ptcl is typically an aggressive, di˜ cult to diagnose non ... file3 clinical characteristics,...

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.2Please see additional Important Safety Information on pages 30-31 and accompanying

Full Prescribing Information in pocket.

Indications for ISTODAX® (romidepsin) for injection

� Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy

� Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy

These indications are based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.

Important Safety InformationWARNINGS AND PRECAUTIONS� Myelosuppression: ISTODAX® (romidepsin) for injection can cause

thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary

PRESS AHEADWITH 2ND-LINE ISTODAX

PTCL is typically an aggressive, di� cult to diagnose non-Hodgkin lymphoma largely associated with a poor prognosis1-3

PTCL incidence has increased and accounts for ~10% of non-Hodgkin lymphomas3,4

� Improved recognition of previously underdiagnosed lymphoma subtypes and growth in an aging population may account for increased incidence of the disease3,5

AITL=Angioimmunoblastic T-cell Lymphoma; ALCL=Anaplastic Large Cell Lymphoma; PTCL-NOS=Peripheral T-cell Lymphoma, not otherwise specifi ed

1992

1993

Year of Diagnosis

Age

-adj

uste

d In

cide

nce

Rat

e(p

er 1

00,0

00 p

opul

atio

n)

1994

1995

1996

1997

1998

1999

2000

2001

2002

20032004

2005

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PTCLCombineda PTCL-NOS ALCL AITL Extranodal

nasal

PTCL INCIDENCE RATES BY SUBTYPE (3287 CASES DIAGNOSED FROM 1992-2005)3

a Includes all subtypes in chart and 3 subtypes not listed due to low incidence: hepatosplenic gamma/delta T-cell lymphoma, enteropathy-type intestinal T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

75% of patients diagnosed with PTCL are comprised of 3 subtypes: PTCL-NOS, AITL, ALCL2

3

PTCLClinical characteristics, presentation, and antigen expression can vary between PTCL subtypes2,6-8

a PTCL diagnoses in North America (N=332). The other 25% of diagnosed PTCL subtypes include natural killer T-cell lymphoma, adult T-cell leukemia/lymphoma, enteropathy-type, hepatosplenic, primary cutaneous ALCL, subcutaneous panniculitis-like, and unclassifi able.2

PTCL-NOS AITL ALCL

Diagnosis by Subtype (% of PTCL)2,a

34% 16% 24%

Clinical Characteristics6

Lymph node enlargement, B symptoms, extranodal involvement

Generalized lymphadenopathy, rash (often pruritic), systemic symptoms, hepatosplenomegaly, polyclonal hypergammaglobulinemia, pleural e� usion, arthritis, ascites, immunodefi ciency

Peripheral and/or abdominal lymphadenopathy (often with extranodal infi ltrates and bone marrow involvement) with B symptoms, especially high fever in ALK-1(+)

Clinical Presentation2

� Median age: 60 years� Stage III/IV: 69%

� Median age: 65 years� Stage III/IV: 89%

ALK-1(-)� Median age: 58 years� Stage III/IV: 58%

ALK-1(+)� Median age: 34 years� Stage III/IV: 65%

Antigen Expression7,8

� Most cases express one of the major subset antigens: CD4 >CD8

� CD30 expression is most often very low

� Characterized by CD10 antigen expression

� Also expresses CD4, CXCL 13, and sometimes BCL-6

� Expression of the CD30 antigen is a hallmark of ALCL

� Expression of CD2 and CD4 in a majority of cases

� CD8 is usually negative, with CD3 and CD5 lost in a majority of cases

DIFFERENTIAL DIAGNOSIS OF COMMON PTCL SUBTYPES

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.2Please see additional Important Safety Information on pages 30-31 and accompanying

Full Prescribing Information in pocket.

Indications for ISTODAX® (romidepsin) for injection

� Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy

� Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy

These indications are based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.



PRESS AHEADWITH 2ND-LINE ISTODAX

PTCL is typically an aggressive, di� cult to diagnose non-Hodgkin lymphoma largely associated with a poor prognosis1-3

PTCL incidence has increased and accounts for ~10% of non-Hodgkin lymphomas3,4

� Improved recognition of previously underdiagnosed lymphoma subtypes and growth in an aging population may account for increased incidence of the disease3,5

AITL=Angioimmunoblastic T-cell Lymphoma; ALCL=Anaplastic Large Cell Lymphoma; PTCL-NOS=Peripheral T-cell Lymphoma, not otherwise specifi ed

1992

1993

Year of Diagnosis

Age

-adj

uste

d In

cide

nce

Rat

e(p

er 1

00,0

00 p

opul

atio

n)

1994

1995

1996

1997

1998

1999

2000

2001

2002

20032004

2005

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PTCLCombineda PTCL-NOS ALCL AITL Extranodal

nasal

PTCL INCIDENCE RATES BY SUBTYPE (3287 CASES DIAGNOSED FROM 1992-2005)3

a Includes all subtypes in chart and 3 subtypes not listed due to low incidence: hepatosplenic gamma/delta T-cell lymphoma, enteropathy-type intestinal T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

75% of patients diagnosed with PTCL are comprised of 3 subtypes: PTCL-NOS, AITL, ALCL2

4Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.

ISTODAX—evaluated in 2 multicenter, single-arm, international clinical studies

CR=complete response; CRu=complete response unconfi rmed; ECOG=Eastern Cooperative Oncology Group; NCI=National Cancer Institute; ORR=objective disease response rate; PR=partial response.

