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INSIGHTS INTO OPTIMIZING THERAPEUTIC APPROACHES
FOR T-CELL LYMPHOMAS
Integrating Current and Emerging Agents/Regimens to Develop Evidence-Based 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 treatmentGisselbrecht C, et al. Blood. 1998;92:76-82. Armitage J, et al. J Clin Oncol. 1998;16:2780–2795.
Mature T-/NK-cell Lymphomas
Adapted from Swerdlow SH, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 2008.
CTCL
Mycosis Fungoides (MF)
Extranodal LeukemicNodal
Aggressive
Transformed MF
Sézary Syndrome
Primary Cutaneous CD30+ T-cell Disorders
Primary Cutaneous Gamma/Delta TCL
NK/TCL Nasal Type
Enteropathy- associated TCL
Hepatosplenic TCL
Subcutaneous Panniculitis-like TCL
Peripheral TCL-NOS
Anaplastic Large Cell Lymphoma (ALK +/-)
Angioimmunoblastic TCL
Adult T-cell Leukemia/Lymphoma
Aggressive NK-Cell Leukemia
T-cell Prolymphocytic Leukemia
T-cell Large Granular Lymphocytic Leukemia
2008 WHO Classification of TCL
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
Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.
26%
19%
10%
10%
7%
6%
5%2%1%
1%
3%12% Peripheral T-cell lymphoma NOS
AngioimmunoblasticNatural killer/T-cell lymphomaAdult T-cell leukemia/lymphomaAnaplastic large cell lymphoma ALK+Anaplastic large cell lymphoma ALK-Enteropathy-type T-cellPrimary cutaneous ALCLHepatosplenic T-cellSubcutaneous panniculitis-likeUnclassifiable PTCLOther disorders
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 studiesImages 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+Gr
B+
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 SubtypeThe International PTCL and NK/TCL Study
PTCL Subtypes
ALK+ ALCL ALK– ALCL PTCL-NOS AITL NK/TCL ATLL
5-yr OS rate, % 70 49 32 32 32 14
• 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]
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.
OS
(%
)
Yrs
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20
ALCL, ALK+ALCL, ALK-All NK/T-cell lymphomasPTCL-NOSAITLAdult T-cell leukemia/lymphoma
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 subtypeRizvi 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
• 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.
Most common subtypes
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.
Disease-Specific Survival by Stage Risk of Progression by Stage
1. Zackheim HS, et al. J Am Acad Dermatol. 1999;40:418-425. 2. Kim YH, et al. Arch Dermatol. 1996;132:1309-1313.
Skin Stage at Diagnosis 10-Yr Relative Survival,% P Value
T1 100 NS
T2 67 .002
T3 39 < .001
T4 41 < .001
Prognosis by Stage in CTCL—MF/SS
CURRENT THERAPEUTIC OPTIONS FOR PTCL AND CTCL
1ST-LINE TREATMENTS
NCCN Guidelines—Initial Treatment of PTCL
Patient Population
Stage Induction Therapy Consolidation Therapy
ALCL, ALK+ I, II CHOP-21 or CHOEP-21* (3-6 cycles) ± ISRT (30–40 Gy)
Not needed if in remission
ALCL, ALK+ III, IV Multiagent chemotherapy* (6 cycles) Consider consolidation with high-dose therapy and stem cell rescue for all patients except low-risk (aaIPI)
PTCL, NOSALCL, ALK - AITLEATL
I-IV • 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
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
Stage IIINo blood involvement Skin directed therapy
Blood involvementSystemic therapies (Category A) ±skin directed therapy
Stage IVSezary Syndrome
•Systemic therapies (Category A)• Combination therapies
Non Sezary or Visceral diseaseSystemic therapies (Category B or C)Multiagent chemotherapy ±RT
NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.
