Therapeutic Management of Early Cutaneous Mycosis Fungoides

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1 Therapeutic Management of Early Cutaneous Mycosis Fungoides L Frank Glass, MD Cutaneous Lymphoma Programs H Lee Moffitt Cancer Center and Research Institute George Washington University Dermatology and Pathology

2 Table 1: WHO-EORTC Classification Cutaneous T-cell and NK-cell lymphoma Mycosis fungoides Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Sézary syndrome Primary cutaneous CD30+ lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma* Primary cutaneous CD4-positive small/medium T-cell lymphoma* Subcutaneous panniculitis-like T-cell lymphoma Primary cutaneous peripheral T-cell lymphomas, unspecified

3 Cutaneous T-cell Lymphoma

4 Clinical Staging for CTCL or 20% of cells *Vonderheid ED et al. J Am Acad Dermatol. 2002;46: *Slater DN Br J Dermatol 2005;153:

5 Prognosis Stage 1A Stage 1B 5 yr OS 66% 10 yr OS 49% T1 >= general population Zackheim H, JAAD 40;1999 T2 (patch) = 83% at 10 yrs (96%, 5 yr)

6 Stage II Stage III T3= 28.9% at 10 yrs (80% 5 yr) T4= 29.7 at 10 yrs Zackheim H, JAAD 40;1999

7 Disease progression Stage IA 1.1% (2/174 T1) Stage IB 4.0% (8/199 T2) up to 20% All stages 15-20% will die of their disease Zackheim H, JAAD 40;1999

8 CTCL Therapeutic Algorithm IA (limited patch, plaque) IB, IIA (generalized patch, plaque) IIB (tumors) III (erythroderma) IVA, IVB (visceral involvement) Topical corticosteroids Treatment Failures Nitrogen mustard (NM) Targretin gel UVB Targretin capsules Electron beam IFN Photopheresis ONTAK PUVA or UVB (±Targretin) HDAC Chemotherapy (Gemcitabine/Doxorubicin) Alemtuzumab, zanolibumab, Allogeneic Transplant Source: Adapted from Zic et al. In: Wintrobe s Clinical Hematology. Philadelphia: Lippincott, Williams & Wilkins; 2004.

9 Selection of Therapy Stage of Disease Expected response rate and durability of response Patient convenience Distance to center for treatment, (eg, phototherapy, photopheresis) Cost and insurance coverage Quality of life palliation of itching or appearance Side effects

10 Corticosteroids Bexarotene gel Nitrogen Mustard Stage IA Phototherapy

11 Stage IIB Phototherapy Electron Beam Oral Bexarotene

12 Stage Modality Efficacy I A Watch and wait Topical corticosteroids Class III-IV T1 T2 94% OR (63% CR) 82% OR (25% CR) Topical HN2 PUVA or UVB narrow band T1 93% OR (65% CR) T1 (90% CR) Radiation therapy (electron beam, total dose 30-40Gy; 2 Gy 5x weekly) (84-96% CR) Bexarotene gel OR 42 (CR 21%) I B II B PUVA or UV B/UVB narrow band Topical HN2 Radiation therapy (76% CR) 72% OR (34% CR) (56-81% CR)

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16 Home UVB 31 patients treated with 280 to 350 nm ultraviolet phototherapy (NBUVB 311 nm) CR in 23 patients (74%) Median duration = 51 months (range 5 months to > 15 years) Phototherapy was well tolerated without evidence of significant photodamage or photocarcinogenicity 1. Resnik KS, Vonderheid EC. Home ultraviolet phototherapy of early mycosis fungoides: preliminary observations. J Am Acad Dermatol (3): Resnik KS, Vonderheid EC. Home UV phototherapy of early mycosis fungoides: long-term follow-up observations in thirty-one patients. J Am Acad Dermatol 1993,29(1):73-7.

17 Home Narrow Band UVB Objective of the study was to determine whether as safe and as effective PASI 50 Home vs outpatient NBUVB = 70% vs 73% Total cumulative doses similar = 51.5 v 46.1 J/cm(2) Occurrence of short term side effects did not differ. Burden of undergoing ultraviolet B phototherapy was significantly lower for patients treated at home (differences 1.23 to 3.01, all p <=0.001). Quality of life increased equally regardless of treatment Home NBUVB patients rated their experience with the therapy as "excellent = 42% vs 23%, P=0.001).

