Transcript characterization of t-cell lymphomas

INSIGHTS INTO OPTIMIZING
THERAPEUTIC APPROACHES
FOR T-CELL LYMPHOMAS
Integrating Current and Emerging
Agents/Regimens to Develop EvidenceBased Clinical Management Strategies
Faculty
Disclosures
Educational Objectives
After completing this program, participants should be able to:
1.
Distinguish between the various T-cell lymphoma subsets, including
the molecular, histopathologic, and clinical features that aid in
accurate diagnosis and guide treatment decisions
2.
Describe current treatment options for peripheral (PTCL) and
cutaneous (CTCL) T-cell lymphoma subtypes and how recent clinical
trial data with existing and emerging agents can be integrated into
evidence-based clinical management strategies
3.
Evaluate the efficacy and safety data from studies of current and
emerging treatment options to improve outcomes in patients with
PTCL and CTCL
4.
Summarize new data and possible treatment algorithms that can be
used in community practice to achieve the best outcomes for patients
PTCL and CTCL
CHARACTERIZATION OF
T-CELL LYMPHOMAS
T-cell Lymphomas (TCLs)
• TCLs account for 7%-10% of all Non-Hodgkin Lymphomas in
the US
• Most are clinically aggressive
• Heterogeneous in their clinical presentation, features, and
prognosis
• Challenges in treatment:
– Increasing number of subtypes, making it very difficult to understand
and diagnose these entities
– Each entity is encountered infrequently
– Lack of effective treatment
Gisselbrecht C, et al. Blood. 1998;92:76-82. Armitage J, et al. J Clin Oncol. 1998;16:2780–2795.
2008 WHO Classification of TCL
Mature T-/NK-cell Lymphomas
CTCL
Extranodal
Nodal
Leukemic
Mycosis Fungoides
(MF)
NK/TCL
Nasal Type
Peripheral TCL-NOS
Adult T-cell Leukemia/
Lymphoma
Transformed MF
Enteropathy- associated TCL
Anaplastic Large Cell
Lymphoma (ALK +/-)
Aggressive NK-Cell
Leukemia
Sézary Syndrome
Hepatosplenic TCL
Angioimmunoblastic
TCL
T-cell Prolymphocytic
Leukemia
Primary Cutaneous CD30+
T-cell Disorders
Subcutaneous
Panniculitis-like TCL
T-cell Large Granular
Lymphocytic Leukemia
Primary Cutaneous
Gamma/Delta TCL
Aggressive
Adapted from Swerdlow SH, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 2008.
CHARACTERIZATION OF
T-CELL LYMPHOMAS
PERIPHERAL T-CELL
LYMPHOMA (PTCL) SUBTYPES
Overview of PTCLs
• A rare heterogeneous group of NHL
• Refers to mature “post-thymic” T-cell lymphoma
• Characterized by the proliferation of abnormal
T lymphocytes
• Outcomes are poor
–
–
–
–
Low response rates
5-year OS ~32%
5-year failure-free survival ~20%
Most patients relapse within 2-3 years
Gisselbrecht C, et al. Blood. 1998;92:76-82. Armitage J, et al. J Clin Oncol. 1998;16:2780–2795. Weisenburger DD, et al. Blood.
2011;117:3402-3408.
Global Frequencies of PTCL
Subtypes
• PTCL– not otherwise specified (PTCL-NOS) is the most common
subtype
• Anaplastic large cell lymphoma (ALCL) ALK+/- and
angioimmunoblastic lymphoma are also common subtypes
1%
2%
2%
Peripheral T-cell lymphoma NOS
12%
Angioimmunoblastic
1%
26%
Natural killer/T-cell lymphoma
5%
Adult T-cell leukemia/lymphoma
5%
Anaplastic large cell lymphoma
ALK+
Anaplastic large cell lymphoma
ALKEnteropathy-type T-cell
7%
19%
10%
Primary cutaneous ALCL
10%
Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.
PTCL-NOS
Clinical Presentation
• Advanced stage disease with
BM, liver, spleen and other
extranodal involvement are
common
• B symptoms and para-neoplastic
symptoms are common
• PTCL-NOS diagnosis is made
when other specific entities have
been excluded; “waste-basket” of
PTCL
• The latter paradigm might be
changing based on GEP
signature studies
Images courtesy of Dr. Shustov.
AngioimmunoblasticT-cell Lymphoma
(AITL)
Clinical Presentation
• Generalized lymphadenopathy,
splenomegaly, hepatomegaly, skin and
bone marrow involvement are common
• Autoimmune phenomena are common
–
–
–
–
–
–
–
Pleural effusion, ascites
Arthralgia
Dermatitis
Coomb’s+ hemolytic anemia
Polyclonal hypergammaglobulinemia
Rh+, SMAb+, cold agglutinins
Commonly associated with EBV, however
the neoplastic cells are EBV negative
Images courtesy of Dr. Shustov.
