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The prognosis and treatment for mycosis fungoides has dramatically improved over the last several years. New immunotherapies and directed chemotherapeutic agents enable oncologists to treat and sometimes cure a difficult cancer.



Circulating T-Cells
Second malignancies
Staging Systems


Electron Beam therapy
Extracorporeal Phototherapy
Immunomodulatory Agents
Retinoic Acid Receptor
Stem cell transplantation

Commonly Used Terms  

POOR PROGNOSTIC FACTORS Ann Intern Med 1988;109:372-382

Peripheral eosinophilia
Cutaneous tumors
Peripheral blood involvement
Lymph node or visceral involvement

Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.

Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT.

Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Arch Dermatol. 2003 Jul;139(7):857-66 Abstract quote

OBJECTIVES: To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sezary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression.

DESIGN: A single-center, retrospective cohort analysis.

SETTING: Academic referral center for cutaneous lymphoma.

PATIENTS: Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999.

MAIN OUTCOME MEASURES: We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations. RESULTS: The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected.

CONCLUSIONS: Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.


Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy.

Ferenczi K, Yawalkar N, Jones D, Kupper TS.

Harvard Skin Disease Research Center, Boston, MA 02115, USA.


Arch Dermatol. 2003 Jul;139(7):909-13 Abstract quote

BACKGROUND: The prognosis of patients with stage IV cutaneous T-cell lymphoma (CTCL) is grim and therapeutic options are limited. Treatment of advanced-stage CTCL is aimed at suppressing the dominant T-cell clone, which is typically present in the skin, peripheral blood, and lymph nodes.

OBSERVATIONS: We detected the expansion of 1 T-cell clone expressing the T-cell receptor V beta 14 in the peripheral blood of a patient with stage IVA CTCL. Before initiation of combination therapy with photopheresis and low-dose interferon alpha, the dominant T-cell clone represented 84% of the total T-cell population. After successful therapy, this clone showed a dramatic decrease to 6% of the T-cell population after 6 months of treatment. This reduction in the percentage of the malignant T-cell population in response to therapy was paralleled by clinical skin improvement from initial generalized erythroderma to undetectable skin disease.

CONCLUSIONS: This case demonstrates that response to combination treatment with photopheresis and low-dose interferon alpha in patients with advanced CTCL may be accurately and quantitatively followed up by monitoring the percentage of the malignant T-cell clone (when identifiable) within the total circulating T-cell population by flow cytometry.


Prognostic Value of Blood Eosinophilia in Primary Cutaneous T-Cell Lymphomas

Emmanuelle Tancrède-Bohin, etal.

Arch Dermatol 2004;140:1057-1061. Abstract quote

Objective  To investigate the prognostic value of initial characteristics including blood eosinophilia in patients with primary cutaneous T-cell lymphoma.

Design  A retrospective inception cohort, patients included from date of diagnosis (1982-1998).

Setting  Two dermatology departments of a university hospital.

Patients  A total of 104 patients with cutaneous T-cell lymphoma, including patients with mycosis fungoides (n = 69), Sézary syndrome (n = 13), and nonepidermotropic cutaneous lymphoma (n = 22). The following variables were recorded: age, sex, diagnosis according to the European Organization for Research and Treatment of Cancer (EORTC) classification, type of skin involvement at the time of diagnosis, initial eosinophil absolute count, lactate dehydrogenase value, date of disease progression, and cause and date of death or date of last contact.

Main Outcome Measures  Time from diagnosis to disease progression and to disease-specific death.

Results  The median follow-up was 43 months (range, 7-197 months). Estimated rates of disease progression and disease-specific death for 3 years were 19.5% (95% confidence interval [CI],11.3%-27.6%) and 9.9% (95% CI, 2.8%-13.6%), respectively. Univariable analysis of initial variables possibly influencing disease progression revealed significant prognostic value for diagnosis according to EORTC classification (hazard ratio [HR], 2.77; 95% CI, 1.04-7.41; P = .04), type of skin involvement (HR, 2.70; 95% CI, 1.00-7.25; P = .04), raised blood eosinophil absolute count (HR, 7.33; 95% CI, 2.84-18.91; P<.001), and raised serum level of lactate dehydrogenase (HR, 3.72; 95% CI, 1.58-8.78; P = .001).Concerning disease-specific death, significant prognostic indicators were diagnosis according to the EORTC classification (HR, 6.62; 95% CI, 1.68-26.12; P = .007) and a raised blood eosinophil absolute count (HR, 10.57; 95% CI, 2.28-49.0; P<.001). In multivariable analysis, only blood eosinophilia was associated with disease progression and disease-specific death.

Conclusion  These results strongly suggest that blood eosinophilia at baseline is a prognostic factor in patients with primary cutaneous T-cell lymphoma


IL-15 and IL-16 overexpression in cutaneous T-cell lymphomas: stage-dependent increase in mycosis fungoides progression.

Asadullah K, Haeussler-Quade A, Gellrich S, Hanneken S, Hansen-Hagge TE, Docke WD, Volk HD, Sterry W.

Department of Dermatology, University Hospital, Charite, Berlin Humboldt University, Germany.

Exp Dermatol 2000 Aug;9(4):248-51 Abstract quote

Cytokines are of major importance for the pathogenesis of cutaneous T-cell lymphomas (CTCL). Recent data suggested that IL-15 and IL-16 are survival/growth factors for the malignant T cells in these entities.

To investigate the expression of IL-15 and IL-16 in mycosis fungoides (MF) and CD30+ pleomorphic T-cell lymphoma in vivo, we established a competitive RT-PCR technique. Analyzing skin biopsies from CTCL patients at different stages in comparison to psoriatic and healthy skin, we found IL-15 and IL-16 mRNA overexpression in both CTCL entities. Remarkably, there was some evidence for a stage-dependent increase during MF progression. We found only slight overexpression in early stage MF, when only few tumor cells are detectable within the infiltrates, whereas marked overexpression was found in more advanced lesions, which are characterized by a higher density of malignant cells.

These results suggested that CTCL cells themselves might produce the cytokines. To further elucidate this hypothesis, two CTCL cell lines were analyzed but gave conflicting results. Therefore, the cellular origin of the IL-15 and IL-16 overexpression in CTCL remains unclear. Considering the significant overexpression of IL-15 and IL-16 and their biological capacities it is likely that these cytokines contribute to the tumor development. So, they might be involved in growth and skin homing of CTCL cells.


Risk of second malignancy after cutaneous T-cell lymphoma.

Kantor AF, Curtis RE, Vonderheid EC, van Scott EJ, Fraumeni JF Jr.

Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland.

Cancer 1989 Apr 15;63(8):1612-5 Abstract quote

Risk of second primary malignancy was assessed in a population-based follow-up survey of all persons who developed cutaneous T-cell lymphoma (CTCL) in nine geographic areas of the United States covered by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute during the period 1973 to 1983.

Among 544 patients with a first primary tumor reported as CTCL, a second cancer developed in 35 (6%), yielding a significantly elevated relative risk (RR) of 1.7, which reflects excesses for cancers of the lung and colon and non-Hodgkin's lymphoma.

Although the excess of lymphoma may be related to the evolution of CTCL to less differentiated T-cell lymphoma, additional studies are needed to clarify the immunologic, genetic, viral, and environmental factors that may contribute to the development of second cancers.


Lymph node grading for staging of mycosis fungoides may benefit from examination of multiple excised lymph nodes.

