Mycosis fungoides

Abstract

PUVA has become a common form of treatment for early stage mycosis fungoides (MF). The purpose of this retrospective study was to review the clinical data of 51 MF patients (96% stage IA or IB) treated with PUVA at the Mt. Sinai MF clinic over the past 20 years. We analyzed the efficacy, safety, and remission duration in patients who were treated with a modified PUVA regimen. Forty-four of 51 patients (86%) achieved complete clinical clearing for all stages after initial PUVA therapy. The mean duration of remission with maintenance treatment was more than 27 months (range: 3 weeks to 130 months). The mean duration of disease from start of first PUVA therapy for all patients was 4.8 years (range: 0.7 to 130 months). PUVA for patients with early-stage MF is a safe and effective therapeutic modality with prolonged disease-free remissions, however, PUVA alone was not adequate for more advanced disease.

**********

Introduction

Since the introduction of psoralen plus UVA (PUVA) for the treatment of mycosis fungoides (MF) more than 20 years ago, the death rate in MF has decreased by more than 50%. (1) Several other studies have also documented the beneficial effects of PUVA therapy for MF. (2-6) Furthermore, a recent study showed that aggressive therapy with radiation and chemotherapy did not improve the prognosis for patients compared with conservative topical therapy. (7) Therefore, PUVA has become a common form of treatment for early stage MF. We review here the Mt. Sinai experience over the past 20 years of 51 MF patients treated with PUVA.

Patients and Methods

Patients

We reviewed the clinical data of 51 patients with mycosis fungoides treated with PUVA at the Mt. Sinai MF clinic. All patients who attended the Mt. Sinai MF clinic from 1985 to 2004 were included in the study. Epidemiological and treatment data were collated and analyzed. Diagnosis of mycosis fungoides was made on the basis of clinicopathologic correlation according to established criteria. (8) The stage of disease at initial presentation to the clinic was based on the TNMB classification of MF. (9) Routine examination included a complete blood cell count, a blood smear to identify circulating atypical mononuclear cells, and liver and renal function tests. Clinical examination was performed on all patients and included palpation of lymph nodes, the liver, and the spleen. When clinically indicated, additional tests were performed--chest radiography, computed tomography of liver and spleen, and bone marrow aspiration and biopsy.

Methods

The protocol for PUVA therapy was a modification of the standard PUVA regimen. Prior to UVA exposure, patients ingested 8 methoxypsoralen. Oxsoralen ultra[R] was used at a dose of approximately 0.4 mg/kg. The starting dose of UVA was based on the patient's skin type according to recommended standards for photochemotherapy for MF. PUVA applications began at the maximum UVA dosage at 3 times weekly until complete clearing was observed. Then a tapered maintenance regimen with a gradual taper of UVA dose was followed with PUVA treatment given twice per week for 4 weeks, then once per week for 4 weeks, then every 2 weeks for 4 weeks, and then monthly with the UVA exposure held at the lowest effective dose. Unlike other maintenance regimens which continue the highest tolerated dose of UVA, we tapered UVA doses by one increment per week missed down to 1 to 3 J/[cm.sup.2]. If new lesions were noted clinically, the frequency of treatments was increased to 3 times weekly until complete clearing was achieved again. Treatments were then gradually reduced according to the above maintenance regimen.

BSA was followed and clinical efficacy of PUVA was classified as complete response (CR), partial response (PR), or progressive disease (PD). A response was required to last for at least 4 weeks to be considered an event. A complete response was total clinical clearing of lesions considered at 4 weeks while on PUVA. Once CR was achieved, PUVA was tapered to twice per week for 4 weeks and then tapered further. A partial response was a minimum of 50% reduction in size of measurable lesions and body surface area. Patients with the appearance of new lesions or an increase in body surface area by more than 25% were defined as having progressive disease.

