Systemic T-cell Lymphoma

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Clinical Exchanges in T-cell
Lymphomas: Expert Insight
into Current Issues and
Future Directions
Steven Horwitz, MD
Memorial Sloan Kettering Cancer Center
New York, NY
WHO 2008 CLASSIFICATION OF MATURE T/NK-CELL
NEOPLASMS
T-cell prolymphocytic leukemia
Mycosis fungoides
T-cell large granular lymphocytic leukemia
Sezary syndrome
Chronic lymphoproliferative NK cells
Primary cutaneous CD30+
lymphoproliferative
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
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+ Tcell lymphoma (provisional)
Use of Term PTCL

Peripheral T-cell lymphoma is a mature T-cell
lymphoma
 Cutaneous T-cell lymphoma: Largely (but not always) indolent
 Peripheral T-cell lymphoma::Mostly aggressive, in general poor
prognosis with a few exceptions
 Peripheral T-cell lymphoma-NOS: Most common subtype of
PTCL
NOS = not otherwise specified
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
Sezary syndrome
Subcutaneous panniculitis-like
Primary cutaneous ALCL
Lymphomatoid papulosis
Primary cutaneous small/medium CD4+ Tcell lymphoma
Primary cutaneous aggressive
epidermotropic CD8+ cytotoxic 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)
Cancers of Immature T-cells
lymphoblastic lymphoma and acute
lymphoblastic leukemia
Peripheral T-cell Lymphomas, PTCL refers to usually aggressive
systemic T-cell lymphomas (Clinical Definition)
“Usually Aggressive Systemic Tcell Lymphoma (PTCL)”
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*
“Aggressive CTCL”
“Usually Indolent CTCL”
Mycosis Fungoides
Primary cutaneous aggressive
Sezary syndrome
epidermotropic CD8+
Subcutaneous panniculitis-like
cytotoxic T-cell lymphoma
Primary cutaneous ALCL
Lymphomatoid papulosis
Primary cutaneous small/medium
CD4+ T-cell lymphoma
Hepatosplenic T-cell lymphoma (may be
derived from an immature T-cell)
*skin lesions are common in these
entities
Cancers of Immature T-cells
lymphoblastic lymphoma and acute
lymphoblastic leukemia
Expert Agreement: Consensus Diagnosis
Subtype
Agreement
Subtype
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%
ALCL = anaplastic large-cell lymphoma
ATLL = adult T-cell leukemia/lymphoma
Vose J, et al. J Clin Oncol. 2008;26:4124-4130.
Agreement
International PTCL Study
Major NHL Types by Region
Percent
North
America
Europe
Asia
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 J, et al. J Clin Oncol. 2008;26:4124-4130.
Prognosis:
Overall and Failure-free Survival
1.0
Peripheral T-cell Lymphoma-NOS
Proportion
0.9
0.8
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
Time
Vose J, et al. J Clin Oncol. 2008;26:4124-4130.
11
12
13
14
15
16
17
18
Mature T and NK Lymphomas:
FFS of Different Histologies
1.0
0.9
Proportion
0.8
ALCL ALK+
0.7
0.6
0.5
0.4
ALCL ALK-
0.3
AITL
0.2
PTCL
NK/T-nasal type
EATCL
0.1
ATLL
0.0
0
1
2
3
4
5
6
7
8
9
10
Time
.
Vose J, et al. J Clin Oncol. 2008;26:4124-4130.
11
12
Prognosis in Mycosis Fungoides and
Sezary Syndrome
Disease-Specific Survival by Stage
Kim YH, et al. Arch Dermatol. 2003;139:857-866.
Risk of Progression by Stage
ISCL/EORTC Revisions to the
Classification and Staging of
Mycosis Fungoides and Sezary Syndrome
T (Skin)
T1
Limited patch/plaque
(< 10% of total skin surface)
T2
Generalized patch/plaque
(> 10% of total skin surface)
T3
Tumors
T4
Generalized erythroderma
M (Viscera)
N (Nodes)
N0
No clinically abnormal LNs
N1
Clinically abnormal LNs; histopath
Dutch Gr 1 or NCI LN0-2 (clone +/-)
N2
Clinically abnormal LNs; histopath
Dutch Gr 2 or NCI LN3 (clone +/-)
N3
Clinically abnormal LNs; histopath
Dutch Gr 3-4 or NCI LN4 (clone +/-)
Nx
Clinically abnormal LNs, no histo info
B (Blood)
M0
No visceral involvement
B0
No significant blood involvement
M1
Visceral involvement
B1
Low blood tumor burden
B2
High blood tumor burden
Olsen E, et al. Blood . 2007;110:1713-1722.
Spectrum of CD30-Positive Cutaneous
Lymphoproliferative Disorders




