3.3 Pharmacology: Drugs for Mycosis Fungoides

T1

limited patches, papules and/or plaques covering <10% of skin

T2

patches, papules and/or plaques covered >10% of skin

T3

one or more tumors (>1 cm diameter)

T4

confluence of erythema covering >80% of BSA

common treatment in early stages (1A-1B/2A)

-UV light
-radiation
-steroid creams on skin
-chemotherapy

skin-directed therapies of early stage (IIA or below)

1. topical corticosteroids
2. bexarotene
3. topical nitrogen mustards (carmustine, mechlorethamine)
4. imiquimod
5. total skin electron beam therapy (TSEBT)

X-rays

-low energy X-rays used for treatment of isolated lesions
-one of most effective treatments for localized MF
-short & long term toxicities limit use

electron beam radiation therapy (EBRT)

electrons of appropriate energy applied to superficial skin layers to avoid damage to deeper tissue

EBRT administration

-for patches or plaques radiation to lesions w/ 1-1.5 cm margins
-usual total dose for local treatment is 8-12 Gy administered in 1-6 fractions
-good monotherapy for managing uni-lesional or stage IA disease
-can be followed by topical maintenance regimen e.g. topical mechlorethamine or topical corticosteroids

EBRT toxicity

-toxicity dependent on dose of radiation used & location of tumor lesion
-side effects incl. erythema & hair loss; lower dose radiation may have fewer side effects

phototherapy (UVB & PUVA) administration

using special lamp or laser that directs radiation at skin

ultraviolet B (UVB broad or narrow band)

-commonly used for patch disease
-narrow-band UV B and broad-band used as skin-directed treatment for early-stage MF

PUVA (psoralen + ultraviolet A photochemotherapy)

-thicker patch/plaque lesions
-cumulative doses of UV light - associated w/ an increaed risk of certain skin neoplasms -> avoid in pts. w/ history of multiple non-melanoma skin cancers or melanoma

total skin electron beam (TSEB) radiation used in

stage 1B/2A mycosis fungoides & sezary syndrome

TSEB

machine aims electrons at skin covering whole body; may also be used as palliative therapy to relieve symptoms and improve quality of life

Stage 1A disease therapies

1. topical corticosteroids
2. Bexarotene
3. chemotherapy: Mechlorethamine or carmustine
4. topical Imiquimod
5. local radiation
6. phototherapy

super-high potency (group 1)

-betamethasone dipropionate

-clobetasol

-fluocinonide

-halobetasol

high potency (group 2)

-clobetasol

-fluocinonide

-amcinonide

-desoximetasone

-diflorasone

-halcinonide

topical corticosteroids therapeutic effects

-relieve red, swollen, inflamed skin
-effective for early stage MF:
short term: high potency to clear patch-stage
long term: use lowest effective dose, alternative treatment days

topical corticosteroids adverse effects

-adrenal suppression -> Cushing's syndrome

-increased gastric acid -> ulceration & bleeding

-skin atrophy

-osteoporosis

Bexarotene (topical gel; retinoid) MoA

-binds to and activates retinoid X receptor subtypes
-modulate cell growth, apoptosis, and differentiation
-induce tumor regression in vivo and in some animal models

Bexarotene adverse effects

-rash
-pruritus
-pain
-infection
-contact dermatitis
-headache
-teratogenic for both topical & systemic treatment

incidence of Bexarotene adverse effects

>10%

mechlorethamine (HN2)

-nitrogen mustard
-alkylating agent -> crosslinks DNA thereby inhibiting DNA synthesis & function

mechlorethamine adverse effects

-vesicant: blistering, crusting, irritation
-acute toxicity: n/v
-delayed: moderate depression of blood count; high doses produce severe bone marrow depression w/ leukopenia, thrombocytopenia, and bleeding

topical carmustine (BCNU)

-used for patch/plaque MF w/ minimal skin involvement
-applied to affected areas once daily
-monitor CBC q2wks

topical carmustine (BCNU) MOA

alkylates & crosslinks DNA -> disrupts DNA function, cell cycle arrest, apoptosis

topical carmustine (BCNU) adverse effects

hematologic toxicities due to systemic absorption -> leukopenia, thrombocytopenia, and anemia

Imiquod adverse effects

-local inflammatory rxn w/ erythema, edema, vesicles, and ulceration/erosion
-severe reactions may be accompanied by systemic flu-like symptoms

systemic therapies for MF

-retinoids (Bexarotene) or intererons

-HDAC inhibitors

-low dose methotrexate, bretuximab, mogalizumab

*HDAC & low dose methotrexate for stage IIB-IV*

when are systemic therapies for MF used?

-skin symptoms are extensive/severe

-skin directed therapies fail

-pts. have poor prognosis e.g. folliculotropic MF, large cell transformation, early blood involvement

how to treat limited/localized skin involvement

1. corticosteroids
2. bexarotene
3. phototherapy; NB-VB, PUVA
4. topical chemotherapy; nitrogen mustard, carmustine
5. local radiation
6. imiquod (off label); lasers

how to treat generalized skin involvement

1. topical corticosteroids
2. topical chemotherapy; mechlorethamine, carmustine
3. phototherapy; NB-UVB, PUVA
4. total skin electron beam therapy

category A systemic therapies

1. oral retinoids: Acitretin, bexarotene
2. interferon alpha or gamma
3. methotrexate

category B systemic therapies

1. liposomal doxorubicin
2. gemcitabine
3. etoposide

mechlorethamine median time to skin clearance

6-8 months

mechlorethamine relapse

-most patients relapse on discontinuation at some point but respond to second course of therapy
-20-25% of patients treated w/ topical will have durable CR lasting more than 10 years