Duration of disease was calculated from the date of initial PUVA treatment until the patient's last clinic visit since patients began PUVA therapy shortly after diagnosis of MF. Periods of freedom from relapse were calculated from the date of complete response. The research protocol was submitted for IRB approval and an exemption was granted since the study involved an anonymous chart review.

Results

A total of 51 patients, 28 men and 23 women, 11 to 88 years of age (mean age: 49 years) were identified with MF and treated with PUVA. The stage of disease at initial presentation to our clinic was the following: 6 patients (12%) with stage IA, 43 patients (84%) with stage IB, and 2 patients (4%) with stage IIB. All patients began PUVA therapy shortly after diagnosis except for 1 stage IB patient who received electron beam therapy and subsequently was treated with PUVA maintenance treatment. A few patients were treated concomitantly with topical steroids (31%) and topical retinoids (10%).

Of the 51 subjects, 44 (86%) were complete responders and 4 (8%) were partial responders and 3 had progressive disease despite PUVA treatment. The median time to best response (complete response or partial response) for all patients was 3.7 months (range: 3 weeks to 34 months). The forty-four patients who achieved a complete response had a mean duration of remission with maintenance treatment of more than 27 months (range: 3 weeks to 130 months). Sixty-four percent (28 of 44) of patients who achieved a complete response had a relapse after initial therapy. The other 16 patients (36%) remained free of disease throughout the study period. The relapse rate included all complete responders who had a recurrence at some point but may have cleared again later on. Fifty-seven percent (16 of 28) of initial complete responders who had a relapse cleared with reinitiating PUVA therapy and remained clear at the last clinic visit. Sixty-three percent of all patients achieved a complete response by the last clinic visit.

For the 6 patients diagnosed with stage IA disease, 5 patients (83%) had a complete response, 1 patient had a partial response and no patient had progressive disease after initial therapy. Four of 5 (80%) initial complete responders with stage IA disease remained clear at the last clinic visit. The median time to clearing was 5.7 months and the mean duration of complete remission was more than 31 months (range: 3.4 to 73 months). Of the 3 stage IA patients who experienced 1 or more episodes of relapse after initial therapy, 2 (62%) were clear at the last clinic visit after reinitiating PUVA treatment. No patient with stage IA disease developed pathological lymph nodes or visceral disease.

For stage IB disease, 39 (91%) patients achieved a complete response, 3 (7%) achieved a partial response, and 1 (2%) had progressive disease. Fourteen of 39 (36%) patients with CR had no recurrences and were clear at the end of the study. The mean duration of these patients who achieved CR and subsequently had no recurrences was more than 45 months (range: 2.7 to 130 months). Twenty-five of 39 (64%) patients with CR experienced a relapse since initiation of PUVA treatment. By reinitiating PUVA treatment 3 times weekly, 14 of these patients were clear at their last clinic visit. Twenty-eight of 43 (65%) patients were clear at the last clinic visit. No patients with stage IB disease developed adenopathy or organomegaly.

The remaining 2 patients had tumors (stage IIB). Despite PUVA therapy 3 times weekly, one patient's condition continued to worsen with the manifestation of new lesions. A trial of acitretin was attempted with no response. Finally, electron beam therapy was administered and the patient obtained a complete response with elimination of all ulcerations, plaques, and macules. The other patient with stage IIB disease was treated with electron beam therapy and subsequently received maintenance PUVA therapy. After 3 years of PUVA and topical retinoids with good response, the disease began to worsen and the patient was to be reevaluated for radiation therapy.

Duration of Disease

The duration of disease was calculated from the day PUVA therapy was started until the last clinic visit, since patients began PUVA therapy shortly after diagnosis of MF. No deaths were recorded during the study. The mean duration of disease from start of first PUVA therapy for all patients was 4.8 years. The median for the entire group (3.3 years) had not been reached. The duration of disease for all patients by stage of disease was the following: stage IA patients had a mean disease duration of 9.6 years (0.2 to 18 years), stage IB patients had a mean disease duration of 5 years (0.3 to 16.7 years) and stage IIB patients had a mean disease duration of 4 years (3.3 to 4.3 years).

