Cutaneous T-Cell lymphoma (CTCL) is a rare type of Non-Hodgkin’s Lymphoma (NHL) which specifically affects T-cells. In its most prevalent form (Mycosis Fungoides), early stage disease is characterized by waxing and waning tumors, lesions and plaques representing migration of the malignant T-cells to the skin. More severe disease (called Sézary Syndrome) is characterized by more systemic disease and has a lower survival rate. Treatment of early stage disease provides symptomatic relief and may slow disease progression. While there are no FDA-approved first-line therapies, there are off-label treatments as well as a number of therapies for second-line treatment and severe disease. CTCL is usually a chronic disease, requiring life-long attention. Therefore, treatment options must be carefully managed to minimize side effects, including potential risks for more serious cancer such as melanoma.
Some Quick Facts About CTCL
CTCL includes a number of different T-cell cancers and represent approximately 6% of the almost 700,000 Non-Hodgkin’s Lymphomas in the US
CTCL cancers are generally indolent in time course, meaning they spread slowly and are usually not life-threatening particularly in the early stages of disease
CTCL is more common in men than women and generally occurs more often in patients older than 50 years of age. Since the disease has a slow course and diagnosis is sometimes difficult, there are probably many more people living with CTCL than currently estimated
CTCL symptoms are often characterized by a skin rash looking like eczema or psoriasis and this presentation is often diagnosed as the subtype Mycosis Fungoides. The lesions generally occur in areas not exposed to sun and can be scaly and/or itchy. It can be difficult to treat and can be present for years prior to diagnosis. The disease can progress to tumors on the skin and may spread to the lymph nodes, liver, spleen, lungs or blood. The 5-year survival rate for Mycosis Fungoides is approximately 88%.
Sézary Syndrome is a more aggressive lymphoma where the malignant cells are in the skin, blood and lymph nodes. It is characterized by more wide-spread involvement of the skin on the body and can look like sunburn with red, itchy and peeling skin. Disease progression can involve other organs and patients with Sézary Syndrome often have weakened immune system and higher risk for infection. The 5-year survival rate for Sézary Syndrome is approximately 24%.
Treatment for CTCL can be divided into 2 main treatment types: skin-directed therapies and systemic therapies. In the context of a more indolent disease course, and chronic disease, side-effect profiles of the various treatment options must be carefully managed.
There is NO FDA-approved first-line therapy for CTCL.
Skin-directed (topical) Therapies
Directed specifically to the skin to minimize systemic side effects, skin therapies can nonetheless be associated with a number of significant side effects, including increased risk of skin cancer.
Specific Skin-Directed Therapies
Corticosteroids are steroid creams that have modest efficacy but can be helpful in areas more difficult to reach with other forms of treatment and to alleviate itching. Side effects including thinning of the skin, stretch marks, striae, acne/pimples and hair growth. Steroids can be used in combination with other treatments.
Phototherapy can include both light therapy alone (UV A or UV B light used to destroy T-cells in a directed manner) or with photosensitizing agents which are activated by light (psoralen + UV A light). Side effects include enhanced risk of skin cancers (including melanoma).
Photodynamic therapy is a combination of a photoactivated drug with light therapy to target treatment. PUVA (psoralen + UV A light) is used off-label for the treatment of CTCL and prolonged use is associated with increased risk of skin cancers (including melanoma).
Topical chemotherapy chemically modifies the DNA of targeted cells, resulting in cell death. There are a number of options in this treatment class including nitrogen mustard and carmustine. Side effects can include redness, irritation, and/or allergy (dermatitis), development of fine, dilated blood vessels, or darkening of the skin in the treated area.
Immunotherapy stimulates the release of interferon and cytokines, which have anti-tumoral effects. Although not specifically tested in CTCL, clinical practice seems to indicate that imiquimod is useful in CTCL. Imiquimod is usually reserved for use in patients that have failed at least one other topical therapy and may be particularly relevant for refractory disease. Side effects can include back pain, chest pain, squamous cell carcinoma, application site reaction, flu-like infections and immune suppression.
Retinoid compounds derived from vitamin A that regulate many biological processes, including cell growth. Options include bexarotene and tazarotene gel. Topical bexarotene is approved by the US Food and Drug Administration (FDA) for the treatment of Stage 1A and 1B CTCL in patients who have not responded to or tolerated other therapies. Side effects include redness, itching, warmth of the skin, swelling, burning, scaling, and other skin irritations. Treated areas are also photosensitive and should be protected from UV light.
Orthovoltage X-rays can successfully treat recurrent lesions but will also penetrate and damage the underlying tissues, such as blood vessels, muscles, and bone marrow and are usually reserved for more advanced disease (stage III).
Electron beam therapy can successfully treat lesions but is associated with typical radiation related side-effects, including hair loss and increased risk for skin cancer. Treatment includes fractionated radiation application totaling approximately 36 Gy over up to 10 weeks.
Brachytherapy includes treatment of lesions using small catheters to direct radiation directly to tumor cells. Associated with increased risk of skin cancer and generally reserved for more advanced disease.
Generally reserved for more severe/advanced disease, systemic therapies involve whole-body exposure to the therapy.
Specific Systemic Therapies
Extracorporeal photopheresis involves removal of the patients blood, poisoning of the malignant white cells, and reintroduction of the blood to the patient.
Interferon cytokines (either the alpha or gamma version) can be administered directly into the bloodstream to stimulate the body’s immune system to respond to the cancer. Side effects can include flu-like syndrome, fatigue, low blood cell counts, low calcium or high glucose or triglycerides, changes in liver enzyme levels, weight loss, and hair loss. Neuropathy can also occur and usually resolve after treatment is completed.
Retinoids can also be given systemically. As with topical treatment, photosensitivity is a significant side effect, as well as an increase in blood lipids and an underactive thyroid gland.
Monoclonal antibodies can also be administered as an immunotherapy, helping the immune system to target the cancer cells. They may also be attached to chemotherapy agents to aid in killing the tumor cells. Side effects include killing of healthy kills, and an increased susceptibility to infection.
Histone deacetylase inhibitors stop the growth and proliferation of cells. Serious side effects can occur, including diarrhea, nausea, and thrombocytopenia (low platelets), and treatment is generally directed to more advanced disease.
Chemotherapy in CTCL usually focuses on the use of single agents and is generally reserved for the treatment of more advanced disease. Chemotherapy agents commonly used include methotrexate (an anti-metabolite), liposomal doxorubicin, cyclophosphamide, and gemcitabine (agents that interfere with the DNA of cancer cells), pentostatin (a kind of antibiotic), chlorambucil, etoposide, temozolomide, and pralatrexate.
Where Soligenix Comes in
HyBryte™ is designed to be a safe alternative for front line treatment of CTCL, ideally enabling patients to undergo more treatments to manage their disease while accumulating significantly less risks/toxicities.
HyBryte™ is a synthetically manufactured hypericin ointment which is combined with a precise dose of visible fluorescent light to deliver a photodynamic therapy.
Hypericin is one of the most photoactive compounds known – it is easily activated with relatively low energy light. This makes it ideal for photodynamic therapy because it can be activated with fluorescent light, instead of UV A or UV B light, which are associated with increased cancer risks.
HyBryte™ is currently being tested in a Phase 3 clinical trial (“FLASH”).
Information on CTCL disease progression and treatment options is also available at the following sites: