Choices in the Treatment of Cutaneous T-Cell Lymphoma

February 1, 2007

Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.

Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.

From the perspective of a medical oncologist, mycosis fungoides (MF, a subset of cutaneous T-cell lymphoma [CTCL]) is often regarded as a low-grade lymphoma that shows several similarities to low-grade B-cell lymphomas. For example, MF is disseminated at diagnosis; that is, by the time lymphoma is seen in the skin, there is already blood and bone marrow involvement, although this may be subclinical. In addition, MF is responsive to treatment but resistant to cure. Thus, patients can expect long-term survival, at least by stage-adjusted or prognostic-feature-adjusted disease, but will require control of symptoms.

When MF is divided by stage, patients with patch- and plaque-stage disease (stages IA, IB, and IIA) have an excellent duration of survival. Those who have Sézary syndrome have a median survival of about 30 months, whereas the duration for stage IV disease is much shorter than this.[1] Therefore, the oncologist's therapeutic approach should be tailored to disease stage and to the patient's expected duration of survival. Patients with early-stage disease may survive for many years, thus irreversible treatment-related toxicities should be avoided; for those patients with more aggressive forms of the disease, a more toxic, less well-tolerated treatment may be acceptable.

Mycosis Fungoides: Responsive to Treatment But Resistant to Cure

One of the few randomized, controlled trials in MF was conducted by Kaye et al.[2] Patients were randomized to receive either conservative therapy with topical nitrogen mustard or combined-modality systemic and skin-directed therapy consisting of electron beam therapy plus cyclophosphamide, doxorubicin, etoposide, and vincristine. This produced the somewhat disappointing result in that there was really no difference in outcomes for these two approaches, thus demonstrating that the use of early aggressive therapy appears to provide no overall survival benefit over sequential topical therapies. Therefore, the approach of sequential, palliative single-agent therapies, similar to the approach adopted for patients with low-grade B-cell lymphomas, might be a useful one.

However, there are certain critical differences that distinguish MF from follicular B-cell lymphomas. First (due to skin lesions), CTCL is almost invariably symptomatic at onset, and the presence of these skin lesions means that a "watch and wait" approach is not feasible. Second, the loss of the integument as a host defense is an important feature of this disease. If patients are left untreated, they are likely to suffer not only from the neoplastic process but also from infections, which can have lethal consequences. Third, the histopathologic diagnosis of CTCL may be difficult and consequently often delayed. Finally, CTCL is amenable to more treatment modalities, such as phototherapy, cytokines, and immunotherapy, than low-grade B-cell lymphomas.

The focus of this manuscript will primarily be on drug therapies for CTCL. The reader is referred elsewhere for further information on the use of radiotherapy.[3-7]

Treatment Toxicities

One of the major concerns in treating patients with antineoplastic agents is acute toxicity, commonly myelosuppression by non-stem-cell-toxic therapies, and immunosuppression. In addition, there are side effects such as hyperlipidemia and hyperthyroidism, which are common with retinoids. Other chronic toxicities with MF treatments include photodamage to the skin (such as premature ageing), telangectasia, skin ulcerations, the induction of secondary malignancies, the induction of stem-cell injury by certain chemotherapeutic agents, and prolonged T-cell anergy, which can be produced by some chemotherapies as well as some recently available biologic agents.

Skin-Directed Therapies

As shown in Figure 1, the available skin-directed therapies are generally effective in producing good, long-term responses in patients at early disease stages, providing complete response rates of about 60%.[8-11] In particular, psoralen plus ultraviolet A (PUVA) plus retinoids or interferon (IFN) can achieve very high overall response rates in these patients. However, all of these agents have associated side effects. The most common toxicity of nitrogen mustard is hypersensitivity. In addition, myelosuppression and the induction of secondary malignancies are both possible toxicities, though these are not usually seen in clinical practice.

Topical carmustine (BCNU), on the other hand, is more often associated with myelosuppression. For PUVA, the principal toxicities are skin erythema and secondary malignancies including melanoma. During treatment with topical corticosteroids, skin atrophy is seen, along with systemic effects from absorption of high-potency steroids. Electron beam radiotherapy can result in anhydrosis, telangiectasia, and induction of secondary malignancies. Treatment decisions must therefore take into account both the benefits and possible drawbacks of therapy.

