Current treatment of Cutaneous T-Cell Lymphoma
University of Texas, MD Anderson Cancer Center
Madeleine Duvic MD
Dermatology Online Journal 7(1): 3
Cutaneous T-cell lymphomas are a heterogeneous group of cutaneous non-Hodgkin's lymphomas. In the United States, the incidence of these diseases is rising faster than any other cancer. Environmental triggers may be important in the evolution of malignancy. Current therapy is reviewed with emphasis on a new retinoid, Targretin.
Cutaneous T-Cell Lymphoma(CTCL) and Mycosis Fungoides(MF) are terms which are often used interchangeably. This is not really correct, as MF is really a subset of CTCL that evolves from cutaneous patches and plaques. In addition, the leukemic variant of MF, Sezary syndrome, has not been strictly defined. The International Society for Lymphomas is attempting to reach a consensus definition. Furthermore, there are rare, anaplastic large cell lymphomas that are CD30 antigen positive, similar to Reed-Sternberg cells in Hodgkin's lymphoma. This type of large cell lymphoma is on a spectrum with lymphomatoid papulosis which may wax and wane without progression. However, if a lesion progresses, we rename it anaplastic large cell lymphoma. This particular entity may begin in the skin or the nodes, but has a better prognosis if skin is the origin. Other, rarer CTCLs include subcutaneous T-cell lymphoma, panniculitic T-cell lymphoma and angiocentric T-cell lymphoma.
There are a limited number of FDA approved therapies for CTCL. Longstanding approved therapies include nitrogen mustard, vinblastine, and methotrexate, the only oral medication approved for CTCL. Photopheresis was approved in 1987, and though it was originally used only in erythrodermic patients, it is now used more widely. Finally last year, Ontac(DABIL-2), which is a fusion toxin binding the CD25 IL-2 receptor, was approved. Other, as yet unapproved therapies are being developed and will also be discussed.
T-cells, both CD4 and CD8 are lymphocytes that are stimulated by macrophages(MHCDR and Class I bearing, respectively). Once stimulated, a T-cell undergoes proliferation and expansion. Some of these cells will become memory cells. Others will undergo apoptosis or programmed cell death. In CTCL, a memory cell continues to grow and accumulate. Therefore, an attractive hypothesis is that in MF there is a persistent formation of clonally stimulated T-cells. A subsequent loss of the memory cell ability to undergo apoptosis is one of the early steps in lymphoma development.
Skin homing receptors are also crucial to the development of CTCL. CTCL is a disease of the skin homing T-lymphocyte. In CTCL, cells that lack CD7 are attracted to the skin where they may encounter a variety of antigens and be stimulated to divide. The stimulating antigen could be a skin antigen, virus, bacteria or fungus. The important antigens have not been characterized and may be different in individual CTCL patients as is suggested by the wide T-cell receptor variation in these patients. Up to 30% of MF patients may have had stimulation with staphylococcus as a superantigen. Some have actually shown dermatophyte in their CTCL biopsy and have responded to anti-fungal treatment. A few have had leprosy and CTCL in the same lesion and showed CTCL remission with leprosy treatment. Similarly, patients with staphylococcal folliculitis within their MF lesions will substantially improve or clear with dicloxacillin and mupirocin treatment. We have also had a number of patients whose CTCL seemed to be stimulated by certain medications. Stopping the medications enhanced clearing. Other types of chronic inflammatory stimuli may also lead to MF development. One patient fell and embedded gravel in his hip. A chronic plaque developed at that one site which histologically appeared as parapsoriasis. Fifteen years later the biopsy was diagnostic for MF.
Stage I MF patients usually have undergone multiple biopsies to make the diagnosis. Making the diagnosis of MF is hard because it evolves from a chronic eczematous dermatitis or psoriasiform dermatitis. It is benign at the outset, but on the cusp between inflammation and malignancy. In a similar way, we now know that the mucosa associated lymphoid tissue (MALT) lymphoma, a B-cell lymphoma, is stimulated by inflammation due to Helicobacter pylori.
It is now appreciated that as patients progress from Stage I to Stage III (erythrodermic) or IV (nodal effacement) there is a shift in the immune response from the Th1 response (gamma-interferon, IL-2) which we see in early MF lesions, to a Th2 response. As patients develop Sezary syndrome, peripheral eosinophilia develops. Two cytokines, IL-10 and IL-12 may be important in shifting this parameter.
The good news for CTCL patients are the two recent papers from Stanford and UCSF that show that early Stage IA patients have a survival no different from normal controls. Only one in ten will progress to systemic lymphoma. Even 80% of Stage IB or IIA patients are alive and well at ten years. This type of prognosis argues for very different therapy that other types of lymphomas.
