Management of Cutaneous

T cell lymphomas

Professor H Miles Prince

Peter MacCallum Cancer Centre

Melbourne, Australia

CTCL Management Guidelines

EORTC

NCCN

ESMO

• Trautinger et al

• Eur J Cancer 2006 42: 1014-1030

• Kim et al

• www.nccn.org

• Dummer et al

• Ann Onc 2008 19: 72-76

MF/SS Staging System

Skin

• T1 patches/plaques <10% (IA)

• T2 patches/plaques >10% (IB)

• T3 – tumours (IIB)

• T4 – erythroderma(III)

Nodes

• N0 - no nodes

• N1 –dermatopathic(IIA)

• N2 – non-palpable nodes lymphoma (IVA)

• N3 – lymphoma (IVA)

Visceral

• M0 - no visceral disease

• M1 - visceral disease (IVB)

• B0 - no blood disease

• B1 - >5% Sezarycells

Olsen et al Blood 2008

STAGE LESIONS NODES VISCERAL

clinical Pathological

IA 10 % patches

and plaques - -

IB 10 % patches

and plaques - -

IIA any patches

and plaques + -

IIB Tumours*+/- -

III erythroderma+/- -

IVA any+/- +

IVB any +/- +/- +

* minimum = 10 mm x 10 mm x 5 mm per study protocols

Advanced Stage

CTCL Staging: T1, T2 skin stages

• Approximately 50% to 70% of patients with

MF/Sézary syndrome will present with isolated

patches or plaque

type lesions

T1 T2Kim, Y. H. et al. Arch Dermatol 2003;139:857-866

tumor

erythroderma

Arulogan et al. Blood 2008

SVH/Peter Mac Cutaneous Lymphoma Clinic

Long-term outcome for MF (n = 297)

N= 205

N= 92

Arulogan et al. Blood 2008

SVH/Peter Mac Cutaneous Lymphoma Clinic

Long-term outcome for MF (n = 297)

(n=41),

(n=36),

(n=12).

CTCL is an

Immune-modulated

disease

Stage Dependent Treatment

Stage IA-IIA

• Early stage disease

• Excellent prognosis

Stage IB-III

• Stage IB - resistance to SDT

• Stage III - erythrodermic disease

• Intermediate prognosis

Stage IIB/IV

• Advanced disease (heterogeneity - stage IIB)

• Poor prognosis

CTCL Treatment AlgorithmStage IA Stage IB, IIA Stage IIB Stage III Stage IVA, B

denileukin diftitox

Electron Beam (incl. TSEB)

Photopheresis ± IFN ± Bex

UVB

Topical corticosteroids

bexarotene gel

PUVA (± IFN or ± Retinoid)

topical nitrogen mustard, BCNU

bexarotene capsules

Chemotherapy

or AlloSCTChemotherapy

or AlloSCT

alemtuzamab (anti-CD52w)*

HDACi**

**vorinostat [SAHA], romidepsin [depsipeptide], panobinostat *? zanolimumab (HuMax-CD4)

Stage IA-IIA Mycosis Fungoides

Skin directed therapy

• Expectant

• Topical chemotherapy

• Phototherapy-PUVA/UVB

• Radiotherapy (local/TSEB)

PUVA in Mycosis Fungoides

• 55-79% CRStage IA

• 39-59% CR

• Sanctuary sites often resistantStage IB

• IA - 45%

• IB - 62%

Relapse rate

PUVA Combinations

• CR: 62-84% (IFN monotherapy CR: 10-27%)

• PUVA+IFN vs PUVA+Acitretin: CR -78% vs30%

• PUVA vs PUVA+IFN: similar CR but reduced cumulative UVA dose/increased duration of response with combination

PUVA + alpha

Interferon

• Acitretin: CR - 70% with reduced cumulative UVA dose

• EORTC 21011 – PUVA vs PUVA+Bexarotene

PUVA + Retinoids

Chemotherapy (Stage IIB-IV)

• 32% CR: median response duration of 3-22mos

• Gemcitabine and Liposomal doxorubicin – OR: 60-80%

Single-agent chemotherapy

• 38% CR with median response duration of 5-41mos

Multi-agent chemotherapy

Chemotherapy for CTCL

Stem Cell Transplantation

Autologous SCT: high rate of CR but short duration of response (85% relapse at 2 mos: n=20)

Allogeneic SCT: Durable CRs/high mortality (71% alive without disease at 3yrs: n=21)

Reduced intensity allo SCT: Graft vs lymphoma effect and durable responses (56.7% OS at 4 years)

Patient selection and debulking therapy/conditioning regime?

