T-Cell LymphomasApplying Emerging Evidence in Practice

Steven Horwitz, MDAssociate Attending

Memorial Sloan Kettering Cancer Center

Associate Professor of MedicineWeil Cornell Medical College

DisclosuresDr. Horwitz discloses the following commercial relationships:

– Celgene (consultant, grants/research support)– Kyowa Kirin (grants/research support)– Millennium Pharmaceuticals (consultant, grants/research

support)– Seattle Genetics (consultant, grants/research support)– Spectrum Pharmaceuticals (consultant, grants/research

support)– Infinity Pharmaceuticals (grants/research support)

Nursing Learning Objectives

Describe clinical challenges associated with the contemporary management of T-cell lymphoma

Evaluate patient- and tumor-related factors that inform evidence-based treatment planning

Recognize the clinical application of novel therapies in the treatment of newly diagnosed and relapsed/refractory T-cell lymphoma

Assess side-effect profiles of novel therapies for T-cell lymphoma

T-Cell Lymphomas:Overview and Prognostic Factors

WHO 2008 Classification of Mature T/NK-Cell Neoplasms

T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive natural killer (NK) cell leukemia Chronic lymphoproliferative NK cells Adult T-cell lymphoma/leukemia Systemic Epstein-Barr virus (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 Anaplastic large cell lymphoma, ALK-positive Anaplastic large cell lymphoma, ALK-

negative Peripheral T-cell lymphoma, not otherwise

specified (PTCL-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)

Swerdlow et al, 2008.

Peripheral T-cell Lymphoma Subtypes

PTCL-NOS is the most common subtype Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic

lymphoma are also common subtypes

Vose et al, 2008.

TCL: Overall SurvivalSwedish National Registry

Ellin et al, 2014.

ALK+ ALCL

ALK+ ALCLALK U ALCLPTCL NOSAITL

TCL-U

Overall Survival Based on Prognostic Score

Prognostic Index for PTCL-U (N=322)

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

Months

OS

(%)

Group 1(0 adverse factors)

Group 2 (1 factor)

Group 3 (2 factors)

Group 4 (3-4 factors)

PTCL-U by IPI

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16

Years

OS

(%)

P<0.00001 IPI 4/5 (n=27)

IPI 2/3 (n=54)

IPI 0/1 (n=36)

PTCL-U = peripheral T-cell lymphoma-unspecified; IPI = International Prognostic Index; OS = overall survival.Savage et al, 2004; Gallamini et al, 2004.

Adverse factors include age >60 years, PS ≥2, lactate dehydrogenase elevation, and bone marrow involvement.

PTCL-NOS Mixture of medium and large atypical cells 34% of PTCLs in North America

(most common subtype)  5-year OS of 32%  Patients commonly present with :

- B-symptoms and lymph node enlargement- Extranodal involvement

• Skin and gastrointestinal tract are most common

• Lung, salivary gland, and central nervous system (CNS) are less frequent

Diagnosis should be made only when other specific entities have been excluded 

Antigen expression – Most cases express one of the major subset

antigens: CD4 > CD8– CD30 expression is most often very low

Diffuse infiltrates of large lymphoid cells with pleomorphic, irregular nuclei and prominent nucleoli

Swerdlow et al, 2008; Vose et al, 2008; Hoffman et al, 2008; Rodriguez-Abreu et al, 2008.

Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic lymphoma (AITL)Characterized by polymorphous infiltrate of

lymph nodes with the normal nodal architecture commonly effaced with opened and dilated peripheral sinuses

T-cell receptor (TCR) clonality is often important for diagnosis; CD4 expression more common than CD8

May have CD20 positive cells, EBV+Expresses CXCL13 and PD-1Often associated with paraneoplastic

syndromes (hypergammaglobulinemia, vasculitis, arthritis)

Rizvi et al, 2006.