PTCL Study 4 (NCI-sponsored trial)9

� 47 patients were treated and evaluated

TRIAL DESIGN� ISTODAX was evaluated in a single-arm clinical study in patients with PTCL who had

failed prior therapy� Patients could be treated until disease progression at their discretion and that of

the investigator

PTCL STUDY 39,10

� E� cacy and safety were evaluated in the largest prospective single-arm PTCL study (Study 3)

� 131 patients were treated and evaluated for safety; 130 patients with histologically confi rmed PTCL were evaluated for e� cacy

� Patients received ISTODAX at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days

TRIAL DESIGN� 6 treatment cycles were planned, and responding patients continued

to receive treatment at their discretion and that of the investigator until study withdrawal criteria were met

� Response was determined by an independent review committee using the International Workshop Response Criteria (IWC)– A 2-step response evaluation process using separate review of

radiological and clinical assessments was employed

PATIENT CRITERIA� Histologically confi rmed PTCL� Failed at least 1 prior therapy� ECOG performance status score: 0-2

CRITICAL ENDPOINTS� Primary: complete response (CR + CRu)� Secondary: duration of response; objective disease response

(ORR; CR + CRu + PR)

PTCL Failed Prior

Therapy

ECOGScore

WARNINGS AND PRECAUTIONS� Myelosuppression: ISTODAX® (romidepsin) for injection can cause thrombocytopenia,

leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary

5

ISTODAX—studied in a histologically diverse population that included heavily pretreated patients

� 37% of patients in Study 3 received ≥3 prior therapies10

� 16% (n=21) and 38% (n=18) of patients received prior autologous stem cell transplant in Study 3 and Study 4, respectively9

� 24% (n=31) and 40% (n=19) of patients received prior radiation therapy in Study 3 and Study 4, respectively9

WARNINGS AND PRECAUTIONS (cont'd)� Infections: Fatal and serious infections, including pneumonia, sepsis, and viral

reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case

aStage of disease was reported at time of diagnosis for Study 3 and at the time of study entry for Study 4.

CHARACTERISTIC Study 3(N=130)

Study 4(N=47)

AgeMean (SD) 59 (13) 59 (13)Median 61 59Sex, n (%)Men 88 (68%) 25 (53%)Women 42 (32%) 22 (47%)Race, n (%)White 116 (89%) 40 (85%)Black 7 (5%) 4 (9%)Asian 3 (2%) 3 (6%)Other 4 (3%) 0PTCL subtype based on central diagnosis, n (%)PTCL Unspecifi ed (NOS) 69 (53%) 28 (60%)Angioimmunoblastic T-cell lymphoma (AITL) 27 (21%) 7 (15%)ALK-1(–) anaplastic large cell lymphoma (ALCL) 21 (16%) 5 (11%)Other 13 (10%) 7 (16%)Stage of disease, n (%)a

I/II 39 (30%) 2 (4%)III/IV 91 (70%) 45 (96%)ECOG performance status, n (%)0 46 (35%) 20 (43%)1 67 (51%) 22 (47%)2 17 (13%) 4 (9%)Number of prior systemic therapiesMedian (range) 2 (1-8) 3 (1-6)

PATIENT BASELINE CHARACTERISTICS IN STUDY 3 AND STUDY 49-11

ISTODAX was studied in a broad age range of patients: 20 to 83 years (median age 61) in Study 3, and 27 to 84 years (median age 59) in Study 49-11

Study 3 and Study 4 included 9 and 11 confi rmed histologies, respectively10,11

Patients received from 1 to 8 prior therapies (median of 2 in Study 3, and 3 in Study 4)9

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.6

An objective disease response rate (CR + CRu + PR) of 26% (34/130) was achieved

7

A complete response rate of 15% (20/130) was achieved9

Similar CR rates were observed across the 3 major PTCL subtypes in Study 3 (20/130)9

WARNINGS AND PRECAUTIONS (cont’d)� Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX.

Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate

� Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX

PTCL-NOS AITL ALK-1(–) ALCL

ISTODAX was studied in patients with relapsed or refractory PTCL across subtypes, including 34 patients with AITL9


Study 4(N=47)




Similar complete responses achieved in Study 49

� The percentage of patients achieving CR/CRu in Study 4 was similar to that in Study 3

WARNINGS AND PRECAUTIONS (cont’d)� Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX.

In patients with congenital long QT syndrome, patients with a history of signifi cant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to signifi cant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confi rm that potassium and magnesium levels are within the normal range before administration of ISTODAX

RES

PON

SE

0 4010 20 30

Patients (%)

50

26% ORR (n=34; CI: 18.8, 34.6a)

11% PR (n=14; CI: 6.0, 17.4a)

15% CR/CRu (n=20; CI: 9.7, 22.8a)

a Two-sided 95% confidence interval.Response rates above are rounded to the nearest whole number.

RESPONSE RATES IN STUDY 3 (N=130)9

Primary Endpoint

a Stage of disease was reported at time of diagnosis for Study 3 and at the time of study entry for Study 4.

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.6

An objective disease response rate (CR + CRu + PR) of 26% (34/130) was achieved

7

A complete response rate of 15% (20/130) was achieved9

Similar CR rates were observed across the 3 major PTCL subtypes in Study 3 (20/130)9

WARNINGS AND PRECAUTIONS (cont’d)� Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX.