• Olavarria et al Brit J Haematol 2001

• Guitart et al Arch Dermatol 2002

• Molina et al J Clin Oncol 2005

• Duarte et al BMT 2007

Total Skin Electron Beam

TherapyResponses - stage dependent

• Stage IA-IIA - 96% CR

• Stage IIB - 36% CR

• Stage III - 60% CR

Duration of CR

• >26Gy (4-9MEV) in 30-36#

• EORTC TSEB guidelines: Jones et al JAAD 2002; 47: 364-370

New Treatment options

• Bexarotene

• Alemtuzumab (Campath-1H; CD52w)

• Zanulimomab (CD4)

• Denileuklin diftitox (Ontak)

• Extracorporeal Photopheresis

• Histone deacetylase inhibitors

• Lenalidomide

• Proteasome inhibitors

• Forodesine

BEXAROTENE (TARGRETIN®)

• LGD1069

• Formula:

C24H28O2

• MW: 348

COOH

• Novel synthetic retinoid analogue

• Selective binding and activation of

RXR receptors

• Potentially unique biologic properties

TWO RETINOID SIGNALING PATHWAYS

COOH

Tretinoin

(all-trans-retinoic acid)

RAR-

RAR-

RAR-

RXR-

RXR-

RXR-

COOH

Panretin®

(alitretinoin)

(9-cis-retinoic acid)

Targretin®

(bexarotene)

COOH

RETINOID RECEPTOR BIOLOGY

RAR RXR

Regulation of Cell

Growth and Differentiation

Regulation of

Apoptosis

RAR RXRAlitretinoin

Tretinoin

Bexarotene

Oral Bexarotene in CTCL

Baseline Week 12

Week 28

RXR Retinoids in CTCL

Study No Stage OR CR TTR TTP DOR Refs

Bexarotene

oral

6.5-650mg/m2

Phase

II

multi

58

IB-IIA

30/54

54%

3/54

7%

8.1w 30w > 73w Duvic

Arch

Dermatol

2001

Bexarotene

oral

300-650mg/m2

Phase

II

multi

40

IIB-IVB

19/40

48%

4/17SS

26w 43w Olsen

JCO 2001

Bexarotene Clinical Usage

• PUVA combination

• Maintenance therapy after SDT

Early stage disease

• Poikilodermatous MF

• Folliculotropic MF

Clinical variants

• Maintenance of response

• Erythrodermic MF/SS

Advanced disease

Alemtuzumab (Campath-1H): structure

Humanized anti-human CD52w monoclonal antibody

VL

C

VH

C1

Human constant Fc region

Human constant region

Murine variable regions

Variable region: murine IgG1 kappa anti-CD52w

Constant region: human IgG1 heavy chain and kappa light chain

A.Ng et al. Hematologica (2005) 90: 1672-9

Primary treatment

type

Total

number

patients

treated

Number tested

for CMV

DNAemia

N (%)

Number with

positive CMV

DNAemia

N (%)

Conventional

chemotherapy

1636 61 (3.7%) 13 (21%)

HyperCVAD 62 15 (24.2%) 6 (40%)

Fludarabine 151 31 (20.5%) 7 (22.6%)

Autologous SCT 191 34 (17.8%) 8 (23.5%)

Denileukin diftitox 33 6 (18.2%) 2 (33%)

Rituximab 225 17 (7.5%) 6 (35.3%)

Alemtuzumab 12 6 (50%)* 6 (100%)

0.8%

4.6%

2.6%

50%

Erythrodermic MF/SS (Stage III/IV)

1st line

Methotrexate(PUVA)

Radiotherapy (nodes)

Photopheresis

Alpha Interferon

Bexarotene

2nd line

Chemotherapy

(single agent)

High dose (SCT)

TSEB

Alemtuzumab

Denileukin diftitox

ISCL criteria for diagnosis of Sezary Syndrome Vonderheid et al JAAD 46: 95 2002

T cell immunosurveillence• Alteration in Th1 and Th2 repertoire

• Cytotoxic T-cells in tumour tissue

• Immunomodulation Rx effective:

– Allogeneic transplant effective

– Interferon, imiquimod (Toll-R) effective

– Photopheresis

– Immunotherapy i.e vaccination (in future)

Extracorporeal Photopheresis

(ECP)• PB lymphocytes (mononuclear) cells collected

• continuously photosensitized by exposing PBL to 8 methoxypsoralen =

8-MOP = methoxsalen = Uvadex

• exposure to UVA radiation in an extracorporeal circuit

• in-line re-infused into the patient

Background - Extracorporeal

Photopheresis

Edelson et al, PNAS (2000)