Breneman DL, Raju US, Breneman JC, Steele PE, McFadden DW, Cualing HD, Nussbaum MS, Swerdlow SH.

Department of Dermatology, University of Cincinnati Medical Center, Ohio 45267-0523, USA

J Am Acad Dermatol 2003 May;48(5):702-6 Abstract quote

BACKGROUND: Lymph node (LN) histopathologic class has been shown to be a significant determinant of survival in patients with mycosis fungoides. Often, histopathologic evaluation of just 1 node is used in staging patients with cutaneous T-cell lymphoma.

OBJECTIVE: We examined whether sampling multiple nodes alters the staging and prognostic group placement of patients with mycosis fungoides as compared with sampling just 1 node.

METHODS: Multiple LNs were obtained from a single, local region for histopathologic evaluation and grading in 8 patients with mycosis fungoides.

RESULTS: Differences in histopathologic grading using multiple nodes were found in 5 of 8 patients. There was a potential upstaging of the assigned disease stage, compared with the stage that might have been assigned had just 1 node been sampled, in 3 patients. The differences in LN grading also potentially led to differences in prognostic group placement in 4 patients.

CONCLUSION: Determining histopathologic grades from multiple LNs may allow a more accurate stage and prognosis to be assigned to patients.

A modified staging classification for cutaneous T-cell lymphoma

Mohammed Kashani-Sabet, MD
Alex McMillan, PhD
Herschel S. Zackheim, MD

San Francisco, California

J Am Acad Dermatol 2001;45:700-6 Abstract quote

Background: Despite refinements in the diagnosis of cutaneous T-cell lymphoma (CTCL), since 1979 there have been no changes to the staging of CTCL used to classify mycosis fungoides and Sézary syndrome.

Objective: We reviewed the current staging of CTCL and examined the usefulness of a new staging scheme for mycosis fungoides and Sézary syndrome. Methods: We determined overall survival of 450 patients with mycosis fungoides and Sézary syndrome using the current and modified staging classifications.

Results: There were no significant differences between survival of patients with stage IB (patches/plaques involving greater than 10% body surface area) and IIA (peripheral adenopathy) disease and of patients with stage IIB (tumor) and III (erythroderma) disease. There was a significant difference in survival between patients with extensive patch versus extensive plaque stage disease. Modification of the current classification by splitting T2 into patch versus plaque stage disease and incorporating tumors and erythroderma into stage III proved superior to the current scheme in predicting overall survival.

Conclusion: Modification of the current staging classification for CTCL yields subgroups useful in the prognostic assessment of CTCL.

Quantifying Skin Disease Burden in Mycosis Fungoides–Type Cutaneous T-Cell Lymphomas The Severity-Weighted Assessment Tool (SWAT)

Seth R. Stevens, MD; Malcolm S. Ke, MD; Eileen J. Parry, MD; Julie Mark, MD; Kevin D. Cooper, MD

Arch Dermatol. 2002;138:42-48 Abstract quote

To develop a quantitative tool to assess severity of mycosis fungoides.

Prospective analysis of a cohort.

University department of dermatology–based cutaneous lymphoma clinic.

From 1984 to 1995, 1186 visits from 323 referred patients seen in a multidisciplinary cutaneous lymphoma program.

Main Outcome Measures
Severity-weighted assessment tool (SWAT) scores were obtained for patients at each visit. This score represents the product of the percentage total body surface area (%TBSA) involvement of each lesion type (patch, plaque, and tumor or ulceration), multiplied by a weighting factor: SWAT = (patch %TBSA 1) + (plaque %TBSA 2) + (tumor or ulcer %TBSA 3). In addition, the standard measurements of TBSA involvement and physician global assessments were recorded for comparison.

The SWAT score correlated well with %TBSA (r = 0.95, P<.001), physician global assessment (r = 0.60, P<.001), and time to complete remission during psoralen–UV-A therapy (r = 0.80, P<.001), therefore indicating validity against standard measures. Analysis of individual and subsets of patients demonstrated that the SWAT score more accurately quantified changes in skin disease burden, including mixed responses to treatment, than did %TBSA alone.

The SWAT score is a useful clinical measurement for mycosis fungoides. The SWAT score captures overall physician impressions of disease status on a continuous dimensionless numerical scale, therefore providing a defined, objective, and sensitive quantitative measure. This tool is suitable for individual patient assessment, clinical trials, and outcome comparisons.


Arch Dermatol 1996;132:1309-13

Progression to a more advanced stage has been reported to occur in about 10% of patients with a stage Ia CTCL

GENERAL PRINCIPLES In general, the therapy should match the stage of the disease
Skin-directed +/- biological response modifiers
Biological response modifiers, Skin directed with BRM, Chemo
Skin directed>skin directed + BRM, Chemo
BRM, chemo
Lymph node
RT, chemo

Low-dose methotrexate to treat mycosis fungoides: A retrospective study in 69 patients.

Zackheim HS, Kashani-Sabet M, McMillan A.
J Am Acad Dermatol. 2003 Nov;49(5):873-8. Abstract quote  

BACKGROUND: Although low-dose methotrexate has been used to treat mycosis fungoides for many years, documentation is very limited.

OBJECTIVE: Our purpose was to review our experience with methotrexate in the treatment of 69 patients with patch/plaque and tumor stage mycosis fungoides observed for up to 201 months.

METHODS: This was a retrospective study. Data are presented in terms of response rates and time to treatment failure.

RESULTS: The greatest number of patients (60) had patch/plaque stage T2 disease (>/=10% skin involved). Of these, 7 (12%) achieved complete remission and 13 (22%) achieved partial remission for a total response rate of 20 of 60 (33%). The median time to treatment failure was 15 months. Only 1 of 7 patients with tumor stage disease responded. Side effects caused treatment failure in 6 (9%) of the total cohort of 69 patients.

CONCLUSION: Low-dose methotrexate may be of value in the treatment of a subset of patients with patch/plaque mycosis fungoides resistant to other therapies.
Nitrogen mustard

Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: Results of the phase III clinical trial.

Heald P, Mehlmauer M, Martin AG, Crowley CA, Yocum RC, Reich SD.
J Am Acad Dermatol. 2003 Nov;49(5):801-15. Abstract quote  

OBJECTIVES: We sought to determine the safety and efficacy of topical bexarotene (Targretin; Ligand Pharmaceuticals, La Jolla, Calif) gel 1% in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.

METHODS: We conducted a multinational, open-label, phase III study of 50 patients with stage IA to IIA cutaneous T-cell lymphoma. The primary end point classification was the overall complete and partial response rate by the higher of 2 measures: the Physician's Global Assessment of Clinical Condition or the Composite Assessment of Index Lesion Disease Severity.

RESULTS: The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The most common adverse events possibly related to study medication were mild to moderate irritant dermatitis, pruritus, pain (ie, primarily burning at application site), and skin disorder (eg, skin inflammation, excoriation, and new lesions). There were no serious treatment-related adverse events.

CONCLUSIONS: Topical bexarotene gel was generally well tolerated and demonstrated substantial efficacy in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.

Phase 1/2 pilot study of methotrexate-laurocapram topical gel for the treatment of patients with early-stage mycosis fungoides.

Demierre MF, Vachon L, Ho V, Sutton L, Cato A, Leyland-Jones B.

Skin Oncology Program, Boston Medical Center, Boston, Mass.