Extranodal NK/T-cell Lymphoma,
Nasal Type
Clinical Presentation
•
Most prevalent in Asians, Native
American population of Mexico,
Central America and South
America; adult males
•
Strong association with EBV
•
Most commonly extranodal with
typical involvement in the nasal
cavity
– Extranasal sites include skin, soft
tissue, GI tract, and testis
•
Symptoms include nasal
obstruction, epistaxis, extensive
midfacial destructive lesions,
facial pain
•
Often localized to upper
aerodigestive tract at diagnosis
cCD3-CD2+CD56+cCD3+TIA1+GrB+
Images courtesy of Dr. Shustov.
Anaplastic Large Cell Lymphoma
(ALCL)
Clinical Presentation
• Two types of ALCL: ALK- and ALK+
• Clinical presentation similar; ALK+ > in
younger patients
• Important to distinguish ALK- disease
from:
– Primary cutaneous ALCL when skin
involvement is present
– EATL when GI involvement is present
• Majority of patients present with
advanced stage disease, involving both
LNs and extranodal sites
• B symptoms are very common;
paraneoplastic phenomena are also
common (pruritus, rash, arthralgia)
Images courtesy of Dr. Shustov.
PTCL Prognosis by Subtype
• Median OS for most subtypes
of PTCL is 1–3 years [1,2]
− 5-year OS is
approximately 26% [3]
− ALK+ ALCL is an
exception, with a 5-year
survival of 65%–90% [2]
OS (%)
The International PTCL and NK/TCL Study
ALCL, ALK+
ALCL, ALKAll NK/T-cell lymphomas
PTCL-NOS
AITL
Adult T-cell leukemia/lymphoma
100
90
80
70
60
50
40
30
20
10
0
0
2
4
6
8
10
Yrs
12
14
16
18
PTCL Subtypes
5-yr OS rate, %
ALK+ ALCL
ALK– ALCL
PTCL-NOS
AITL
NK/TCL
ATLL
70
49
32
32
32
14
International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130. [1] Armitage JO, et al. Ann Oncol. 2004;15:1447–1449.
[2] Savage KJ. Blood Rev. 2007;21:201–216. [3] Rüdiger T, et al. Ann Oncol. 2002;13:140-149.
20
CHARACTERIZATION OF
T-CELL LYMPHOMAS
CUTANEOUS T-CELL LYMPHOMA
(CTCL) SUBTYPES
Overview of CTCLs
• Characterized by skin lesions with epidermal and
dermal involvement
• 3 histological patterns:
– Epidermotrophic
– Dermal
– Subcutaneous
• Classified by their histological, cytogenetic, and
immunologic features
• Some subtypes are indolent
• Survival and management varies depending upon
clinical presentation and specific subtype
Rizvi MA, et al. Blood. 2006;107:1255-1264.
Swerdlow SH. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 2008.
CTCL Incidence
• CTCL represents 4% of all
NHLs
• Aged–adjusted incidence of 6
cases per 1 million
• Twice as common in men as in
women
• Incidence is increasing
• Incidence increases with age
– Average age of onset is between
50 and 60 years
Criscione VD, Weinstock MA. Arch Dermatol. 2007;143:854-859. Bradford P, Devesa S, Anderson WF, Toro JR. Blood.
2009;113:5064-5073. Figure reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY
CTCL Entities
Category
Neoplasm
Extranodal-cutaneous • Mycosis fungoides
• Sézary syndrome
Most common subtypes
• Primary cutaneous CD30+ lymphoproliferative
disorders
− Lymphomatoid papulosis
− Primary cutaneous ALCL
• Primary cutaneous  T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
Rosen S, Querfeld C. Hematology Am Soc Hematol Educ Program. 2006;2006:323–330.
Clinical Features—
Mycosis Fungoides (MF)
• Classical
– Persistent and progressive skin lesions
– Sun-protected skin
– Large (> 5 cm), pruritic, and multifocal
• Variations
– Unusual anatomic sites (palmoplantar,
isolated alopecia)
– Solitary lesion (pagetoid reticulosis)
– Clinical variations (hypopigmented)
– Association with masking clinical
conditions (ichthyosis)
• Long clinical course
• Stepwise clinical progression
Kinney MC, Jones D. Am J Clin Pathol. 2007;127:670-686.
Images courtesy of Dr. Foss
Clinical Features—
Sézary Syndrome (SS)
• Systemic and aggressive variant
• Exfoliative erythroderma, ectropion, alopecia, palmoplantar
keratoderma
• Severe pruritus
• Circulating, atypical, malignant T lymphocytes
– Sézary cells: CD3+, CD4+, CD5+, CD7+/–, CD8–, CD25+/–, CD26–, CD30-,
CD45RO+, CD52+, CD158+
Querfeld C, et al. Management of Hematologic Malignancies. 2011.
