Cutaneous Lymphoma Programs H Lee Moffitt Cancer Center and Research Institute George Washington University Dermatology and Pathology

L Frank Glass, MD

Therapeutic Management of Early Cutaneous Mycosis Fungoides

Table 1: WHO-EORTC Classification 20086

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

Cutaneous T-cell Lymphoma

Clinical Staging for CTCL

*Vonderheid ED et al. J Am Acad Dermatol. 2002;46:95-106 *Slater DN Br J Dermatol 2005;153:874-880

or 20% of cells

T1 >= general population T2 (patch) = 83% at 10 yrs (96%, 5 yr) Zackheim H, JAAD 40;1999

Prognosis Stage 1A Stage 1B

5 yr OS 66% 10 yr OS 49%

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

Stage II Stage III

• 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

Alemtuzumab, zanolibumab, Allogeneic Transplant

IA (limited patch,

plaque)

IB, IIA (generalized

patch, plaque)

IIB (tumors)

III (erythro- derma)

IVA, IVB (visceral

involvement)

Topical corticosteroids

Electron beam

ONTAK

Targretin gel

Nitrogen mustard (NM)

Chemotherapy (Gemcitabine/Doxorubicin)

Photopheresis

CTCL Therapeutic Algorithm

Targretin capsules

HDAC

UVB

IFN

Treatment Failures

Source: Adapted from Zic et al. In: Wintrobe’s Clinical Hematology. Philadelphia: Lippincott, Williams & Wilkins; 2004.

PUVA or UVB (±Targretin)

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

Bexarotene gel

Phototherapy

Corticosteroids

Nitrogen Mustard

Stage IA

Phototherapy

Oral Bexarotene

Electron Beam

Stage IIB

Stage

Modality

Efficacy

I A Watch and wait Topical corticosteroids Class III-IV

Topical HN2 PUVA or UVB narrow band

T1 94% OR (63% CR) T2 82% OR (25% CR) T1 93% OR (65% CR) 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)

1. Resnik KS, Vonderheid EC. Home ultraviolet phototherapy of early mycosis fungoides: preliminary observations. J Am Acad Dermatol 1982 6(3):355-62. 2. 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.

• 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

Home UVB

• 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).

Objective of the study was to determine whether as safe and as effective

Home Narrow Band UVB

10 lesions in 5 patients

7 lesions in 4 patients

Stage

Modality

Efficacy

I A Watch and wait Topical corticosteroids Class III-IV

Topical HN2 UV B/UVB narrow band PUVA

T1 94% OR (63% CR) T2 82% OR (25% CR) 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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Bexarotene

• Mechanism – “Rexinoid” – Binds to RXR

Receptors

NR

RXR α, β, γ

RAR RXR

Regulation of Cell Growth and Differentiation

Regulation of Apoptosis

Stage

Modality

Efficacy

I A Watch and wait Topical corticosteroids Class III-IV

Topical HN2 UV B/UVB narrow band PUVA

T1 94% OR (63% CR) T2 82% OR (25% CR) 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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Stage

Recommended therapy First line

Recommended therapy Second line

Comments

II B PUVA + IFN-α Radiation therapy for tumors Topical HN2 / BCNU

Low-dose methotrexate Oral bexarotene Total body electron beam Denileukin diftitox

Consider maintenance therapy with PUVA+IFN-α or bexarotene when remission is achieved

III * PUVA + IFN-α Topical HN2 / BCNU Extracorporeal photopheresis

Low-dose methotrexate Oral bexarotene Total body electron beam Chlorambucil /corticosteroids Low-dose long distance (2m) soft x-rays Vorinostat

Consider maintenance therapy with PUVA+IFN-α or bexarotene when remission is achieved

Localized EBRT – Tumors: 9-12 MeV, 2 cm margins – Total dose: 20-30 Gy

Total skin EBRT – 6-9 MeV electrons via linear accelerator – 6 field technique – Total dose: 30-36 Gy

Targets lymphocytes, radiosensitive cell

Efficacy (n = 561 combined analysis, OR rates 100%) Stage CR, % Relapse free,

% (2.5 yrs)

IA 84-96 64-73

IB 56-81 35-40

llA 63-74 21-37

llB 24-53 7-26

lll 26-50 10-23

15-yr progression free survival

Early disease (IA, IB, IIA) ~ 25%

Advanced disease (IIB, III, IV) < 10%

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

Alemtuzumab, zanolibumab, Allogeneic Transplant

IA (limited patch,

plaque)

IB, IIA (generalized

patch, plaque)

IIB (tumors)

III (erythro- derma)

IVA, IVB (visceral

involvement)

Topical corticosteroids

Electron beam

ONTAK

Targretin gel

Nitrogen mustard (NM)

Chemotherapy (Gemcitabine/Doxorubicin)

Photopheresis

CTCL Therapeutic Algorithm

Targretin capsules

SAHA

UVB

IFN

Treatment Failures

Source: Adapted from Zic et al. In: Wintrobe’s Clinical Hematology. Philadelphia: Lippincott, Williams & Wilkins; 2004.

PUVA or UVB (±Targretin)

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.