Treatment Algorithm—MF/SSIA
(limited patch, plaque)
IB, IIA (generalized patch, plaque)
IIB(tumors)
III(erythroderma)
IVA, B(visceral
involvement)
Topical corticosteroids
(class I)
Bex gel
NM
UVB
Photopheresis ± IFN ± bexAlemtuzumab
Chemotherapy or AlloSCT
PUVA (± IFN or ± retinoid)
Bexarotene capsulesVorinostat
Denileukin diftitox
Spot radiation therapy
Bex capsules
Romidepsin
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
RELAPSED/REFRATORY PTCL• Pralatrexate • Belinostat• Romidepsin • Brentuximab
CURRENT THERAPEUTIC OPTIONS FOR PTCL
Candidates forHigh-dose Therapy
Non-candidates for High-dose
Therapy
NCCN Guidelines. Peripheral T-Cell Lymphomas. Version 2.2015
Clinical trial or 2nd-line therapy* or
Palliative RT
Clinical trial or 2nd-line therapy†
Complete or Partial response
No response
Clinical trial orAllogenic transplant or
High-dose therapy w/autologous
transplant
Clinical trial orAlternative 2nd-line or
Best supportive care orPalliative 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—R/R PTCL
Relapsed/Refractory PTCL—Single-Agent 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
AgentRegimen 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
cycle120 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; 33:2492-2499.
PRALATREXATE—Antineoplastic Folate Analog
RFC-1
Cell membrane
Extracellular
Cytosol
DNA
10-formyl
THF
5.10-methenyl
THF
PDX
THF
Folate
DHF
PRPPGARFT
PDX-Glu(n)
IMP
AICARFT
AMP
GMP
dUMP
dTMP
DHFR
RNADNA
TS
FPGS
Pralatrexate>>>MTXRFC-1
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
• 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.
Outcome Patients (N=109 evaluable)
ORR 29%
• CR 11%
• PR 18%
Median DOR 10.1 months
Median PFS 3.5 months
Median OS 14.5 months3 6 9 12 15 180
0.25
0.50
1.00
0.75
Months
Pro
po
rtio
n
Permanently censored (eg, transplant) (n = 8)Continue in follow-up for response (n = 8)
ROMIDEPSIN—HDAC Inhibitor
Activation of apoptosis[4]
Caspase 3
Caspase 8
PARP
BAX
BAK
HDI – +
HAT
HDAC
Control HDI
Cell cycle arrest[4]
100806040200
Co
un
ts
FL2-A
FL2-A0
10
20
30
Co
un
ts
FL2-A
Gene regulation[1]Protein acetylation[3]
Anti-angiogenesis[5]
Histone acetylation/Transcription induction[2]
Romidepsin
Hsp70
Hsp70AcAc
+ HDI
Proteasome
Hsp70 acetylation andclient protein degradation
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.
Coiffier BD, et al. J Clin Oncol.2012;30:631-636
• 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
N= 131• PTCL (MF or SS excluded) • Failed ≥1 prior systemic therapy• ECOG PS ≤2
Romidepsin 14 mg/m2 IVDays 1,8, and 15 q28d
ROMIDEPSIN—R/RPTCL
Outcome Patients
ORR 25%
• CR/CRu 15%
• PR 11%
• SD 25%
Response by Primary Diagnosis Patients
PTCL-NOS 29%
AITL 30%
ALK-ALCL 24%
BELINOSTAT—HDAC Inhibitor
Belinostat
Belinostat [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. Revised 7/2104.
FDA granted accelerated approval in July 2014 for R/R PTCL
BELINOSTAT— R/R PTCL
Response Efficacy Analysis Set
n=120; n(%)CR+PR 31 (26) [95% CI, 18-35]
CR 13 (11) [95% CI, 6-18]PR 18 (15)SD 18 (15)PD 48 (40)NE 23 (19)
O’Connor O. et al. ASCO 2013. Abstract 8507.