Arch Dermatol 2003 May;139(5):624-8 Abstract quote

Objectives To assess the safety and tolerability of a topical gel formulation combining methotrexate and laurocapram and to obtain preliminary information on the therapeutic potential of methotrexate-laurocapram in patients with early-stage mycosis fungoides (stage IA or IB).

DESIGN: An open-label, phase 1/2 pilot study.

SETTING: Two academic referral centers.Patients Ten patients 18 years or older with histologically confirmed stage IA or IB mycosis fungoides.Intervention The gel formulation of methotrexate-laurocapram was applied to the total body surface, excluding genital, perianal areas, nipples, face, and skin under the breasts, on an every-other-day basis for 24 consecutive weeks.

MAIN OUTCOME MEASURES: The safety of methotrexate-laurocapram was assessed in this study by reviewing adverse events and laboratory data. Efficacy outcomes included changes in lesion condition and severity assessments, reduction in area of sample lesions, and the investigator's global evaluation.

RESULTS: Adverse events consisted of skin reactions of mild severity. No clinically significant laboratory abnormalities were observed. Based on the investigator's global evaluation at the end of the treatment phase (week 24), 7 (78%) of 9 patients demonstrated a slight-to-moderate response to treatment with methotrexate-laurocapram. Statistical significance (P =.049) was reached for induration and pruritus, a trend (P =.10) was observed for erythema, and no change was found for scaling (P =.37).

CONCLUSIONS: These findings indicate that the topical administration of methotrexate-laurocapram is safe and in general well tolerated. This treatment may represent a new therapeutic potential for patients with mycosis fungoides.

Topical nitrogen mustard in the management of mycosis fungoides: update of the stanford experience.

Kim YH, Martinez G, Varghese A, Hoppe RT.

Department of Dermatology, Stanford University School of Medicine, 900 Blake Wilbur Dr, No. W0069, Stanford, CA 94305.

Arch Dermatol 2003 Feb;139(2):165-73 Abstract quote

OBJECTIVE: To evaluate and update the response and survival outcomes and toxic effects in patients treated with topical nitrogen mustard (mechlorethamine hydrochloride) as primary therapy.

DESIGN: A single-center, retrospective cohort analysis.

SETTING: Academic referral center for cutaneous lymphoma.

PATIENTS: A total of 203 patients with mycosis fungoides (clinical stages I-III) treated with topical nitrogen mustard as initial therapy.

MAIN OUTCOME MEASURES: Long-term actuarial survival, freedom-from-relapse, and freedom-from-progression results as calculated by the Kaplan-Meier method.

RESULTS: The overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve complete response was 12 months (T1, 10 months; T2, 19 months), and the median time to relapse was 12 months. The duration of complete response increased with longer maintenance therapy; however, after completion of therapy, the response duration or relapse rate was similar regardless of maintenance regimen. Patients with T1 disease had better response and survival outcomes than those with T2 disease, with overall and complete response rates in T1 of 93% and 65%, respectively, and in T2, 72% and 34%, respectively. A similar clinical response was seen for patients with stage IIA vs IB. Sixty-eight percent of 203 patients received only topical nitrogen mustard therapy throughout their follow-up course, including most of the patients who achieved an initial complete response. The clinical response to topical nitrogen mustard as salvage therapy was similar to initial response rates. The efficacy results were similar in patients treated with aqueous vs ointment preparations. Freedom-from-progression rates in T1 disease (no progression to higher T classification or worse clinical stage) at 5 and 10 years were 92% and 85%, respectively, and in T2, 83% at 5 and 10 years. Fewer than 10% of patients experienced contact hypersensitivity reactions when topical nitrogen mustard was used as an ointment preparation. Only 8 patients (4%) developed secondary cutaneous malignancy, none attributable to topical nitrogen mustard monotherapy. Pediatric patients experienced no significant toxic effects with topical nitrogen mustard therapy.

CONCLUSIONS: Topical nitrogen mustard remains an effective primary initial or salvage therapy in mycosis fungoides for patients with T1 and T2 disease. Long-term follow-up results confirm its safety.


Oral bexaortene
Extracorporeal photochemotherapy

Ontak fusion protein (Combines cell destructive portion of diptheria toxin with IL-2)
Retinoid therapy
Anti-viral (IFN and AZT)

A phase III, randomized, double-blind, placebo-controlled study of peldesine (BCX-34) cream as topical therapy for cutaneous T-cell lymphoma

Madeleine Duvic, etal.

J Am Acad Dermatol 2001;44:940-7 Abstract quote

Background: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor.

Objective: 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).

Methods: 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 (50%) clearing of patches and plaques.

Results: 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).

Conclusion: 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.

Phase 2 and 3 Clinical Trial of Oral Bexarotene (Targretin Capsules) for the Treatment of Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma

Madeleine Duvic, etal.

Arch Dermatol. 2001;137:581-593 Abstract quote

For the Worldwide Bexarotene Study Group

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/m2 per day (with crossover for progression) vs 650 mg/m2 per day (later modified to 300 mg/m2 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.

Main Outcome Measures
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 (50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m2 per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m2 per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m2 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/m2 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/m2 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/m2 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/m2 per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.

Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.

Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter-Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J.

Duke University Medical Center, Durham, NC 27710, USA.

J Clin Oncol 2001 Jan 15;19(2):376-88 Abstract quote

PURPOSE: 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 AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Phase 1 and 2 Trial of Bexarotene Gel for Skin-Directed Treatment of Patients With Cutaneous T-Cell Lymphoma

Debra Breneman, PhD; Madeleine Duvic, MD; Timothy Kuzel, MD; Richard Yocum, MD; Joseph Truglia, MD; Victor J. Stevens, MD

Arch Dermatol. 2002;138:325-332 Abstract quote

To evaluate the safety, dose tolerance, and efficacy of topical bexarotene gel in patients with early-stage cutaneous T-cell lymphoma (CTCL).

Phase 1 and 2, open-label, dose-escalation clinical trial of bexarotene gel.

Three university-based clinics.

Sixty-seven adults with early-stage (TNM stages IA-IIA) CTCL.

Bexarotene gel, 0.1%, 0.5%, and 1.0%, applied in incremental dose adjustments from 0.1% gel every day to 1.0% gel 4 times daily or the maximal tolerated dose.

Main Outcome Measures
Patients were followed for efficacy and safety, and treatment continued as long as they benefited. Response (50% improvement) was evaluated by the Physician's Global Assessment of cutaneous disease and by an overall severity assessment of cutaneous disease, including signs of CTCL and area involved.

Most patients tolerated topical bexarotene at 1% gel twice daily for routine use. Adverse events were generally mild to moderate in severity and were confined to treatment sites. Treatment-limiting toxic effects were associated with skin irritation and increased with gel exposure. Patients achieved an overall response rate of 63% and a clinical complete response rate of 21%. Median projected time to onset of response was 20.1 weeks (range, 4.0-86.0 weeks), and the estimated median response duration from the start of therapy was 99 weeks. Patients with no previous therapy for mycosis fungoides responded at a higher rate (75%) than those who previously underwent topical therapies (67%).

Bexarotene gel was well tolerated, was easily self-applied, and had a substantial response rate in treating patients with early-stage CTCL.

Optimizing bexarotene therapy for cutaneous T-cell lymphoma.

Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M.

Division of Internal Medicine, Department of Dermatology, The University of Texas M. D. Anderson Cancer Center.