Background - Previous Studies

• 19 studies reporting 438 patients worldwide

First author,

Year

n Participants Complete

response (%)

Overall

response* (%)

Edelson,

1987

29 Erythrodermic - 83

Gottlieb,

1996

24 Sezary syndrome 29 83

Russell-

Jones, 1997

19 Sezary syndrome 16 53

*Response definition highly variable between studies

JAAD 2008

Results – Response to ECP

• March 2006: ceased

ECP/PNL, continued on

maintenance bexarotene

(225mg/d)

• April 2010: remains in

complete clinical and

haematologic remission

(64 months)

• Female, 79 years

• May 2002: commenced ECP + Bexarotene + PNL

• March 2003: resolution of itch, erythroderma and LDN,

normalised LDH and total lymph count

Diptheria toxin

portionIL-2

sequence

Fusion Junction

| S

|

S

|

| S

|

S

|

• recombinant DNA-derived, cytotoxic fusion protein expressed in E. coli

• amino acid sequence for the diphtheria toxin catalytic and membrane

translocation domains and IL-2

• directs cytocidal activity of diphtheria toxin to cells expressing IL-2R

ONTAK® (denileukin diftitox)

ONTAK® Mechanism of Action

Receptor Binding and Internalization

Waters CA, Schimke PA, Snider CE, et al. Eur J Immunol 20:785-791, 1990

Williams DP, Snider CE, Strom TB, Murphy JR. J Biol Chem 265:11885-11889, 1990

ONTAKØ•IL-2R•(high-affinity)

IL-2R(medium-affinity)

Cleavage &

Toxin release

IL2

DTProtein

synthesis

CELL

DEATH

Protein synthesis

•Terminated by toxin-mediated ADP

•ribosylation• of elongation factor 2

Internalization

Cell exterior

•Cell interior

Cell membrane

IL2DTIL2DT

IL2DT

IL2DT

Copyright © American Society of Clinical Oncology

Prince, H. M. et al. J Clin Oncol; 28:1870-1877 2010

Fig 2. Overall response rate (ORR) in 144 patients who were randomly assigned to receive placebo, denileukin diftitox (DD) 9 {micro}g/kg/d, or DD 18 {micro}g/kg/d. ORRs (values above bars) were the

combination of complete response (CR), clinical complete response (CCR), and partial response (PR) (values within bars)‏

Copyright © American Society of Clinical Oncology

Prince, H. M. et al. J Clin Oncol; 28:1870-1877 2010

Fig 3. Kaplan-Meier estimates of progression-free survival (PFS; N = 144)‏

Histone Deacetylase

Inhibitors

Deacetylation of Histones by HDAC Can Prevent Gene Expression

Acetylation by histone acetyltransferases (HATs) allows transcription and gene expression

Deacetylation by histone deacetylases (HDACs) can prevent transcription and gene expression

HAT

HISTONE ACETYLATION

HISTONE DEACETYLATION

HDAC

Acetylated Histone

Open chromatin Transcription factors can access DNA

Deacetylated Histone

Closed chromatin Transcription factors cannot access DNA

Ac: acetyl group

HDAC depicts a class I deacetylase

Transcription factors –Ac

Ac–

Ac–

Published Clinical Trials of HDACi

Prince, Bishton, Johnstone

1 2 3 4 5 6 7 8 14 15139 1110 12Day

Depsipeptide Depsipeptide Depsipeptide

28 days

Feb 04Jan 04

Piekarz et al. ASCO 2007

Romidepsin in CTCL

2/11/02

2/13/02 4/10/02

4/27/02Romidepsin in CTCL

Piekarz et al. ASCO 2007

Romidepsin in CTCL: Phase II trial

(n=71)

ORR = 34%

CRs observed

Responses in stage IV

DOR = 13.7 months

Durable responses observed

Now approved by FDA

Piekarz: JCO 2009

Romidepsin in PTCL

All patients (46) 2+ cycles (32)

ORR 15 (33%) 15 (47%)

PR 10 (22%) 10 (31%)

CR 5 (11%) 5 (16%)

Median age – 59 (28 – 84)

Mean prior Rx = 4.8 (1-14)

Mean number or cycles received = 6.8 (1-47)

Median duration of response = 9.0m (1.8m – 5.8 yrs)

CR patients

Median duration of response = 6.0m (2.8m – 5.8 yrs)

Piekarz et al. ASH 2009 # 1657

Visible Improvements in Skin Manifestations

With Vorinostat*Baseline: Stage IVA Mycosis Fungoides

BaselineWeek 21 Response (Initial)76% in SWAT Score

Week 37 Response68% in SWAT Score

In the pivotal trial, 30% (22/74, 95% CI [19.7% to 41.5%]) of patients

experienced an objective response.

