Systemic Therapy of Cutaneous T-Cell Lymphomas (Mycosis Fungoides and the Sezary Syndrome)

  1. Paul A. Bunn, MD;
  2. Stephen J. Hoffman, MD;
  3. David Norris, MD;
  4. Loren E. Golitz, MD; and
  5. John L. Aeling, MD
  1. From the University of Colorado Cancer Center and Health Sciences Center, Denver, Colorado. Requests for Reprints: Paul A. Bunn, Jr., MD, University of Colorado Cancer Center, 4200 East Ninth Avenue, Campus Box B-188, Denver, CO 80262. Acknowledgments: The authors thank Sandra Stricker for editorial assistance and Robin Hohsfield, RN, for data management support. Grant Support: In part by National Institutes of Health grants 1 P50 CA58187-01 and 1 P30 CA46934-06.
     
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    Abstract

    Objective: To review recent studies of systemic therapy for mycosis fungoides and the Sezary syndrome (cutaneous T-cell lymphomas).

    Data Sources: English-language articles indexed in MEDLINE from 1988 through 1994.

    Study Selection: All therapeutic studies were selected.

    Data Extraction: The data were abstracted without judgments on response criteria or patient numbers. Data quality and validity were assessed by independent author reviews.

    Data Synthesis: No systemic therapy cures patients with cutaneous T-cell lymphomas. Single and combined chemotherapeutic agents produce high response rates. Whether any of these is preferred is not established. A randomized trial comparing combination chemotherapy plus radiation therapy with topical therapy showed no survival benefit for the combination. Several adenosine analogs and retinoids were active, but their optimal use is uncertain. Interferons are as active as chemotherapeutic agents and may be less toxic. Interferon combined with psoralen plus ultraviolet A light therapy produces high complete response rates and long-lasting remissions. Combinations with other systemic therapies do not increase response rates. Photopheresis therapy should be regarded as experimental. Promising preliminary results were seen with interleukin-2 fusion toxins and several antibody conjugates.

    Conclusions: Systemic therapy should be considered effective and palliative. The principles of treating all low-grade lymphomas can be applied. Randomized trials are needed to evaluate new agents (such as a comparison of psoralen plus ultraviolet light with or without interferon), and large phase II trials are needed for new agents such as photopheresis, interleukin-2 fusion toxin, temozolomide, and others.

    Mycosis fungoides and the Sezary syndrome are low-grade, non-Hodgkin lymphomas that have a mature helper T-cell phenotype and that are always associated with cutaneous involvement [1-3]. Although they are often collectively called “cutaneous T-cell lymphomas,” they must be distinguished from other intermediate- and high-grade non-Hodgkin lymphomas, which may have cutaneous involvement such as peripheral T-cell lymphoma, adult T-cell leukemia-lymphoma, or B-cell non-Hodgkin lymphomas [3]. That mycosis fungoides and the Sezary syndrome are lymphomas was recognized only in 1970. Before then, systemic therapies were used exclusively when late progression to a visceral lymphoma occurred. Studies since 1970 have shown that systemic spread occurs early in the course of the illness, before it is clinically evident. Therefore, many studies evaluating systemic treatment approaches were reported in the last 20 years. We reviewed them, focusing particularly on reports of new agents in the past 10 years. We included older data on chemotherapeutic agents for comparison.

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    Cytotoxic Chemotherapy

    Single-Agent Chemotherapy

    The largest body of information exists on cytotoxic chemotherapeutic agents, the first systemic therapies ever evaluated. Previous reviews summarized literature studies of single cytotoxic chemotherapeutic agents [1-3]. If we define an active agent as one that produces an objective response (complete response or partial response) in more than 20% of patients, there are many active chemotherapeutic agents, including alkylating agents, antimetabolites, antitumor antibiotics, vinca alkaloids, topoisomerase II inhibitors, corticosteroids, and others. The list of active agents is similar to the list of active agents for B-cell lymphomas. Table 1 shows that among 528 patients reported in single-agent chemotherapy trials, the complete response rate was 32% and the objective response rate was 62% [2, 4-6]. The median duration of response ranged from 3 to 22 months. No patient was reported to be cured by this approach, although other cutaneous therapies were unsuccessful in all treated patients. Based on our review, we cannot assert that any particular single agent is preferred to another, and no large, randomized studies comparing agents have been reported. The most data exist for methotrexate, which was active in many doses and schedules [2, 4]. It is not clear that high-dose methotrexate with leucovorin rescue is superior to lower-dose methotrexate therapy without leucovorin rescue [4, 5]. An exciting new cytotoxic chemotherapeutic agent is temozolomide, which showed activity in malignant gliomas and malignant melanoma in phase I clinical trials in humans. The phase I studies included two patients with mycosis fungoides, and both had complete responses [6]. Thus, prospective phase II studies of this agent should be done.