J Am Acad Dermatol 2002 Nov;47(5):672-84 Abstract quote

BACKGROUND: Bexarotene (Targretin oral capsules), the first RXR-selective retinoid "rexinoid" approved for all stages of cutaneous T-cell lymphoma (CTCL), had a response rate (RR) of 45% at the optimal dose of 300 mg/m(2) per day in 2 multicenter trials. With hypertriglyceridemia reported at 79%, bexarotene is often administered with lipid-lowering agents (LLAs). Statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) may modulate class II major histocompatibility class expression and T-cell responses.

OBJECTIVE: We attempted to optimize the clinical response to bexarotene by controlling dose-limiting hypertriglyceridemia and combining bexarotene with other active agents.

METHODS: We prospectively evaluated 70 patients with CTCL at M. D. Anderson Cancer Center who were treated with oral bexarotene as monotherapy or in combination with other active agents.

RESULTS: Fifty-four patients receiving bexarotene monotherapy achieved an overall RR of 48%. Thirteen had stage IA-IIA disease (RR = 53%, 1 complete response [CR]); 41 had stage IIB-IVB disease (RR = 46%, 2 CRs). Forty-two (77%) of these also required one or more LLAs: atorvastatin (n = 29, RR 43%), atorvastatin plus fenofibrate (n = 10, RR 90%), or gemfibrozil (n = 3, RR 33%). Gemfibrozil was discontinued because it increased bexarotene and triglyceride levels. Patients taking 2 LLAs had a significantly higher RR of 90% during monotherapy than those taking one or no LLAs (P <.0001). Forty of 54 patients (74%) received thyroid hormone replacement to normalize thyroxine levels. Four patients receiving monotherapy have complete CRs of >3 years' duration and received maintenance dosing. Sixteen patients with advanced disease treated with bexarotene (225-750 mg/d) in combination with other CTCL therapies achieved an overall RR of 69% (11/16) with concomitant statin therapy. Bexarotene was safely combined with psoralen ultraviolet A (PUVA) plus interferon alfa (IFN-alpha) (n = 2, RR = 50%), with extracorporeal photopheresis (ECP) (n = 8, RR = 75%, 1 CR), with ECP/IFN-alpha (n = 4, RR =50%), with ECP/IFN-alpha/PUVA (n = 1, RR = 100%), and with IFN-alpha/PUVA/topical nitrogen mustard (n = 1, RR = 100%). Two patients receiving IFN-alpha had slight leukopenia, but rhabdomyolysis associated with multiple LLAs did not occur.

CONCLUSION: This single-center study supports the safety and efficacy of bexarotene as both a monotherapy and a combination therapy for CTCL. Long durable CRs may be achieved with oral monotherapy. Use of statins with bexarotene may also increase RRs by permitting higher doses to be administered without interruption, by modulating the immune response, or both. When bexarotene is combined with other active CTCL therapies, higher RRs were achieved in patients with advanced disease, without unacceptable side effects.

Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome.

Departments of Dermatology, Centre Hospitalier Universitaire, Nantes, France.


Arch Dermatol. 2008 Jun;144(6):727-33. Abstract quote

OBJECTIVE: To assess the rate of objective response to pegylated liposomal doxorubicin hydrochloride (Caelyx) in patients with advanced or refractory cutaneous T-cell lymphoma (CTCL).

DESIGN: Prospective, open, multicenter study.

SETTING: Thirteen dermatology departments in France.

PATIENTS: Twenty-five patients with either (1) stage II to stage IV CTCL previously unsuccessfully treated with at least 2 lines of treatments or (2) histologically transformed epidermotropic CTCL requiring chemotherapy.

INTERVENTION: Administration of Caelyx intravenously once every 4 weeks at a dose of 40 mg/m(2).

MAIN OUTCOME MEASURES: The response to treatment was evaluated by clinical evaluation.

RESULTS: At the end of treatment, we observed an objective response (primary end point) in 56% of the patients (14 of 25): 5 complete responses and 9 partial responses. The median overall survival time was 43.7 months. For the 14 patients who experienced an objective response, the median progression-free survival time after the end of treatment was 5 months.

CONCLUSIONS: This prospective study demonstrates the effectiveness of Caelyx in treating CTCL, with an overall response rate of 56% in spite of the high proportion of patients with advanced-stage disease. Responses were observed in 2 subpopulations of patients in which the prognosis is known to be poorer: Sézary syndrome (overall response rate, 60%) and transformed CTCL (overall response rate, 50%). Moreover, this study shows that dose escalation to 40 mg/m(2) does not seem to improve the effectiveness but increases toxic effects (especially hematologic toxic effects) compared with the dose previously tested of 20 mg/m(2).

Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma.

Duvic M, Apisarnthanarax N, Cohen DS, Smith TL, Ha CS, Kurzrock R.

Division of Internal Medicine, Department of Dermatology, University of Texas M. D. Anderson Cancer Center, Houston 77030-4095, USA.


J Am Acad Dermatol. 2003 Jul;49(1):35-49. Abstract quote

BACKGROUND: Although cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sezary syndrome, is often responsive to treatment, few current therapies increase survival or consistently induce durable remissions, especially in advanced disease.

OBJECTIVE: In an effort to improve treatment efficacy and outcome in CTCL, a combined modality protocol using 3 to 4 consecutive phases of therapy was initiated in 1987 at M.D. Anderson Cancer Center, Houston, Tex.

METHODS: During a period of 15 years between 1987 and 2001, 95 patients with early-stage (Ia-IIa, n = 50) and late-stage (IIb-IVb, n = 45) MF were treated with subcutaneous interferon-alpha and oral isotretinoin, followed by total-skin electron beam therapy, and long-term maintenance therapy with topical nitrogen mustard and interferon-alpha. Patients with late-stage (IIb-IVb) disease also received 6 cycles of combination chemotherapy before electron beam therapy.

RESULTS: Combined modality therapy yielded a response rate of 85% with a 60% complete response rate. Among 38 patients with early-stage disease and 18 patients with late-stage disease achieving complete response, 9 (24%) patients with early-stage MF and 3 (17%) patients with late-stage MF achieved sustained remissions lasting more than 5 years. The median disease-free survival (DFS) for early and late stages of disease was 62 and 7 months, with 5-year Kaplan-Meier estimated rates of 50% and 27%, respectively. Current median overall survival times on combined modality are 145 months for patients with early-stage disease and 36 months for those with late-stage disease. Death was attributable to CTCL disease in 17 (55%) of 31 cases. The Kaplan-Meier estimates for 5-year survival are 94% for early-stage and 35% for late-stage disease. Univariate survival analysis in this patient population reveals statistically significant associations of clinical stage with overall response rates (P =.02), DFS (P =.03), and overall survival (P <.0001); age with DFS (P =.001) and overall survival (P =.04); and T stage (P <.0001) and lactate dehydrogenase (P =.007) with overall survival. By multivariate analysis using a Cox proportional hazards model, only age was significantly associated with DFS (hazard ratio 2.9), and only stage with overall survival (hazard ratio 18.2).

CONCLUSION: This nonrandomized and uncontrolled CTCL study gives supportive evidence that this multiphased combined modality regimen is well tolerated and may yield higher response rates and DFS than total-skin electron beam therapy alone, but provides no evidence for a change in survival.

Extent of skin involvement as a prognostic indicator of disease free and overall survival of patients with T3 cutaneous T-cell lymphoma treated with total skin electron beam radiation therapy.

Quiros PA, Kacinski BM, Wilson LD.

Dpeartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Cancer 1996 May 1;77(9):1912-7 Abstract quote

BACKGROUND: The goal of this study was to define the prognostic significance of the extent of skin involvement (ESI) with respect to disease free survival (DFS) and overall survival (OS) of patients with T3 cutaneous T-cell lymphoma (CTCL) after total skin electron beam therapy (TSEBT).

METHODS: Between 1974 and 1993, TSEBT (36 Gray [Gy], 1 Gy/day for 9 weeks, 6 MeV electrons) was administered to a total of 213 patients. Forty-six of the 213 patients were classified as having T3 CTCL based on the presence of tumor nodules on the skin at diagnosis. Patient records were evaluated retrospectively, and the percentage of total skin surface involved was calculated. Patients were analyzed with respect to response to therapy, disease free and overall survival. The median follow-up was 37.5 months (range, 1.6-93 months).

RESULTS: Thirty-six of 46 patients achieved complete clinical response (CCR) by the completion of TSEBT. DFS was 12% at 36 months with approximately 28% OS. When stratified by extent of skin involvement, 100% of patients with 9% or less ESI were disease free at 18 months compared with patients with 10% or greater ESI, all of whom had relapsed by 18 months (78% achieved CCR). Fifty percent of those with 9% or less ESI remained disease free at 36 months; median DFS and OS were not reached at 63 and 65 months, respectively. The median DFS and OS for the 10% or greater ESI group were 4 and 24 months, respectively. These differences were statistically significant (P < or = 0.005). Toxicity of therapy was minimal.

CONCLUSIONS: The extent of skin involvement of patients with T3 CTCL is a prognostic indicator of disease free and overall survival for those who have been treated definitively with TSEBT.

Total skin electron radiation in the management of mycosis fungoides: Consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group.

Jones GW, Kacinski BM, Wilson LD, Willemze R, Spittle M, Hohenberg G, Handl-Zeller L, Trautinger F, Knobler R.

Department of Radiation Oncology, Cancer Care Ontario, Hamilton, Canada.

J Am Acad Dermatol 2002 Sep;47(3):364-70 Abstract quote

Radiotherapy has been successfully implemented in the treatment of mycosis fungoides (MF) for almost a century. With the development of the modern linear accelerator, it has become possible to treat extended areas of the skin with accelerated electrons. Total skin electron beam radiation (TSEB) has been in use for several decades, and a number of technical modifications have been made with the goals of optimizing dose distribution and improving clinical outcome. Emerging evidence from recent studies suggests an association between TSEB techniques and efficacy in the treatment of MF.

Based on this evidence, the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group, in association with experts from radiotherapy centers in North America, has reached a consensus on acceptable methods and clinical indications for TSEB in the treatment of MF.

The aims of this report are to enhance accessibility of this highly efficacious treatment modality to patients with MF and to provide a point of reference for further clinical research.


Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a single institution.

Gottlieb SL, Wolfe JT, Fox FE, DeNardo BJ, Macey WH, Bromley PG, Lessin SR, Rook AH.

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia 19104, USA. B

J Am Acad Dermatol 1996 Dec;35(6):946-57 Abstract quote

BACKGROUND: Extracorporeal photopheresis is a pheresis-based therapy that permits the direct targeting of psoralen-mediated photochemotherapy to circulating pathogenic T cells. Although photopheresis is currently used to treat cutaneous T-cell lymphoma (CTCL), limited data are available regarding overall response rates and durability of responses among patients with advanced disease. Furthermore, little is known about the effectiveness and tolerability of combined regimens employing other biologic response modifiers including interferon alfa.

OBJECTIVE: Our purpose was to determine the efficacy of photopheresis among 41 patients with the clinical and laboratory diagnosis of CTCL; the majority of patients had stage III or IV disease with the presence of circulating malignant T cells.

METHODS: A retrospective chart review during a 10-year period at a single university hospital was performed for all patients receiving either photopheresis monotherapy on two consecutive days every 4 weeks (one cycle) and for an additional 12 patients who also received interferon alfa 1.5 to 5 million U subcutaneously three to five times weekly.

RESULTS: Thirty-one of 41 patients (76%) were treated for six or more cycles. The remaining 10 were treated with less than six cycles because of rapidly progressing disease (n = 6), death unrelated to CTCL (n = 2), or withdrawal from treatment (n = 1); one of the 10 patients had only received five cycles of treatment but is still receiving therapy. Twenty-eight of the 31 patients treated for six or more cycles received photopheresis alone. Among the 28, seven patients (25%) had a complete remission, 13 (46%) had a partial remission defined as more than 50% clearing of skin disease, and eight (29%) did not respond to treatment. The presence of Sezary cells in the peripheral blood was associated with a favorable response. Median time to treatment failure was 18 months, whereas median survival from initiation of therapy was 77 months and from the time of diagnosis exceeded 100 months. Nine of these 28 patients went on to receive combination therapy with interferon alfa and, in some cases, other agents. Among these nine patients, five had an enhanced clinical response to the combination therapy compared with treatment with photopheresis monotherapy. The combined regimen was well tolerated.

CONCLUSION: These results indicate that patients with advanced CTCL can achieve a high response rate for an extended period with photopheresis and that interferon alfa combined with photopheresis is a well-tolerated regimen that appears to produce higher response rates than photopheresis alone.

Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous T-cell lymphoma: a 9-year retrospective study at a single institution.

Bisaccia E, Gonzalez J, Palangio M, Schwartz J, Klainer AS.

Departments of Dermatology and Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.

J Am Acad Dermatol 2000 Aug;43(2 Pt 1):263-71 Abstract quote

BACKGROUND: Extracorporeal photochemotherapy (ECP; photopheresis) is a treatment option for cutaneous T-cell lymphoma (CTCL).

OBJECTIVE: This study describes the outcomes obtained with ECP alone or with adjuvant therapy in treating CTCL.

METHODS: A 9-year retrospective study was performed at a single institution.

RESULTS: Among 69 patients, 37 were treated with 6 months or more of ECP alone over an average of 36.9 months. Of these patients, 68% (25/37) had stage T2, 5% (2/37) had stage T3, and 27% (10/37) had stage T4 CTCL. Complete response (no skin or systemic disease for 1 month or more) and partial response (50%-99% skin improvement for 1 month or more) were achieved by 14% (5/37) and 41% (15/37) of patients, respectively, giving an overall response rate of 54% (20/37). In recalcitrant patients, adjuvant therapy significantly increased the response rate from 31% (4/13) to 69% (9/13) (P = 0.004). ECP was well tolerated in the entire patient population.

CONCLUSION: Response rates in this study compared favorably with those in previous studies, underscoring the potential value of ECP in treating CTCL. To our knowledge, this investigation included the largest group of CTCL patients ever treated with ECP at a single institution.

Extracorporeal photochemotherapy (ECP) for early stage (Ia and Ib) CTCL

Br J Dermatol 2000;143:894-896

8 stage Ib patients were treated for 1 year with ECP alone and for at least 5 years thereafter with ECP as part of combined therapy

Patients received no treatment 6 months prior to the trial

After 5 years, 2 patients cleared and 4 had a partial response

No change in disease activity for remaining 2 patients

Small uncontrolled study suggests that ECP had no significant advantages over conventional therapies

Survival of patients with cutaneous T-cell lymphoma after treatment with extracorporeal photochemotherapy.

Wollina U, Liebold K, Kaatz M, Looks A, Stuhlert A, Lange D.

Department of Dermatology and Allergology, Friedrich Schiller University Jena, D-07740 Jena, Germany.

