There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon α, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.
Only a limited number of therapies are approved for cutaneous T-cell lymphoma (CTCL), the most common disorders of which are mycosis fungoides (MF) and Sézary syndrome (SS). The most recently approved therapies for CTCL are vorinostat (Zolinza), a histone deacetylase inhibitor (in 2006); denileukin diftitox (Ontak), an interleukin (IL)-2 fusion protein (in 1999); and bexarotene (Targretin), the first retinoid-X receptor (RXR)-selective retinoid (in 1999). Treatment strategies in the management of MF are aimed at removal of the persistent antigen stimulus, reversal of the shift from Th2 to Th1 cytokine expression, induction of an increase in CD8+ cells, avoidance of immunosuppression, and prophylaxis or treatment of associated infectious complications.
A number of treatment options are available for different disease stages of MF. Patients in early disease stages are prescribed skin-directed topical therapies, including steroids, bexarotene gel or topical mustargen, or phototherapy. For intermediate stages such as extensive plaques, biologic response modifiers (such as oral bexarotene, interferons [IFNs], and denileukin diftitox) are available and increase the immune response. In patients with tumors or nodal disease, single-agent nucleoside analogs (such as gemcitabine [Gemzar] and pentostatin [Nipent]),[2,3] combination chemotherapy, or targeted therapy (with fusion toxins, antibodies, and small molecules) is used. If patients at late stages can produce a good partial response, allogeneic bone marrow transplant (BMT) may offer the possibility of complete remission. However, it is possible that efficacy of treatment could be increased by combining these agents.
The question of whether to use a series of single conservative therapies or intensive early combination therapy was first addressed in a clinical trial in the 1980s. Sequential conservative therapy produced the same overall survival rates as intensive combination chemotherapy, and there were early deaths in the latter arm. However, this study is out of date and should be repeated using some of the newer agents available. How best to integrate the new agents with existing therapies will require additional well-designed, randomized trials. Our goal should be to produce rational combinations of drugs that can either induce a cure or prolonged complete response in patients. But how can such combinations be identified without conducting a huge number of clinical trials to test the many possible combinations? The aim of this manuscript is to look at some of the evidence available on a number of combination therapies, based on published data and on the author's experience in the clinical management of CTCL, with a particular focus on advanced, progressive refractory MF.
Retinoids or Rexinoid Therapy
Retinoids are the major biologic response modifiers that have been used in CTCL since the 1980s.[5-11] Retinoic acid receptor (RAR) agonists (isotretinoin, etretinate [Tegison]) have been demonstrated to produce an overall response rate of about 58%, but the complete response rate is low, at about 19% for the RAR retinoids.[9,12-15] Furthermore, these drugs are more effective in patients with early disease than in those with advanced CTCL. However, combination with psoralen plus ultraviolet A (PUVA) or IFN increases overall response rates to about 70%, as discussed elsewhere in this supplement.
Several oral retinoids are currently available: isotretinoin, acetretin (Soriatane), bexarotene, and all trans-retinoic acids. Many more are in development, each showing different selectivity for the retinoid receptors. If clear evidence was available to identify which retinoid receptors are key for putting CTCL in remission, it is possible that these selective retinoids could be combined in a rational manner to improve their effectiveness. Bexarotene, for example, is a retinoid that is selective for the RXR (described as a rexinoid), and is highly active in CTCL for both early and advanced disease and as a topical formulation. At high concentrations, this drug also has RAR activity, which may possibly be important for its efficacy, as the response rates showed a dose response.
Bexarotene has been shown to induce T-cell modulation and to increase the number of circulating CD8+ T cells among responders. Among 33 patients with MF and 4 with other lymphomas, 32 had high CD4:CD8 ratios at baseline. Following treatment with bexarotene at 150-300 mg/m2/d for 13 months (range: 4-18 months), a total of 26 patients showed normalization of CD8+ cell counts after 6.5 weeks (range: 3.5-12 weeks). The patients who responded to bexarotene therapy had higher numbers of CD8+ cells than those who did not (975 vs 221/mm3; P = .002) and lower CD4:CD8 ratios (0.8 vs 2.5; P = .005). In addition, a subsequent reduction in CD8+ cell count was associated with relapse. As an increase in CD8+ cells is a desirable outcome in the treatment of CTCL, this provides a rationale for the use of bexarotene in combination with a number of other agents.