Anaplastic Large Cell Lymphoma 5% of non-Hodgkin lymphoma (NHL)

in adults, 20-30% in children Tumor cells express CD30 and IL-2R (2,5) NPM-ALK (nucleophosmin-

anaplastic lymphoma kinase) fusion in 60% of ALCL

B-symptoms common (66%) Extranodal involvement in 60% (skin,

bone, soft tissues) Blood involvement rare Cutaneous ALCL usually ALK- ALCL associated with breast implants

NCCN, 2016.

Sibon et al, 2012; Parrilla Castellar et al, 2014; Bekkenk et al, 2000.

Survival by ALK Expression in ALCL

Cutaneous ALCL

Management of T-Cell Lymphomas

NCCN Guidelines for Initial Treatment of PTCL

CR = complete response; PR = partial response; NR = no response; RT = radiation therapy; HDT = high-dose therapy; SCR = stem cell rescue. NCCN, 2016.

NCCN Guidelines for Initial Treatment of PTCL

Suggested regimens:

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) CHOEP (cyclophsophamide, doxorubicin, vincristine, etoposide,

prednisone) HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and

dexamethasone) alternating with high-dose methotrexate and cytarabine

Dose-adjusted EPOCH (etoposide, prednisone, vincristine,cyclophosphamide, doxorubicin)

EATL only IVE (ifosfamide, etoposide, and epirubicin) alternating with

intermediate-dose Methotrexate [New Castle Regimen]

NCCN, 2016; Rosenstein & Link, 2008.

Is CHOP the Best Regimen for Frontline Treatment? German Studies With CHOEP

PTCL Subtype nALCL, ALK+ 78ALCL, ALK- 113PTCL-NOS 70

AITL 28Other 31Total 320

EFS, aged <60 yrs

Benefit

EFS = event-free survival.Schmitz et al, 2010.

100

Pat

ient

s (%

)EFS, other subtypes

No Benefit

Mos

Non-etoposide (n=29)

1100 10 20 30 40 60 70 80 90 10050

80

60

20

0

40

Etoposide (n=69)

P=0.057

Mos1100 10 20 30 40 60 70 80 90 10050

100

80

60

20

0

40

Pat

ient

s (%

)

P=0.003

6 x CHOP-14/21 (n=41)

6 x CHOEP-14/21 (n=42)

Mos1100 10 20 30 40 60 70 80 90 10050

100

80

60

20

0

40

Pat

ient

s (%

)

P=0.012

Non-etoposide (n=12)

Etoposide (n=34)

EFS, ALCL, ALK+Benefit

Autologous Stem Cell Transplantation as First-line Therapy in PTCL

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72months

160 100 85 65 52 39 17 Number at risk

95% CI Survivor function

PFS, whole cohort

5-year PFS: 44%4-year PFS: 44%

Auto-SCT ITT (n=128)

Non-auto-SCT (n=124)

5 yr OS 48% 26%5 yr PFS 41% 20%

Nordic MSKCC

Swedish Registry

PFS = progression-free survival; Auto-SCT = autologous stem cell transplantation; ITT = intent to treat.D’Amore et al, 2012; Mehta et al, 2013; Ellin et al, 2014.

Type of Therapy by Regiona

Europe USA South America Asia0

20

40

60

80

100

4 4

14

22 4 5

71 68

79

67

23 24

7

25

No therapy/Palliation RT CHT HDT

%

N %No Tx/palliation 46 6

RT 21 3CHT 564 71HDT 158 20

aincludes all subtypes, Tx in CR1/PR1 + relapse.RT = radiation therapy; CHT = chemotherapy; HDT = high-dose therapy. Courtesy of Monica Bellei and Massimo Federico.

How Do I Approach a Frontline Patient?