    Combination Chemotherapy

    Table 1 summarizes a literature review of studies that reported results with combination chemotherapy alone or combination chemotherapy with electron beam irradiation or topical nitrogen mustard [7-25]. In these studies, which included 331 patients, the objective response rate was 81%, the complete response rate was 38%, and the response duration ranged from 5 to 41 months. These figures are slightly higher than those with single-agent therapy, but the differences are not striking. There were no randomized trials comparing combinations with single-agent regimens. In low-grade B-cell non-Hodgkin lymphomas, there were no survival differences between single-agent or combination chemotherapy in randomized trials. Most of the 331 patients listed in Table 2 had advanced stages (IIB to IV), and combination chemotherapy was not curative for these patients. A few patients with early-stage disease (IA to IIA) had complete responses and were disease free at the time of the reports [18, 20, 24]. The follow-up durations were too short to determine whether any of them were long-term, disease-free survivors with possible cure. In the two randomized trials comparing one combination with another [10, 14], we found no differences in response rates or survival; however, the number of patients was too small to preclude considerable differences.

    View this table:
    Table 1. Chemotherapy for Advanced Mycosis Fungoides and the Sezary Syndrome*
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    Table 2. Studies of Interferons in Mycosis Fungoides and the Sezary Syndrome*

    One randomized study conducted by the National Cancer Institute (NCI) compared combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and etoposide plus total-skin, electron beam irradiation with conservative therapy and topical nitrogen mustard [20]. The objective (90% compared with 65%) and complete (38% compared with 18%) response rates were higher with the combined therapy, but the survival times were similar and the toxicity of the combined therapy was considerably greater. The investigators' conclusion was that the conservative approach was favored as initial therapy. This study included only a few patients with early-stage disease, some of whom had complete responses to both therapies. Although we could argue that chemotherapy should be considered in an attempt to cure these patients, the randomized study showed no obvious advantage. In addition, other studies showed considerably higher complete response rates with the combination of psoralen, ultraviolet A light (PUVA) therapy, and interferon compared with chemotherapy studies (see below).

    Recently, investigators have shown interest in using very-high-dose combination chemotherapy followed by autologous bone marrow transplant or peripheral blood stem cell support to treat various lymphomas. This type of therapy has curative potential in relapsed but chemosensitive, high-grade lymphomas. There is less experience in low-grade lymphomas. Bigler and colleagues [26] reported a trial of high-dose combination therapy followed by autologous bone marrow transplantation in six patients. Five of the six had complete responses, but three of the responses lasted fewer than 100 days. Two patients were disease free after 1 year. This highly experimental approach should be studied only in institutions that have experience with this technique and should be limited to patients with chemosensitive lymphomas.

    Interferons

    Recombinant interferons were evaluated for mycosis fungoides and the Sezary syndrome in the early 1980s, immediately after phase I studies were completed. Table 2 summarizes the results of studies that used various types of interferon, alone [27-42] and combined with retinoids [43-48] and PUVA [49, 50]. Table 3 summarizes the results of combination studies with adenosine analogs [51, 52]. The first phase II study of recombinant interferon-α [27, 28] used a very high dose (50 MU/m2) given subcutaneously three times each week. This high dose was reported to be the maximally tolerated dose in the phase I study. This phase II study showed that interferon was active (45% response rate), that responses developed gradually over weeks to months, and that the dose was actually greater than the maximally tolerated dose. The National Cancer Institute (NCI) group also evaluated a high-dose, intermittent schedule of interferon [29]. This also proved to be active (29% response rate) but toxic. Because the dose and schedule have considerable effects on toxicity and cost, a randomized study was begun to determine whether high-dose therapy was superior to low-dose therapy (3 MU three times each week) [30]. Unfortunately, the study did not accrue enough patients to address dose. The study confirmed that recombinant interferon-α is active and that the activity (response rate) is greater in patients with early-stage disease and in patients who are less heavily pretreated. The response rate was slightly higher (but not significantly so) in the higher-dose arm. This was due in part to late responses in patients who were crossed over to the high-dose arm. Although the investigators attributed this to a dose effect, the NCI study showed that late responses occur even when the dose is being lowered [27, 28]. Another randomized dose study in B-cell indolent non-Hodgkin lymphomas also showed no significant differences in response rate or duration with high-dose compared with low-dose interferon [53]. Therefore, we believe that 3 MU given three times each week is optimal based on current information.

