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An Overview of Systemic Therapies
Pierluigi Porcu, M.D.
Associate Professor of Internal Medicine

Article previously published in the Cutaneous Lymphoma Foundation's Forum Spring/Summer 2012 newsletter.

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).

In cutaneous lymphoma, and particularly in mycosis fungoides, in the early stages of the disease, the lymphoma cells are mostly limited to the skin, and one can have excellent and durable responses with just skin directed therapy – for example, ultraviolet light (UV) phototherapy. In patients who have only partial or short responses to phototherapy or topical drugs, and certainly in more advanced stages, the use of systemic therapy is warranted. The rationale for combining skin directed and systemic therapies, even in patients with skin limited disease, is what one could call a “sandwich effect.” Skin directed therapy works from the outside in and systemic therapy works from the inside out. In addition, there is evidence that skin directed therapies and systemic therapies may enhance each other’s effect against the lymphoma cells.

In the past, the main form of systemic therapy was “chemotherapy,” a term used to define cytotoxic drugs with the well-known side effects of nausea, hair loss, mouth sores, and immune suppression. Some of these drugs are still used in patients with very advanced cutaneous lymphoma, or in preparation for a bone marrow transplant, but are not appropriate for patients with earlier stages. More recently, a number of new drugs have been approved that can be given systemically for the treatment of cutaneous lymphoma which do belong to the old class of “cytotoxic drugs,” but they do not have those undesirable side effects (although they often have others). Some of these drugs are explored here.

Interferons (IFN)
Interferon is a naturally occurring protein that carries antiviral, anti-cancer, and immune stimulatory properties, and can be manufactured in large amounts for use as a drug. In the management of cutaneous T cell lymphoma (CTCL), physicians seek especially the immune stimulatory effects. Interferon alfa 2b (Intron A®) and Interferon gamma 1b (Actimmune®) represent two different categories of synthetic interferons used in treating this disease. Interferon is patient administered by subcutaneous injection 2 3 days per week. Laboratory tests to monitor complete blood count and liver function are required. Most often interferons are used in combination with other therapeutic modalities such as photopheresis.

Bexarotene (Targretin ®) Capsules
Bexarotene or Targretin® is a Vitamin A derived agent that belongs to a larger class of medicines called retinoids. Bexarotene stimulates a specific class of cell receptors, retinoid X receptors (RXRs), which, when engaged, steer abnormal T cells toward cell death. Oral Targretin® is a systemic agent approved for all stages of CTCL. Laboratory monitoring (blood tests) of both lipids and thyroid hormone are required during the course of this therapy.

Denileukin Diftitox (Ontak®)
Denileukin diftitox or Ontak® is an approved drug for the treatment of recalcitrant cutaneous lymphoma. It is a fusion toxin formed by the combination of diphtheria and interleukin 2. Ontak® is selectively cytotoxic to malignant T cells. Nurses administer Ontak® by intravenous infusion over the course of a 1 1/2 hour time period. Typically patients receive Ontak® 5 consecutive days (a cycle) every 3 weeks for 6 cycles. Maintenance therapy may be recommended if clinical remission is achieved. At the time of publication of this newsletter, the company that makes Ontak® has stopped manufacturing the medication and there is no information as to when production may resume.

Vorinostat (Zolinza®)
Vorinostat or Zolinza® is a histone deacetylase inhibitor (HDAC) oral agent for patients with progressive or persistent manifestations of cutaneous lymphoma. HDAC inhibition allows a cell’s DNA to be transcribed so that cancer cells may die off. This medication requires frequent blood, electrolyte, platelet count and electrocardiogram (EKG) monitoring for the initial weeks of therapy. Zolinza® is used alone or in combination with other therapies.

Romidepsin (Istodax®)
Romidepsin or Istodax® is another histone deacetylase inhibitor (HDAC) agent available for patients with cutaneous lymphoma who have received at least one prior systemic therapy. Istodax® is administered by intravenous infusion over 4 hours every week, for 3 weeks, followed by a rest week. Similar to other HDAC agents, monitoring of blood tests including electrolytes, magnesium and platelets is essential.

Chemotherapy

Chemotherapy administered as single agent or in combination may be used to treat the manifestations of advanced cutaneous lymphoma. Combination or multi-agent chemotherapy is usually reserved for advanced stages of disease. The following chemotherapy drugs are used in the treatment of various subsets of cutaneous lymphomas. There is no optimal chemotherapy drug, and the risks and benefits of their potential use in each patient need to be very carefully considered by the treating physician. With most of these agents, physicians will monitor blood counts and kidney and liver function.

