A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Intralesional interferon in the treatment of early mycosis fungoides. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. Transfer factor therapy in mycosis fungoides: a double-blind study. A phase III, randomized, double-blind, placebo-controlled study of peldesine (BCX-34) cream as topical therapy for cutaneous T-cell lymphoma. Psoralen plus ultraviolet A +/- interferon-alpha treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-kappaB and T-cell receptor pathways. Recombinant interferon alfa-2b in plaque-phase mycosis fungoides. Intralesional and low-dose intramuscular therapy. A randomized cross-over study to compare PUVA and extracorporeal photopheresis in the treatment of plaque stage (T2) mycosis fungoides. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Imiquimod 5% cream in the treatment of mycosis fungoides--a pilot study.
Mycosis fungoides is a T-cell lymphoma that arises in the skin and progresses at highly variable rates. Nonradomized studies have suggested that early aggressive therapy may improve the prognosis in this usually fatal disease. We studied 103 patients with mycosis fungoides, who, after complete staging, were randomly assigned to receive either combination therapy, consisting of 3000 cGy of electron-beam radiation to the skin combined with parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or sequential topical treatment (n = 51). The prognostic factors were well balanced in the two groups. Combined therapy produced considerable toxicity: 12 patients required hospitalization for fever and transient neutropenia, 5 had congestive heart failure, and 2 were later found to have acute nonlymphocytic leukemia. Patients receiving combined therapy had a significantly higher rate of complete response, documented by biopsy, than patients receiving conservative therapy (38 percent vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however, there was no significant difference between the treatment groups in disease-free or overall survival. We conclude that early aggressive therapy with radiation and chemotherapy does not improve the prognosis for patients with mycosis fungoides as compared with conservative treatment beginning with sequential topical therapies. Cutaneous T-cell lymphoma (CTCL) constitutes a malignant proliferative disease involving mostly CD4(+) T cells arising in the skin. Because of the lack of curative treatment options, interferons (IFN) have been introduced into the therapy of CTCL. Although effective even in advanced disease, response rates were about 50% and the duration of response was short. To improve the results of interferon monotherapy, combinations of IFN with oral photochemotherapy (PUVA) or retinoids were investigated in nonrandomized trials showing higher response rates. We have therefore conducted this prospective randomized multicenter trial to compare these two combination therapies, ie, IFN plus PUVA and IFN plus acitretin. IFN -2a was administered at 9 MU three times weekly subcutaneously in both groups, with lower increasing doses during the first week. Photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) 5x weekly during the first 4 weeks, 3x weekly from weeks 5 through 23, and 2x weekly from weeks 24 through 48, with escalating doses beginning with 0.25 J/cm2. Twenty-five milligrams of acitretin was administered daily during the first week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients were evaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretin group. With 70% complete remissions in the IFN+PUVA group, this treatment was significantly superior to the IFN+acitretin group with only 38.1% complete remissions. Time to response was significantly shorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild to moderate and did not differ significantly in both treatment groups. However, there were more adverse events leading to study discontinuation in the IFN+acitretin group. Based on these findings, we conclude that IFN plus oral photochemotherapy is superior to IFN plus acitretin, inducing more complete remissions in patients with CTCL stages I and II. Twelve patients with early mycosis fungoides were enrolled in a randomized, double-blind, placebo-controlled study. Isolated plaques were injected three times a week with recombinant alpha 2-interferon in nine patients and with the vehicle in three patients. Two additional plaques were evaluated in each patient; one was left untreated, and another was treated topically with either placebo ointment or betamethasone ointment. Biopsies were taken from an untreated, representative plaque prior to treatment and from all test sites following treatment for light microscopy and T lymphocyte subsets. Three of the nine lesions injected with interferon cleared, and all showed improvement. Thirteen of eighteen noninjected lesions improved in patients who received interferon, showing a systemic effect. In the control group, none of the injected lesions improved and only two of the noninjected lesions showed any change. Histopathologic changes confirmed the clinical impression. This study shows that intralesional interferon may be given safely and has a beneficial effect, both locally and systemically. The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.
                Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.
                Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.
                Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions. Sixteen patients with mycosis fungoides (MF) were given either active transfer factor (TF) or heat-inactivated TF as additional therapy to topical nitrogen mustard or PUVA. The TF was prepared from non-selected healthy blood donors. The clinical evaluation after 2 years of therapy showed that among 8 patients treated with active TF, none went into complete remission of their disease 4 patients had partial remission, one was unchanged, 2 progressed, and one died of active MF. In the placebo-treated group, 5 patients achieved complete remission and 2 partial remission. One patient died early in the trial due to cardiac disease. Immunological studies during the first year of therapy revealed cutaneous anergy towards tuberculin in most patients. This anergy did not change during TF therapy and differed from normal lymphocyte reactivity in vitro after tuberculin stimulation. At the start of treatment the patients had diminished levels of T lymphocytes in peripheral blood. A temporary increase was observed in the total number of T lymphocytes in patients after one month of treatment with active TF. After one year the T lymphopenia had disappeared in both groups. The mitogen reactivity of lymphocytes was found to be normal (PHA, PWM) or somewhat reduced (Con A). It is concluded that under the conditions employed in this trial, TF was not able to prevent progression of early mycosis fungoides, when viewed over a period of 2 years. The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor.
                We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL).
                Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques.
                Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677).
                Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL. Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment.
                To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients.
                The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment.
                Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma.
                Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment. A two-part clinical trial was conducted to determine the therapeutic efficacy of recombinant interferon alfa-2b in plaque-phase mycosis fungoides. In an initial randomized double-blind study, each of six patients had two representative plaques injected intralesionally with 1 X 10(6) U of recombinant interferon alfa-2b per site and two control plaques injected with placebo three times weekly for four consecutive weeks. Complete clinical regression of disease was observed at ten of 12 recombinant interferon alfa-2b sites compared with one of 12 placebo-treated sites four weeks after treatment with injections was stopped. Subsequently, in an open-labeled study, five of these patients were treated intramuscularly with 5 X 10(6) U of recombinant interferon alfa-2b three times weekly for four weeks and two patients were treated with a second, more extended course of therapy lasting 12 to 16 weeks. Three of the five patients treated systemically showed some improvement overall, but the responses were judged not to be clinically significant. The differential response observed from intralesional and intramuscular injections may be related to differences in concentration of recombinant interferon alfa-2b achieved in lesional skin by the two methods of administration. PUVA is a well-established and effective treatment for plaque stage mycosis fungoides (MF) but its use is limited on a long-term basis because of the risk of cutaneous carcinogenesis. A further disadvantage is that nonexposed areas (sanctuary sites) often develop persistent disease. Therefore it is important to find alternative methods of treatment. Extracorporeal photopheresis (ECP) is a form of photochemotherapy that involves exposure of white blood cells to UVA with psoralens and can be effective in Sézary syndrome and erythrodermic cutaneous T-cell lymphoma. The aim of this study was to compare the efficacy of PUVA and ECP in the treatment of patients with T2 plaque stage (Stage 1B) MF who had a detectable peripheral blood T-cell clone. The study was of a cross-over design. Sixteen patients were randomized to receive either PUVA twice weekly for 3 months followed by ECP once monthly for 6 months at relapse, or vice-versa. Response was assessed by monthly skin scores and peripheral blood T-cell clonality. Ten patients received PUVA initially and six ECP initially. Eight patients completed the study. Skin scores taken at the completion of each treatment arm in patients who completed the study were 113 units better (confidence interval, 42-184 units) following 3 months PUVA than 6 months ECP (P = 0.002). Peripheral blood T-cell clones were detectable in all patients post-treatment. This study indicates that ECP is not effective in the treatment of plaque stage (1B/T2) MF even in patients with molecular evidence of a peripheral blood T-cell clone. Although PUVA was more effective than ECP, neither treatment modality cleared malignant T-cells from the peripheral blood. Hypericin is a known photodynamic agent that has been demonstrated to induce apoptosis in normal and malignant B and T lymphocytes, and has potential to treat benign and malignant disorders of the skin, including psoriasis and cutaneous T-cell lymphoma.
                We wished to test whether topical hypericin was an effective, safe, and well-tolerated therapy for patch or plaque phase mycosis fungoides and for plaque psoriasis.
                We conducted a phase II placebo-controlled clinical study in patients who had either patch or plaque phase mycosis fungoides or plaque type psoriasis vulgaris. Representative lesions were treated twice weekly for 6 weeks with topically applied hypericin or placebo followed 24 hours later by exposure to visible light at 8 to 20 J/cm(2).
                After 6 weeks of twice-weekly therapy, several concentrations of hypericin resulted in the significant improvement of treated skin lesions among the majority of patients with cutaneous T-cell lymphoma and psoriasis whereas the placebo vehicle was ineffective.
                The clinical trial involved a small number of patients.
                Overall, the data from this study support the conclusion that topical hypericin/visible light photodynamic therapy is an effective and well-tolerated alternative to standard psoralen plus ultraviolet A treatment of these disorders.
                Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved. To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif).
                The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998.
                Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers.
                Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies).
                Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer.
                Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes.
                Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day.
                Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication. nan
This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.