Systemic Therapies

Patients are candidates for non-skin-directed therapies: if they present with high-stage disease (stage IIB or greater); their disease has progressed; or they have dose-limiting toxicities, particularly melanoma, skin atrophy, or photosensitivity. The first choice for systemic agents would be cytokines or rexinoids. The overall response rates to these treatment modalities are acceptable, but rates of complete response are much lower than those produced by skin-directed therapies in early-stage disease (Figure 2).[12-17]

Cytokines

The response rates for biologic agents such as interleukin (IL)-2 and IL-12, which are experimental drugs, and IFN are comparable to those for the systemic retinoids.[12] The good response to these agents may result from the fact that there are immunologic lesions in CTCL, which is a malignancy of the memory T cells and is therefore characterized by the presence of dysfunctional and dysregulated T cells. There is a skewed Th2 vs Th1 phenotype in CTCL, which predisposes patients to infections and perhaps to other malignancies.[13] As a consequence of this derangement, there is reduced production of IFNγ. Patients with higher-stage MF have progressive CD8 cell depletion, and there is a good correlation between response to therapy and survival with CD8 cell numbers.[14] In addition, there is some evidence in CTCL for chronic antigen stimulation via the dendritic cells interacting with CD4+ cells, which may generate CD4+, CD25+ T-regulatory cells; this population of cells may also contribute to the immune depletion seen in patients with advanced MF.[14]

Thus, cytokines provide a rational approach to treating CTCL. These agents have the advantage of producing relatively high response rates and a long duration of response. In addition, toxicity of these biologic agents, particularly of IFNα, is largely reversible, and they are not immunosuppressive. Some cytokines may cause mild leukopenia, but growth factors are usually not required to counteract this effect. The principal disadvantages of the cytokines are the need for parenteral administration and systemic toxicities, such as fever, chills, myalgia, arthralgia, and, occasionally, depression.

The clinical experience with IFNα in MF is generally positive; patients who respond to the IFNs show a prolonged response and may remain in unmaintained remission for a number of years.[18] Thus, reversing the immune dysregulation in this disease may have important long-term consequences for the success of treatment.

The use of IL-2 as a therapy in MF might seem counterintuitive, as it is a growth factor for T cells; nevertheless, it has been evaluated and has shown some efficacy. In a phase I/II study, high-dose IL-2 showed activity in MF with several durable responses.[15] Another phase II study of IL-2 (11 mU subcutaneously daily for 5 days each week for 6 weeks, followed by 2 weeks' rest), reported 4 responders out of 18 patients treated.[15] Toxicities were mild, as the dose of IL-2 was much lower than that used to treat solid tumors such as melanomas or renal cell carcinoma.

Interleukin-12 may also have a therapeutic role in CTCL. A phase I study of 50, 100, and 300 ng/kg twice weekly showed responses in five out of nine patients with CTCL at various stages. Interestingly, the regressing skin lesions contained large numbers of CD8+ cells. This may indicate that IL-12 was inducing immune reconstitution. In addition to receiving this agent systemically, a group of patients received intralesional IL-12, which produced flattening and reduction of the tumors, again with CD8+ infiltrates.[12,16] A phase II trial tested a similar dose of IL-12 (100 ng/kg twice weekly for 2 weeks, then 300 ng/kg twice weekly for 24 weeks) in patients with stage I-IIA MF. Of the 23 patients enrolled, there were 10 partial responses, giving a 43% response rate.[19] Patients experienced the expected cytokine-type adverse events: fever, fatigue, headache, and myalgia.

There is a rationale for the use of combination therapy with IL-2 and IL-12, as prolonged IL-12 therapy has been shown to downregulate the IL-12 receptor and therefore produce a tachyphylaxis in its induction of IFNγ production. Interleukin-2 can counteract this effect and restore IFNγ production induced by IL-12. A trial of this combination is underway in patients with stage IB disease or greater, who were selected to have more than 15% of CD8+ lymphoid cells in peripheral blood (ie, a reasonably good immune function).

Denileukin Diftitox

The therapeutic effect of IL-2 and IL-12 needs to be distinguished from the effect of denileukin diftitox (Ontak). This drug, which was approved for the treatment of MF in the United States in 2000, is a fusion protein combining IL-2 bound to the A chain of diphtheria toxin. It utilizes the IL-2 sequence to target the molecule to cells expressing the IL-2 receptor. This receptor is composed of intermediate-affinity (CD122/132) and low-affinity (CD25) receptors, which can combine to form a high-affinity receptor that enhances IL-2 binding to the cell.[20-22] After binding to the cell, the ligand-receptor complex is internalized and incorporated into a lysosome; the molecule is proteolysed and the A chain is released into the cytoplasm. One molecule of the toxin is capable of killing one cell by interfering with protein synthesis. Although there are some concerns that only cells expressing the CD25 component of the IL-2 receptor might be susceptible to this drug, it must be remembered that this is not a monoclonal antibody; binding of its IL-2 domain may occur via the intermediate-affinity IL-2 receptors, which would not be detected by assays measuring only CD25.[20-22]