PTCL NOS, AITL and ALK-ALCL– Clinical trial if available– CHOEP or CHOP, depends on performance status/comorbidities– Transplant in first line if candidate

ALK+ ALCL– Clinical trial if available– CHOP, no transplant if low IPI– CHOP or CHOEP, consider transplant if high IPI

EBV-driven lymphoma More common in Asia and

Central/South America– NA: 4-5% of TCL

– Asia: >20% of TCL

Almost always presents in the nose or nasopharynx

Less often: paranasal sinuses, tonsil, Waldeyer’s ring, and oropharynx

Other sites: skin, salivary glands, testis, and gastrointestinal tract

Nasal pan-endoscopy Quantitative of plasma EBV prognostic

and predictive

NK/T-Cell Lymphoma

NK/T-Cell Lymphoma

Pathology

AngiocentricVascular invasionTissue necrosis

Phenotype CD2, other T-cell markers may

be absent

CD16, CD56, cytoplasmic CD3ε

TCR – (usually)

EBV+

Granzyme B+,TIA-1+

CD30 +/-

CD3 CD8 CD56 EBERImages courtesy of Ahmet Dogan, MD.Tan et al, 2013.

PFS Stage IE, N=82

Prognosis favors early stage/localized to nasopharynx

Historically no benefit to CMT over RT alone

RT alone doses >50Gy Patterns of failure

Overall Survival

Nasal

Extra-Nasal

RT Alone

CMT

NK/T-Cell Lymphoma: Early Stage

Vose et al, 2008; Li et al, 2006.

0.00 10.00 20.00 30.00 40.00 50.00Months

0.0

0.2

0.4

0.6

0.8

1.0

Prog

ressio

n free

Surv

ival

Outcomes for Chemotherapy With Radiotherapy in Stage I/II Nasal NK/T

VIPD

Long Term PFS withRT-2/3DeVIC

RT + cisplatin followed by– Etoposide 100 mg/m2 IV D 1-3– Ifosfamide 1200 mg/m2 IV D 1-3– Cisplatin 33 mg/m2 IV D 1-3– Dexamethasone 40 mg IV or orally D 1-4

Concurrent radiation with– Dexamethasone 40 mg IV D 1-3– Etoposide 67 mg/m2 IV D 1-3– Ifosfamide 1000 mg/m2 IV D 1-3– Carboplatin 200 mg/m2 IV D 1

Kim et al, 2009. Yamaguchi et al, 2012.

Drug Dose Route DayMethotrexate 2000 mg/m2 IV 1Dexamethasone 40 mg IV 2,3,4Ifosfamide 1500 mg/m2 IV 2,3,4Etoposide 100 mg/m2 IV 2,3,4Pegy-L-asparaginase

1500-2500 IU/m2

IM/IV ~ 5

XRT 4500 cGy

Shunan Qi A. YahalomM. Lunning

N=11 N=9

CR 80%

Modified from Yamaguchi et al, 2008.

NK/T-Cell Lymphoma:MSKCC Results With mSMILE According to Stage

Treatment Algorithm for NK/T-Cell Lymphoma

Tse & Kwong, 2013.

Enteropathy-Associated T-Cell Lymphoma

Rare subtype– 5.8% of T-cell NHL in US– 9.1% in Europe

Involves intestinal epithelium Differential includes NK/T-cell

lymphoma if EBER+ Presentation

– Pain 80%– Perforation 40%

5-year survival 20%

CD3+ CD8+Delabie et al, 2011.

Differential Diagnostic Considerations for EATL

PTCL-NOS– More common than EATL– Broad morphologic spectrum and typically presents as nodal

involvement, but any site may be affected– Involvement of small intestine should always raise suspicion for EATL

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract– Dense small, non-destructive lymphoid infiltrate– Little or no involvement of the crypt or surface epithelium– CD3+, CD8+, CD5+, CD56-, TIA-1+, TCR-BF1+

NK Enteropathy– CD56(+)/TIA-1(+)/granzyme B(+)/cCD3(+)– Does not invade the glandular epithelium

EATl = enteropathy-associated T-cell lymphoma.Perry et al, 2013; Malamut et al, 2014; Mansoor et al, 2011.