• 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%)
BELIEF Study• PTCL (N=129)• Failed ≥1 prior systemic therapy• Platelets ≥ 50,000/µL• No prior HDACi therapy
Belinostat1000mg/m2
Day 1-5 x 21 day cycle
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 HL
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 Months
OR (95% CI) 13.2 (5.7, NE)
Response in patients with CR (95% CI) Not reached (13, NE)
Pro B, et al. J Clin Oncol. 2012;30:2190-2196
• 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%)
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
Brentuximab vedotin 1.8 mg/kg IV every 21 days until
progression or unacceptable toxicity
Clinical Response,
n(%)
AITL (n=13)
PTCL-NOS
(n=22)Total
ORR 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)
Horwitz SM, et al. Blood. 2014;123:3095-3100.
• Grade 3/4 AEs: neutropenia (14%), peripheral sensory neuropathy (9%), and hyperkalemia (9%)
PFS
RELAPSED/REFRATORY CTCL• Romidepsin • Pralatrexate• Vorinostat • Brentuximab
CURRENT THERAPEUTIC OPTIONS FOR CTCL
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
NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.
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
Relapsed/Refractory CTCL—Select Systemic Agents
Agent Regimen N ORR, % Response Duration, Mos
Romidepsin[1] • 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. 167 35 11-15
Vorinostat[2] • 400 mg once daily• Could be reduced for toxicity to 300
mg orally daily or 300 mg orally five days a week
74 30 5
Pralatrexate[3] • 15 mg/m2 weekly for 3 weeks of a 4-week cycle 54 41 NR
Brentuximab[4
]• 1.8 mg/kg every 21 days.• Patients achieving CR received 2
additional doses • PR after 8 cycles could receive up
to 16 doses
48 71 9-10 (MF)
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
Romidepsin
GPI Study[1] NCI Study[2]
Stage N ORR, % N ORR, %
All stages 96 34 71 34
IB-IIA 28 25 8 62.5
IIB 21 43 15 47
III 23 39 6 33
IV 24 33 41 22
Vorinostat[3]
Stage N ORR, %
All stages 74 29.7
IB-IIA 13 30.8
≥ IIB 61 29.5
SS 30 33.3
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.
• 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
Horwitz SM, et al. Blood. 2012;119:4115-4122.
PRALATREXATE—R/R CTCL
• ORR: 41% (22/54)• Grade 3-4 AEs: mucositis (17%), thrombocytopenia (3%)
Cohort >15 mg/m2 N=41Median PFS: 388 days
• Phase I• R/R CTCL (n = 54)• Failed ≥ 1 prior therapy
Pralatrexate15 mg/m2 weekly for 3 weeks of a
4 week cycle
BRENTUXIMAB—R/R CTCL
Primary Diagnosis
Total pts Response
(ORR: 71%) Time to Response
(wks) Median DOR
(wks) MF 28 12PR, 2 CR 50% 10.5 13.5 LyP 9 5 CR, 4 PR 100% 3 23 pc-ALCL 2 2 CR 100% 3 18 LyP/MF 7 6 CR, 1 PR 100% 3 18 ALCL/LyP 2 2 CR 100%
Duvic M, Tetzlaff M, Clos AL, et al. 2013 ASH Annual Meeting. Abstract 367. Duvic M, et al. Blood . 2013;122:367.
• Phase II; N = 48• Primary cutaneous CD30+
including LyP and pc-ALCL or CD30+ MF
• Failed ≥ 1 prior therapy
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
• 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).
EMERGING TREATMENT STRATEGIES FOR
PTCL AND CTCL
• Alisertib • Mogamolizumab
• IPI-145 (duvelisib) • Tipifarnib• Crizotinib •
Combination trials
.
ALISERTIB—Aurora A Kinase Inhibitor• Leads to mitotic arrest
– Abnormal spindles, unseparated centrosomes– Cells undergo apoptosis
• 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.
Untreated Treated Treated
ALISERTIB—R/R PTCL, Transformed MF
Barr, et al. J Clin Oncol. 2015;33:2399-2404.