Prognosis by Stage in CTCL—
MF/SS
Disease-Specific Survival by Stage
Skin Stage at Diagnosis
Risk of Progression by Stage
10-Yr Relative Survival,%
P Value
T1
100
NS
T2
67
.002
T3
39
< .001
T4
41
< .001
1. Zackheim HS, et al. J Am Acad Dermatol. 1999;40:418-425. 2. Kim YH, et al. Arch Dermatol. 1996;132:1309-1313.
CURRENT THERAPEUTIC
OPTIONS FOR
PTCL AND CTCL
1ST-LINE TREATMENTS
NCCN Guidelines—
Initial Treatment of PTCL
Patient
Population
Stage
ALCL, ALK+
I, II
ALCL, ALK+
III, IV
PTCL, NOS
ALCL, ALK AITL
EATL
I-IV
Induction Therapy
Consolidation
Therapy
CHOP-21 or CHOEP-21* (3-6 cycles) ±
ISRT (30–40 Gy)
Not needed if in
remission
Multiagent chemotherapy* (6 cycles)
Consider
consolidation with
high-dose therapy
and stem cell rescue
for all patients except
low-risk (aaIPI)
• Clinical trial preferred
• Multiagent chemotherapy* (4-6 cycles)
± ISRT (30–40 Gy)
*Suggested regimens:
• CHOP-14 or CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisone)
• CHOEP (cyclophsophamide, doxorubicin, vincristine, etoposide, prednisone)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine,cyclophosphamide, doxorubicin)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose
methotrexate and cytarabine
• CHOP followed by IVE (ifosfamide, etoposide, epirubicin) alternating with intermediate-dose
methotrexate [Newcastle Regimen] [studied only in patients with EATL]
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose
methotrexate and cytarabine
NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.
Standard of Care for PTCL
• Historical approaches
– CHOP-based strategies in first-line therapy for patients
with PTCL
• ORR: 60%-70%, CR: 40%-60%
– Relapse @ 2 years >70%-80% in most series
• Limited clinical data due to relative rarity and
heterogeneity of subtypes
• New approaches
– CHOP as platform?
– High dose chemotherapy and autologous stem-cell
transplant in PR1/CR1
– New agents
NCCN Guidelines—
Initial Treatment of CTCL (MF/SS)
Patient Population
Primary Therapy
Stage IA
Skin directed therapies
Stage IB-IIA
Generalized skin treatment ± adjuvant local skin
treatment
Stage IIB
Stage III
Generalized
tumor,
transformed,
and/or
folliculotropic
disease
Limited extent
tumor disease
± patch/plaque
disease
•Local RT
•Systemic therapies (Category A) ± skin directed
therapies ±RT
Generalized extent
tumor, transformed,
and/or folliculotropic
disease
•Total skin bean electron therapy (TSBE)
•Systemic therapies (Category A, B or C) ± skin
directed therapies
No blood involvement
Skin directed therapy
Blood involvement
Systemic therapies (Category A) ±skin directed
therapy
Sezary Syndrome
•Systemic therapies (Category A)
• Combination therapies
Non Sezary or Visceral disease
Systemic therapies (Category B or C)
Multiagent chemotherapy ±RT
Stage IV
NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.
Treatment Algorithm—MF/SS
IA
(limited patch,
plaque)
Topical
corticosteroids
(class I)
Bex gel
IB, IIA (generalized
patch, plaque)
IIB
(tumors)
III
(erythroderma)
IVA, B
(visceral
involvement)
Photopheresis ± IFN ± bex
Alemtuzumab
Romidepsin
PUVA (± IFN or ± retinoid)
NM
Bex capsules
Bexarotene
capsules
Vorinostat
UVB
Denileukin diftitox
Spot radiation therapy
Chemotherapy or AlloSCT
Standard of Care for CTCL—MF/SS
• Low CR rate (≤ 10%) for all medications approved for
MF over the past 15 yrs
– Most new drugs for MF expected by the FDA to
achieve 30% ORR (PR + CR)
• Patients require long-term treatment to prevent
progression
• As opposed to other areas of oncology, treatments are
often used multiple times during the course of the
disease
– MR or PR not considered failures
CURRENT THERAPEUTIC
OPTIONS FOR PTCL
RELAPSED/REFRATORY PTCL
• Pralatrexate
• Romidepsin
• Belinostat
• Brentuximab
NCCN Guidelines—R/R PTCL
Candidates for
High-dose
Therapy
Complete or Partial
response
Clinical trial or
2nd-line therapy†
No response
Non-candidates
for High-dose
Therapy
Clinical trial or
2nd-line therapy* or
Palliative RT
Clinical trial or
Allogenic transplant or
High-dose therapy
w/autologous
transplant
Clinical trial or
Alternative 2nd-line or
Best supportive care or
Palliative RT
*Alemtuzumab,
bendamustine, belinostat, bortezomib, brentuximab vedotin (sALCL excluding primary
cutaneous ALCL, sCD30+ PTCL), cyclosporine (AITL), dose-adjusted EPOCH, gemcitabine,
pralatrexate, romidepsin
†Bendamustine,
belinostat, brentuximab vedotin (sALCL excluding primary cutaneous ALCL, sCD30+
PTCL), DHAP, ESHAP, dose-adjusted EPOCH, GDP, GemOx, ICE, pralatrexate, romidepsin
NCCN Guidelines. Peripheral T-Cell Lymphomas. Version 2.2015
Relapsed/Refractory PTCL—SingleAgent or Combination Therapies?