Oncol Rep 2000 Nov-Dec;7(6):1197-201 Abstract quote

Few studies have assessed the long-term outcome of patients with cutaneous T-cell lymphoma (CTCL) treated with extracorporeal photochemotherapy (ECP).

Our objective was to assess the efficacy, safety, and survival of a cohort of patients with refractory CTCL in stages Ib to III who were treated with ECP. A retrospective study was performed. Twenty patients (19 male, 1 female) aged 38 to 87 years with CTCL of the mycosis fungoides type (n=17) and primary cutaneous Ki-1 lymphoma (n=2) were treated twice a month. Sixteen had an adjunctive treatment with interferon alpha (IFN alpha) s.c. 3 times a week in the maximal tolerable dosage (i.e. up to 21x106).

A complete response was achieved in 10 patients, a partial response in three and a stable disease in seven patients (response rate 65.0%). The overall survival was 29.4+/-16.0 months, the event-free survival was 26.2+/-12.4 months, and the progression-free survival was 23. 4+/-12.2 months. Four patients died of causes unrelated to CTCL and two patient died of CTCL. Median survival time was 26 months. No severe side effects were noted. ECP is a safe alternative therapy for CTCL. In particular when combined with IFN alpha it can induce long-term remissions.

Treatment of stage II cutaneous T-cell lymphoma with interferon alfa-2a and extracorporeal photochemotherapy: A prospective controlled trial

J Am Acad Dermatol 2001;44:253-60 Abstract quote

Prospective controlled study was performed

Fourteen patients (all male) aged 38 to 72 years with CTCL of the mycosis fungoides type, stage IIa/IIb, and a 72-year-old male patient with a Ki-1 lymphoma

Treated twice a month for 6 months with extracorporeal photochemotherapy using oral 8-methoxypsoralen as photosensitizer in combination with interferon alfa-2a subcutaneously 3 times a week in the maximal tolerable dosage (ie, up to 18 × 106 U)

The effects were investigated by a skin score, staging, histologic score (density of the T-cell infiltrate; from 0 = absent to 3 = heavy), immunohistology, and laboratory investigations including total peripheral T-cell count, CD4/CD8 ratio, and soluble interleukin 2 receptor (sIL-2R)

Results: After 6 months:
Complete response (CR) in 4 patients
Partial response (PR) in 3
Stable disease (SD) in 7 of 14 patients (overall response rate [CR + PR] 50%)

In responders the time to best response was 4.3 ± 1.4 months
Skin score decreased from 22.5 ± 8.1 to 15.1 ± 11.0 (P < .001)
Histologic score decreased from 2.57 ± 0.51 to 1.21 ± 0.80 (P < .001)
Percentage of CD4 cells decreased from 75% to 51% (P = .038) and Ki-67-positive cells decreased from 6.7% to 2.4% (P = .001)

Total T-cell count/µL decreased from 1018.9 ± 557.1 to 667.9 ± 417.9 (P = .012), and the CD4/CD8 ratio also decreased from 1.88 ± 0.92 to 1.51 ± 0.67 (P = .038)
sIL-2R levels did not change significantly during the first 4 months of treatment

Among patients of stage IIa the response rate was 60% in contrast to only 25% of those in stage IIb

Side effects were seen temporarily, ranging from grade 0 to grade 3. There was no need for additional therapy, but interferon dose was decreased because of side effects

After 1 year of follow-up the total response rate was 46.2% (6 of 13 patients): 5 of 9 with stage IIa(55.6%) and 1 of 4 with stage IIb (25.0%).

Conclusion: These results indicate that patients with CTCL stage IIa can achieve a total response rate of 56% with combined interferon alfa-2a and extracorporeal photochemotherapy. Responders seem to experience their best response within the first 6 months of treatment. The treatment is well tolerated and does not cause severe side effects

Circulating CD4+CD7- Lymphocyte Burden and Rapidity of Response: Predictors of Outcome in the Treatment of Sezary Syndrome and Erythrodermic Mycosis Fungoides With Extracorporeal Photopheresis.

Stevens SR, Baron ED, Masten S, Cooper KD.

Department of Dermatology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106.

Arch Dermatol 2002 Oct;138(10):1347-50 Abstract quote

BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment for cutaneous T-cell lymphoma. Controversy has arisen regarding its ability to improve survival rates in Sezary syndrome (SS). We describe our experience with ECP in the treatment of SS and erythrodermic mycosis fungoides, with particular emphasis on early predictors of long-term outcome.

OBSERVATIONS: We included 17 patients (15 with SS and 2 with erythrodermic mycosis fungoides) who received ECP as initial treatment. Four of these patients were moribund on presentation (Eastern Cooperative Oncology Group Performance Status score, 4) and underwent only 1 to 2 cycles of ECP. The median survival was 56 months for the 11 patients with SS and an Eastern Cooperative Oncology Group Performance Status score of less than 4. If all 15 patients with SS are considered, median survival was 34 months. Response after 5 months of ECP correlated with long-term survival. A low number (<6.0 x10(3)/ micro L) of circulating CD4(+)CD7(-) lymphocytes correlated with response after 5 months of ECP.

CONCLUSIONS: Extracorporeal photopheresis is a safe, effective, and well-tolerated treatment for erythrodermic mycosis fungoides and SS. Low numbers of CD4(+)CD7(-) cells in the circulation and a positive response after 5 months of therapy predicted long-term survival. Moribund patients are much less likely to benefit from ECP.

A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides.

Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.

J Am Acad Dermatol. 2006 Nov;55(5):807-13. Abstract Quote

BACKGROUND: Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells.
OBJECTIVE: To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial.

METHODS: rhIL-12 was administered biweekly (100 ng/kg for 2 weeks; 300 ng/kg thereafter). A modified severity-weighted assessment tool (SWAT) and the longest diameter of 5 index lesions measured efficacy.

RESULTS: Twenty-three MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) had previously received >3 therapies. Ten of 23 patients (43%) achieved partial responses (PR); 7 (30%) achieved minor responses; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve (52%) ultimately progressed with mean time to progressive disease of 57 days (range, 28-805). Ten completed 6 months of therapy; 1 completed 24 months. Of patients not completing 6 months of therapy, 6 progressed and 6 others discontinued because of adverse events or withdrew consent. Seventeen patients had treatment-related adverse events that were generally mild or moderate in severity, including asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, elevated aspartate and alanine aminotransferase levels, anorexia, and sweating. One patient in PR died of hemolytic anemia, possibly exacerbated by rhIL-12 treatment.

LIMITATIONS: The original company was purchased during the conduct of the trial and rhIL-12 is currently unavailable. The quality of life data were not available for inclusion.

CONCLUSION: Twice-weekly subcutaneously administered rhIL-12 (100 ng/kg escalated to 300 ng/kg) showed antitumor activity with a response rate of 43% in refractory patients. It was relatively well-tolerated in early-stage MF.

Pilot study of etanercept in patients with relapsed cutaneous T-cell lymphomas.

Tsimberidou AM, Giles FJ, Duvic M, Kurzrock R.

Department of Leukemia, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.

J Am Acad Dermatol. 2004 Aug;51(2):200-4. Abstract quote  

BACKGROUND: Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL).

OBJECTIVE: To assess the toxicity, safety, and efficacy of etanercept (soluble TNF receptor) in patients with relapsed CTCL.

METHODS: Etanercept was administered twice weekly at a dose of 25 mg subcutaneously. Patients with improvement after two months could be continued on treatment.