Lymphomatoid papulosis (ALK-)
Primary cutaneous ALCL (usually ALK-)
Systemic ALCL with skin involvement (ALK+/-)
All CD30+ and rearranged TCR genes
Primary Cutaneous
ALCL
1.0
0.9
0.8
Proportion
0.7
0.6
ALCL, ALK+
0.5
0.4
ALCL, ALK-
0.3
0.2
0.1
Transformed MF
PTCL-NOS
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
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 J, et al. J Clin Oncol. 2008;26:4124-4130.
.
13
14
Case Study




A 68-year-old woman presents with swollen
cervical lymph nodes
Other complaints include low-grade fever and
fatigue
The only abnormal physical finding was the
presence of prominent palpable cervical,
axillary, and groin lymph nodes
She is prescribed a course of antibiotics
Case Study

Patient returns reporting no improvement
following antibiotic treatment

Excision of a left cervical lymph node showed
marked proliferation of carbonizing vessels and
a diffuse infiltrate of T-cells that was:
CD4 positive
CD20 positive
CD10 positive
CD30 weakly positive (5-10% of cells)
CD2 negative
ALK negative
CD5 negative
Polling Question 1
The most likely diagnosis is?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
Case Study




PET/CT shows diffuse lymphadenopathy (LAN)
Bone marrow biopsy shows small T-cells similar
to those seen in the nodes
Multiple chemistry panels were all normal except
LDH 414 U/L; ECOG Performance Status is 1
Prognostic scores:
– International Prognostic Index (IPI) score (age,
stage, LDH) and Prognostic Index for PTCLU
(PIT) score (age, LDH, marrow) are 3
Polling Question 2
What is her estimated 5-year OS with
standard-dose CHOP?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
Polling Question 3
She is otherwise healthy and has a left
ventricular ejection fraction of 60%. Which of the
following is true about initial therapy for her?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
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)
• 7 DSHNHL trials enrolling 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 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 N, et al. Blood. 2010;116:3418-3425.
Treatment and Prognosis of Mature T-cell and
NK-cell Lymphoma: Event-free survival
Younger patients treated on NHL-B1/Hi-CHOEP trial
EFS
ALCL, ALK+
Schmitz N, et al. Blood. 2010;116:3418-3425.
EFS
Other subtypes
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


PTCL
39%
AITL
33%
ALCL
16%
Med age
46.5
(30-65)
AA-IPI
L-LI
49%
HI-H
51%
TBI + CY-ASCT
Median F/U: 33 months
CR/CHOP 39%
PR/CHOP 40%
Reimer P, et al. J Clin Oncol. 2009;27:106-113.
ASCT
66%
POD
29%
(22% CHOP)
Autologous stem cell transplantation as firstline therapy in PTCL: Survival
Disease-free
survival53%
3-year
DFS:
1
1
0,8
0,8
DFS probability
Survival probability
Overall survival
3-year
OS: 48%
0,6
0,4
0,2
0,6
0,4
0,2
0
0
0
12
24
36
48
Time (months)
Time
(months)
(n=83)
(n=83)
Reimer P, et al. J Clin Oncol. 2009;27:106-113.
60
0
12
24
36
48
Time (months)
(n=55)
(n=83)
Time (months)
60
Case Study