• Factors to consider: patient specific
– Performance score, comorbidities
– Goals of therapy: palliative vs curative intent
• Factors to consider: regimen specific
– Toxicities of the regimen
– ORR if transplant candidate
– Meaningful endpoints: PFS, response rate, and
duration
– Relevant targets if targeted therapies are available
NCCN Guidelines. Peripheral T-Cell Lymphomas. Version 2.2015
Relapsed/Refractory PTCL—FDA
Approved Agents
Agent
Regimen
N
ORR, %
CR, %
Response
Duration, Mos
Pralatrexate[3]
(Pivotal)
30 mg/m2 weekly x 6
of 7 wks
111
29
11
10.1
Romidepsin[1]
(NCI)
14 mg/m2 weekly x 3
every 28 days
47
38
18
8.9
Romidepsin[2]
(Pivotal)
14 mg/m2 weekly x 3
every 28 days
131
25
14
17.0
Brentuximab
vedotin[4] (ALCL)
1.8 mg/kg every 21 days
58
86
57
12.6
Belinostat[5]
1,000 mg/m2 once daily
on days 1-5 of a 21-day
cycle
120
25.8
10.8
8.4
1. Piekarz RL, et al. Blood. 2011;117:5827-5834. 2. Coiffier B, et al. J Clin Oncol. 2012;30:631-636. 3. O’Connor OA, et al. J Clin
Oncol. 2011;29:1182-1189. 4. Pro B, et al. J Clin Oncol. 2012;30:2190-2196. 5. O’Connor OA, et al. J Clin Oncol. 2015; 33:24922499.
PRALATREXATE—Antineoplastic
Folate Analog
Pralatrexate>>>MTX
RFC-1
Extracellular
Folate
PDX
Cell membrane
DNA
FPGS
DHF
dTMP
DHFR
TS
PDX-Glu(n)
Cytosol
THF
dUMP
AMP
RNA
DNA
IMP
5.10methenyl
THF
10formyl
THF
AICARFT
GARFT
PRPP
GMP
FDA granted accelerated approval in September 2009 for R/R PTCL
Pralatrexate [package insert]. Westminster, CO: Allos Therapeutics, Inc. Revised 9/2009.
PRALATREXATE—R/R PTCL
Patients
(N=109
evaluable)
ORR
29%
• CR
11%
• PR
18%
Median DOR
10.1 months
Median PFS
3.5 months
Median OS
14.5 months
1.00
Proportion
Outcome
0.75
0.50
0.25
Permanently censored (eg, transplant) (n = 8)
Continue in follow-up for response (n = 8)
0
3
6
• Most common grade 3/4 AEs (n=111 evaluable):
–
–
–
–
Thrombocytopenia (32%)
Mucositis (22%)
Neutropenia (22%)
Anemia (18%)
O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.
9
12
Months
15
18
ROMIDEPSIN—HDAC Inhibitor
Histone acetylation/
Transcription induction[2]
Gene regulation[1]
Protein acetylation[3]
HAT
Hsp70
+ HDI
HDAC
AcAc
Hsp70
Proteasome
Hsp70 acetylation and
client protein degradation
Romidepsin
Activation of apoptosis[4]
HDI –
Cell cycle arrest[4]
100
80
60
40
20
0
HDI
30
Counts
Counts
Control
Anti-angiogenesis[5]
Caspase 3
Caspase 8
PARP
20
BAX
10
0
FL2-A
+
BAK
FL2-A
FL2-A
1. Peart MJ, et al. Proc Nat Acad Sci. 2005;102:3697-3702. 2. Bolden JE, et al. Nat Rev Drug Discov. 2006;5:769-784. 3. Wang Y, et al.
Biochem Biophys Res Commun. 2007;356:998-1003. 4. Celgene Corp. Data on file. 5. Kwon HJ, et al. Int J Cancer. 2002;97:290-296.