RESULTS: Twelve out of the 13 patients enrolled on study were evaluable (Stage I-IIA, 3 patients; Stage IIB-IV disease, 9 patients). The median number of previous therapies was 7 (range, 3-12). Etanercept induced partial remission in one patient (8%) and minor response in one patient (8%), both of whom had Stage IB disease. Most patients experienced no side effects.

CONCLUSION: This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL. The effect of etanercept in a larger cohort of patients with early disease merits investigation.

Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution.

Suchin KR, Cucchiara AJ, Gottleib SL, Wolfe JT, DeNardo BJ, Macey WH, Bromley PG, Vittorio CC, Rook AH.

Department of Dermatology, Hospital of the University of Pennsylvania, 2 Rhoads Pavilion, 3600 Spruce St, Philadelphia, PA 19104-4283.

Arch Dermatol 2002 Aug;138(8):1054-60 Abstract quote

OBJECTIVE: To determine the efficacy of multimodality biologic response therapy for patients with cutaneous T-cell lymphoma (CTCL).

DESIGN: Retrospective cohort study over a 14-year period.

SETTING: Tertiary care university hospital.

PATIENTS: A consecutive sample of patients was studied, all 47 of whom carried the clinical and laboratory diagnosis of CTCL: 68% of patients had stage III or IV disease, and 89% had circulating malignant T cells.

INTERVENTIONS: All 47 patients received photopheresis for 6 or more cycles. Thirty-one patients received treatment with a combination of photopheresis and 1 or more systemic immunostimulatory agents, including interferon alfa, interferon gamma, sargramostim, or systemic retinoids for 3 or more months.

MAIN OUTCOME MEASURES: Differences in pretreatment prognostic factors, response rates, and survival between patients receiving multimodality therapy and single-modality therapy or historical controls.

RESULTS: A total of 79% of patients responded to therapy: 26% had complete remission, and 53% had a partial remission. Median survival from initiation of therapy was 74 months. Median survival for patients with stages III and IV and peripheral blood involvement was 55 months compared with 31 months for historical controls. Compared with the photopheresis monotherapy group, the patients receiving combination immunomodulatory therapy had a worse prognosis at the time of treatment initiation based on multiple prognostic factors. The positive response rates and median survival times were 84% and 74 months, respectively, compared with 75% and 66 months, respectively, for the combination immunomodulatory and photopheresis monotherapy groups (P =.47 for positive response rates and P =.51 for survival).

CONCLUSIONS: Patients with advanced CTCL and multiple poor prognostic factors who receive treatment with combination immunomodulatory therapy experience higher clinical response rates and longer survival than historical controls. Although the group who received combination therapy had worse prognostic factors at baseline, they had better response rates and overall survival compared with those receiving photopheresis monotherapy.

Novel multimodality biologic response modifier therapy, including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa cutaneous T-cell lymphoma.

Shapiro M, Rook AH, Lehrer MS, Junkins-Hopkins JM, French LE, Vittorio CC.

Departments of Dermatology, University of Pennsylvania, Philadelphia, and Geneva University Hospital.

J Am Acad Dermatol 2002 Dec;47(6):956-61

Psoralen Plus Long-Wave UV-A (PUVA) and Bexarotene Therapy: An Effective and Synergistic Combined Adjunct to Therapy for Patients With Advanced Cutaneous T-Cell Lymphoma.

McGinnis KS, Shapiro M, Vittorio CC, Rook AH, Junkins-Hopkins JM.

Department of Dermatology, University of Pennsylvania, Philadelphia.

Arch Dermatol. 2003 Jun;139(6):771-5 Abstract quote

BACKGROUND: Multimodality biological response-modifier therapy that includes photopheresis, interferon, and bexarotene is the standard of care in our institution for advanced cutaneous T-cell lymphoma with peripheral blood involvement. We added psoralen plus long-wave UV-A (PUVA) to this regimen in 5 patients with Sezary syndrome.

OBSERVATIONS: All patients responded with decreased Sezary counts, resolution of lymphadenopathy, and clearing of skin disease after the addition of PUVA. Adverse effects were well tolerated and managed via close clinical and laboratory follow-up.

CONCLUSIONS: The addition of PUVA to a multimodality immunomodulatory regimen in patients with Sezary syndrome can result in rapid and sustained remission of both skin and blood-borne disease. Further in vitro and in vivo studies are needed.

Narrowband UVB and psoralen-UVA in the treatment of early-stage mycosis fungoides: A retrospective study.

Diederen PV, Van Weelden H, Sanders CJ, Toonstra J, Van Vloten WA.

Department of Dermatology, University Medical Center Utrecht.


J Am Acad Dermatol 2003 Feb;48(2):215-9 Abstract quote

BACKGROUND: Treatment of early-stage mycosis fungoides (MF) consists of topical steroids, phototherapy (UVB), photochemotherapy (psoralen plus UVA [PUVA]), topical nitrogen mustard, or total skin electron-beam irradiation. It has been reported that the same effective UVB dose is safer than PUVA regarding carcinogenicity and produces fewer side effects. Narrowband UVB (311 nm) results in less irritation and erythema and is more effective compared with broadband UVB.

OBJECTIVE: Our purpose in this retrospective study was to analyze the response to treatment, relapse-free interval, and irradiation dose in 56 patients with early-stage MF (stage Ia and Ib). A total of 21 patients were treated with narrowband UVB (311 nm); 35 patients were treated with PUVA.

RESULTS: Narrowband UVB treatment led to complete remission in 17 of 21 patients (81%), partial remission in 4 of 21 (19%), and none showed progressive disease. PUVA treatment led to complete remission in 25 of 35 patients (71%), partial remission in 10 of 35 (29%), and none showed progressive disease. The mean relapse-free interval for patients treated with UVB was 24.5 months (range, 2-66 months) and for patients treated with PUVA, 22.8 months (range, 1-43 months).

CONCLUSION: Narrowband UVB therapy for patients with early-stage MF is an effective treatment modality. It has several advantages over treatment with broadband UVB and PUVA. When treating patients with early-stage MF it may be beneficial to start with narrowband UVB therapy and, if there is progression or no response, switch to PUVA therapy.

“High-dose” UVA1 therapy of widespread plaque-type, nodular, and erythrodermic mycosis fungoides

Cristina Zane, etal.

J Am Acad Dermatol 2001;44:629-633. Abstract quote

Background: UVA1 (340 to 400 nm) was found to be effective in the treatment of early-stage mycosis fungoides (MF).

Objective: The purpose of this study was to assess the efficacy of UVA1 phototherapy for widespread plaque-type, nodular, and erythrodermic MF.

Methods: Thirteen patients (8 with stage IB, 4 with IIB, and 1 with III MF) received 100 J/cm2 UVA1 daily until remission. Four patients also had lesions inaccessible by UVA1 that were considered control lesions. Immunocytologic studies of skin infiltrates and circulating T cells were done before and after the therapy.

Results: Eleven patients showed complete clinical and histologic responses. Two patients had a partial improvement. Unirradiated control lesions never improved. Serious short-term side effects were not recorded. Circulating CD4+/CD45RO+ and CD4+/CD95+ lymphocytes were significantly reduced by the therapy.

Conclusion: UVA1 therapy is an effective and well-tolerated treatment for advanced MF. The therapeutic relevance of the effects on circulating lymphocytes remains to be established because lesions in nonexposed cutaneous areas did not respond.

Narrowband UVB phototherapy for early-stage mycosis fungoides.