Both high-dose (18 µg/kg/d) and low-dose (9 µg/kg/d) regimens of denileukin diftitox have been described for the treatment of MF. With either regimen an overall response rate of 30% and a complete response rate of 10% have been reported. The median duration of the response was 4.4 months from the time of first response, or 6.9 months from the time of first dose.[22] Toxicities include acute hypotension, pruritus, and erythema. These can usually be controlled with a combination of histamine blockade, acetaminophen, and dexamethasone. In some patients, a delayed capillary leak syndrome is seen 7 to 14 days following treatment. This is usually most pronounced in patients who have hypoalbuminemia; thus, it is recommended that the drug is not given to patients whose serum albumin is < 3 g/dL.[22] As the amount of IL-2 in this fusion protein is much lower than the amount of IL-2 given as an unmodified protein, the mechanism of the capillary leak phenomenon may not be the same.

The Retinoids and Bexarotene

Retinoid acid receptor alpha (RAR-α) retinoids have been used in the management of CTCL for many years. However, most of the supporting data available are from studies with small numbers of patients, case series, or case reports rather than controlled trials. Although overall response rates of 43% to 80% and complete response rates of 12% to 30% have been reported, the duration of responses was brief and, as nonstandard criteria were used to evaluate response,[17] direct comparison with other agents is difficult. This lack of convincing clinical trial data is reflected in recent consensus guidelines from the European Organisation for Research and Treatment of Cancer, which do not recommend use of retinoids as monotherapy.[23] In addition, the symptomatic toxicity of the RAR-α retinoids (including chelitis, alopecia, xerostomia, headache, and osteophyte formation) is greater than that seen with the retinoid-X receptor agonists.[17]

Bexarotene (Targretin) is a synthetic retinoid with pure retinoid-X agonist activity. It has pleiotropic biologic activities, including immunologic activation and proapoptotic effects on tumor cells. The advantages of this drug are its high response rates in all stages of the disease, durable responses, minimal myelosuppression, and absence of immunosuppression. Bexarotene is also a conveniently administered oral medication. The main side effects experienced are hyperlipidemia and hypothyroidism, and lipids and thyroid function therefore require monitoring and management.

Among 84 patients who were treated with bexarotene (300 mg/m2/d initial dose), good response rates (ranging from 32% to 67%) were achieved across all tumor stages (Figure 3).[24,25] This seems to be an underestimate of the usual effects observed in clinical practice. The median survival time of a group of 94 heavily pretreated patients with stage IIb-IVb CTCL treated with similar doses of bexarotene was just under 1 year, and some patients showed a sustained response for as long as 6 or 7 years.[25]

Purine Analog Chemotherapeutic Agents

The advantages of systemic chemotherapies are that these agents produce rapid responses and high overall response rates; however, responses are usually only of brief duration and are achieved at the expense of myelosuppression and immunosuppression. Gemcitabine (Gemzar) is reported to produce good overall response rates (70%) against MF, with a complete response rate of about 10%.[26] In studies of the purine analogs in CTCL (Table 1) there were overall response rates of up to 100%, but complete response rates were relatively infrequent and the median duration of these remissions was relatively brief, ranging from 2 to 7.5 months.[27-34] Thus, these analogs showed good activity in reducing disease activity, but did not eliminate it.

The advantages of these agents are obvious, as patients with extensive plaque-stage disease show skin clearing following treatment. However, the disadvantages are equally obvious: patients who receive these immunosuppressive therapies are at a great risk of infection and require aggressive prophylaxis with trimethoprim and sulphonamide, or alternatives for Pneumocystis carinii pneumonia (PCP), the antifungal antibiotic fluconazole, and acyclovir or an alternative for varicella-zoster virus (VZV). They must also be screened for cytomegalovirus (CMV) reactivation.

Chemotherapeutic Drugs in Development

A number of chemotherapeutic drugs show promise in CTCL. Liposomal anthracyclines produce a high overall response rate (87% to 100%) with a good rate of complete response (42% to 66%).[35] Bortezomib (Velcade) is a proteosomal inhibitor that is thought to interfere with proteosomal inhibition of nuclear factor κB, thereby reducing the transcriptional effects of tumor necrosis factor (TNF). Many genes in the TNF pathway, including those for the TNF receptor, STAT-4, and CD40 ligand, are all downregulated in MF cells.[36] Therefore, this would appear to be a rational choice for drug treatment of CTCL. Investigations of this drug are ongoing.