ROMIDEPSIN—R/RPTCL
N= 131
• PTCL (MF or SS excluded)
• Failed ≥1 prior systemic therapy
• ECOG PS ≤2
Outcome
Patients
ORR
25%
• CR/CRu
15%
• PR
11%
• SD
25%
•
•
•
Romidepsin 14 mg/m2 IV
Days 1,8, and 15 q28d
Response by Primary
Diagnosis
Patients
PTCL-NOS
29%
AITL
30%
ALK-ALCL
24%
Grade 3/4 AEs (> 10%): neutropenia, thrombocytopenia, anemia, infections
FDA granted accelerated approval in June 2011 for treatment of patients with
PTCL who have received ≥ 1 prior therapy
Ro-CHOP vs CHOP ongoing in Europe
Coiffier BD, et al. J Clin Oncol.2012;30:631-636
BELINOSTAT—HDAC Inhibitor
Belinostat
FDA granted accelerated approval in July 2014
for R/R PTCL
Belinostat [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. Revised 7/2104.
BELINOSTAT— R/R PTCL
BELIEF Study
• PTCL (N=129)
• Failed ≥1 prior systemic therapy
• Platelets ≥ 50,000/µL
• No prior HDACi therapy
Response
CR+PR
CR
PR
SD
PD
NE
Belinostat
1000mg/m2
Day 1-5 x 21 day cycle
Efficacy Analysis Set
n=120; n(%)
31 (26) [95% CI, 18-35]
13 (11) [95% CI, 6-18]
18 (15)
18 (15)
48 (40)
23 (19)
• Median OS (n=120): 7.9 months
• Grade 3-4 AEs (≥ 5%): thrombocytopenia (13%), neutropenia (13%), anemia
(10%), dyspnea (6%), pneumonia (6%), and fatigue (5%)
O’Connor O. et al. ASCO 2013. Abstract 8507.
BRENTUXIMAB VEDOTIN—
Antibody-drug Conjugate
FDA-approved in 2011 for:
• HL after failure of ASCT or after failure of ≥ 2 multiagent chemotherapy regimens
in patients who are not ASCT candidates
• Systemic ALCL after failure of at least 1 prior multiagent chemotherapy regimen
Brentuximab vedotin [package insert]. Bothell, WA:Seattle Genetics, Inc. Revised 9/2011.
BRENTUXIMAB—R/R PTCL
Pivotal Study
• R/R HL
• Age > 12 years
• Measurable disease FDG-avid
• ECOG 0-1
Brentuximab vedotin
• 1.8 mg/kg IV every 21 days
• Max 16 cycles for SD or better
• Restage * at cycles 2, 4, 7, 10,
13, 16
Clinical Response
N=58
ORR (95% CI)
86% (75, 94)
CR rate (95% CI)
59% (45, 71)
Median Duration
OR (95% CI)
Response in patients with CR (95% CI)
Months
13.2 (5.7, NE)
Not reached (13, NE)
• Kaplan-Meier estimated 4-year survival rate: 64% (95% CI, 51%-76%)
• Grade 3/4 AEs (>10%): neutropenia (21%), thrombocytopenia (14%), and
peripheral sensory neuropathy (12%)
Pro B, et al. J Clin Oncol. 2012;30:2190-2196
BRENTUXIMAB—R/R PTCL
•
•
•
•
Phase II
R/R AITL, R/R PTCL-NOS
Median of 2 prior therapies (1-9)
63% refractory to most recent
therapy
Clinical
Response,
n(%)
Brentuximab vedotin
1.8 mg/kg IV every 21 days until
progression or unacceptable
toxicity
PFS
AITL
(n=13)
PTCLNOS
(n=22)
Total
7 (54)
7 (33)
14 (41)
CR
5 (38)
3 (14)
8 (24)
PR
2 (15)
4 (19)
6 (18)
SD
3 (23)
3 (14)
6 (18)
PD
3 (23)
11 (52)
14 (41)
ORR
• Grade 3/4 AEs: neutropenia (14%), peripheral sensory neuropathy (9%), and
hyperkalemia (9%)
Horwitz SM, et al. Blood. 2014;123:3095-3100.
CURRENT THERAPEUTIC
OPTIONS FOR CTCL
RELAPSED/REFRATORY CTCL
• Romidepsin
• Vorinostat
• Pralatrexate
• Brentuximab
NCCN Guidelines—R/R CTCL
• Patients who relapse may respond when retreated with the same regimen
• Patients with relapse or persistent disease after primary treatment should
be considered for clinical trial
Suggested Treatment Regimens for Second-line Therapy of CTCL
(in alphabetical order)
CR/PR or Inadequate Response
Refractory Disease or Progression
•Retreatment with initial therapy
•Alemtuzumab
•Allogenic transplant
•Clinical trial
•Combination therapy
•Multiagent chemotherapy
•Systemic chemotherapy
•Systemic therapy
•Systemic therapy ± skin-directed therapy
•TSEBT
NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.
Relapsed/Refractory CTCL—Select
Systemic Agents
Agent
Romidepsin[1]
Regimen
• 14 mg/m2 on days 1, 8, and 15 of
a 28-day cycle.