Phase II trial of Vorinostat in Unresponsive CTCL

Partial response to Vorinostat (400 mg qd) in a patient with stage IVB CTCL

This patient had received 6 prior therapies

Baseline

Duvic M, et al. Proc Am Soc Clin Oncol. 2005. Abstract 6571.

Results (cont’d)

Week 8 Week 24

+ = Response ongoing.

CI = Confidence Interval; NR = Not Reached

‡ Stages IIB, III, IVA, and IVB

† Objective Response: confirmed complete response or partial response

NR (55, 280+) 31 (29-87) (7.8, 45.4) (22.7%)522Patients with tumor disease

NR (34+, 244+) 56 (28-171) (17.3, 52.8) (33.3%)1030Patients with Sezary

syndrome

NR (34+, 280+) 56 (28-171) (18.5, 42.6) (29.5%)1861Stage IIB or Higher‡

NR (34+, 322+) 55 (28-171) (19.7, 41.5) (29.7%)2274All Patients

Median (Range) Median

(Range)

(95% CI) N (%)

Duration of

Objective

Response (days)

Time to

Objective

Response†

(days)

NPopulation

Patients with an Objective Response†

Vorinostat Pivotal Study

30% Objective Response Rate

(21.2,41.5)(32.3%)2165≥ 3 points

(14.3, 39.6) (25.5%)1351Without an objective response

(25.7, 70.2) (47.6%)1021With an objective response

(25.5, 62.6) (43.3%)13307-10 points (severe pruritus)

With baseline pruritus score

(95% CI) N (%)

Patients with Pruritus ReliefNPopulation

Vorinostat Pivotal Study

Pruritus Relief

• In those patients with the most severe pruritus (baseline scores of 7 to 10 points),

43.3% had pruritus relief, including

– 5 of 16 SS patients.

– 30% who achieved a score < 3 at two or more consecutive

visits.

• The median time to and duration of pruritus relief among patients with stage IIB or

higher disease were 16 and 113 days, respectively.

Panobinostat (LBH589)

Best Response

Tumor Type n CR PR SD PD

CTCL (30 mg) 1 1 0 0 0

CTCL (20 mg) 9 1 4 2 2

RCC 6 2 4

Melanoma 6 1 5

Mesothelioma 1 1 0

Parotid Gland 1 1 0

Others 8 8

6/10

Ellis et al. Clin Canc Res 2008

Responses of Patients to LBH589

19 July 05

Discontinued therapy due to toxicity Ellis et al. Clin Canc Res 2008

Cycle 24, Day 11

Cycle 1, Day 1

Ellis et al. Clin Canc Res 2008

Adverse Events

Regardless of Causality: 20mg cohort

• The most common all grades adverse events, regardless

of causality included:

– anorexia

– nausea

– fatigue

– Diarrhea

– Transient thrombocytopenia

Differentially Expressed Genes# That Respond to

LBH589 Consistently Over Time in All Patients

• IGF1 and CCND1 (encoding cyclin D1), previously identified in in vitro studies as HDACi-regulated genes, were identified*

• Moreover, genes that mediate biological responses known to be downstream of HDAC inhibition were identified – GUCY1A3 (angiogenesis)

– Angiopoietin-1 (angiogenesis)

– COUP-TFII (NR2F2) (Transcription Factor)

– SORBS2 (apoptosis)

– CCND1 (cyclin D1)

– TM4SF18 (cell proliferation)

– LAIR1 (immune modulation)

– Septin10 (membrane dynamics)

– TEF (apoptosis transcription factor)

*Sandor V et al. Br J Cancer 2000;83(6):817-25.

*Mitsiades CS et al. Proc Natl Acad Sci U S A 2004;101(2):540-5.#p < 0.0001

Before After 1 cycle (28 days)

Lenalidomide

Pralatrexate Mechanism of Action

Cell membrane

Extracellular

Cytosol

Pralatrexate

10-

formyl

THF

5.10-

methenyl

THF

Pralatrexate

THF

Folate

DHF

PRPP

GARFT

Pralatrexate-Glu(n)

IMP

AICARFT

AMP

GMP

dUMP

dTMP

DHFRTS

FPGS

RFC-1

Reduced flux due to

decreased THF levels

Rationally designed antifolate to improve cellular uptake and retention

DNA

RNADNA

PROPEL

Histology

*Two treated patients excluded from efficacy analysis.