Gathers RC, Scherschun L, Malick F, Fivenson DP, Lim HW.

Department of Dermatology, Henry Ford Health System.

J Am Acad Dermatol 2002 Aug;47(2 Pt 1):191-7 Abstract quote

BACKGROUND: Narrowband UVB (NB-UVB) phototherapy has been shown to be effective for the treatment of various dermatoses.

OBJECTIVE: We evaluated the effect of NB-UVB in the treatment of early stage mycosis fungoides (MF).

METHODS: The response of 24 patients (12 stage IA, 12 stage IB) with patch stage MF to thrice weekly NB-UVB was assessed. Twelve patients had skin phototypes I-III, and 12 had types IV-VI. Seven patients had hypopigmented MF. Mean follow-up period was 29.0 weeks.

RESULTS: Thirteen patients (54.2%) had a complete response (CR), 7 (29.2%) had partial response (PR), and 4 (16.7%) had no response. Specimens from a repeat biopsy in 10 patients with CR showed histologic clearing in 9 of them. Upon discontinuation of treatment, 4 patients with CR relapsed, with a mean time to relapse of 12.5 weeks.

CONCLUSION: NB-UVB is a viable, comparably safe, and easily administered alternative in the management of early stage MF.

Bexarotene treatment of late-stage mycosis fungoides and Sezary syndrome: development of extracutaneous lymphoma in 6 patients.

Bouwhuis SA, Davis MD, el-Azhary RA, McEvoy MT, Gibson LE, Knudsen JM, Kist JM, Pittelkow MR.

Departments of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Am Acad Dermatol. 2005 Jun;52(6):991-6. Abstract quote  

Bexarotene is a retinoid drug that is approved for the treatment of cutaneous T-cell lymphoma.

We report 6 cases in which the initiation of bexarotene therapy for cutaneous T-cell lymphoma was temporally associated with the progression of internal disease despite improvement in cutaneous signs and symptoms.

It is possible that bexarotene contributed to this progression. Although bexarotene therapy may alleviate symptoms and signs of cutaneous T-cell lymphoma, careful surveillance of lymph nodes and solid organs during treatment is advised.

Comparison of selective retinoic acid receptor- and retinoic X receptor-mediated efficacy, tolerance, and survival in cutaneous t-cell lymphoma.

Querfeld C, Rosen ST, Guitart J, Rademaker A, Fung BB, Posten W, Kuzel TM.

Departments of Dermatology and Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, and Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University USA.
J Am Acad Dermatol. 2004 Jul;51(1 Pt 1):25-32. Abstract quote  

Primary cutaneous T-cell lymphomas are non-Hodgkin's lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sezary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy.

The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/Sezary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity.

In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.

Induction of complete remission of advanced stage mycosis fungoides by allogeneic hematopoietic stem cell transplantation.

Masood N, Russell KJ, Olerud JE, Sabath DE, Sale GE, Doney KC, Flowers ME, Fefer A, Thompson JA.

Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98109-1023, USA.

J Am Acad Dermatol 2002 Jul;47(1):140-5 Abstract quote

Advanced mycosis fungoides (MF) is incurable with conventional treatments. High-dose chemoradiotherapy with autologous bone marrow transplantation has induced remissions in a small number of patients with MF, but this modality is limited by a high relapse rate.

We report induction of complete remission in a 37-year-old woman with rapidly progressive stage IV MF with allogeneic stem cell transplantation (Allo SCT). She remains in continuous complete remission 2 years after transplant. Allo SCT for MF is theoretically attractive, because there is no contamination of the graft by malignant cells, and because of the possibility of graft-versus-tumor effect.

Although the results in this patient are encouraging, more patients and longer follow-up are needed to define the usefulness of Allo SCT in the treatment of MF.

Long-term Remission After Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Cutaneous T-Cell Lymphoma.

Guitart J, Wickless SC, Oyama Y, Kuzel TM, Rosen ST, Traynor A, Burt R.

Department of Dermatology, Northwestern University Medical School, 675 N St Clair St, Suite 19-150, Chicago, IL 60611.

Arch Dermatol 2002 Oct;138(10):1359-65 Abstract quote

BACKGROUND: Allogeneic hematopoietic stem cell transplantation has proved to be an effective therapeutic option in various hematologic neoplastic disorders. Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis, with minimal possibilities of sustained remission, we studied the therapeutic potential of hematopoietic stem cell transplantation.

OBSERVATIONS: Three young patients with refractory tumor stage mycosis fungoides underwent allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched peripheral blood stem cell transplantation after cytoreductive chemotherapy and total-body irradiation. Complete and sustained clinical and histologic remission was achieved in 2 patients, and both remain disease free 4(1/2) years and 15 months later. One patient was in complete remission for 9 months, followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor effect have contained the recurring disease as a low-grade process.

CONCLUSIONS: Allogeneic hematopoietic stem cell transplantation has the potential for sustained remission and the possibility of cure for young patients with advanced and recalcitrant cutaneous T-cell lymphoma. Even in the absence of complete remission, an allogeneic graft-vs-tumor effect may provide an immune mechanism to control the malignant T-cell process and alter the natural history of disease.


The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma.

Berger CL, Longley J, Hanlon D, Girardi M, Edelson R.

Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut 06520, USA.

Ann N Y Acad Sci 2001 Sep;941:106-22 Abstract quote

To develop cancer vaccines for the treatment of cutaneous T cell lymphoma (CTCL), immunogenic peptides were identified by two approaches.

First, through the use of "reverse immunology" the peptide sequence of the idiotypic region of the beta chain of the T cell receptor (TCR) was determined and a series of overlapping peptides synthesized and tested for CD8 T cell recognition. In two patients, the idiotypic CDR3 region provided immunogenic epitopes that were recognized in a class I-restricted fashion by autologous CD8 T cell lines.

In a second strategy, peptides were isolated directly from class I MHC molecules on the CTCL surface and sequenced. A peptide with partial homology to sequences contained in the conserved variable portion of the clonotypic TCR beta chain was recognized as immunogenic by autologous CD8 T cells. Therefore, both approaches demonstrated that the clonotypic TCR in CTCL is a source of immunogenic tumor epitopes. To confirm that recognition of TCR-derived sequences provides immunoprotection against tumor growth, a murine model of T cell lymphoma was studied. The immunogenicity of a thymoma, which lacks cell surface TCR expression, was enhanced by transfection of the beta chain of the TCR.

The studies reviewed in this paper demonstrate that the TCR can serve as one source for immunogenic tumor peptides in T cell lymphoma in vitro and in vivo. Presentation of TCR epitopes on dendritic cells that express high levels of MHC, costimulatory, and adhesion molecules may provide an effective means for immunization against T cell malignancy.

T cell antigen receptor vaccines for active therapy of T cell malignancies.

Reddy SA, Okada C, Wong C, Bahler D, Levy R

Stanford University Medical Center, California 94305, USA

Ann N Y Acad Sci 2001 Sep;941:97-105 Abstract quote

T cell lymphoproliferative disorders continue to be serious management problems, and so alternative therapeutic modalities are continuously being explored. One such strategy involves immunotherapy using the T cell receptor (TCR) as a target. Specifically we are attempting to develop a T cell receptor idiotype (TCR-Id) vaccine because the TCR-Id can serve as a tumor-specific antigen.

In this article we will briefly review the rationale for TCR-Id vaccines, the preclinical models as developed in our laboratory, and a discussion of our current plans for a vaccine trial in mycosis fungoides.

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