PTCL-NOS AITL ALK-1(–) ALCL

ISTODAX was studied in patients with relapsed or refractory PTCL across subtypes, including 34 patients with AITL9


Study 4(N=47)




Similar complete responses achieved in Study 49

� The percentage of patients achieving CR/CRu in Study 4 was similar to that in Study 3



RES

PON

SE

0 4010 20 30

Patients (%)

50

26% ORR (n=34; CI: 18.8, 34.6a)

11% PR (n=14; CI: 6.0, 17.4a)

15% CR/CRu (n=20; CI: 9.7, 22.8a)

a Two-sided 95% confidence interval.Response rates above are rounded to the nearest whole number.

RESPONSE RATES IN STUDY 3 (N=130)9

Primary Endpoint

a Stage of disease was reported at time of diagnosis for Study 3 and at the time of study entry for Study 4.

9

Median time to objective disease response (CR+CRu+PR) was 56 days (1.8 months)

Median time to complete response in Study 3 (N=130)9,10

� The median time to complete response was 105.5 days (3.5 months; ~4 cycles) for patients who achieved a CR/CRu (n=20)

SERIOUS ADVERSE REACTIONS (cont’d)� Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL

patients in clinical trials in Western population enrolled in Study 3 and Study 4

� Deaths due to all causes within 30 days of the last dose of ISTODAX® (romidepsin) occurred in 7% of patients in Study 3 and 17% of patients in Study 4

� In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock

� In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause

0 4321

Months

56 DAYS (1.8 months; n=34) MEDIAN TIME TO OBJECTIVE DISEASE RESPONSE

~2 cycles

MEDIAN TIME TO OBJECTIVE DISEASE RESPONSE IN STUDY 3 (N=130)9,10


60% (12/20) of complete responses were known to exceed 11.6 months

8642

Months

12 14 1610

>11.6 MONTHS (12/20, 60%)

0

COMPLETE RESPONSE

DURATION OF COMPLETE RESPONSE IN STUDY 3 (n=20)9

� Responses in 12 of the 20 patients achieving CR/CRu were known to exceed 11.6 months9

� Follow-up was discontinued in the remaining 8 patients prior to 8.5 months9

� Patients received a median of 2 prior systemic therapies (range: 1-8)9

SERIOUS ADVERSE REACTIONS� Infections were the most common type of serious adverse event reported. In Study

3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections

� Serious adverse reactions reported in ≥2% of patients in Study 3 were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%)

� In Study 4, serious adverse reactions in ≥2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter-related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%)


Safety: adverse reactions

ADVERSE REACTIONS OCCURRING IN ≥10% OF PATIENTS WITH PTCL IN STUDY 3 AND CORRESPONDING INCIDENCE IN STUDY 4 REGARDLESS OF CAUSALITY (N=178)9

Adverse Reactions, n (%)

Study 3 (N=131)

Study 4 (N=47)

All grades Grade 3 or 4 All grades Grade 3 or 4

Any adverse reactions 128 (97%) 88 (67%) 47 (100%) 40 (85%)

Gastrointestinal disorders

Nausea 77 (59%) 3 (2%) 35 (75%) 3 (6%)

Vomiting 51 (39%) 6 (5%) 19 (40%) 4 (9%)

Diarrhea 47 (36%) 3 (2%) 17 (36%) 1 (2%)

Constipation 39 (30%) 1 (<1%) 19 (40%) 1 (2%)

Abdominal pain 18 (14%) 3 (2%) 6 (13%) 1 (2%)

Stomatitis 14 (11%) 0 3 (6%) 0

General disorders and administration site conditions

Asthenia/Fatigue 72 (55%) 11 (8%) 36 (77%) 9 (19%)

Pyrexia 46 (35%) 8 (6%) 22 (47%) 8 (17%)

Chills 14 (11%) 1 (<1%) 8 (17%) 0

Edema peripheral 13 (10%) 1 (<1%) 3 (6%) 0

Blood and lymphatic system disorders

Thrombocytopenia 53 (41%) 32 (24%) 34 (72%) 17 (36%)

Neutropenia 39 (30%) 26 (20%) 31 (66%) 22 (47%)

Anemia 33 (25%) 14 (11%) 29 (62%) 13 (28%)

Leukopenia 16 (12%) 8 (6%) 26 (55%) 21 (45%)

Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL in clinical trials in Western populations enrolled in Study 3 and Study 4.9

11


ADVERSE REACTIONS OCCURRING IN ≥10% OF PATIENTS WITH PTCL IN STUDY 3 AND CORRESPONDING INCIDENCE IN STUDY 4 REGARDLESS OF CAUSALITY (cont’d)9


Study 3 (N=131)

Study 4 (N=47)


Metabolism and nutrition disorders

Anorexia 37 (28%) 2 (2%) 21 (45%) 1 (2%)

Hypokalemia 14 (11%) 3 (2%) 8 (17%) 1 (2%)

Nervous system disorders

Dysgeusia 27 (21%) 0 13 (28%) 0

Headache 19 (15%) 0 16 (34%) 1 (2%)

Respiratory, thoracic, and mediastinal disorders

Cough 23 (18%) 0 10 (21%) 0

Dyspnea 17 (13%) 3 (2%) 10 (21%) 2 (4%)

Investigations

Weight decreased 14 (11%) 0 7 (15%) 0

Cardiac disorders

Tachycardia 13 (10%) 0 0 0

Overall discontinuation rate9

STUDY 3� 19% of patients discontinued treatment due to an adverse event

� Thrombocytopenia and pneumonia were the only events that led to treatment discontinuation in at least 2% of patients