Category N = 37 (%)
PTCL response rate 30%
Transformed MF response rate 0%
Complete response 2 (5)
Partial response 21 (57)
Stable disease 7 (19)
• S1108: Phase II• R/R PTCL or transformed MF
Alisertib• 50 mg po BID x 7 days, 21–day
cycle• Dose reduction to 40 g BID, 30
mg BID for toxicity
Grade 3/4 AEs (≥ 5%): neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%)
50
ALISERIB—R/R PTCL
• LUMIERE: Phase III• R/R PTCL or transformed MF
Alisertib• 5×10-mg twice daily orally on
days 1-7 in a 21-day cycle
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 Clinicaltrials.gov ClinicalTrials.gov Identifier:NCT01482962.
Results available soon
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—Defucosylated Humanized Anti-CCR4 Antibody
• CCR4 is highly expressed
(~ 90%) in ATLL[3]
• Significantly associated with skin involvement (P < .05) and unfavorable outcomes[3]
• Mogamulizumab has enhanced ADCC due to defucosylated Fc region[1,2]
Extracellular regions
N-terminal
Slide courtesy of T. Ishida
KW-0761
Asn297
Fucose
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
• 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
– Direct effects on tumor cells
– Disrupting tumor cell interactions within the microenvironment
IPI-145
DiNitto J, et al. Keystone Symposia 2013. Abstract 1032. Palombella V, et al. Keystone Symposia 2013. Horwitz S, et al. ASCO 2013. Abstract 8518.
CI O
N
N
N
HNN
NH
PI3K Isoform PI3K-δ PI3K-γ
ExpressionPrimarily
LeukocytesPrimarily
Leukocytes
Biochemical Activity (KD) 23 pM 243 pM
Whole Blood Assay (IC50)
96 nMAnti-FcƐR1
1028 nM fMLP
IPI-145-02 (DUVELISIB)—Advanced Hematologic Malignancies
Horwitz S, et al. ASH 2014. Abstract 803.
• Phase I• 33 patients with R/R TCL
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)
Population
Best Response, n (%)Median Time to
Response, months(Range)
n CR PR SD PD ORR
All TCL 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)• Clinical activity observed across PTCL and CTCL subtypes• Most AEs were Grade 1 or 2 • Grade 3 ≥ AEs : ALT/AST increase, rash, and pneumonia
Witzig T, et al. Blood. 2011;118;4882-4889.
• Phase II• R/R NHL
• Aggressive B-NHL (n = 42)• Indolent B-NHL (n = 15)• T-NHL and HL (n = 36)
Tipifarnib• 300 mg bid 21 days of
28-day cycles`
Disease Type Number ORR
Cohort 3 (TCL and HL) 11/36 (6 CRs; 5 PRs) 31%
HL 4/19 21%
MF 2/4 50%
PTCL-NOS 4/8 (3 CRs, 1PR) 50%
ALCL 1/5 (1 CR cutaneous) 20%
• DOR: median 7.5 months• OS: median 19.7 months• Grade 3/4 AEs: neutropenia (37%), thrombocytopenia (32%), anemia (11%)
TIPIFARNIB—Farnesyl Transferase Inhibitor: R/R TCL and HL
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 brentuximabXALKORI® (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
Fanale M, et al. J Clin Oncol. 2014;32:3137-3143.
Single agent 1.8 mg/kg Brentuximab vedotin every
3 weeks for 10 cycles
• Phase I• R/R NHL
1.8 mg/kg Brentuximab + Standard-dose CHP every 3
weeks for 6 cycles
sALCL(n=19)
Other diagnoses(n=7)
Total(N=26)
Objective response rate, n (%) 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+)
• 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%)
Agents in Clinical Trials—Anticipated Frontline Treatments
Agent(reference) Phase Number of patients Response
Romidepsin + CHOPNCT01796002, (Delarue 2013)
3• Currently recruiting• Goal of 420 pts
Romidepsin + CHOPRo-CHOP Study(Dupuis et al, 2014)
1b/2 37ORR = 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 33PTCL
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
PTCLEFS 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
PTCLPFS
Recruiting
1. ClinicalTrials.gov NCT00646854. 2. ClinicalTrials.gov NCT01482962. 3. ClinicalTrials.gov NCT01777152 4. ClinicalTrials.gov NCT01796002
*European study
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/Refractory 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
Recommended