A NOVEL THERAPEUTIC REGIMEN FOR FOLLICULOTROPIC MYCOSIS

FUNGOIDES

ALAIN H ROOK, PROFESSOR OF DERMATOLOGY

DIRECTOR, CUTANEOUS LYMPHOMA PROGRAMPERELMAN SCHOOL OF MEDICINE

UNIVERSITY OF PENNSYLVANIA

PotentialConflicts

• Galderma:Clinicaltrial;license

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van Doorn, R. et al. Arch Dermatol 2002;138:191-198.

CLINICAL APPEARANCES OF FOLLICULAR MYCOSIS FUNGOIDES

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van Doorn, R. et al. Arch Dermatol 2002;138:191-198.

Actuarial disease-related survival of 49 patients with follicular mycosis fungoides (FMF), 122 with generalized plaque-stage mycosis fungoides (MF) (T2 N0 M0), and 36 with tumor-stage MF

(T3 N0 M0)

The Immune Response Plays a Critical Role in Control of Cutaneous T-Cell Lymphoma in Early Stage Disease, AND, in Late Stage Disease

Localized Folliculotropic MF

• Excellentprognosisistypical

• Imiquimod

• Potenttopicalsteroids

• Carmustine(BCNU)ointment0.03-04%

• Electronbeam

ImidazoquinolinesAre Powerful TLR Agonists

Toll Like Receptor Agonists Are Therapeutically Active for Cutaneous T-Cell Lymphoma

mDC pDC

TLR 8(Resiquimod)

TLR 9(CpG)

TLR 7(Imiquimod)(Resiquimod)

IL-12,15,18 IFNα

(IFNγ) NK, CTLAntigen Processing

NK, CTL, Antigen Processing

CD80

CD86

CD80CD80

CD86

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Suchin, K. R. et al. Arch Dermatol 2002;138:1137-1139.

Site A before treatment measured 4.0 x 2.4 cm

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Suchin, K. R. et al. Arch Dermatol 2002;138:1137-1139.

Site A after 2 months of therapy

CARMUSTINE(BCNU)

0.03%-0.04% ointment

ResponseofFMFtoCarmustine (BCNU)Ointment

Carmustine Induced Telangiectases

ExtensiveFolliculotropic MF• Prognosisworsethanepidermotropicvariants

• Combinationofsystemicandskindirectedtherapy

• Carmustinetopically

• Electronbeam

• Interferongamma(longtermuseiscritical)

• Isotretinoin

• Potenttopical/Intralesionalsteroids

EffectsofInterferonGamma

• PotentAlternativeTherapytoInterferonα

• BetterToleratedThanInterferonα

• ActivatesAPCs

• PotentlyActivatesCD8+T-cellsandNKCells

• InhibitsGrowthofMalignantT-cells

Interferon gamma

Perifollcular CD8T-Cells

CD4Cells CD8Cells

ISOTRETINOIN

EFFECTSOFISOTRETINOIN

• Apoptosisofsebocytesandatrophyofsebaceousunit

• ApoptosisofmalignantT-cells

• MalignantT-cellrecruitmenttoskininhibited

• Possiblesynergywithinterferongamma

CCR4

TARC

CLA

TS Kupper. Inflammatory Skin Diseases, T Cells, & Immunosurveillance. NEJM 2000 341:1817-28

Skin Trafficking T-Cells

Effects of Bexarotene on CCR4 expression

8.2%

50.0%45.1%

58.3%

7.2%

27.8%

20.5%

27.9%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

Nl Ctrl Patient 1 Patient 2 Patient 3

No Treatment Bexarotene (10uM)

CCR4 Expression at 72Hrs

%CCR4PositiveLymphocytes

25-30%

S. Richardson, et al., Am J Hematol

Effects of Bexarotene on Chemotaxis

6.4%

29.2%

36.4%

23.6%

5.4%

17.7%21.3%

6.2%

0.0%

10.0%

20.0%

30.0%

40.0%

Nl Ctrl Patient 1 Patient 2 Patient 3

No Trx Bexarotene (10uM)

Chemotaxis at 72Hrs in response to TARC (6.25ng/ml)

%Chemotaxis

12-17%

S. Richardson, et al., Am J Hematol

Toll Like Receptor Agonists Are Therapeutically Active for Cutaneous T-Cell Lymphoma

mDC pDC

TLR 8(Resiquimod)

TLR 9(CpG)

TLR 7(Imiquimod)(Resiquimod)

IL-12,15,18 IFNα

(IFNγ) NK, CTLAntigen Processing

NK, CTL, Antigen Processing

CD80

CD86

CD80CD80

CD86

Resiquimod InducesRegressionofBothTreatedandUntreatedCTCLSkinLesions

FolliculotropicMFResponsetoResiquimodGel

5A 5B

Patient 11

Pre-treatment

8 weeks

Clone: 19% T cells

Clone: 0% T cells

Clearance of Malignant Clone and Restoration of Clonal Diversity

PercentChangeinMalignantCloneDuringTherapy

Patients

PriortoMultimodality Therapy

DuringMultimodality Therapy

TherapyforFolliculotropicMycosisFungoides

• Imiquimodcreamforlimiteddisease

• 0.03-0.04% topicalcarmustine(BCNU)ointmentforlimitedorextensiveapplication

• Isotretinoininlowdose(10-20mgdaily)

• Interferongammaforextensivedisease(Combinationtherapyforaggressivediseaseisrecommended)

• Electronbeamradiation