EATL Type I vs Type IIClassic EATL (Type I) Type II EATL

Frequency80-90% 10-20%

EpidemiologyComplication of celiac disease (1-2%) Occurs sporadically

Northern Europe Asia

>90% have celiac disease-associated HLA-DQ2/-DQ8 haplotypes

Patients with refractory celiac disease at high risk

Clinical PresentationMultifocal involvement of small intestine,

intestinal ulcers, stenosis, perforationSimilar but ~20% may involve the large

intestine

Adapted from Ferreri et al, 2011; Arps et al, 2013.

EATL: Prognosis With “Standard” Therapy

Gale et al, 2000; Delabie et al, 2011.

N=31 25/31 diagnosed at laparotomy 42% (13/31) emergency surgery/perf PS 2-4 in 72% (18/25) 29%, (9/31) died quickly with no treatment or

complication of 1 cycle of chemotherapy. Bleeding, infection

EATL: Apparent Benefit of More Intensive ApproachesO

vera

ll Su

rviv

al

IVE/MTX-ASCT (n=26)

CHOP-like (n=31)

BEAM = carmustine/etoposide/cytarabine/melphalan; TBI = total body irradiation.Sieniawski et al, 2010; d’Amore et al, 2012.

OS Time (months)

CHOP x 1 IVE

- Ifosfamide 3000 mg/m2 D 1-3- Epirubicin 50 mg/m2 on D 1, - Etoposide 200 mg/m2 on D 1-3

Alternating with:

Methotrexate 1,500 mg/m2 BEAM or TBI-ASCT

ASCT for EATL: EBMT and Nordic

TRM = treatment-related mortality.Jantunen et al, 2013; D’Amore et al, 2012.

OS

OS CR1/PR1

Other

Relapse

TRM

EATL (N=21)

Nordic: CHOEP-ASCT

Nordic: CHOEP-ASCT

PFS OS proportion

Initial Treatment of EATL Many series contain subjects to ill to safely tolerate therapy Series with more aggressive strategies do not appear to include

these patients Treat like other PTCL? - Depends on how you treat them? CHOP alone results in few long-term survivors More intensive therapy appears to have better results

– Possible selection bias - responders/better PS– ASCT in CR1/PR1– CHOEP-ASCT – IVE/MTX-ASCT

Clinical Challenges With Existing PTCL Therapy

Role of dose-intensified regimens and etoposide in frontline not well defined except for ALK+ patients

Defining who will benefit from autologous bone marrow transplant (auto-BMT)– No randomized trial – Should poor-risk or high-IPI patients receive different

treatment? How to individualize therapy for different subtypes

– Enteropathy– NK/T-cell

NCCN, 2016.

NCCN Treatment Guidelines for Relapsed/Refractory PTCL

NCCN recommends clinical trials for treatment of relapsed or refractory PTCL

Patients may be evaluated as candidates for high-dose therapy

Patients who are not candidates for high-dose therapy may receive experimental treatments or palliative RT

NCCN, 2016.

NCCN Treatment Guidelines for Relapsed/Refractory PTCL

NCCN, 2016

Response to ICE 70% Received ASCT 68%

Transplantation in Relapsed T-cell Lymphoma

CIBMTR = Center for International Blood and Marrow Transplant. Smith et al, 2013; Horwitz et al, 2005; Mehta-Shah et al, MSKCC data.

Allogeneic

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

%

ASCT as 2nd line

Median PFS 6 months by ITT

CIBMTR: PFS Excluding Pt in CR1

(Most Patients ALCL)

• N=65• 2-Year OS: 59%• 2-Year PFS: 48%• Median PFS 20.26 mo

N=40

Relapsed/Refractory PTCL: FDA-Approved Agents

Agent Regimen N ORR (%)

CR (%)

DOR (mos)

Romidepsin (NCI)

14 mg/m2 weekly x 3 every 28 days

47 38 18 8.9

Romidepsin (pivotal)

14 mg/m2 weekly x 3 every 28 days

131 25 14 17.0

Pralatrexate(pivotal)

30 mg/m2 weekly x 6 of 7 wks

111 29 11 10.1

Brentuximab vedotin (ALCL)

1.8 mg/kg every 21 days 58 86 57 12.6

Belinostat 1,000 mg/m2 UV D 1-5 q 21 days

129 26 12 13.6

DOR = duration of response.Piekarz et al, 2011; Coiffier et al, 2012; O’Connor et al, 2011; Pro et al, 2012; O’Connor et al, 2013.

Brentuximab Vedotin: Mechanism of Action

SGN-35 antibody-drug conjugate CD30-targeted antibody (cAC10)

conjugated to an auristatin (monomethyl auristatin E, or MMAE), an antitubulin agent

Selectively induces apoptosis in HL and ALCL cells– Binds to CD30– Becomes internalized– Releases MMAE

SGN-35 Antibody-Drug Conjugate

SGN-35 binds CD30

Endocytosis

ADC traffics to lysosome

Enzymatic linker cleavage releases MMAE

from ADC

MMAE binds tubulin

G2/M cell cycle arrest & apoptosis

CD30

SGN-35 Antibody-Drug Conjugate

SGN-35 binds CD30

Endocytosis

ADC traffics to lysosome

Enzymatic linker cleavage releases MMAE

from ADC

MMAE binds tubulin

G2/M cell cycle arrest & apoptosis

CD30

HL = Hodgkin lymphoma.Foyil et al, 2010.

Brentuximab Vedotin Phase II Study in Relapsed/Refractory Systemic ALCL

AEs = adverse events.Pro et al, 2010.

Multicenter, Open-Label Study (N=58)Administration 1.8 mg/kg every

3 wks30-min infusion Premeds not

requiredPatient characteristics

Median of 2 prior systemic lines

62% refractory to frontline therapy

50% refractory to most recent therapy

Grade 3/4 AEs(≥10%)

Neutropenia Peripheral sensory neuropathy

Responses ORR: 86% CR: 57% Median DOR:13.2 mos

Brentuximab Vedotin in Other Aggressive T-Cell Lymphomas

Best Clinical Responseper Investigator

 Overall ResponseCR + PR

n (%) CR

n (%)PR

n (%)SD

n (%)PD

n (%)Mature T/NK-cell lymphomas (n=34)

8 (24)

6 (18) 6 (18) 14 (41)

14 (41)

AITL (n=13) 5 (38)

2 (15) 3 (23) 3 (23) 7 (54)

PTCL-NOS (n=21) 3 (14)

4 19) 3 (14) 11 (52) 7 (33)Median duration of objective response: 7.6 months(range 1.4-14+ months); 5.5 months for AITL and 7.6 months for PTCL-NOS

PD = progressive disease; SD = stable disease.Horwitz et al, 2014.

Pralatrexate: Pivotal Trial in PTCL

Open-Label Study (N=109)Administration 30 mg/m2 weekly x

6 of 7 wks3-5 min push Premeds not

required

Patient Characteristics

Median 3 prior systemic lines

48% ≤2 prior lines52% >2 prior lines

63% refractory to most recent therapy

Grade 3/4 AEs(>10%)

NeutropeniaThrombocytopenia

Anemia Mucositis

ORR (%) CR (%) Median DOR (mos)Responses 29 (IWC)

39 (invest) 10 (IWC) 16 (invest)

10.1 (IWC) 8.1 (invest)

IWC = International Workshop Criteria.O’Connor et al, 2011.

Patients ORRHistology PTCL-NOS 59 (54) 32

Anaplastic LC 17 (16) 35Angioimmunoblastic 13 (12) 8Transformed MF 12 (11) 25Other 8 (7) 38

Prior systemic therapy

1 regimen 23 (21) 352 regimens 29 (27) 24>2 regimens 57 (52) 30

Prior transplant Yes 18 (17) 24No 91 (83) 29

Pralatrexate: Response Across Subsets

Response rates similar except for AILT, active in patients with prior transplant and heavily pretreated/refractory patients

O’Connor et al, 2011.