STUDY 4� 28% of patients discontinued treatment due to an adverse event

� Events that led to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%)


26% ORR

ISTODAX is a 2nd-line treatment for PTCL



� Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case

DURATION OF RESPONSE (DOR)9

� 60% (12/20) of complete responses were known to exceed 11.6 months� Follow-up was discontinued in the remaining 8 patients prior to 8.5 months

MEDIAN TIME TO RESPONSE (TTR)10

� Median time to objective disease response (CR + CRu + PR) was 56 days for the 34 patients who achieved an objective response

COMPLETE RESPONSE RATE (CR/CRu)9 PRIMARY ENDPOINT� 15% (20/130) of patients achieved a complete response

15% CR

>11.6 Months

56Days

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.This indication is based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.

OVERALL DISEASE RESPONSE RATE (ORR; CR + CRu + PR)9

� 26% (34/130) of patients achieved an objective disease response� 11% (14/130) of patients achieved a partial response

Romidepsin (ISTODAX) has a category 2A recommendation from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for PTCL based on Study 3 and Study 4 11-13

ISTODAX is a 2nd-line treatment for PTCL9

• Regardless of subtype, transplant eligibility, and number of prior treatments

Please see additional Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.

CTCL

PRESS AHEADWITH ISTODAX

For the 2nd-line systemic treatment of CTCL

ISTODAX® (romidepsin) for injection for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

This indication is based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.




CTCL is a heterogeneous group of non-Hodgkin lymphomas that is associated with poor prognosis in later stages of the disease14,15

Mycosis fungoides and Sézary syndrome are the most common forms of CTCL16

Mycosis Fungoides (MF)17 Sézary Syndrome (SS)18

Diagnosis by Subtype (% of CTCL)12

50% to 70%

1% to 3%

Clinical Presentation6,19

� Characterized by erythematous patches, evolving into plaques or tumorous areas

� Progression is variable and any clinical manifestation may present initially or occur simultaneously

� Patients often present with erythroderma, generalized lymphadenopathy, pruritus, onychodystrophy, alopecia, ectropion, and palmoplantar hyperkeratosis

� Patients are predisposed to opportunistic infections due to defective T-cell function

Clinical Characteristics6

� Epidermotropic CTCL characterized by proliferation of small- to medium-sized T lymphocytes with cerebriform nuclei

� ≥1 of the following in the peripheral blood:– Sézary cell count ≥1000 cells/mm3

– CD4/CD8 ratio >10– Loss of 1 or more T-cell antigens

DIFFERENTIAL DIAGNOSIS OF COMMON CTCL SUBTYPES

There are approximately 16,000 to 20,000 patients with MF in the United States—and nearly 3000 new cases are diagnosed each year20,21

15

Diagnosis of CTCL can often be delayed or missed in early-stage patients19

Romidepsin (ISTODAX) has a category 2A recommendation from the NCCN Guidelines® for CTCL based on Study 1 and Study 212,23,24

� Clinical, pathologic, and histologic features of CTCL can resemble benign infl ammatory skin diseases19

� Pruritus is the most frequent and earliest symptom of CTCL22

� The time between the onset of skin lesions and defi nite diagnosis ranges from 4 to 10 years, with a mean of 6 years19

FACTORS TO CONSIDER WHEN DIAGNOSING CTCL

ISTODAX® (romidepsin) for injection is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

This indication is based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.


ISTODAX—a body of evidence in CTCL (Studies 1 and 2)

� 185 patients were treated and evaluated for safety; 167 patients were evaluated for e� cacy

� Patients received ISTODAX at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days

TRIAL DESIGN� ISTODAX was evaluated in 2 multicenter, single-arm, international

clinical studies� Objective disease response was evaluated according to a composite

endpoint that included assessments of: skin involvement, lymph node involvement, abnormal circulating T cells (Sézary cells), and visceral involvement (Study 2 only)

� Patients could be treated until disease progression at the discretion of the investigator and local regulators

PATIENT CRITERIAStudy 1; N=96� CTCL, stage IB-IVA� Failed at least 1 prior systemic therapy

Study 2; N=71� CTCL, stage IA-IVB� Received at least 2 prior skin-directed therapies or 1 or more

systemic therapies

CRITICAL ENDPOINTS� Primary: overall objective disease response rate (ORR, CR + PR)

– CR was defi ned as no evidence of disease– PR was defi ned as ≥50% improvement in disease

� Secondary: duration of response; time to response

CTCL Failed Therapy

SystemicTherapies



Safety and e� cacy were evaluated in 2 single-arm CTCL studies9

ISTODAX—evaluated in 2 multicenter, single-arm, international clinical studies involving 43 centers across the United States, Europe, and Australia9,10

17

ISTODAX—studied across all disease stages in a pretreated population

WARNINGS AND PRECAUTIONS (cont'd)� Infections: Fatal and serious infections, including pneumonia, sepsis, and viral

reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case

ISTODAX can be used for 2nd-line systemic therapy across CTCL subtypes, including mycosis fungoides and Sézary syndrome, in patients who have received at least one prior systemic therapy9,10

71% and 87% of patients were stage IIB or greater in Study 1 and Study 2, respectively9

Patients received a median of 2 prior skin-directed therapies in Study 1 and 1 prior skin-directed therapy in Study 2 (range: 0-6)9