She is treated with CHOP followed by HDTASCT and is in remission for 2 years
A follow-up CT scan shows new inguinal
lymphadenopathy up to 3 cm
Biopsy shows recurrent AITL
She is now 70 years old
She is having mild fatigue and again develops
low-grade fevers
You discuss therapeutics options at this time
Polling Question 4
What do you recommend?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
PROPEL Pivotal Trial: Pralatrexate in
Relapsed/Refractory PTCL
N=115
• Single-arm
• Phase II
• Relapsed or
refractory PTCL
Pralatexate 30 mg/m² IV
x 6 weeks in 7 week
cycles*
Primary endpoint
• Response rate
Secondary 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.
PROPEL: Response Analysis by Subsets
Number of
Patients
Proportion of
Patients
ORR
Age
• < 65 years
• ≥ 65 years
70
39
64%
36%
27%
33%
Number prior systemic
regimens
• 1
• 2
•≥3
23
29
57
21%
27%
52%
35%
24%
30%
Prior transplant
• Yes
• No
18
91
17%
83%
33%
29%
Histology
• PTCL-NOS
• AILT
• ALCL
• Transformed MF
• Other
59
13
17
12
8
54%
12%
16%
11%
7%
32%
8%
35%
25%
38%
Factor
O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
PROPEL
Adverse Events ≥ Gr 3 Occurring in ≥ 3% of Patients (n=111)
Adverse event
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’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
Pivotal Trial of Romidepsin in
Relapsed/Refractory PTCL
N=131
• Single-arm
• Phase II
• PCTL failing ≥1
prior systemic
therapy
• Systemic disease

Romidepsin 14 mg/m2 IV
on Days 1,8,15 every 28
days
T-cell lymphoma subtypes (n):
 PTCL-NOS (53)
 AITL (21)
 ALCL (ALK-1-neg) (16)
 Other (10)
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
 Median age: 61 years (range, 20-83)
 Median of 2 prior regimens (range, 1-8)
 38% refractory to most recent therapy
Coiffier B, et al. J Clin Oncol. 2012;30:631-636.
Romidepsin in Relapsed/Refractory PTCL





ORR (by IRC): 25% (33/130)
15% CR
Median duration of response: 17 months (<1 to 34.0+
months
89% of patients in CR/CRu had no disease progression
after median follow-up of 13.4 months
Safety profile consistent with CTCL studies
– Most common grade ≥3 AEs: thrombocytopenia (24%);
neutropenia (20%), and infections (19%)
Coiffier B, et al. J Clin Oncol. 2012;30:631-636.
IRC-Assessed PFS with Romidepsin in
Relapsed/Refractory PTCL
All patients: 4 months
Patients in Cr/CRu: 18 months
Patients in PR: 7 months
Patients in SD: 6 months
©2012 by American Society of Clinical Oncology
Coiffier B, et al. J Clin Oncol. 2012;30:631-636.
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
Dysgeusia
Events with a missing toxicity grade are included.
≥ Grade 3
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
G2/M cell cycle
arrest and
apoptosis
 Preclinical activity observed both
in vitro and in vivo
ADC=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
• Single-arm
• Phase II
• Relapsed or
refractory
systemic ALCL
Brentuximab vedotin 1.8
mg/kg IV every 21 days
 Median age: 52 years (range, 14-76)
 Median of 2 prior regimens (range, 1-6)
 62% refractory to frontline therapy
Shustov AR, et al. ASH 2010. Abstract 961.
Primary endpoint
• ORR by independent
review
Secondary endpoints
• CR rate
• Duration of response
• PFS
• OS
Responses to Brentuximab Vedotin in
Relapsed/ Refractory Systemic ALCL
N=58
Overall response rate (95% CI)
IRF
86% (75, 94)
Complete remission
53%
Partial remission
33%
Stable disease
3%
Progressive disease
5%
Histologically ineligible
3%
Not evaluable
2%
Outcomes
Median duration of OR (95% CI)
12.6 months
Median duration of CR (95% CI)
13.2 months
Median PFS (95% CI)
13.3 months
Median OS
Not reached
Shustov AR, et al. ASH 2010. Abstract 961.
Polling Question 5
What do you see as the greatest barriers to
successful treatment of your patients with PTCL?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s) will
be discussed in the subsequent slides and commentary.
Case Study