Vorinostat[2]
• 400 mg once daily
• Could be reduced for toxicity to
300 mg orally daily or 300 mg
orally five days a week
Pralatrexate[3]
• 15 mg/m2 weekly for 3 weeks of a
4-week cycle
Brentuximab[4]
N
ORR, %
Response
Duration, Mos
167
35
11-15
74
30
5
54
41
NR
48
71
9-10 (MF)
• 1.8 mg/kg every 21 days.
• Patients achieving CR received 2
•
additional doses
PR after 8 cycles could receive up
to 16 doses
1. FDA Approval for Romidepsin. Available at http://www.cancer.gov/about-cancer/treatment/drugs/fda-romidepsin. 2. FDA Approval for
Vorinostat. Available at http://www.cancer.gov/about-cancer/treatment/drugs/fda-vorinostat. 3. Horwitz SM, et al. Blood.
2012;119:4115-4122. 4. Duvic M, et al. Blood. 013, 122 : 367.
HDAC INHIBITORS IN MF/SS
Stage
All stages
IB-IIA
IIB
III
IV
Romidepsin
GPI Study[1]
NCI Study[2]
N
ORR, %
N
ORR, %
96
34
71
34
28
25
8
62.5
21
43
15
47
23
39
6
33
24
33
41
22
Vorinostat[3]
Stage
N
ORR, %
All stages
74
29.7
IB-IIA
13
30.8
≥ IIB
SS
61
30
29.5
33.3
•
Romidepsin: FDA-approved in 2009 for use in patients with CTCL who
have received ≥ 1 prior systemic therapy
•
Vorinostat: FDA-approved in 2006 for use in patients with of CTCL who
have progressive, persistent, or recurrent disease on or following two
systemic therapies
1. Whittaker SJ, et al. J Clin Ocol. 2010;28:4485-4491. 2. Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417. 3. Olsen EA, et al.
J Clin Oncol. 2007;25:3109-3115.
PRALATREXATE—R/R CTCL
• Phase I
• R/R CTCL (n = 54)
• Failed ≥ 1 prior therapy
Pralatrexate
15 mg/m2 weekly for 3 weeks of a
4 week cycle
Cohort >15 mg/m2 N=41
Median PFS: 388 days
• ORR: 41% (22/54)
• Grade 3-4 AEs: mucositis (17%), thrombocytopenia (3%)
Horwitz SM, et al. Blood. 2012;119:4115-4122.
BRENTUXIMAB—R/R CTCL
• Phase II; N = 48
• Primary cutaneous CD30+
including LyP and pc-ALCL
or CD30+ MF
• Failed ≥ 1 prior therapy
Primary
Diagnosis
MF
LyP
pc-ALCL
LyP/MF
ALCL/LyP
Total pts
28
9
2
7
2
Brentuximab
• Infused at 1.8 mg/kg every 21 days
• Patients achieving CR received 2
additional doses
• PR after 8 cycles could receive up
to 16 total doses
Response
Time to Response Median DOR
(ORR: 71%)
(wks)
(wks)
12PR, 2 CR
50%
10.5
13.5
5 CR, 4 PR 100%
3
23
2 CR
100%
3
18
6 CR, 1 PR 100%
3
18
2 CR
100%
• The most common AE of any grade was peripheral neuropathy (60%)
• Grade 3/4 AEs: neutropenia (n=5), nausea (n=2), chest pain (n=2), deep vein
thrombosis (n=1), transaminitis (n=1) and dehydration (n=1).
Duvic M, Tetzlaff M, Clos AL, et al. 2013 ASH Annual Meeting. Abstract 367. Duvic M, et al. Blood . 2013;122:367.
EMERGING TREATMENT
STRATEGIES FOR
PTCL AND CTCL
• Alisertib
• IPI-145 (duvelisib)
• Crizotinib
• Mogamolizumab
• Tipifarnib
• Combination trials
ALISERTIB—Aurora A Kinase
Inhibitor
• Leads to mitotic arrest
– Abnormal spindles, unseparated centrosomes
– Cells undergo apoptosis
Untreated
Treated
Treated
• Ongoing studies in TCL:
– International randomized phase III trial comparing alisertib to
investigator’s choice1
– Phase I: combination with romidepsin2
– Phase I: combination with vorinostat3
– Preclinical: combination with PI3K inhibition
.
Friedberg J, et al. J Clin Oncol. 2014;32:44-50 . ClinicalTrials.gov. [1] NCT01482962,[2] NCT01897012 [3] NCT01567709.