Patients received a median of 2 prior systemic therapies (range: 0-8)9

PATIENT BASELINE CHARACTERISTICS IN STUDY 1 AND STUDY 29


Study 2(N=71)

AgeMean (SD) 57 (12) 56 (13)Median (range) 57 (21-89) 57 (28-84)Sex, n (%)Men 59 (61%) 48 (68%)Women 37 (39%) 23 (32%)Race, n (%)White 90 (94%) 55 (77%)Black 5 (5%) 15 (21%)Other/not reported 1 (1%) 1 (1%)

Stage of disease at study entry, n (%)IA 0 1 (1%)IB 15 (16%) 6 (9%)IIA 13 (14%) 2 (3%)IIB 21 (22%) 14 (20%)III 23 (24%) 9 (13%)IVA 24 (25%) 27 (38%)IVB 0 12 (17%)Number of prior skin-directed therapiesMedian (range) 2 (0-6) 1 (0-3)Number of prior systemic therapiesMedian (range) 2 (1-8) 2 (0-7)


An objective disease response was seen in up to 35% (25/71) of patients in 2 CTCL studies



19

The fi rst FDA-approved treatment for CTCL to evaluate a global tumor (composite) response in all of the following disease sites9,23

WARNINGS AND PRECAUTIONS (cont'd)� Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX.



BLOOD

SKIN

LYMPH NODES

VISCERA (Study 2 only)


STU

DY

1ST

UD

Y 2

0 4010 20 30

Patients (%)

50

34% ORR Primary Endpoint (n=33; CI: 25, 45a)

6% CR (n=6; CI: 2, 13a) 28% PR (n=27; CI: 19, 38a)


6% CR (n=4; CI: 2, 14a) 30% PR (n=21; CI: 20, 43a)

a95% confidence interval. Response rates above are rounded to the nearest whole number.

RESPONSE RATES IN STUDY 1 (N=96) AND STUDY 2 (N=71)9


An objective disease response was seen in up to 35% (25/71) of patients in 2 CTCL studies



19

The fi rst FDA-approved treatment for CTCL to evaluate a global tumor (composite) response in all of the following disease sites9,23

WARNINGS AND PRECAUTIONS (cont'd)� Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX.



BLOOD

SKIN

LYMPH NODES

VISCERA (Study 2 only)


STU

DY

1ST

UD

Y 2

0 4010 20 30

Patients (%)

50


6% CR (n=6; CI: 2, 13a) 28% PR (n=27; CI: 19, 38a)


6% CR (n=4; CI: 2, 14a) 30% PR (n=21; CI: 20, 43a)

a95% confidence interval. Response rates above are rounded to the nearest whole number.

RESPONSE RATES IN STUDY 1 (N=96) AND STUDY 2 (N=71)9


A durable response was achieved with a median duration of response of 15 months (range: 1-20+a) and 11 months (range: 1-66+a)

� Responses were evaluated in an advanced-stage population with 71% of patients in Study 1 and 87% of patients in Study 2 at stage IIB or greater9

SERIOUS ADVERSE REACTIONS� Infections were the most common type of serious adverse event reported in both

studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection

� Serious adverse reactions reported in >2% of patients in Study 1 were sepsis and pyrexia (3%)

� In Study 2, serious adverse reactions in >2% of patients were fatigue (7%), supraventricular arrhythmia, central-line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter-related infection, hypophosphatemia, and dyspnea (4%)

0

Months

246

STU

DY

1ST

UD

Y 2

11-month DOR (range: 1-66+a)

15-month DOR (range: 1-20+a)

12 18

MEDIAN DURATION OF OBJECTIVE DISEASE RESPONSES IN STUDY 1 (n=33) AND STUDY 2 (n=25)9

aDenotes censored value.

21

A median time to objective disease response was seen in 2 months in 2 CTCL studies

SERIOUS ADVERSE REACTIONS (cont’d)� Most deaths were due to disease progression. In Study 1, there were two deaths due to

cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome

42

Months

6

2 MONTHS

0

MEDIAN TIME TO OBJECTIVE DISEASE RESPONSE STUDY 1 (n=33)STUDY 2 (n=25)

(range: 1-6 months)

MEDIAN TIME TO OBJECTIVE DISEASE RESPONSE IN STUDY 1 (N=96) AND STUDY 2 (N=71)9

Median time to complete response in Study 1 (N=96) and Study 2 (N=71)9

� The median time to complete response was 4 months and 6 months in Study 1 (n=6) and Study 2 (n=4), respectively (range: 2-9 months)

ISTODAX demonstrated a durable response in a population that included all disease stages (IA-IVB) in 2 clinical studies9




Study 1 (N=102)

Study 2 (N=83)


Any adverse reactions 99 (97%) 36 (35%) 83 (100%) 68 (82%)

Nausea 57 (56%) 3 (3%) 71 (86%) 5 (6%)

Asthenia/Fatigue 54 (53%) 8 (8%) 64 (77%) 12 (14%)

Infections 47 (46%) 11 (11%) 45 (54%) 27 (33%)

Vomiting 35 (34%) 1 (<1%) 43 (52%) 8 (10%)

Anorexia 23 (23%) 1 (<1%) 45 (54%) 3 (4%)

Hypomagnesemia 22 (22%) 1 (<1%) 23 (28%) 0

Diarrhea 20 (20%) 1 (<1%) 22 (27%) 1 (1%)

