Systemic Therapies

This piece was written by Guide Contributors

The term systemic therapy defines any drug treatment that, after absorption, reaches the bloodstream and is therefore distributed across the body “system.” Any drug that is taken by mouth, given as a suppository, injected under the skin, taken under the tongue, or directly infused through a blood vessel will eventually reach all body organs and tissues (including the skin), with the exception of the brain, which by design is protected by a specific “barrier.”

In the treatment of cutaneous lymphoma, “systemic therapy” is usually contrasted to “skin directed therapy,” which includes treatments that stay in the skin, such as ultraviolet light, radiation, and topical drugs (i.e., steroids, nitrogen mustard, and retinoids that are applied directly to the skin).



Alain H. Rook, MD, Professor of Dermatology, University of Pennsylvania, Perelman School of Medicine

Extracorporeal Photopheresis

Extracorporeal photopheresis is a treatment for disease that has traveled beyond the skin and into the bloodstream. This treatment has similarities to phototherapy. It is a 1.5- to 5-hour procedure, depending on the equipment used, during which a portion of the patient’s blood is removed from the vein and placed into a portable machine that separates the white blood cells, mixes them with a photosensitizing drug (methoxsalen), and exposes them to UVA light. The cells that are returned to the body are better able to fight infection.

Patients are typically treated on 2 successive days, 3 to 4 weeks apart. 


Interferon is a cytokine, a naturally occurring protein in the body that is normally present in very small amounts. Interferon can also be made in a laboratory and used as a drug. Interferon may be given as an injection into a vein or muscle, or under the skin. Interferon alfa (Intron® A [interferon alfa-2b] or Roferon®-A [interferon alfa-2a]) or gamma stimulate the body’s immune system to fight some types of cancer. Although how it works is not fully understood, it is thought that these molecules interact with receptors on the surface of cells, where they may interfere with the cancer cell’s ability to divide or reduce the ability of the cancer cells to protect themselves from the immune system, and/or they may strengthen the patient’s immune system.

The most common side effects are 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.37,38 Some patients, especially the elderly, might experience cognitive effects that may include difficulty concentrating and remembering. Peripheral neuropathy (numbness and tingling of hands and feet and sometimes loss of taste) can also occur, which usually slowly resolves when the medication is stopped. 


Bexarotene is a retinoid that is available as a capsule that is taken orally, as well as being used in a skin cream. Oral bexarotene is approved by the FDA for the treatment of patients with refractory or persistent CTCL after trying at least one other therapy.

The most common side effects with use of oral bexarotene are an increase in blood lipids and an underactive thyroid gland. When taking oral bexarotene, your skin may become more sensitive to sunlight, so you must wear sunscreen and protective clothing while in the sun. Grapefruit or grapefruit juice may interact with bexarotene and could cause additional side effects. Other drugs can also interact with oral bexarotene. Patients should check with their doctor or pharmacist to make sure they are avoiding products containing ketoconazole, itraconazole, gemfibrozil, or erythromycin, or any other medications that may interact with bexarotene.


Monoclonal antibodies are the most common biologic agents used for lymphoma therapy.

The immune system uses antibodies to recognize and destroy foreign invaders such as bacteria and viruses. Scientists can now produce “monoclonal antibodies” in the laboratory that recognize certain kinds of cancer cells. Once in the blood, monoclonal antibodies travel throughout the body and attach themselves to their specific target. Antibodies are thought to work by stopping or slowing the growth of cancer cells, or by making it easier for the person’s immune system to destroy the tumor cell. Healthy cells can also be affected by the antibody, but the body can usually replace these cells after the treatment with biologic therapy has stopped. However, patients taking a biologic treatment may be susceptible to infection.

Alemtuzumab (Campath®) is a monoclonal antibody that targets the CD52 antigen on the cell surface of cancerous lymphocytes. Alemtuzumab can be given as a low-dose regimen that can reduce malignant T cells without affecting healthy T cells.39-43 Mogamulizumab, a bioengineered, humanized monoclonal antibody against CCR4, is a newer antibody treatment being tested in CTCL.44 

Monoclonal antibodies can also be made with a chemotherapy drug, radioactive particle, or toxin attached to it.

These antibodies bring the drug, radioactive particle, or toxin to its target on the malignant cell. One example of this is brentuximab vedotin (Adcetris®), a monoclonal antibody that targets the CD30 antigen on cancer cells.45 This antibody is attached to a drug (monomethyl auristatin E) that can kill the cancer cell after the antibody attaches to it. Common side effects experienced by patients receiving brentuximab were fatigue, fever, diarrhea, and nausea. This drug is being tested in primary cutaneous CD30-positive CTCLs.46 

Denileukin diftitox is a “fusion protein,” meaning that it is made of 2 different molecules: a biologic agent called interleukin 2 and diphtheria toxin.45 The interleukin 2 attaches to the cancer cell, and the diphtheria toxin kills the cell. Denileukin diftitox is used to treat persistent or recurrent CD25-positive CTCL. The supply of denileukin diftitox (Ontak®) for general use is on hold and it is currently available only through a clinical trial.

Targeted Therapy
Histone Deacetylases

Histone deacetylase (HDAC) inhibitors like vorinostat (capsule)47,48 and romidepsin (intravenous)49 are a newer group of drugs that are thought to work by blocking enzymes in cells called histone deacetylases. Stopping these enzymes changes the amount of proteins made in cells, which affects the rate at which these cells can grow and divide.

The FDA approved vorinostat, which showed a 30% response rate in patients with CTCL highly resistant to therapy; however, the duration of response is mixed and limited.47 There are also serious side effects associated with treatment, including diarrhea, nausea, and thrombocytopenia (low platelets).

Romidepsin, also approved by the FDA for treatment of CTCL,50 showed 40% responses in CTCL highly resistant to therapy with higher duration of response, sometimes exceeding 20 months. Clearing of skin lesions and blood and nodal disease was also observed in patients with advanced forms of CTCL. 


Most chemotherapy drugs for cutaneous T-cell lymphoma have been in use for decades, but several have been developed more recently. While these agents are frequently used in combination for the treatment of many cancers, they are mostly used in CTCL as “single agents,” meaning they are given independently. Chemotherapy agents used for CTCL include methotrexate (an anti-metabolite), liposomal doxorubicin,51cyclophosphamide, and gemcitabine52 (agents that interfere with the DNA of cancer cells), pentostatin (a kind of antibiotic), chlorambucil, etoposide, temozolomide, and pralatrexate.53

Combination chemotherapies are reserved for patients whose disease does not respond to single agents or for selected patients who have solid organ involvement. 


Link to References found throughout page

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When it comes to family planning, using even mild therapies for a long period of time can be an issue. Because many therapies only work while they are being given, aspects of family planning often need to be considered when choosing a therapy.

Staging Cutaneous T-cell Lymphoma

Staging describes how much of the body is affected by cutaneous lymphoma and where. Identifying your stage is important in determining appropriate treatment.
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