Transcript T cell lymphoma

How Can We Improve Therapy
for T-cell Lymphoma?
T cell lymphoma: What are the current standards of treatment?
Should all patients be tested for CD30?
Jia Ruan, M.D., Ph.D.
Center for Lymphoma and Myeloma
Weill Cornell Medical College
New York Presbyterian Hospital
Incidence of Peripheral T-cell Lymphoma
 5-10% of all NHL in Western countries
Most common: PTCL-nos, angioimmunoblastic, and ALCL
 Higher incidence, 15-20% of all lymphomas, in Asia
Most common: PTCL-nos, NK/TCL, and ATLL
J Clin Oncol 2008;26:4124-4130
WHO 2008 CLASSIFICATION: Mature NK/T-cell Neoplasms
Nodal
Disseminated
•PTCL, NOS
•AITL
•ALCL, ALK+
•ALCL, ALK-
Cutaneous
•T-cell PLL
•Mycosis fungoides
•Sezary syndrome
•T-cell LGL
•Chronic lymphoproliferative •Primary cutaneous
CD30+ LPD
NK cells
•Primary cutaneous
•Aggressive NK-cell leukemia
ALCL
•ATLL
•Lymphomatoid
papulosis
•Systemic EBV+ TCL
•Subcutaneous
Extranodal
panniculitis-like Tcell lymphoma
•NK/T-cell, nasal type
•Primary cutaneous
•Enteropathygamma-delta T-cell
associated TCL
•Other
•Hepatosplenic TCL
Blood. 2008;112:4384-4399
Peripheral T-cell Lymphoma: Prognosis
International Prognostic Index (IPI)
•
•
•
•
•
Age >60 years
Performance status ≥2
Serum lactate dehydrogenase level greater than the ULN
Extranodal sites >1
Ann Arbor stage III or IV
Prognostic Index for PTCL (PIT)
•
•
•
•
Age >60 years
Performance status ≥2
Serum lactate dehydrogenase level greater than the ULN
Bone marrow involvement
Blood 2004; 103; 2474-2479
PTCL: Outcome varies by subtypes and IPI
5-yr OS
Diagnosis
%
IPI 0/1
IPI 4/5
PTCL-NOS
32%
50%
11%
AITL
32%
56%
25%
ALCL, ALK+
70%
90%
33%
ALCL, ALK-
49%
74%
13%
ATLL
14%
28%
7%
NKTCL, nasal
42%
57%
0
NKTCL, extranasal
9%
17%
0
Enteropathy-type
20%
29%
14%
Hepatosplenic
7%
0
0
Subcutaneous panniculitis-like
64%
60%
0
J Clin Oncol 2008;26:4124-4130
Challenges in Management of T-cell lymphoma
New Diagnosis
Chemotherapy
CHOP vs Other
Relapse
Chemotherapy
Novel agents
Transplantation
Challenges: Difficulty to induce high quality and durability of responses.
International T-cell Project: Role of Anthracycline
PTCL-NOS
AITL
 Other than ALK+ ALCL, no benefit of an anthracycline-containing
regimen over a non–anthracycline-containing regimen.
J Clin Oncol 2008;26:4124-4130
What do we actually get with first line CHOP?
Citation
Subtypes
N
ORR%
CR %
% Survival
Savage et al
PTCL-NOS
117
84
64
29 (5 yr-PFS)
AITL
157
NR
46
30% (7-yr OS)
PTCL(32)
AITL(27)
ALCLalk-(13)
83
79
39
ASCT
PTCL(30)
AITL(8)
ALCL(5)
43
62
39
PTCL
29%
41 (2 yr-EFS)
Lower for
PTCL
PTCL(34)
AITL(12)
46
NR
39
26 (3 yr-OS)
Ann Oncol 2004
Mourad et al
Blood 2008
Reimer et al
JCO 2009
Simon et al
BJH 2010
Akagi et al
J Clin Exp Hematop 2011
 ORR 60-80+%, CR 30-60+%
 Durable remissions <20-30%
 Stratification based on IPI/PIT/Subtype
PTCL: Can we do better than CHOP?
Adding to the CHOP backbone