Pyrexia 20 (20%) 4 (4%) 19 (23%) 1 (1%)

Anemia 19 (19%) 3 (3%) 60 (72%) 13 (16%)

Thrombocytopenia 17 (17%) 0 54 (65%) 12 (14%)

Dysgeusia 15 (15%) 0 33 (40%) 0

Constipation 12 (12%) 2 (2%) 32 (39%) 1 (1%)

Neutropenia 11 (11%) 4 (4%) 47 (57%) 22 (27%)

Hypotension 7 (7%) 3 (3%) 19 (23%) 3 (4%)

Pruritus 7 (7%) 0 26 (31%) 5 (6%)

Hypokalemia 6 (6%) 0 17 (20%) 2 (2%)

ADVERSE REACTIONS OCCURRING IN >20% OF PATIENTS IN EITHER STUDY 1 OR STUDY 2 REGARDLESS OF CAUSALITY (N=185)9

23


ADVERSE REACTIONS OCCURRING IN >20% OF PATIENTS IN EITHER STUDY 1 OR STUDY 2 REGARDLESS OF CAUSALITY (cont’d)9


Study 1 (N=102)

Study 2 (N=83)


Dermatitis/Exfoliative dermatitis

4 (4%) 1 (<1%) 22 (27%) 7 (8%)

Hypocalcemia 4 (4%) 0 43 (52%) 5 (6%)

Leukopenia 4 (4%) 0 38 (46%) 18 (22%)

Lymphopenia 4 (4%) 0 47 (57%) 31 (37%)

Alanine aminotransferase increased

3 (3%) 0 18 (22%) 2 (2%)

Aspartate aminotransferase increased

3 (3%) 0 23 (28%) 3 (4%)

Hypoalbuminemia 3 (3%) 1 (<1%) 40 (48%) 3 (4%)

Electrocardiogram ST-T wave changes

2 (2%) 0 52 (63%) 0

Hyperglycemia 2 (2%) 2 (2%) 42 (51%) 1 (1%)

Hyponatremia 1 (<1%) 1 (<1%) 17 (20%) 2 (2%)

Hypermagnesemia 0 0 22 (27%) 7 (8%)

Hypophosphatemia 0 0 22 (27%) 8 (10%)

Hyperuricemia 0 0 27 (33%) 7 (8%)

Overall discontinuation rate9

� The discontinuation rate due to adverse events was 21% in Study 1 and 11% in Study 2

� Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia


ISTODAX demonstrated a durable response in a CTCL population that included all disease stages




MEDIAN TIME TO RESPONSE (TTR)9

� Median time to objective disease response was 2 months (range: 1-6 months) in 2 large, multicenter, single-arm, international clinical studies

MEDIAN DURATION OF RESPONSE (DOR)9

� 15 months (range: 1-20+) in Study 1� 11 months (range: 1-66+) in Study 2

ISTODAX® (romidepsin) for injection is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. This indication is based on response rate. Clinical benefi t such as improvement in overall survival has not been demonstrated.

OVERALL RESPONSE RATES (ORR; CR + PR)9

� An objective disease response was seen in 34% (33/96) and 35% (25/71) of patients in Study 1 and Study 2, respectively

Romidepsin (ISTODAX) has a category 2A recommendation from the NCCN Guidelines® for CTCL based on Study 1 and Study 2 12,23,24

Up to35% ORR

Up to15

Months

2Months

ISTODAX—for 2nd-line systemic therapy across CTCL subtypes, including mycosis fungoides and Sézary syndrome

25

MO

A

The mechanism of the antineoplastic e� ect of romidepsin observed in nonclinical and clinical studies has not been fully characterized9

ISTODAX is a histone deacetylase (HDAC) inhibitor9,25,26

HDACs catalyze the deacetylation

of histone and non-histone

proteins9

ISTODAX is an HDAC inhibitor9

HDAC–Non-HistoneProtein Interaction

HDAC-HistoneInteraction

Romidepsin

Romidepsin-HDACInteraction

Acetylated Histones

Acetylated Non-Histone Protein

Cell Nucleus

In vitro, ISTODAX causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with

IC50 values in the nanomolar range9

USE IN PREGNANCYAdvise women to avoid pregnancy. Based on its mechanism of action and fi ndings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.


Administered once a week for 3 weeks—with 1 week o� each dosing cycle

The recommended dose is 14 mg/m2 administered intravenously over a 4-hour period on Days 1, 8, and 15 of a 28-day cycle9

� ISTODAX® (romidepsin) is supplied as a kit which includes a 10 mg single-dose vial of ISTODAX and one single-dose vial with 2.2 mL (deliverable volume) of diluent

ONLY 3 DOSES EVERY 28 DAYS9

Day 1

Day 8

Day 15

Day 22

Notreatment

Day 3

Day 10

Day 17

Day 24

Day 6

Day 13

Day 20

Day 27

Day 2

Day 9

Day 16

Day 23

Day 5

Day 12

Day 19

Day 26

Day 4

Day 11

Day 18

Day 25

Day 7

Day 14

Day 21

Day 28

3 WEEKS ON

1 WEEK OFF

Cycles should be repeated every 28 days provided the patient continues to benefi t from and tolerate the drug9

PATIENT COUNSELING INFORMATION FOR TUMOR LYSIS SYNDROME� Advise patients of the risk of tumor lysis syndrome (especially those with advanced stage

disease and/or high tumor burden) to maintain high fl uid intake for at least 72 hours after each dose