Romidepsin: Pivotal Phase II Trial in Relapsed/Refractory PTCL

aMedian duration of response 28 months.Coiffier et al, 2012.

Multicenter, Open-Label Study (N=130)Administration 14 mg/m2 weekly x

3 every 28 days4 hrs Premeds required

Patient characteristics

Median 2 prior systemic lines

63% ≤2 prior lines37% >2 prior lines

38% refractory to most recent therapy

Grade 3/4 AEs(>10%)

NeutropeniaThrombocytopenia

Anemia Infections

ORR (%) CR (%) Median DOR (mos)Responses 25 (IRC)

29 (invest) 10 (IRC) 15 (invest)

16.6 (IRC)a

11.6 (invest)

Prior Stem Cell TransplantationYes 2/21 (10) 5/21 (24)No 17/109 (16) 28/109 (26)

Number of Prior Systemic Therapies<3 11/82 (13) 18/82 (22)≥3 8/48 (17) 15/48 (31)

Primary Diagnosis Complete Responsesn/N (%)

Objective Responses n/N (%)

PTCL-NOS 10/69 (14) 20/69 (29)

AITL 5/27 (19) 8/27 (30)

ALK-1 negative ALCL 4/21 (19) 5/21 (24)

Romidepsin Phase II Study: Response by Subset

Response rates similar between subtypes, active in AITL, active in patients with prior transplant and heavily pretreated/refractory patients

Coiffier et al, 2012.

Belinostat BELIEF Study Phase II BELIEF study

– Open-label, single-arm, efficacy and safety study of belinostat as a monotherapy for relapsed/refractory PTCL

• 30 min IV infusion at 1,000 mg/m2 on D 1-5 of a 3-week cycle

NE = not evaluable.O’Connor et al, 2013.

How to Select a Treatment for a Relapsed Patient?

Is the intention transplant? YES

– Attain a CR or minimal disease state with combination chemotherapy or single agent then proceed to transplant.

– Quality of response > Durability NO

– Use single-agent therapies for palliation, consider patient benefit and side effects

– Durability and toxicity > Response rate Always consider a clinical trial

NCCN, 2016.

New and Emerging Therapies for T-Cell Lymphomas

On the Horizon Antibodies (CCR4 antibody) Aurora kinase inhibitor PI3 kinase inhibitors PD-1 and PD-1L inhibitors Lenalidomide and combinations Bendamustine New doublets including novel agents

Higher ADCC due to a defucosylated Fc region by POTELLIGENTⓇ

CCR4 (CC chemokine receptor 4)

KW-0761

Fucose

Asn297

Highly expressed (>90%) in ATLApproved in Japan for ATL

Clinical trial underway in US in CTCL

Novel Antibodies for T-cell Lymphomas: Anti-CCR4 Antibody, KW-0761

Extracellular regions

N-terminalApproved in Japan for ATL

ADCC = antibody-dependent cellular cytotoxicity; ATL = adult T-cell leukemia and lymphoma.Ishii et al, 2010; Shinkawa et al, 2003; Ishida et al, 2003.

IPI-145-Oral PI3K-δ, γ Inhibitor

Potent oral inhibitor of both the PI3K-δ and PI3K-γ isoforms

Selective for PI3Ks over other protein and lipid kinases

Inhibits malignant B‐ and T‐cell survival- Direct effects on tumor cells- Disrupting tumor cell interactions

within the microenvironment

O

N

Cl

NHN

N

HNN

IPI-145

PI3K Isoform PI3K-δ PI3K-γ

Expression Primarily leukocytes Primarily leukocytes

Biochemical activity (KD) 23 pM 243 pM

Whole blood assay (IC50)96 nM

Anti-FcƐR11028 nM

fMLP

Horwitz et al, 2014.