CHOP + alemtuzumab
CHOP + denileukin diftitox
CHOP + bortezomib
CHOP + etoposide
Alternative intensive regimens
Upfront SCT consolidation
Novel strategies
CHOP vs CHOP+ vs non-CHOP
Possible incremental benefit by adding therapies to CHOP
Benefit not equivalent in all subtypes (ALCL)
Incremental benefit unlikely to significantly change prognosis
Near MTD and toxicity soon outweighs benefit
Non-CHOP intensive regimens are generally not better
Autologous SCT as First-line Therapy in PTCL
PFS, whole cohort
3-year PFS 36%
5-year PFS: 44%
1.0
4-year PFS: 44%
0.8
N=83
N=160
0.6
N=65
0.4
0.2
0.0
Time (months)
0
12
160
100
Number at risk
24
60
Time
85
65(months)
52
39
95% CI
CHOP: ORR 79%, CR 39%
Transplant rate 66%
36
48
months
72
17
Time (months)
Survivor function
CHOEP: ORR 82%, CR 51%
Transplant rate 72%
Reimer et al JCO 2009;27:106-113
D’Amore et al JCO 2012;30:3093-3099
MSKCC data (S Horwitz)
CHOP/CHOP-ICE
ORR 82%, CR 51%
Relapsed PTCL: Spectrum of Disease
BCCA registry 1976-2010: 191 patients with PTCL-nos, AITL, ALCL
38 received transplant (SCT 69%); 153 non-transplant candidates
Panel 1:
All 153 non-transplant pt
Panel 2:
89 pt received chemoRx
Median PFS
3.1 months
Median PFS
3.7 months
Median OS
5.5 months
Median OS
6.5 months
J Clin Oncol 2013;31:1970-76
Novel Therapy in Relapsed PTCL
Agents
Patient
No.
ORR
%
CR%
PFS
(mon)
DOR
(mon)
OS
(mon)
Chemo (BCCA)
89
55
26
3.7
N/A
6.5
39
51
23
N/A
N/A
N/A
111
29
11
3.5
10.1
14.5
130
25
15
4
28
11.3
58
86
57
13.3
12.6
NR
60
50
28
3.6
3.5
6.2
54
22
11
2.5
3.6
N/A
31- AITL
15-AITL
4.6-AITL
3.5-AITL
JCO 2013
Gemcitabine
Ann Oncol 2010
Pralatrexate
JCO 2011
Romidepsin
JCO 2012 a
Brentuximab
JCO 2012 b
Bendamustine
JCO 2013
Lenalidomide
EJC 2013
a:
based on ASH2012 update
b: includes ALCL patients only
Histone Deacetylase (HDAC) Inhibitors
Agents
Romidepsin
Belinostat
Drug class
Class I HDACi
Class I&II HDACi
14 mg/m2 IV 4h, weekly 3
of 4 wks
1000 mg/m2 IV 30min,
daily x 5, every 3 wks
Dosing
PTCL subtypes
PTCL
PTCL
AITL
Pt number
130
129
22
ORR
25%
26%
45%
CR
15%
10%
18%
TTR
1.8 months
DOR
28 months
8.3 months
7.5 months
PFS
4 months
N/A
5.8 months
OS
11.3 months
N/A
9.2 months
Thrombocytopenia (gr 3/4)
Neutropenia (gr 3/4)
Anemia (gr 3/4)
5.6 wk
24%
20%
11%
JCO 2012;30:631-636
ASCO2013, abstract 8507; ICML2013, abstract 153
13%
13%
10%
Brentuximab Vedotin: Antibody-Drug Conjugates
CD30 Expression in PTCL
195 cases of PTCL from western Europe.
Semi-quantitative evaluation of IHC positive tumor cells %.
Transcriptomic CD30 mRNA levels were evaluated in parallel.
ICML2013, abstract 151
Brentuximab Vedotin: Phase II study in CD30+ NHL
•NCT01421667
•29 patients with PTCL enrolled: AITL (11) and PTCL-NOS (18)
•CD30 expression ranged from 5-100%
•Brentuximab vedotin 1.8 mg/kg IV over 30 min every 21 days
•22 evaluable: ORR 36% (6 CR, 2 PR), DoR not reached
•Subset in AITL (10): ORR 50% (4 CR, 1 PR), DoR NR
•Safety data consistent with profile of BV
Ongoing Analysis of Correlation of CD30 expression with response
ICML2013, abstract 152
Other Potentially Promising Drugs/Combinations
 KW-0761, (CTCL and PTCL)
 HuMax CD4 (CTCL and PTCL)
 Aurora Kinase Inhibitor
 PI3K inhibitor IPI-145
 Plitidepsin
 L-asparaginase (NK/T cell Lymphoma)
 Pralatrexate-Romidepsin
 Romidepsin-Bortezomib
 Romidepsin-lenalidomide
 Carfilzomib
T-cell Lymphoma: New Treatment Paradigms
Chemotherapy
New Diagnosis
CHOP vs Other
Clinical Trials
Relapse
Novel
Treatment
Clinical Trials
Transplantation
Changing Standard Treatment Paradigms
Moving New Therapies Upfront?
Pharma/Registration/FDA guided approaches = X+CHOP vs CHOP
Ongoing or planned randomized upfront studies

BV+CHP vs CHOP (NCT01777152)

Romi+CHOP vs CHOP (NCT01796002)

Belinostat+CHOP vs CHOP (NCT01839097)

?Aurora kinase + CHOP vs CHOP

?HuMax CD4 + CHOP vs CHOP
Maintenance Strategies

CHOP +/- Pralatrexate maintenance (NCT01420679)
Consolidation

High dose + autoSCT

High dose + autoSCT + romidepsin (NCT01908777)
Optimize Treatment in TCL: More Questions than Answers
Frontline setting



CHOP is inadequate for most
Standard of care should be clinical trial when possible
Is adding a new drug to CHOP a winning strategy?
• Entirely new regimens? e.g. SMILE for NK/T
• Novel biologics based therapy?
• HD consolidation vs. maintenance strategies?
Relapse/refractory setting



When to prioritize chemo over biologics?
Is there an algorithm to cycle through various biologics?
SCT vs. maintenance?
Acknowledgement
Lymphoma program, Weill Cornell Medical College
• John Leonard, M.D.
• Morton Coleman, M.D.
• Richard Furman, M.D.
• Peter Martin, M.D.
Lymphoma program, MSKCC
• Steve Horwitz, M.D.