DRUG INTERACTIONS� Monitor more frequently prothrombin time and International Normalized Ratio in patients

concurrently administered ISTODAX and warfarin or coumarin derivatives

� Romidepsin is metabolized by CYP3A4– Monitor patients for toxicity related to increased romidepsin exposure and follow

dose modifi cations for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors

– Avoid co-administration of ISTODAX with rifampin and other potent inducers of CYP3A4

� Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

27

Dosing modifi cation for hematologic and nonhematologic toxicities

DISCONTINUATIONS� Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11%

in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia

� 19% of patients in Study 3 and in 28% of patients in Study 4 discontinued due to an adverse event. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%)

Patients stayed on ISTODAX for a mean duration of 5.6 months in both CTCL studies and PTCL Study 3. The mean duration was 9.6 months in PTCL Study 49

DO

SING

NONHEMATOLOGIC TOXICITIES (EXCEPT ALOPECIA)9

Grade 2 or 3 nonhematologic toxicity

Delay dose until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2

Recurrent Grade 3 nonhematologic toxicity Grade 4 nonhematologic toxicity

Delay dose until toxicity returns to ≤Grade 1 or baseline, then therapy should be permanently reduced to 10 mg/m2

Treatment should be discontinued if Grade 3 or 4 nonhematologic toxicities recur after dose reduction.

HEMATOLOGIC TOXICITIES9

Grade 3 or 4 neutropenia

Grade 3 or 4 thrombocytopenia

Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion

Delay treatment until the ANC returns to ≥1.5 x 109/L or baseline, then therapy may be restarted at 14 mg/m2

Delay treatment until platelets return to ≥75 x 109/L or baseline, then therapy may be restarted at 14 mg/m2

Delay dose until specifi c cytopenia returns to ≤Grade 1 or baseline, then therapy should be permanently reduced to 10 mg/m2


How ISTODAX is supplied

ISTODAX is supplied as a kit including a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin and 22 mg of the bulking agent, povidone, USP9

� Each kit includes one single-dose sterile diluent vial containing 2.4 mL (2.2 mL deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP

The recommended dose is 14 mg/m2 administered intravenously over a 4-hour period on Days 1, 8, and 15 of a 28-day cycle9

USE IN SPECIFIC POPULATIONS� Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes

pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus

� Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

� Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

NDC 59572-984-01:

ISTODAX KIT containing one 10 mg single-dose vial of ISTODAX and one single-dose vial with 2.2 mL (deliverable volume) of diluent

� ISTODAX must be stored at 20° to 25°C, excursions permitted between 15° to 30°C

29

How ISTODAX is reconstituted

ISTODAX is a cytotoxic drug. Use appropriate handling procedures9

RECO

NSTITU

TION

RECONSTITUTION9

� ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion

� ISTODAX and diluent vials contain an overfi ll to ensure the recommended volume can be withdrawn at a concentration of 5 mg/mL

� Each 10 mg single-dose vial of ISTODAX must be reconstituted with 2.2 mL of the supplied diluent

– With a suitable syringe, aseptically withdraw 2.2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX for injection vial

– Swirl the contents of the vial until there are no visible particles in the resulting solution

– The reconstituted solution will contain ISTODAX 5 mg/mL

– The reconstituted ISTODAX vial will contain 2 mL of deliverable volume of drug product

– The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature

ADMINISTRATION9

� Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique

� Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP

– Infuse over 4 hours� Parenteral drug products should be inspected visually

for particulate matter and discoloration before administration, whenever solution and container permit

� The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible

30 Please see accompanying Full Prescribing Information in pocket.

Important Safety Information

WARNINGS AND PRECAUTIONS

� Myelosuppression: ISTODAX® (romidepsin) for injection can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary


� Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history of signifi cant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to signifi cant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confi rm that potassium and magnesium levels are within the normal range before administration of ISTODAX

� Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate


ADVERSE REACTIONS

Peripheral T-Cell Lymphoma

The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%). (Continued on next page)

31

Important Safety Information

SAFETY

ADVERSE REACTIONS

Cutaneous T-Cell Lymphoma

The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%), and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS

� Monitor more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives

� Romidepsin is metabolized by CYP3A4

— Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifi cations for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors

— Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4

� Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS

� Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus

� Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

� Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution


References

References:

1. Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. Peripheral T-cell lymphoma. Blood. 2011;117(25):6756-6767.

2. Vose J, Armitage J, Weisenburger D. International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology fi ndings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.

3. Abouyabis AN, Shenoy PJ, Lechowicz MJ, Flowers CR. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma. 2008;49(11):2099-2107.

4. Armitage JO, Vose JM, Weisenburger DD. Towards understanding the peripheral T-cell lymphomas. Ann Oncol. 2004;15(10):1447-1449.

5. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107(1):265-276.

6. Swerdlow SH, Campo E, Harris NL, et al. WHO Classifi cation of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.

7. Ja� e ES, Pittaluga S. The pathologic basis for the classifi cation of non-Hodgkin lymphomas. In: Ho� mann R, Furie B, McGlave P, et al. Hematology: Basic Principles and Practice. Philadelphia: Churchill-Livingstone; 2009.

8. Rodriguez-Abreu D, Filho VB, Zucca E. Peripheral T-cell lymphomas, unspecifi ed (or not otherwise specifi ed): a review. Hematol Oncol. 2008;26:8-20.

9. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2016.

