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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
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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
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Cutaneous T-cell Lymphoma
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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
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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%
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T3= 28.9% at 10 yrs (80% 5 yr) T4= 29.7 at 10 yrs Zackheim H, JAAD 40;1999
Stage II Stage III
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• 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
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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)
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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
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Bexarotene gel
Phototherapy
Corticosteroids
Nitrogen Mustard
Stage IA
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Phototherapy
Oral Bexarotene
Electron Beam
Stage IIB
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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)
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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
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• 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
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10 lesions in 5 patients
7 lesions in 4 patients
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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
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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%
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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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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)
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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.