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    Table 3. Studies of Adenosine Analogs in Advanced Mycosis Fungoides and the Sezary Syndrome*

    The literature summary in Table 2 shows that the overall response rate for interferons was 55% among 207 patients, with a 17% complete response rate. These studies clearly show that interferons are active agents that produce responses nearly as often (55% compared with 62%) as single-agent chemotherapy, but with less toxicity when low doses are used. In addition, one or more chemotherapeutic drugs were successful in the patients treated with interferon. There were no apparent differences between the recombinant α-2a and α-2b interferons. Patients with early-stage disease who received less pretreatment therapy were more likely to respond.

    Subsequent studies also showed that recombinant β and γ interferons have similar activity to recombinant α interferons (Table 2). The response rate to these latter interferons was 41%, with 15% complete responses among 32 patients in 3 studies [41, 42]. These interferons offered no major advantages over α interferons, so they have been largely abandoned. No phase II studies combined various types of interferons in mycosis fungoides or the Sezary syndrome, but studies in chronic myelogenous leukemia showed no advantage to combining recombinant α and γ interferons compared with interferon-α alone.

    Surprisingly, no studies evaluated interferon combined with the standard cytotoxic chemotherapeutic agents. We found several such combination studies in low-grade, B-cell lymphomas and in multiple myeloma, but the data are somewhat conflicting, with some studies showing improved response rate, survival, or response duration benefit [54-58] and others showing no benefit [57] or benefit only in patient subsets [58]. Overall, these studies suggest that there may be a small advantage, especially in response duration. We found no randomized studies of interferon compared with no therapy in any type of lymphoma.

    Many studies evaluated the combination of interferon with retinoids, including 13-cis retinoic acid and etretinate [43-48] (Table 2). The response rate among 102 patients in seven studies was 60%, and the complete response rate was 11%. These response rates are similar to the response rates for interferon alone. No randomized studies have been done to determine whether the combination is superior to interferon alone, but these single-arm studies do not suggest a major advantage.

    The combination of interferon and PUVA provided more exciting results, although the studies were preliminary [49, 50] (Table 2). Kuzel and colleagues [49] reported that the combination produced 14 responses among 15 patients (93%) and 12 (80%) complete responses that were histologically confirmed by serial skin biopsies. This rate of complete response is higher than that reported from the NCI with combination chemotherapy and total-skin electron irradiation [20]. Many of the patients who had complete responses remain in remission. A subsequent study confirmed the high objective (100%) and complete (43%) response rates using the combination of interferon and PUVA [50]. However, many unanswered questions remain about interferon and its combination with PUVA, including the optimal dose of interferon and the duration of maintenance therapy. These studies showed that interferon has some photosensitizing effects, so the initial ultraviolet A light dose must be reduced. Low-dose interferon (3 MU) given subcutaneously three times each week or every other day is probably as good as higher doses. Whether the interferon should be continued for 1 year, 2 years, 3 years, or longer is uncertain. Most trials limit the duration of maintenance PUVA to about 1 year because of the potential to induce other skin cancers. No randomized trials have evaluated the combination compared with PUVA alone, although one is being planned in the United States.

    Two studies from the NCI [51, 52] evaluated interferon combined with the adenosine analogs fludarabine and deoxycoformycin (Table 3). The objective response (43%) and complete response rates (6%) were very similar to those reported with the adenosine analog alone and interferon alone. No randomized studies compared the combination to either single agent. These combinations should not be used routinely because of the increased toxicity. Neurologic toxicity is especially problematic with these combinations because both interferon and the adenosine analogs may produce disabling neurologic effects [59].

    Many studies of photopheresis have also included interferon; they are described in the section on photopheresis. We found no published phase II studies of interferon plus photopheresis, topical nitrogen mustard, or electron beam irradiation.