10. Data on fi le, Celgene Corporation, Summit, NJ.

11. Piekarz RL, Frye R, Prince HM, et al. Phase II trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827-5834.

12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.2.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed May 7, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

13. Coi� er B, Pro B, Prince HM, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;23;7(1):11.

14. The Merck Manuals Online Medical Library. http://www.merckmanuals.com/professional/hematology-and-oncology/lymphomas/non-hodgkin-lymphomas. Accessed May 5, 2015.

33

References

15. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139(7):857-866.

16. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739.

17. Willemze R, Ja� e ES, Cerroni L, et al. WHO-EORTC classifi cation for cutaneous lymphomas. Blood. 2005;105(10):3768-3785.

18. Kim EJ, Hess S, Richard SK, et al. Immunopathogenesis and therapy of cutaneous T-cell lymphoma. J Clin Invest. 2005;115(4):798-812.

19. Rosen ST, Querfeld C, Kuzel TM, Guitart J. Cutaneous T-cell Lymphomas: A Guide for the Community Oncologist. 2nd ed. London, England: The Oncology Group, CMPMedica; 2009.

20. Lymphoma Research Foundation. Cutaneous T-cell lymphoma. http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300151. Accessed May 7, 2015.

21. Cutaneous Lymphoma Foundation. A patient’s guide to understanding cutaneous lymphoma. http://www.clfoundation.org/resources/publications. Accessed May 7, 2015.

22. Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas: frequent, often severe and di� cult to treat. Acta Derm Venereol. 2010;90:12-17.

23. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491.

24. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410-5417.

25. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5(10):981-989.

26. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769-784.

27. Rodríguez J, Gutiérrez A, Martínez-Delgado B, Perez-Manga G. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol Hematol. 2009;71(3):181-198.

28. Lymphoma Research Foundation. Focus on peripheral T-cell lymphoma: about PTCL. http://www.focusonptcl.org/content/about-ptcl. Accessed May 7, 2015.

ISTODAX® is a registered trademark of Celgene Corporation.© 2016 Celgene Corporation 08/16 US-IST160018

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.

33

References

15. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139(7):857-866.

16. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739.

17. Willemze R, Ja� e ES, Cerroni L, et al. WHO-EORTC classifi cation for cutaneous lymphomas. Blood. 2005;105(10):3768-3785.

18. Kim EJ, Hess S, Richard SK, et al. Immunopathogenesis and therapy of cutaneous T-cell lymphoma. J Clin Invest. 2005;115(4):798-812.

19. Rosen ST, Querfeld C, Kuzel TM, Guitart J. Cutaneous T-cell Lymphomas: A Guide for the Community Oncologist. 2nd ed. London, England: The Oncology Group, CMPMedica; 2009.

20. Lymphoma Research Foundation. Cutaneous T-cell lymphoma. http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300151. Accessed May 7, 2015.

21. Cutaneous Lymphoma Foundation. A patient’s guide to understanding cutaneous lymphoma. http://www.clfoundation.org/resources/publications. Accessed May 7, 2015.

22. Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas: frequent, often severe and di� cult to treat. Acta Derm Venereol. 2010;90:12-17.

23. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491.

24. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410-5417.

25. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5(10):981-989.

26. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769-784.

27. Rodríguez J, Gutiérrez A, Martínez-Delgado B, Perez-Manga G. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol Hematol. 2009;71(3):181-198.

28. Lymphoma Research Foundation. Focus on peripheral T-cell lymphoma: about PTCL. http://www.focusonptcl.org/content/about-ptcl. Accessed May 7, 2015.

ISTODAX® is a registered trademark of Celgene Corporation.© 2016 Celgene Corporation 08/16 US-IST160018

Please see Important Safety Information on pages 30-31 and accompanying Full Prescribing Information in pocket.

World Health Organization (WHO) Classifi cation of Select Mature T/NK-cell Subtypes14,16,27,28,a

WHO

T/NK-cell Neoplasms

Mature T/NK-cellNeoplasms

Non-HodgkinLymphoma

Extranodal

NK/T-cell Lymphoma(NKTCL), nasal type

Hepatosplenic T-cellLymphoma

(HSTCL)

SubcutaneousPanniculitis-like

T-cell Lymphoma(SPTCL)

Enteropathy-associated T-cell Lymphoma

(EATL)

Leukemic Cutaneous

Adult T-cell Leukemia/Lymphoma (ATLL)

Mycosis Fungoides (MF)

T-cell ProlymphocyticLeukemia

(T-PLL)

Sézary Syndrome(SS)

Primary Cutaneous Gamma/Delta T-cell

Lymphoma

T-cell Large GranularLymphocytic Leukemia

(LGL)

Primary Cutaneous CD30+ T-cell Disorders

Aggressive NK-cellLeukemia

(ANKL)Transformed MF

Nodal

Peripheral T-cell Lymphoma, not

otherwise specifi ed(PTCL-NOS)

AngioimmunoblasticT-cell Lymphoma

(AITL)

Anaplastic Large Cell Lymphoma (ALCL) ALK-1(+)/ALK-1(–)

The nodal subtypes are the most

common PTCL subtypes

Mycosis fungoides and Sézary syndrome are the most common

forms of CTCL

a According to the WHO 2008 classifi cation, there are various mature T/NK-cell subtypes that are categorized as: nodal, extranodal, leukemic, and cutaneous.

ptcl is typically an aggressive, di˜ cult to diagnose non ... file3 clinical characteristics,...

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