E.
G2/M cell cycle arrest and apoptosis
![Page 41: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/41.jpg)
Brentuximab Vedotin in Relapsed/ Refractory Systemic ALCL
Median age: 52 years (range, 14-76) Median of 2 prior regimens (range, 1-6) 62% refractory to frontline therapy
Brentuximab vedotin 1.8 mg/kg IV every 21 days
N=58• Single-arm• Phase II• Relapsed or refractory systemic ALCL
Primary endpoint• ORR by independent review
Secondary endpoints• CR rate• Duration of response• PFS • OS
Shustov AR, et al. ASH 2010. Abstract 961.
![Page 42: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/42.jpg)
Brentuximab Vedotin: Key Response Results
N=58 IRF Investigator
Overall 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
![Page 43: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/43.jpg)
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
![Page 44: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/44.jpg)
.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time
Prop
ortio
n
ALCL, ALK+
Vose, Weisenburger, et al, International T-cell Classification Project
Primary Cutaneous ALCL
ALCL, ALK-
PTCL-NOS
PTCL, if CD30+ in > 80% of cells-worse prognosisHTLV-1/ATLL may be CD30+MF with large cell transformation will be CD30+
Transformed MF
![Page 45: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/45.jpg)
Bendamustine in T-cell lymphoma (BENTLY Trial)
T-cell lymphoma subtypes (n): AILT (24) PTCL-NOS (17) ALCL (4) EATL (1) MF (1)
Bendamustine 120 mg/m2 IV on Days 1,2 every 3 weeks for 3 cycles
N=60• Multicenter, single-arm, phase II study
• Relapsed or refractory T-cell lymphoma
• ≤ 3 prior lines chemotherapy Primary endpoint
• ORR (IWC 1999 criteria)
Secondary endpoints• Safety, tolerability• Duration of response• PFS • OS
If no PD:Additional 3 cycles bendamustine
Damaj G, et al. 11th ICML; Lugano 2011. Abstract 126.
![Page 46: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/46.jpg)
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.
![Page 47: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/47.jpg)
Phase II Trial: Lenalidomide in Relapsed/Refractory TCL
Dueck G, et al. Cancer. 2010;116:4541-4548.
MF=mycosis fungoides.
Lenalidomide 25 mg PO QD on days 1-21 of each 28-day cycleUntil disease progression, death, or unacceptable toxicity
N=24• T-cell lymphoma (other than MF)
• WHO PS ≤3• Previously treated or untreated but not suitable for standard therapy
Primary endpoint• ORRSecondary endpoints• PFS• OS• Safety
![Page 48: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/48.jpg)
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 40AITL 7 0 2 29EATCL 1 0 0 0HSTCL 1 0 0 0PTCL 9 0 3 33
Dueck G, et al. Cancer. 2010;116:4541-4548.
![Page 49: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/49.jpg)
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.
![Page 50: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/50.jpg)
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
![Page 51: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/51.jpg)
Can we move new therapies upfront to change standard treatment paradigms?
New Drug New Drug New Drug Etc.
Combination Alternating or Maintenance
CHOP SGN-35 or similar
•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
![Page 52: Managing T-Cell Lymphoma](https://reader033.vdocument.in/reader033/viewer/2022051816/5443e52fb1af9f680a8b469f/html5/thumbnails/52.jpg)
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
PTCL-see eligibilityNo prior therapy (1 cycle CHOP-like allowed)Appropriate for CHOP based treatment
RANDOMIZE
Pralatrexate Maintenance
RESTAGING
observation
PD not eligible
CR, PR
“CHOP” x 6 cycles
At progression-treat as physician
discretion, including PDX
2:1
Co-Primary Endpoint OS/PFS