ALISERTIB—
R/R PTCL, Transformed MF
• S1108: Phase II
• R/R PTCL or transformed MF
Category
Alisertib
• 50 mg po BID x 7 days, 21–day
cycle
• Dose reduction to 40 g BID, 30
mg BID for toxicity
N = 37 (%)
PTCL response rate
30%
Transformed MF response rate
0%
Complete response
2 (5)
Partial response
21 (57)
Stable disease
7 (19)
Grade 3/4 AEs (≥ 5%): neutropenia (32%), anemia (30%), thrombocytopenia
(24%), febrile neutropenia (14%), mucositis (11%), and rash (5%)
Barr, et al. J Clin Oncol. 2015;33:2399-2404.
ALISERTIB—R/R PTCL
Alisertib
• 5×10-mg twice daily orally on
days 1-7 in a 21-day cycle
• LUMIERE: Phase III
• R/R PTCL or transformed MF
Results available soon
Clinicaltrials.gov ClinicalTrials.gov Identifier:NCT01482962.
Investigators Choice
(single agent)
• Pralatrexate
− 30mg/m2 once weekly
for 6 weeks of 7-week
cycle
• Gemcitabine
− 1,000 mg/m2 on days 1,
8, and 15 of a 28-day
cycle
• Romidepsin
− 14mg/m2 on days 1,8,&
15 of a 28-cycle
50
MOGAMULIZUMAB—Defucosylated
Humanized Anti-CCR4 Antibody
N-terminal
KW-0761
Extracellular regions
Fucose
• Mogamulizumab has enhanced
ADCC due to defucosylated Fc
region[1,2]
• CCR4 is highly expressed
(~ 90%) in ATLL[3]
• Significantly associated with
skin involvement (P < .05) and
unfavorable outcomes[3]
Slide courtesy of T. Ishida
1. Shinkawa T, et al. J Biol Chem. 2003;278:3466-3473. 2. Ishii T, et al. Clin Cancer Res. 2010;16:1520-1531. 3. Ishida T, et al. Clin
Cancer Res. 2003;9:3625-3634.
MOGAMULIZUMAB—TCL
• Active in phase II study in patients with ATLL (N = 28)1
–
–
–
–
ORR: 50% (13/26); 8 CR
Median PFS: 5.2 mos
Median OS: 13.7 mos
AEs: infusion reactions (89%), skin rash (63%)
• Mycosis fungoides/Sezary syndrome (N = 38)2
– ORR: 37% (MF: 29%; SS: 47%)
• Approved in Japan for the treatment of ATLL
• Ongoing multicenter, randomized phase III clinical trial of
mogamulizumab vs vorinostat in patients with MF/SS3
1. Ishida T, et al. J Clin Oncol. 2012;30:837-842. 2. Duvic M, et al. 2012 ASH. Abstract 3697. 3. ClinicalTrials.gov. NCT01728805.
IPI-145 (DUVELISIB)—
A PI3K-δ,γ Inhibitor
PI3K Isoform
PI3K-δ
PI3K-γ
Primarily
Leukocytes
Primarily
Leukocytes
Biochemical Activity (KD)
23 pM
243 pM
Whole Blood Assay (IC50)
96 nM
Anti-FcƐR1
1028 nM
fMLP
Expression
O
CI
• Potent oral inhibitor of PI3K-δ and PI3K-γ isoforms
– Selective for PI3K over other protein and lipid kinases
• Inhibits malignant B-cell and T-cell survival
N
N
N
NH
N
HN
IPI-145
– Direct effects on tumor cells
– Disrupting tumor cell interactions within the microenvironment
DiNitto J, et al. Keystone Symposia 2013. Abstract 1032. Palombella V, et al. Keystone Symposia 2013. Horwitz S, et al.
ASCO 2013. Abstract 8518.
IPI-145-02 (DUVELISIB)—Advanced
Hematologic Malignancies
Duvelisib
• Orally BID in 28-day cycles
• 25 mg (n=1), 50 mg (n=1), 60 mg
(n=4), 75 mg (MTD; n=27), 100 mg
(n=2)
• Phase I
• 33 patients with R/R TCL
Best Response, n (%)
Population
n
CR
PR
SD
PD
ORR
33
2 (6)
12 (36)
7 (21)
12 (36)
14 (42)
1.9 (1.5, 3.8)
PTCL
15
2 (13)
6 (40)
1 (7)
6 (40)
8 (53)
1.9 (1.5, 3.5)
CTCL
18
0
6 (33)
6 (33)
6 (33)
6 (33)
2.4 (1.6, 3.8)
All TCL
•
•
•
Median Time to
Response,
months
(Range)
Clinical activity observed across PTCL and CTCL subtypes
Most AEs were Grade 1 or 2
Grade 3 ≥ AEs : ALT/AST increase, rash, and pneumonia
Horwitz S, et al. ASH 2014. Abstract 803.