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19 10 lesions in 5 patients 7 lesions in 4 patients

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21 Stage Modality Efficacy I A Watch and wait $ Topical corticosteroids Class III-IV T1 T2 94% OR (63% CR) 82% OR (25% CR) $$$ $$ Topical HN2 UV B/UVB narrow band PUVA T1 93% OR (65% CR) T1 71% OR T1 (90% CR) $$$ $$$$ Radiation therapy (electron beam, total dose 30-40Gy; 2 Gy 5x weekly) Bexarotene gel (84-96% CR) OR 42 (CR 21%) I B II B PUVA or UV B/UVB narrow band Topical HN2 Radiation therapy (76% CR) 72% OR (34% CR) (56-81% CR)

22 Bexarotene Mechanism Rexinoid Binds to RXR Receptors NR RXR α, β, γ RAR RXR Regulation of Cell Growth and Differentiation Regulation of Apoptosis

23 Stage Modality Efficacy I A Watch and wait $ Topical corticosteroids Class III-IV T1 T2 94% OR (63% CR) 82% OR (25% CR) $$$ $$ Topical HN2 UV B/UVB narrow band PUVA T1 93% OR (65% CR) T1 71% OR T1 (90% CR) $$$ $$$$ Radiation therapy (electron beam, total dose 30-40Gy; 2 Gy 5x weekly) Bexarotene gel (84-96% CR) OR 42 (CR 21%) I B II B PUVA or UV B/UVB narrow band Topical HN2 Radiation therapy (76% CR) 72% OR (34% CR) (56-81% CR)

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25 Stag e II B III * Recommended therapy First line PUVA + IFN-α Radiation therapy for tumors Topical HN2 / BCNU PUVA + IFN-α Topical HN2 / BCNU Extracorporeal photopheresis Recommended therapy Second line Low-dose methotrexate Oral bexarotene Total body electron beam Denileukin diftitox Comments Consider maintenance therapy with PUVA+IFN-α or bexarotene % (2.5 yrs) when remission is achieved Efficacy (n = 561 combined analysis, OR rates 100%) Stage CR, % Relapse free, IA Low-dose IB Consider methotrexate maintenance lla Localized EBRT Oral bexarotene therapy with Tumors: 9-12 MeV, PUVA+IFN-α 2 cm margins or Total llb body Total electron dose: bexarotene Gy 7-26 when beam lll Total skin EBRT remission is Chlorambucil achieved 6-9 MeV electrons via linear /corticosteroids 15-yr progression free survival accelerator Low-dose Early disease 6 long field (IA, technique IB, IIA) ~ 25% distance (2m) Advanced Total disease dose: (IIB, III, Gy IV) < 10% soft x-rays Vorinostat Targets lymphocytes, radiosensitive cell

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27 Imiquimod - 5% cream in the treatment of mycosis fungoides--a pilot study. Journal of Dermatological Treatment. 15(2):118-9, 2004 Apr. 28 patients IB or greater 78% OR based on composite assessment of an index lesion 3 CR

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30 CTCL Therapeutic Algorithm IA (limited patch, plaque) IB, IIA (generalized patch, plaque) IIB (tumors) III (erythroderma) IVA, IVB (visceral involvement) Topical corticosteroids Treatment Failures Nitrogen mustard (NM) Targretin gel UVB Targretin capsules Electron beam IFN Photopheresis ONTAK PUVA or UVB (±Targretin) SAHA Chemotherapy (Gemcitabine/Doxorubicin) Alemtuzumab, zanolibumab, Allogeneic Transplant Source: Adapted from Zic et al. In: Wintrobe s Clinical Hematology. Philadelphia: Lippincott, Williams & Wilkins; 2004.

31 Summary - Therapeutics Responsive but incurable Aggressive vs. conservative treatment does not effect survival The goal is to induce complete remission, but also reduce tumor burden, reduce symptoms Dermatology participates in IA, IB, IIA, IIB, IIIA Treatment should be individualized, but guided mostly by stage of disease.