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    Adenosine Analogs

    Adenosine deaminase deficiency, an inherited disorder, is very toxic to T lymphocytes, a fact which prompted the study of 2′-deoxycoformycin (DCF) (pentostatin) for T-cell lymphomas and for other indolent B-cell lymphomas. Table 3 summarizes the results of seven studies of DCF in patients with mycosis fungoides and the Sezary syndrome [60-66]. These studies were all small, with only 3 to 18 patients each. The overall response rate was 41% (range, 33% to 67%), with 6% complete responses. These response rates suggest that DCF is active, but the response durations were generally short. Compared with other single-agent chemotherapy (see Table 1), the response rates and durations seem slightly inferior for DCF. However, the patients enrolled in DCF studies had received more extensive pretreatment.

    Fewer patients have been treated with 2-chlorodeoxyadenosine [67, 68] and fludarabine [69] (Table 3). The two studies of 2-chlorodeoxyadenosine showed an overall response rate of 41%, with 19% complete responses. The one study of fludarabine showed a response rate of 19%, with a complete response rate of 3% in patients who received extensive pretreatment. These three agents are also active in hairy cell leukemia, chronic lymphocytic leukemia, and low-grade, B-cell non-Hodgkin lymphomas. It is not clear whether one agent is preferred to another in any disease. In hairy cell leukemia, a randomized study compared interferon with DCF. The complete response rate was much higher with DCF than with interferon. However, there were no differences in survival. In hairy cell leukemia, 2-chlorodeoxyadenosine produced a complete response rate at least as high as that produced by DCF, but no comparative randomized trials have been done.

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    Retinoids

    Retinoids are vitamin A analogs that include vitamin A, its derivatives (retinol, retinal, retinoic acid), and synthetic analogs. They affect neoplastic cells by inhibiting proliferation and by arresting dedifferentiation. Table 4 summarizes the results of five studies evaluating single-agent arotinoid-ethylester [70], 13 cis-retinoic acid [71-73], and etretinate [73, 74] in 120 patients. The overall response rate was 58%, with a complete response rate of 19%. The median duration of response ranged from 3 to 13 months. One randomized trial compared 13 cis-retinoic acid with etretinate [73]. No differences in response or toxicity were found for the two agents. These results suggest that the activity of the retinoids is similar to that of single-agent cytotoxic chemotherapy and various interferons. No randomized trials compared any of the retinoids with chemotherapeutic agents or with interferon. The studies combining retinoids with interferon were discussed previously.

    One study combined retinoids with PUVA [75] (Table 4); in it, 69 patients showed a complete response rate of 73%. The investigators stated that this complete response rate was similar to their historical experience with PUVA alone. No randomized trials have evaluated PUVA plus retinoids with PUVA or retinoids alone. Such studies are indicated, but we believe they have a lower priority than do randomized studies of PUVA alone or with interferon.

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    Table 4. Studies of Retinoids in Mycosis Fungoides and the Sezary Syndrome*
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    Photopheresis (Extracorporeal Photochemotherapy)

    Photopheresis or extracorporeal photochemotherapy is a new and complex therapy that combines oral administration of 8-methoxypsoralen with extracorporeal ultraviolet A irradiation of peripheral blood [76, 77, 80-82] (Table 5). Only a fraction of the total peripheral blood cells are subject to the ultraviolet A light irradiation. The mechanism of action of this approach is unclear, although certainly some lymphocytes, including some malignant lymphocytes, should be killed. The first published trial using this approach was very optimistic, with reported responses in 22 of 41 patients (54%), including 24 of 33 patients with generalized erythroderma (73%) [76]. Six complete responses (15%) were reported, all of which occurred in patients with generalized erythroderma. A subsequent report from many of the same investigators at Yale University reported that among 22 presumably different patients with erythroderma, 5 responded completely (23%) [77]. These studies are difficult to interpret for several reasons. The response criteria were not well defined and were not those generally applied in standard oncology studies. It is unclear what percentage of the patients with erythroderma had the Sezary syndrome with peripheral blood involvement. It is also unclear whether the improvement in erythroderma was due to an antitumor effect or to some change in cytokines that decreased the erythroderma without affecting the tumor burden. Many reviews and non-peer-reviewed summaries of these data have appeared in the literature. Some of these implied that the therapy prolonged the survival of the subset of patients with erythroderma. This conclusion was reached by comparing the survival of the patients with erythroderma with historical controls from the literature. This comparison, of course, is invalid because established prognostic factors in the treated patients with erythroderma were not provided. Several studies [78, 79] show that patients with erythroderma and good prognoses (such as those with normal leukocyte counts and no node or visceral involvement) survive longer than do the treated patients reported by Edelson and colleagues [76] and Heald and colleagues [77]. Another important problem is that many patients were given other therapies. In the Yale report, the authors stated that all of the responding patients who did not have a complete response were treated with additional forms of therapy [77]. Some patients were excluded from analysis because of toxicity and other reasons. These patients should be included in the response analysis as nonresponders. Confirmatory data on the effectiveness of photopheresis are difficult to find. Three small reports [80-82] of 1 to 20 patients reported responses in 55% to 100% of patients and complete responses in about 25% of patients. These were primarily also limited to patients with erythroderma. No randomized studies compared this form of therapy with any other type of treatment.

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    Table 5. Studies of Photopheresis in Mycosis Fungoides and the Sezary Syndrome

    In the United States, photopheresis was approved by the Device Center of the Food and Drug Administration (not the Drug or Biologic Centers). Although hundreds of patients have been treated since that approval (at a huge expense), no reports have confirmed the activity of this approach. Because no positive reports exist, we can assume that most or all of these patients did not respond. To make matters worse, many centers routinely give effective forms of treatment, such as interferon, with photopheresis. This makes interpretation of the photopheresis contribution impossible. We believe that photopheresis is an unproved form of therapy and should be regarded as experimental until convincing data showing its efficacy are published.

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    Cyclosporine

    Cyclosporine is an immunosuppressive drug that inhibits proliferation of T lymphocytes. Thus, it was logical to evaluate cyclosporine in patients with mycosis fungoides and the Sezary syndrome. Scattered reports of cyclosporine activity exist in the literature, but these studies evaluated only 19 patients, and the largest study described 11 patients [83-87]. In these studies (Table 6), 6 of 19 patients (32%) had a partial response, but there were no complete responders. Toxicity was considerable, with immunosuppression, infections, and decreased renal function. We believe these results are not promising for such a toxic agent. Thus, cyclosporine should not be used unless a well-planned study is conducted that shows activity.

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    Table 6. Studies of Cyclosporine in Mycosis Fungoides and the Sezary Syndrome
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    Monoclonal Antibody Therapy

    The antigens expressed on the malignant mature helper T cells are potential targets for immunotherapy with monoclonal antibodies or antibody conjugates. After initial reports that antithymocyte globulin produced transient responses in patients with mycosis fungoides and the Sezary syndrome, the group from Stanford University evaluated a murine monoclonal antibody called T1 that reacts with the CD5 antigen (Table 7). They reported brief partial responses in four of nine treated patients [88]. This response rate was not confirmed in three trials involving 34 patients treated with other murine anti-CD5 monoclonal antibodies reacting with the same antigen [89-91]. In these trials, most patients had transient or minor responses, but objective responses lasting more than 30 days were reported in only 1 of 34 patients, and there were no complete responses. The lack of effect was attributed to the antigen modulation induced by the antibody, the presence of circulating antigen, allergic reactions, and other reasons.

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    Table 7. Studies of Selected New Therapies for Mycosis Fungoides and the Sezary Syndrome*

    The malignant Sezary and mycosis cells express the CD4 (helper) antigen and the mature pan T-cell CD5 antigen. Murine monoclonal anti-CD4 antibody therapy was also evaluated, especially because the CD4 antigen does not modulate in the presence of the antibody [92]. In that study, the investigators observed one partial response (14%) lasting 2 months among seven treated patients. A different approach was to produce an anti-idiotypic antibody by making an antibody to an antibody. This anti-idiotypic antibody (Ab2) recognized an antigen on the original malignant mycosis cells. The idiotypic antibody thus has the same structure as a tumor antigen and can serve as an antitumor vaccine. Three patients were treated with an antibody made using this approach, and, although a biological effect was observed, there were no objective responses lasting 30 days or more [93]. Although patient numbers were small, these approaches with unlabeled antibody are not especially promising.