MF is a difficult disease to diagnose and to treat. There are about one hundred new cases of MF at MD Anderson per year and about one thousand new cases in the United States. There is great heterogeneity in clinical features. Standard practice guidelines have not been established. Unlike many other lymphomas and other malignancies, large clinical trials have not been done. CTCL treatments are mainly directed at palliation of symptoms since there is no cure. Skin-directed therapy is the mainstay, but other treatments include biological response modifiers and systemic cytotoxic therapy. Finally, new areas of treatment utilize targeted toxins. There is also hope of being able to vaccinate each CTCL patient against his or her own malignant clone. Though this is complicated by the fact that some patients do not have monoclonal, but oligoclonal MF.
Only one randomized clinical CTCL trial has been conducted. This NCI study, in 1989, compared treatment with either combination chemotherapy or conservative treatment. Though combination chemotherapy was more likely to produce a complete response, there was no difference in survival. Furthermore, aggressive therapy proved to be more likely to cause death in treated patients. Ideally, what we would like to be able to do is: address the stimulating antigens and sustaining factors that are modulating the T-cell proliferation, selectively reduce the T-cell clones that are causing the disease, and augment the anti-tumor response.
Skin-directed therapy includes a number of topical treatments. High potency (Class I) topical steroids under occlusion yield an 80% response rate in early stage patients. Vitamin D and retinoids have been utilized. Topical chemotherapy with nitrogen mustard or carmustine (BCNU) are also successful. Nitrogen mustard is my favorite and can be used in an Aquaphor or aqueous base. The down side is the high incidence of contact dermatitis (10-20%) and the fact that it can rub off onto other people. But, in my hands, it has a 40% complete response rate. It is often successful even in extensive patch/plaque disease. At least a 3-6 month trial with the Aquaphor based and then the aqueous is warranted. PUVA may also be used as first-line therapy. It has a high rate of success, an 80% response rate, but it is not a cure either and will leave damaged skin and an increased incidence of skin cancer. One also wonders if PUVA will also inhibit the anti-tumor response. PUVA with interferon may be more effective. UVB is effective, but only in patch stage disease. It is administered similarly to its use in psoriasis. Electron beam was developed in the 1950s for CTCL and is, therefore, the oldest treatment. It has been touted as being curative in some instances, but the evidence is not good for this. In patients thought to be cured, MF may return five, ten or twenty years later. After electron beam therapy, the patient should be put on another maintenance therapy immediately. Furthermore, new data from Stanford suggest that nitrogen mustard and electron beam patients have the same survival. Remission times may not be as long with nitrogen mustard, but it is more cost-effective. As an adjunct to any therapies, local X-ray therapy is used for nodal disease and localized tumors.
My first approach in stage I patch MF is to try moisturizers and barrier protection. I did one study with a topical inhibitor of T-cells. Interestingly, the response rate was 28% in both the glycerin vehicle control and the drug groups. Some of the complete responders in the vehicle group are still clear three years later. Skin protection and moisturization are important in MF as they are in psoriasis and eczema. CTCL patients with atopic dermatitis-like skin and xerosis respond especially well. Topical steroids are added in increasing potency as needed and occlusive dressings are often utilized.
The biological response modifiers are very effective in CTCL. They include interferon (alpha and gamma), cytokines, such as interleukins, and a variety of retinoids and combinations thereof. Alpha interferon is an effective single agent (50% response rate) and is usually given 3-5 million units three times weekly. Its efficacy is limited by the development of antibodies and its systemic flu-like symptoms and the remission duration is usually short with a median of six months. Combination therapy of interferon and PUVA or retinoids is highly effective, even in some stage IV or tumor patients. Interleukin-12 (IL-12) has potential beneficial activity in CTCL, probably by inducing differentiation of uncommitted T-cells to produce gamma interferon and Th1 type cytokines. Natural killer (NK) suppressor cells are induced and antigen-specific auto-antibody production is enhanced. Autoimmune reactions have been induced, though, including hemolytic anemia and early studies were stopped due to death of several patients. Therefore, I will concentrate mainly on the retinoids. There are two classed of retinoid receptors, RAR and RXR. Once a retinoid enters the cell, it binds a receptor, forms RAR and RXR heterodimers, and is translocated into the nucleus where it interacts with transcription factors. In this way, retinoids interact with gene promoters to regulate transcription. Well known retinoids such as acitretin, etretinate, and 13-cis retinoic acid interact with RAR receptors, but Targretin is a new RXR selective retinoid. All of these retinoids have been used in CTCL. Small trials have shown similar efficacy for etretinate and 13-cis retinoic acid (50-60% response rate). Anecdotally, acitretin is slightly less effective.