A 41-year-old man presents with stage IA
mycosis fungoides
He is treated with topical NM
He has some response but then progresses and
changed to narrow-band UVB phototherapy
Management of Stage IB/IIA Disease
(Generalized Patch/Plaque, T2)
 CR rate 45-90%
Therapy
CR Rate
ORR
Mechlorethamine
(HN2)
45-70%
75-90%
Psoralen + ultraviolet
A (PUVA)
50-80%
55-95%
1. Querfeld C, et al. Arch Dermatol. 2005;141:305-311.
2. Gathers RC, et al. J Am Acad Dermatol. 2002;47:191-197.
Case Study

The patient does reasonably well on/off NB-UVB
for about 2 years then develops a tumor lesion
on the eyelid
Case Study


Biopsy shows tumor but no evidence of large
cell transformation (<25% large cells)
No other tumors or extracutaneous disease
Polling Question 6
What do you do now?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be
discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
TSEBT + Chemotherapy (cyclophos, dox, vp-16, vincristine)
VS
Sequential topical therapies (NM- +/- MTX- PUVA-TSEBT-Chemo)
N=103
CR 38% vs 18%
Conservative N=51
Stage IA-IIA
31
DFS-ND
NM=51
Stage IIB
12
OS-ND
MTX-16
Stage III
2
PUVA-26
Stage IV
58
TSEBT-13
Chemo-14
vs
Topical therapy
Percent Surviving
EBRT + Chemotherapy
No survival difference
100
90
80
70
60
50
40
30
20
10
0
ALL
No of
Total Deaths
Combination 52
Conservative 51
21
19
P=.72
12
24
36
48
60
72
84
96 108
Survival (mo)
Percent Surviving
Low Risk (IA–IIA)
Higher Risk (≥IIB)
Overall survival—All pts
100
90
80
70
60
50
40
30
20
10
0
Overall survival—Advanced
No of
Total Deaths
P=.74
12
Kaye FJ, et al. N Engl J Med. 1989;321:1784-1790.
12
12
Combination 28
Conservative 28
24
36
48
60
72
Survival (mo)
84
96 108
Selected
Systemic
Therapies
for
MF
Selected Systemic Therapies for Mycosis
Fungoides
Agent
Response
Rate
CR
Comments
45–55%
6%
≥Stage IIB
29.5%
2%
≥Stage IIB
Denileukin diftitox
36%
12%
18ug/kg
Romidepsin
38%
7%
≥Stage IIB
Gemcitabine
68%
8%
1000 mg/m2, 3–4 wk
CAVE + TSEB
88%
31%
≥Stage IIB
Pralatrexate
53%
6%
Stage IIB
Bexarotene
Vorinostat
Horwitz SM. Clin Lymphoma Myeloma. 2008;8(suppl 5):S187
Case Study

He undergoes radiation local electron beam
therapy followed by maintenance low-dose
bexarotene
Case Study