The histone-deacetylase (HDAC) inhibitors are also being developed to target tumor suppressor genes in CTCL. Deacetylation of lysine residues on histones permits tighter binding of DNA and the inhibition of gene expression. Inhibition of this process via HDAC inhibitors may therefore enhance expression of tumor suppressor genes such as p53, p15, and p16, and produce an antitumor effect. There are currently four HDAC inhibitors in clinical development: suberoylanilide hydroxamic acid, depsipeptide, N-hydroxy-3-(phenylsulphamolyphenyl) acrylamide, and PXD101 (hydroxamate).

In a trial of depsipeptide, 27 patients with MF and peripheral T-cell lymphomas who had received many prior therapies were enrolled. There were three complete responses, all in patients with Sézary syndrome, and five partial responses, for an overall response rate of 30%.[37] Patients showed some electrocardiographic changes, but there was no evidence of cardiomyopathy in this study. Electrocardiographic changes appear to be a class effect of all HDAC inhibitors, although cardiomyopathy remains a possible concern. Similar response rates in patients with MF have been reported for suberoylanilide hydroxamic acid.[35]

Monoclonal Antibodies

Although preservation of immune function is important in treating MF, patients may be treated with highly immunosuppressive therapies, such as alemtuzumab (CamPath), when other treatment options have been exhausted. This is an anti-CD52 humanized monoclonal antibody that has been approved for the treatment of chronic lymphocytic leukemia. The drug has demonstrated efficacy in clearing malignant lymphocytes from the bone marrow and peripheral blood, but has little effect on clearing chronic lymphocytic leukemia cells from the lymph nodes and viscera.

Alemtuzumab is severely immunosuppressive, as it depletes all populations of B and T cells as well as myeloid cells. Opportunistic infections including PCP, VZV, and CMV have been described in patients receiving this monoclonal antibody. In addition, alemtuzumab has infusion-related toxicity, including fever, rigor, nausea, rash, hypotension, and fatigue; thus, its intravenous administration needs to be carefully monitored.

Lundin et al reported a phase II study in which 22 patients with advanced MF were treated with intravenous alemtuzumab.[38] They observed an overall response rate of 55%, with a complete response rate of 32%. The response rate for patients with erythroderma was higher (69%) than for those patients with tumors (40%). A total of 59% of the patients required treatment for infusion-related toxicities, and 18% of the patients had reactivation of latent CMV infection.[38]

At my institution, New York University Cancer Institute, seven patients with advanced refractory MF (two patients) or Sézary syndrome (five patients) who had received 4 to 6 prior therapies were treated with subcutaneous alemtuzumab. The monoclonal antibody was administered in an escalating, every other day, schedule of 3, 10, and 30 mg in week 1, then 30 mg three times weekly for 4 weeks. Patients also received prophylaxis for PCP and VZV, and were screened for CMV seropositivity. Those patients who were CMV-seropositive were screened monthly for CMV DNA levels and treated with prophylactic ganciclovir if there was evidence of viral replication. In this cohort of patients, there were four complete responses, two partial responses, and one non-response (unpublished data). Overall, the response rates and duration of response compared favorably with those for other drugs. One patient had an asymptomatic decrease in blood pressure with one treatment; no other acute toxicity was observed. One patient had an episode of PCP associated with noncompliance with the prophylactic therapy. Thus, alemtuzumab is a promising treatment for patients with refractory MF.

Other monoclonal antibodies are in clinical trials, including a humanized anti-CD4 monoclonal antibody and an anti-CD25-pseudomonas exotoxin immunoconjugate. The utility of these agents has yet to be proven.

Treatment Strategy for Patients With CTCL

In early stages of MF (IA, IB, or IIA), skin-directed therapies, including topical steroids, mechlorethamine, ultraviolet B, and bexarotene gel, should be employed. As the disease progresses to a higher stage, systemic agents-such as oral bexarotene, IFNα, fusion proteins such as denileukin diftitox, or methotrexate-can be added to the treatment regimen. Patients who have not responded to a range of biologic agents should then be treated with chemotherapeutic agents, starting with the purine analogs and progressing to combination chemotherapies.

Disclosures:

Dr. Hymes is a consultant for Ligand Pharmaceuticals and a member of the speakers' bureaus for GlaxoSmithKline, Merck, and Celgene.

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