    Because the CD5 antigen is internalized in the presence of antibody, it was logical to evaluate radiolabeled antibodies. The group from the NCI studied Indium-111-labeled and Iodine-131-labeled T101 given intravenously, subcutaneously, and intralymphatically [94-96]. They showed that Indium-111-T101 given intravenously localized in cutaneous, nodal, and visceral sites of disease but nonspecifically localized in the liver. Tracer doses of the radiolabeled antibody produced no serious toxicities, and extracutaneous nodal sites of disease were successfully visualized in all patients. Antibody uptake in these patients was still relatively low, with only 0.01% of the injected dose per gram contained in lymph node tissue. Subcutaneous administration of the antibody into the feet and direct intralymphatic administration in the feet gave much higher nodal uptake (0.5% of injected dose/g), especially in the inguinal, femoral, and para-aortic nodal regions. Indium-111-T101 was superior to Iodine-131-T101 because of dehalogenation of the Iodine-131-label and intracellular processing of the Iodine-131-complex [95].

    Based on the positive results of imaging studies with Indium-111-T101, a therapeutic study with Iodine-131-T101 was instituted. As with the previous imaging study, Iodine-131-T101 localization was inferior to that seen with Indium-111-T101, and rapid dehalogenation occurred in vivo [97]. Nonetheless, responses were reported in five of six treated patients, including three of six who had objective partial responses. It is unclear whether these responses represented total-body irradiation from the free Iodine-131, a direct effect of the Iodine-131-T101, or some of each. A study with Yttrium-90-T101 that uses the same chelate as for Indium-111-T101 is in progress at the NCI.

    Another approach to immunoconjugate therapy was to develop a toxin-labeled antibody rather than a radiolabeled antibody. This approach was tested using the H65 murine monoclonal antibody that also recognizes the CD5 antigen and that was coupled with ricin A chain [98]. Administered to 14 patients with advanced, refractory cutaneous T-cell lymphomas, the HG5-RTA conjugate produced 4 (29%) objective partial responses (Table 7) lasting 3 to 8 months. These immunoconjugate studies show that this form of therapy produces better responses than does antibody alone. However, additional obstacles must be overcome to increase the response rate and duration before these therapies become acceptable.

    Interleukin-2 (IL-2) is a lymphokine that stimulates T-cell activation and proliferation by binding to its cell-surface receptor (IL-2R). There is low expression of IL-2R in resting lymphocytes. Expression of IL-2R on malignant cells in mycosis fungoides and the Sezary syndrome varies. In a few cases, there is no detectable expression; most cases have a low level of expression, and a few cases have high expression. Cases of high-grade adult T-cell leukemia-lymphoma caused by human T-cell lymphotrophic virus type 1 almost always have high expression of IL-2R. Interleukin-2 fusion toxins are recombinant proteins that are produced by hybrid IL-2 and diphtheria toxin genes. These fusion toxins bind to IL-2R.

    Intravenous administration of IL-2 alone or with IL-2 activated killer cells was evaluated as an antitumor therapy in various cancers [99]. Objective responses were noted in several cancers, and IL-2 was approved for use for patients with renal cell cancers. Stimulation of malignant cell proliferation by IL-2 binding to its receptor on the malignant cells can make IL-2 therapy detrimental to patients with mycosis fungoides and the Sezary syndrome. Nonetheless, we found one report of IL-2 used in such patients [100] (Table 7). Objective responses were reported in five of seven patients, including 1 complete response lasting more than 29 months. It is unclear whether the malignant cells from these patients expressed the IL-2R. No prospectively planned phase II studies with sufficient patient numbers to determine a true response rate have been reported. Thus, a phase II study is needed, but until such a study is conducted, this must remain an experimental approach, especially given the high cost and toxicity of the therapy.

    The presence of the IL-2R on the malignant cells prompted another approach used by the biotechnology company Seragen (Hopkinton, Massachusetts). Fusion of the IL-2 gene with the diphtheria toxin A chain gene produced a fusion IL-2 toxin protein. The original IL-2 toxin fusion protein was called DAB486IL-2 because it contained 486 amino acids from the diphtheria toxin protein [101-103]. Phase I clinical trials of this recombinant protein showed that the maximally tolerated dose was 0.1 mg/kg per day administered intravenously for 10 days [102]. Reversible increases of hepatic enzymes comprised the dose-limiting toxicity. Because objective responses were noted in some patients with cutaneous T-cell lymphoma in the phase I trial, the investigators conducted a phase II study [103]. These studies showed that objective responses occurred in 6 of 29 patients (21%). No patients whose malignant cells lacked IL-2R responded to the DAB489IL-2 protein.