Optimizing Therapy by Combination
In an effort to improve treatment efficacy and outcome with retinoids in CTCL, a combined-modality protocol was initiated in 1987 at the M.D. Anderson Cancer Center for patients with advanced, refractory MF, and was updated.[17,20,21] This was a multiphase therapy, beginning with treatment for 4 months with the retinoid oral isotretinoin at 1 mg/kg/d and IFNα at 3-5 MIU three times weekly (tiw). Patients with late-stage (IIB-IVB) disease were then given combined chemotherapy consisting of methotrexate, etoposide, and dexa-methasone for six courses over 6 months. They subsequently underwent electron-beam therapy (3,600 Gy) before entering a maintenance phase in which they received topical mustargen ointment as well as subcutaneous IFNα at 3-5 MIU tiw, for 1 to 2 years, as tolerated until relapse. A total of 91 patients were treated with the combined-modality therapy.
When outcomes were last assessed in 2003, 57 were still alive (62%), there were 24 deaths (26.4%), mostly in the patients at later disease stages, and 11 patients were lost to follow-up. The overall complete response rate was 57%, with a median duration of response of 20.8 months. Patients at all stages showed treatment responses, even patients with stage IVB disease achieved complete remissions. Furthermore, some patients at early disease stages have ongoing complete responses at ≥ 10 years.
This multiphase, combined-modality therapy is capable of achieving good response rates and even complete responses. It is generally well tolerated. The first regimen now includes bexarotene rather than isotretinoin in patients who do not have intrinsic hypertriglyceridemia. In addition, younger patients at later disease stages who are able to achieve a near-complete response following electron-beam therapy are now offered the option of allogeneic BMT, if there is a matched (preferably related) bone marrow or peripheral stem cell donor available. Patients who fail to reach complete response are treated either with experimental agents or a nucleoside analog such as gemcitabine for tumor stage  or deoxycoformycin for SS. Relapsed patients with advanced disease have also shown excellent responses to a combination of reduced doses of gemcitabine, liposomal doxorubicin (Doxil) and bortezomib (Velcade) in an ongoing phase I trial, although myelosuppression and infection are possible side effects.
Combining bexarotene with other biologic response agents or with phototherapy has been shown to increase its efficacy. Thus, in a study of bexarotene in 70 patients with CTCL at our center, 54 received bexarotene monotherapy and showed a response rate of 48%. Tightly controlling hyperlipidemia by adding the lipid-lowering agents fenofibrate and atorvastatin (Lipitor) to the treatment regimen was shown to increase the response rate to 70%, and four patients experienced complete responses lasting longer than 4 years. A total of 16 patients received combination therapy of bexarotene with photopheresis, IFNα, or PUVA, producing an overall response rate of 69% (Table 1).
Bexarotene binds to the RXR receptor; thus its efficacy might be enhanced by the addition of vitamin D, peroxisome proliferator-activated receptor (PPAR) agonists, or retinoids specific for the RAR. We have shown that bexarotene will induce T-cell apoptosis in vitro as a single agent  and demonstrated increased activity when bexarotene is combined with 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), a PPAR agonist. Another possible combined therapy would be with agents such as the histone deacetylase (HDAC) inhibitors that change levels of transcription factors including retinoid receptors at the level of the promoter.
An obvious combination of oral bexarotene with IFNα 2b was tested in a phase II, single-arm, multicentre study. A total of 22 patients with MF stages IB to IV were enrolled. Most of them had advanced disease, and all but one had failed prior therapy. Therapy was initiated with bexarotene at a dose of 300 mg/m2 for 8 weeks. Three patients showed a complete response to this therapy and were not given IFN. In those who did not show a complete response, IFNα 2b at 3 to 5 MIU tiw was added for another 8 weeks. From the 17 of the 22 patients who completed the trial, 6/17 had partial responses and 1 had a complete response, giving an overall response rate of 41%. The mean duration of response in these advanced-stage patients, however, was low at 2.7 months (range: 1-7.6 months).
On this combination of full doses of IFN and bexarotene, the side effects were more prevalent and the response rate was not different from that for either drug alone. Grade 3 or 4 toxicities recorded were high cholesterol and triglyceridemia in five patients, neutropenia in three, lymphopenia in two, and elevated aspartate aminotransferase in two; therefore, the trial was stopped early. A combination of lower doses of both IFN and bexarotene with photopheresis is widely used and effective in the treatment of patients with SS who have remaining CD8+ cells, and excellent response rates have been reported (see discussion below).
Dr. Duvic is principal investigator on clinical trials, an advisory board member and speaker for Ligand, Biocryst, Merck, Genmab, and Novartis.
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