TIPIFARNIB—Farnesyl Transferase
Inhibitor: R/R TCL and HL
• Phase II
• R/R NHL
• Aggressive B-NHL (n = 42)
• Indolent B-NHL (n = 15)
• T-NHL and HL (n = 36)
Disease Type
Tipifarnib
• 300 mg bid 21 days of
28-day cycles`
Number
ORR
11/36 (6 CRs; 5 PRs)
31%
HL
4/19
21%
MF
2/4
50%
4/8 (3 CRs, 1PR)
50%
1/5 (1 CR cutaneous)
20%
Cohort 3 (TCL and HL)
PTCL-NOS
ALCL
• DOR: median 7.5 months
• OS: median 19.7 months
• Grade 3/4 AEs: neutropenia (37%), thrombocytopenia (32%), anemia (11%)
Witzig T, et al. Blood. 2011;118;4882-4889.
CRIZOTINIB—Tyrosine Kinase
Inhibitor of ALK
• Competitive binding to ATP binding pocket
• Inhibits c-Met/Hepatocyte growth factor receptor tyrosine
kinase
• Approved for late-stage ALK expressing NSCLC
– EML-ALK fusion
• 11 ALK+ relapsed NHL patients (9 ALCL)
– Median of 3 prior therapies
– Clinical responses in 10 of 11
• All 9 ALCL pts achieved complete remissions lasting 2-40+ months
• Negative for NPM/ALK by PCR
• 2 -yr PFS 64%
– Non-cross resistant with brentuximab
XALKORI® (crizotinib) [package insert]. NY, NY: Pfizer Inc; Revised 11/13. Gambacorti Passerini et al. J. Natl. Cancer Inst.
2014;106:djt378.
BRENTUXIMAB + CHP—
Combination Therapy in R/R NHL
16 total cycles
• Phase I
• R/R NHL
1.8 mg/kg Brentuximab +
Standard-dose CHP every 3
weeks for 6 cycles
Single agent 1.8 mg/kg
Brentuximab vedotin every
3 weeks for 10 cycles
sALCL
(n=19)
Other diagnoses
(n=7)
Total
(N=26)
19 (100)
7 (100)
26 (100)
CR
16 (84)
7 (100)
23 (88)
PR
3 (16)
--
3 (12)
Median PFS (95% CI)
--
--
-- (4+, 13+)
Median OS (95% CI)
--
--
-- (4+, 13+)
Objective response rate, n (%)
•
Following these assessments, 10 of 26 patients continued therapy with single-agent
brentuximab vedotin
At the end of Cycle 12, ORR=12/13 (92%), CR rate=11/13 (85%)
At the end of Cycle 16, ORR=4/4 (100%), CR rate=4/4 (100%)
−
−
Fanale M, et al. J Clin Oncol. 2014;32:3137-3143.
Agents in Clinical Trials—
Anticipated Frontline Treatments
Agent
(reference)
Romidepsin + CHOP
NCT01796002,
(Delarue 2013)
Romidepsin + CHOP
Ro-CHOP Study
(Dupuis et al, 2014)
Phase
3
Number of patients
•
•
Response
Currently recruiting
Goal of 420 pts
1b/2
37
ORR = 69%
CR = 51%
PR = 17%
Brentuximab vedotin +CHOP
or CHP
(Fanale 2014)
1
26
CD30+ PTCL
CR = 88%
Estimated PFS= 71%
Pralatrexate alternating with
CEOP
(Advani 2013)
2
33
PTCL
ORR = 70%
CR = 52%
PTCL—Ongoing Phase-3 Trials
Intervention
Patient
Population
Primary
Endpoints
Status
CHOP14 + G-CSF + alemtuzumab vs
CHOP14 + G-CSF
Newly
diagnosed
PTCL
EFS
Active
Alisertib vs
pralatrexate or gemcitabine or romidepsin [2]
R/R PTCL
ORR, PFS
Active
Brentuximab vedotin + CHP vs
CHOP [3]
CD30+
TCL
PFS
Recruiting
Romidepsin + CHOP vs
CHOP* [4]
Newly
diagnosed
PTCL
PFS
Recruiting
*European study
1. ClinicalTrials.gov NCT00646854. 2. ClinicalTrials.gov NCT01482962. 3. ClinicalTrials.gov
NCT01777152 4. ClinicalTrials.gov NCT01796002
CTCL—Ongoing Phase-3 Trials
Intervention
Patient Population
Primary
Endpoints
Status
Brentuximab vedotin vs
Methotrexate or Bexotrexate [1]
CD30+ CTCL
ORR
Recruiting
Mogamulizumab vs Vorinostat [2]
Relapsed/Refractor
y CTCL
PFS
Recruiting
1. ClinicalTrials.gov NCT01578499. 2. ClinicalTrials.gov NCT01728805.
Clinical Trials—To Enroll or Not
• Advantages:
– Receive therapy that potentially is better then
standard of care
– Access to agents that are not yet available
– Enhanced monitoring
• Risks
– Receive therapy that is not effective
– Unexpected side effects
– Leak of personal information
DISCUSSION
QUESTIONS & ANSWERS