a novel therapeutic regimen for folliculotropic … f115 - rook... · a novel therapeutic regimen...
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A NOVEL THERAPEUTIC REGIMEN FOR FOLLICULOTROPIC MYCOSIS
FUNGOIDES
ALAIN H ROOK, PROFESSOR OF DERMATOLOGY
DIRECTOR, CUTANEOUS LYMPHOMA PROGRAMPERELMAN SCHOOL OF MEDICINE
UNIVERSITY OF PENNSYLVANIA
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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)
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The Immune Response Plays a Critical Role in Control of Cutaneous T-Cell Lymphoma in Early Stage Disease, AND, in Late Stage Disease
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Localized Folliculotropic MF
• Excellentprognosisistypical
• Imiquimod
• Potenttopicalsteroids
• Carmustine(BCNU)ointment0.03-04%
• Electronbeam
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ImidazoquinolinesAre Powerful TLR Agonists
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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
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CARMUSTINE(BCNU)
0.03%-0.04% ointment
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ResponseofFMFtoCarmustine (BCNU)Ointment
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Carmustine Induced Telangiectases
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ExtensiveFolliculotropic MF• Prognosisworsethanepidermotropicvariants
• Combinationofsystemicandskindirectedtherapy
• Carmustinetopically
• Electronbeam
• Interferongamma(longtermuseiscritical)
• Isotretinoin
• Potenttopical/Intralesionalsteroids
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EffectsofInterferonGamma
• PotentAlternativeTherapytoInterferonα
• BetterToleratedThanInterferonα
• ActivatesAPCs
• PotentlyActivatesCD8+T-cellsandNKCells
• InhibitsGrowthofMalignantT-cells
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Interferon gamma
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Perifollcular CD8T-Cells
CD4Cells CD8Cells
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ISOTRETINOIN
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EFFECTSOFISOTRETINOIN
• Apoptosisofsebocytesandatrophyofsebaceousunit
• ApoptosisofmalignantT-cells
• MalignantT-cellrecruitmenttoskininhibited
• Possiblesynergywithinterferongamma
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CCR4
TARC
CLA
TS Kupper. Inflammatory Skin Diseases, T Cells, & Immunosurveillance. NEJM 2000 341:1817-28
Skin Trafficking T-Cells
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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
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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
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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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Resiquimod InducesRegressionofBothTreatedandUntreatedCTCLSkinLesions
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FolliculotropicMFResponsetoResiquimodGel
5A 5B
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Patient 11
Pre-treatment
8 weeks
Clone: 19% T cells
Clone: 0% T cells
Clearance of Malignant Clone and Restoration of Clonal Diversity
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PercentChangeinMalignantCloneDuringTherapy
Patients
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PriortoMultimodality Therapy
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DuringMultimodality Therapy
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TherapyforFolliculotropicMycosisFungoides
• Imiquimodcreamforlimiteddisease
• 0.03-0.04% topicalcarmustine(BCNU)ointmentforlimitedorextensiveapplication
• Isotretinoininlowdose(10-20mgdaily)
• Interferongammaforextensivedisease(Combinationtherapyforaggressivediseaseisrecommended)
• Electronbeamradiation