    Seragen developed a smaller fusion protein called DAB389IL-2 that has considerably greater binding affinity to IL-2R. This protein produced greater response and less toxicity in experimental systems, so phase I-II human trials were conducted with this protein [104]. Objective responses were again noted in 5 of 11 (45%) patients with cutaneous T-cell lymphoma in the phase I study, including one complete response (9%). The highest dose of protein given was 900 KU/kg per day. This produced no grade 3 or 4 toxic responses, and the investigators observed no responses in the 43% of patients whose malignant cells failed to express IL-2R. Large, multicenter phase II and III studies are being planned for this new agent.

    Another immunologic approach was development of thymopentin, a 5-amino acid peptide that stimulates normal lymphocytes. The first study using thymopentin was optimistic, with 15 objective responses (75%) and 8 complete responses (40%) among 20 patients treated (Table 7), all of whom had the Sezary syndrome [105]. The responses were reported to be long, lasting a median of 22 months. Unfortunately, these optimistic results were not confirmed in a subsequent study in which only 1 partial response was observed among 16 treated patients. There were no responses among 10 patients with generalized erythroderma in this follow-up study [106]. Thus, it is unclear whether thymopentin ultimately will become an active therapeutic agent.

    Reports of a possible viral origin of the cutaneous T-cell lymphomas led to anecdotal reports using acyclovir. As shown in Table 7, three very small studies with 1 to 9 patients showed brief partial responses in 4 of 11 patients [107-109]. No systematic studies of acyclovir and no randomized trials comparing it with other therapies are published, and it should be considered experimental until prospective studies show clinically relevant activity.

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    Conclusions

    Several new systemic therapies are promising for low-grade cutaneous T-cell lymphomas, including mycosis fungoides and the Sezary syndrome. However, only a few well-designed phase II studies have used standard criteria for diagnosis, staging, and response, which allow prioritization of the relative effectiveness of these agents. Further, only two randomized trials have compared different therapeutic strategies [20, 74]. The randomized trial from the NCI [20] showed that therapy with combination chemotherapy and total-skin electron irradiation produced very high response rates but did not prolong survival compared with less toxic topical chemotherapy alone. This suggests that cytotoxic chemotherapy plays only a palliative role in treating cutaneous T-cell lymphomas. The randomized study by the Scandinavian Mycosis Fungoides Cooperative Group showed that the two retinoids etretinate and 13 cis-retinoic are both active and have equivalent rates of efficacy and toxicity [73].

    Where do we go now? The studies that we reviewed show that interferons, retinoids, and adenosine analogs are active systemic agents. However, the roles of these agents in standard therapy are not established, and randomized studies are needed. The most interesting of such studies is a comparison of PUVA, PUVA plus interferon, and interferon alone. This would require a large, multicenter, randomized trial, which could be done now because the doses of each modality in combination are established. Similarly, randomized trials comparing retinoids with a topical treatment with the topical therapy alone would be valuable.

    The preliminary results of combined interferon with the adenosine analogs did not appear promising. Randomized trials of interferon alone or with standard chemotherapy would be valuable. The role of the adenosine analogs is unclear. A randomized trial comparing one of these analogs alone with standard chemotherapy and with the combination would be valuable.

    With respect to the other therapies, their efficacy must be established in formal studies. Because the efficacy of photophoresis is not established, well-designed trials are urgently needed.

    Among the other therapies, the DAB389IL-2 fusion toxin and temozolomide show the most promise and require studies in larger groups of patients. Some of the newer chemotherapeutic agents with novel mechanisms also should be evaluated. These include the topoisomerase inhibitors CPT-11, topotecan, and 9-aminocamptothecan; the tubulin depolymerizating agents taxol and taxotere; and a new antimetabolite, gemcitabine.

    In these uncommon lymphomas, the need for well-designed, multicenter trials is apparent. Single-center studies with fewer than 10 patients are not helpful in defining therapeutic options. No systemic agents are approved for use in the United States, although we believe that the palliative use of many cytotoxic chemotherapeutic agents and interferon are justified by the literature available now. We hope new therapies will be tested with sufficient rigor to allow consideration for approval by the Food and Drug Administration.

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