Histopathology (n=111)

Per Independent

Central Review

n %

Per Investigator

n %

PTCL-nos 59 53 51 46

Anaplastic large cell lymphoma, primary systemic type 17 15 17 15

Angioimmunoblastic T-cell lymphoma 13 12 18 16

Transformed mycosis fungoides 12 11 13 12

Blastic NK lymphoma (with skin, lymph node, or

visceral involvement)

4 4 4 4

T-/NK-cell lymphoma-nasal 2 2 1 <1

Extranodal peripheral T-/NK-cell lymphoma

unspecified

1 <1 2 2

Adult T-cell leukemia/lymphoma (HTLV 1+) 1 <1 2 2

T-/NK-cell leukemia/lymphoma 0 0 1 <1

Mycosis fungoides (not transformed)* 1 <1 0 0

Inconsistent with T-cell lymphoma* 1 <1 0 0

Aggressive T-cell lymphoma 0 0 1 <1

Aggressive large cell T-cell lymphoma 0 0 1 <1

PROPELChange in Tumor Size

*As change from baseline in the sum of the perpendicular diameters

Maximum change* from baseline in tumor size

• 75% of patients with measurable disease (pre and post treatment)

had a decrease in tumor size

*IWC = International Workshop Criteria

O’Connor O, et al. J Clin Oncol. 2009; 27:15s (suppl; abstract 8561)

PROPELResponse by Central Review and Investigator

Best Response

Central Review

(IWC*)

Investigator

Assessment

n % n %

Overall response (CR + PR) 30 28 42 39

Complete response (CR) 10 9 19 18

Partial response (PR) 20 18 23 21

Stable disease (SD) 23 21 22 20

Disease control rate

(CR+PR+SD)

53 49 64 59

Progressive disease (PD) 40 37 40 37

Unevaluable 2 2 0 0

Missing 14 13 5 5

*IWC = International Workshop Criteria

O’Connor O, et al. J Clin Oncol. 2009; 27:15s (suppl; abstract 8561)

PROPEL

Duration of Response• 9.4 month median duration of response

– Duration of response is measured from first day of documented response to loss of response or censoring

– Patients were first assessed for response at the end of cycle 1 (week 7)

– 8 patients were permanently censored (for example, due to transplant)

• 23% of responses exceeded 300 days in duration

O’Connor O, et al. J Clin Oncol. 2009; 27:15s (suppl; abstract 8561)

PROPEL

Progression-free Survival

• Median progression-free survival was 106 days– Stable disease was maintained for 4.8 months

O’Connor O, et al. J Clin Oncol. 2009; 27:15s (suppl; abstract 8561); UE, unevaluable; ND, not determined

PROPEL

Safety Profile

a Treatment emergent

b Stomatitis or Mucosal Inflammation of the gastrointestinal and genitourinary tracts

c Includes 2 MedDRA-preferred terms.

d Only 5 patients had platelet count <10,000/μL.

Adverse event Any Grade Grade 3 Grade 4

Mucositisb 71% 18% 4%

Thrombocytopeniac 41% 14% 19%d

Nausea 41% 4% 0%

Fatigue 36% 5% 2%

Anemiac 34% 15% 2%

Neutropeniac 24% 13% 7%

•The most common adverse events (AEs) were mucositis, thrombocytopenia,

nausea and fatigue

•Toxicities were manageable and consistent with the antifolate class

•Low rates of:– Alopecia (4%, all grade 1)a

– Febrile neutropenia (5%, all grade 3)

Most common grade 3/4 adverse events (% of patients)

O’Connor O, et al. J Clin Oncol. 2009; 27:15s (suppl; abstract 8561)

New Drugs in PTCL/CTCL

Treatment overview

• Early Stage Disease– Topical steroids

– Phototherapy (UVB, PUVA)

– Topical chemotherapy (NM, BCNU)

– Bexarotene

– Oral chemotherapy – methotrexate

– Alpha interferon

• Advanced-stage disease– Biological response modifiers

– Radiotherapy

– Systemic chemotherapy

– TransplantationRetinoid Bexarotene (Targretin)

MoAb Alemtuzumab (Campath)

Immunotoxin denileukin diftitox (Ontak)

HDACi romidepsin, vorinostat

Thank You!