Methotrexate (Matrex®) is an anti-metabolite agent used for a host of immune-based diseases. It interferes with folic acid metabolism in cancer cells. In cutaneous lymphoma, this is mostly used in oral form by taking one or more pills weekly. Methotrexate is particularly effective in the treatment of primary cutaneous CD30+ anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP). Responses can also be seen in other types of CTCL.

Pralatrexate (Folotyn®) is only indicated in the treatment of transformed mycosis fungoides (tMF) for CTCL patients. A diagnosis of tMF requires a skin biopsy, which must be reviewed by a pathologist who is an expert in the diagnosis of CTCL. Pralatrexate is approved for peripheral T-cell lymphoma (PTCL). It is an inhibitor of folate metabolism which targets the same pathway as methotrexate. Patients receiving pralatrexate therapy are given one dose of folic acid and a Vitamin B 12 injection per week for six weeks followed by a rest week. Pralatrexate is given intravenously every 3 weeks, followed by a rest week. The main side effects are the development of mouth ulcers and low blood cell counts.

Alemtuzumab (Campath®) is a monoclonal antibody directed against the CD52 antigen (surface marker) found on both B-lymphocytes and T-lymphocytes. It is typically administered in low-dose form by subcutaneous injection 3 days per week for an 8-12 week course. Patients receiving Campath® are prescribed oral antibiotics and antiviral medications to protect the immune system while on therapy and for up to 6 months afterwards. Campath has been shown to be effective in Sézary syndrome.

Liposomal doxorubicin (Doxil®) is a special formulation of doxorubicin, a drug that interferes with DNA activity in cancer cells. The liposome, or microscopic sphere of fat surrounding the doxorubicin, minimizes side effects and improves activity. Doxorubicin is delivered by intravenous infusion every 2-4 weeks. Certain patients will have an evaluation of heart function performed prior to starting therapy.

Gemcitabine (Gemzar®) is a chemotherapy drug that works by interfering with DNA production in cancer cells. It is delivered by intravenous administration usually weekly for 2-3 weeks with a week of rest before the cycle is repeated.

Multi-Agent Combination Chemotherapy

The use of chemotherapy drug combinations in cutaneous lymphoma should be discouraged because they have never been proven to be more effective than sequential single agents, and they are always much more toxic. Combinations such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), ESAHP (etoposide, solumedrol, high-dose ara-C, and cisplatin), and GND (gemcitabine, navelbine, and doxil) may be used when no other therapy is available, or in rare circumstances as a way to produce brief responses in preparation for a bone marrow transplant.

Extracorporeal Photopheresis (ECP)

Extracorporeal photopheresis (ECP) is an immunotherapy recommended in cutaneous lymphoma patients with an abnormal circulating T-cell population identified in the peripheral blood. During ECP, white blood cells are separated out and exposed (outside the body) to UVA light and then re-infused. It is believed that the UVA-exposed white blood cells produce a vaccine-like effect against malignant T-cells. Other treatments (interferons, Targretin®) are frequently used in concert with ECP therapy. Nurses administer photopheresis treatments two successive days every 3-4 weeks in outpatient settings. ECP is most often used when there is blood involvement. In ECP, the cells are bathed in psoralen medication before being exposed to UVA light.

Oral Corticosteroids

Corticosteroids are medications used to treat a variety of skin diseases that may be acute or chronic in nature. These agents share a wide range of applications for a host of immune-mediated diseases. In cutaneous lymphoma, oral corticosteroids may be used to down-regulate inflammatory cells when the skin disease is extensive and symptoms associated are remarkable. Examples of corticosteroid medications include cortisone, prednisone, and methylprednisolone. Prednisone can be prescribed as a taper whereby the dosage is gradually reduced from 40-60mg to 5mg over the course of a few weeks. In other circumstances, low dose prednisone (10-20 mg) may be administered daily on a long- term basis. Some of the commonly encountered side effects with long-term administration include fluid retention, weight gain, increased blood pressure, increased blood sugar, increased appetite, stomach irritation, mood elevation, sleep disturbance, acne, and delayed wound healing.


Pierluigi Porcu, M.D. is Associate Professor of Internal Medicine, Division of Hematology, Ohio State University Comprehensive Cancer Center (OSUCCC) where he is co-leader of the Cutaneous Lymphoma Program and a member of the Viral Oncology Group of the OSUCCC where he conducts clinical and translational research in lymphoma. Dr. Porcu has worked extensively in the field of cancer and lymphoma education including participation in many of the Cutaneous Lymphoma Foundation’s past Patient Educational Forums along with serving as a Co-Chair of the Foundation’s Cutaneous Lymphoma Summit held in October 2009.  

An Overview of Systemic Therapies - Pierluigi Porcu, MD