He is well for 2 years but then develops new
plaques that fail to respond to increased dose of
bexarotene and addition of phototherapy
Polling Question 7
What is your next step?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s) will
be discussed in the subsequent slides and commentary.
DISCUSSION
Please click on the supplemental tab below to
listen to Dr. Horwitz’s response to this case
study question.
Pralatrexate Response by CTCL Subtype and
Stage
N = 54
Optimal dose = 15 mg/m2
Response rate
Rate at Optimal
CTCL Subtype
at ≥ 15 mg/m2
Stage
Dose/Sched
(per Investigator)
3/4 weeks
% (n/N)
% (n/N)
MF
All patients
IB
IIB
III
IVA
IVB
Overall
Response
Rate
% (n/N)
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)
45% (13/29)
51% (21/41)
41% (22/54)
Horwitz SM, et al. Blood. 2012 Mar 6 [Epub ahead of print].
Pralatrexate for CTCL:
Progression-Free Survival
Cohort >15 mg/m2 N=41
Median PFS: 388 days
Horwitz SM, et al. Blood. 2012 Mar 6 [Epub ahead of print].
Bendamustine in T-cell lymphoma (BENTLY Trial)
N=60
• Multicenter,
single-arm,
phase II study
• Relapsed or
refractory Tcell lymphoma
• ≤ 3 prior lines
chemotherapy
Bendamustine 120
mg/m2 IV on Days 1,2
every 3 weeks for 3
cycles
T-cell lymphoma subtypes (n):
 AILT (24)
 PTCL-NOS (17)
 ALCL (4)
 EATL (1)
 MF (1)
Damaj G, et al. 11th ICML; Lugano 2011. Abstract 126.
If no PD:
Additional 3 cycles
bendamustine
Primary endpoint
• ORR (IWC 1999 criteria)
Secondary endpoints
• Safety, tolerability
• Duration of response
• PFS
• OS
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 TCL
N=24
• T-cell lymphoma
(other than MF)
• WHO PS ≤3
• Previously treated or
untreated but not
suitable for standard
therapy
Lenalidomide 25 mg PO
QD on days 1-21 of each
28-day cycle
Until disease
progression, death, or
unacceptable toxicity
MF=mycosis fungoides.
Dueck G, et al. Cancer. 2010;116:4541-4548.
Primary endpoint
• ORR
Secondary endpoints
• PFS
• OS
• Safety
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
33
Dueck G, et al. Cancer. 2010;116:4541-4548.
Phase II Trial of Belinostat in Relapsed/Refractory
T-Cell Lymphomas
CR/PR/SD
Belinostat 1000 mg/m2, IV
days 1-5, q 21 days x 2 cycles
PODPD
Outcome
Response
ORR
Stable disease
Median response duration
Grade 3/4 adverse events
Grade 2 QTcF Prolongation
Belinostat
up to 6 more cycles or
until PD
Off study
CTCL
PTCL
(N = 21)
(N = 29)
(n = 19)
(n = 29)
6 (32%)
4(14%)
4
18
268+ days
273 days
pruritis, cytopenias (4-6%)
7
Pohlman et al. ASH 2009; abstract 920
Pohlman B, et al. ASH 2009. Abstract 920.
Pivotal Trial >100 pts is accrued,
awaiting data (Early 2012)
Aurora Kinase Inhibitor Alisertib (MLN8237) in
Aggressive B-cell, T-cell NHL
Relapsed/refractory,
aggressive B-cell or Tcell NHL
(N=48)
Alisertib 50 mg PO BID x
7 days in 21-day cycles
 Multicenter, phase II trial
 Median age: 67 years (range, 32-85)
 T-cell lymphoma: 17%
 Median number prior regimens: 3
Friedberg JW, et al. ASH 2011. Abstract 95.
Efficacy of Alisertib by Histology
Category
Response (PR+CR)
n (%)
B-cell lymphoma
DLBCL
3 (20%)
Mantle cell lymphoma
3 (23%)
Transformed follicular
2 (40%)
Burkitt lymphoma
1 (100%)
T-cell lymphoma (PTCL)
4 (57%)
Friedberg JW, et al. ASH 2011. Abstract 95.
Common Serious Adverse Events with
Alisertib
Patients (N = 48)
Event
Number
Percent
Neutropenia*
30
65
Thrombocytopenia
15
31
Stomatitis
7
15
Fatigue
3
6
*7 cases of febrile neutropenia
• Four patients died on study during cycle 1:
– 2 of progressive DLBCL
– 1 of sepsis on day 14 (DLBCL)
– 1 of likely cardiac arrest—cause unknown (T-cell NHL)
Friedberg JW, et al. ASH 2011. Abstract 95.
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=38)
 ORR 79%; CR 45% after 2 cycles
 1-year OS: 55%
 Highly myelosuppressive
– Grade 3/4 neutropenia: 8%/92%
– Grade 3/4 infection: 61%
– Lymphocyte count ≥ 500/mm3 added to eligibility criteria after first 2 patients
died from infection
Yamaguchi M, et al. J Clin Oncol. 2011;29:4410-4416.
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
New Drug
Combination
SGN-35 or similar
New Drug
New Drug
Etc.
Alternating or Maintenance
Supplemental Information
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