Efficacy in CTCL 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 of IPI-145 in TCL

Clinical activity observed across PTCL and CTCL subtypes - PTCL: CRs in 1 EATCL and 1 PTCL NOS

PRs in 2 AITCL, 2 SPTCL, 1 PTCL NOS, 1 ALCL (ALK-negative) - CTCL: PRs in 4 MF, 1 Sézary syndrome, and 1 MF-LCT

Includes evaluable patients = at least 1 on-treatment response assessment or PD without assessment

Horwitz et al, 2014.

Ongoing Phase III Trials in PTCL

Intervention PTCL Patient Primary End Point Status

Alemtuzumab + CHOP14 + G-CSFvs CHOP14 + G-CSF

Newly diagnosed(61-80 yrs of age) EFS Closed

Alemtuzumab + CHOP14 + G-CSFvs CHOP14 + G-CSF

Newly diagnosed(18-60 yrs of age) EFS Closed

Alisertib vs Pralatrexate or Gemcitabine or Romidepsin r/r ORR, PFS Closed

Brentuximab vedotin + CHP vs CHOP Newly diagnosedCD30+ PTCL PFS Recruiting

CHOP → Pralatrexate vs Observation Newly diagnosed PFS, OS Closed

Romidepsin + CHOP vs CHOP Newly diagnosed PFS Recruiting

Belinostat + CHOP vs CHOP Newly diagnosed PFS To open soon

Trumper, 2012; Aarhus University Hospital, 2015; Millenium Pharmaceuticals, 2014; Seattle Genetics, 2015; Spectrum Pharmaceuticals, 2014; Lymphoma Academic Research, 2014.

AITL

Odejide et al, 2014; Palomero et al, 2014; Schatz et al, 2015.

PTCL

Recurrent Mutations in Peripheral T-Cell Lymphomas

AG221-C-003: Treatment Schema

AITL, Glioma,Non-glioma solid

Phase IAITL

Expansion Cohorts

Glioma

Non-glioma solid

Tumor biopsies pretreatment, on therapy, and at progression

Nabhan, 2015.

Key Takeaways Peripheral T-cell Lymphomas are uncommon-confirm pathology Most have a relatively poor prognosis with standard chemotherapy

such as CHOP; long-term PFS between 20-30% Exceptions include ALK+ ALCL-PFS 60-70%, possible DUSP22 ALK-

ALCL Possibly improved outcomes with intensified therapy

– Addition of etoposide– Consolidation with ASCT in CR1

Relapse-allo-tx may be curative Many novel agents can achieve a response but usually durable only

on therapy Clinical trials are essential to move forward

Case Discussion 55-year-old man Right cervical LN biopsy

demonstrated Peripheral T-cell lymphoma, NOS

Symptoms:- Fatigue

Exam- Multiple 2-cm cervical LN- Questionable bilateral

axillary LN

LAB:- CBC – normal- CMP – normal- LDH 421 (nl < 200)

PET – multiple cervical, axillary, periaortic, mesenteric, iliac lymph nodes. SUV Max 10.3

Bone marrow: 20% involvement

Which regimen would you select for this patient?

A. CHOP-21B. CHOP-14C. CHOEPD. Dose adjusted EPOCHE. Hyper CVADF. Chemotherapy – autologous SCT

Case Discussion: Responses

0%20%40%60%80%

100%

0% 0% 0% 0% 0% 0%

Case Discussion (cont.) 55-year-old man Stage IV PIT (Prognostic Index PTCL-

U) = Group 3 (2 factors) Received EPOCH x 4

PET after 4 cycles of EPOCH was Deauville criteria 3

Received EPOCH x 2 more (total of 6)

PET after 6 cycles was Deauville criteria 5

What to do?

Which regimen would you select for this patient?

A. BendamustineB. BelinostatC. DHAP, ESHAP, GDP (gemcitabine,

dexamethasone, cisplatin)D. Pralatrexate E. Romidepsin

Case Discussion (cont.): Responses

0%

20%

40%

60%

80%

100%

0% 0% 0% 0% 0%

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