Targretin, the RXR selective retinoid, is the newest retinoid for CTCL treatment and has been used in both topical and oral forms. The topical gel has been studied in Phase I, II, and III studies and has produced a 58% response rate for treated lesions. We have had good responses with this even in early MF patients who were resistant to multiple other therapies including PUVA, topical chemotherapy and methotrexate. Targretin capsules have also been utilized in Phase I, II, and III trials. Early and late stage refractory or relapse CTCL patients were tested and showed an overall response rate of 50%. Responses were seen in all stages of the disease including Sezary syndrome and patients with large cell transformation. We also studied 33 late stage patients who had been refractory to both ultraviolet light and topical and systemic therapy and who had been treated with 4-5 previous therapies. Oral Targretin produced 16 (50%) partial responses and 3 (10%) complete remissions for an overall response rate in advanced CTCL of 60%. We even saw ulcerated tumors heal in some cases.
Targretin (in vitro) causes apoptosis of various cell lines, but does not inhibit DNA or induce differentiation cell cultures from myelocytic leukemia cell lines. It is known that stimulation of RXRs induces apoptosis, whereas stimulation of RARs induces differentiation. Targretin inhibits squamous cell carcinoma growth in a mouse model and decreases keratinization. In addition, retinoids used in CTCL may improve immunity by stimulating cell-mediated immunity, inhibiting lymphocyte transformation, and increasing reactions to recall antigens.
Targretin is easily administered as an oral capsule. The recommended dose is 300 mg per meter squared, but it's more efficacious at higher doses such as 500 to 600 mg per meter squared. There's very little myelosuppression. During the trials with this drug, there were no patients with neutropenic fever or sepsis.
Targretin does have two significant side effects that require close monitoring. Hypertriglyceridemia can be rapidly induced producing levels as high as 3,000 mg per dl within two weeks. An anti-lipid drug should be started before initiating treatment. The drugs of choice for preventing Targretin-induced hyperlipidemia are atorvastatin (Lipitor) and fenofibrate (Tricor). Gemfibrozil (Lopid) is a less desirable choice as it can increase the serum levels of Targretin. In addition, hypothyroidism can be induced by Targretin. The drug acts directly upon the pituitary to cause a central hypothyroidism with low TSH. Patients should be monitored by symptoms and started on levothyroxine when needed. The effect is entirely reversible within a few days of the cessation of Targretin therapy.
Sezary syndrome must be dealt with somewhat differently. These patients are red, scaly, and itchy and may have a keratoderma. They partially respond to most emollients, even Bag Balm and Oil of Emu. For pruritus, I prescribe doxepin around the clock. In Sezary syndrome, doxepin has been the only antipruritic that has consistently been beneficial and helps with depression as well. Topical steroids and wet dressings are generally very helpful.
Sezary syndrome patients have characteristic biological markers. They usually have high CD4 to CD8 ratios, usually greater that six to one. Their disease appears to be Th2 predominant, leading to prominent eosinophilia. Their soluble IL-2 receptors are well above normal. Many have high lactate dehydrogenase(LDH) levels. We have found that low magnesium levels are frequent and correlate with the stage of the disease. We have begun supplementing these patients, but it is not yet clear if this will affect the disease process. These various biological markers can be used to evaluate response to therapy. Those patients with low quantitative immunoglobulin G levels tend to become infected, though treatment with IV IgG appears to help prevent severe infection.
Infection, particularly with staphylococcus, is common and bacterial erythrotoxins may significantly contribute to the erythroderma. We examined 76 consecutive patients and found that half of them had skin and nasal staphylococcus carriage by culture. I frequently treat Sezary patients with vancomycin or other antibiotics and typically note a partial response in 90% just with antibiotics and topical steroids. It is important to remember that when septic, Sezary syndrome patients usually do not become febrile, but hypothermic. Therefore aggressive culturing and use of antibiotics will improve their condition significantly. I commonly use long courses of antibiotics (three to six months). Bactroban is used liberally particularly at IV or injection sites. Whirlpool baths with Hibiclens or vinegar is helpful. The keratoderma may be caused or exacerbated by dermatophyte in some cases. I check for this and don't hesitate to utilize antifungal agents.
In my opinion the first line therapy for erythrodermic MF or Sezary syndrome is photopheresis. A 15% complete response and about a 50% overall response rate may be expected. Greater efficacy is attained when combined with interferon alpha, low dose methotrexate, or cutaneous PUVA. Electron beam may be added for tumors or as previously mentioned; photopheresis may be used as a maintenance after electron beam therapy. Photopheresis works best when the circulating Sezary cell number is low and when the patient has a short duration of disease. It is important that the CD4/CD8 ratio is relatively normal and that there is normal natural killer cell activity. What may be happening is that the malignant cells are taken and killed with UV, then returned to the host to induce a T-cell reaction to these killed Sezary cells. This type of "vaccination" therapy requires an intact immune system. If combination chemotherapy has already injured the immune system, patients will not respond well to photopheresis.
The response to oral Targretin in erythrodermic Sezary patients is exciting. The combined MD Anderson-Yale experience consists of nine patients, all of whom had a durable, partial response. The responses, actually, were almost complete with a rapid onset of eight weeks and a mean duration of 35 weeks. Many showed significant decreases in their absolute CD4 counts.
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