Toxicity

The side effects of PUVA were minimal. Acute side effects included burns (18%) and nausea (0.2%) and were well-tolerated with no patient discontinuing therapy secondary to these side effects. One patient developed squamous cell carcinoma (SCC) and the cumulative number of PUVA exposures was 31.

Discussion

PUVA therapy has been used in the treatment of mycosis fungoides for over 20 years. Several studies have reported favorable responses with PUVA treatment and documented long-term disease free remissions, especially in early-stage MF (IA or IB). (1,5,6,10-12)

In this study, 51 patients with MF treated with PUVA were identified in the Mt. Sinai MF clinic. Ninety percent of patients with patch-plaque stage MF achieved a complete response. According to our treatment regimen, patients with stage IA or IB disease did not develop clinically detectable pathological lymph nodes or hepatosplenomegaly. Therefore, a significant number of patients with early stage MF experienced clearing with PUVA therapy and were kept disease free for years.

Both patients who had tumor stage disease required electron beam therapy. Therefore, PUVA alone was not adequate for more advanced disease. The side effects of PUVA were minimal. Once clearing was achieved, the frequency of treatment and UVA dosage was tapered. Therefore, the overall exposure of UVA was relatively low compared to other studies (13) where the dose was kept constant during maintenance treatment.

References

1. Swanbeck G, Roupe G, Sandstrom MH. Indications of a considerable decrease in the death rate in mycosis fungoides by PUVA treatment. Acta Derm Venereol. 1994;74:465-6.

2. Honigsmann H, Tanew A, Wolff K. Treatment of mycosis fungoides with PUVA. Photodermatol. 1987;4:55-8.

3. Roupe G, Sandstrom MH, Kjellstrom C. PUVA in early mycosis fungoides may give long-term remission and delay extracutaneous spread. Acta Derm Venereol. 1996;76:475-8.

4. Strauss GH, et al. Methoxypsoralen photochemotherapy. Lancet. 1980;2:1134-5.

5. Lowe NJ, Cripps DJ, Dufton PA, Vickers CF. Photochemotherapy for mycosis fungoides: a clinical and histological study. Arch Dermatol. 1979;115:50-3.

6. Powell FC, Spiegel GT, Muller SA. Treatment of parapsoriasis and mycosis fungoides: the role of psoralen and long-wave ultraviolet light A (PUVA). Mayo Clin Proc. 1984;59:538-46.

7. Kaye FJ, et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med. 1989;321:1784-90.

8. Bunn PA Jr, Lamberg SI. Report of the Committee on Staging and Classification of Cutaneous T-Cell Lymphomas. Cancer Treat Rep. 1979;63:725-8.

9. Fink-Puches R, et al. Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients. Blood. 2002;99:800-5.

10. Molin L, et al. Aspects of the treatment of mycosis fungoides. A report from the Scandinavian Mycosis Fungoides Study Group. Cutis. 1980;25:155-7.

11. Briffa DV, Warin AP, Harrington CI, Bleehen SS. Photochemotherapy in mycosis fungoides. A study of 73 patients. Lancet. 1980;2:49-53.

12. Honigsmann H, Brenner W, Rauschmeier W, Konrad K, Wolff K. Photochemotherapy for cutaneous T cell lymphoma. A follow-up study. J Am Acad Dermatol. 1984;10:238-45.

13. Herrmann JJ, et al. Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol. 1995;33:234-42.

Jennifer Soung MD, Wangui Muigai, Nilam Amin DO, Dana K. Stern MD, Mark G. Lebwohl MD

Address for Correspondence

Mark Lebwohl MD

5 East 98 Street

New York, NY 10029-6574

Phone: 212-241-9728

Fax: 212-876-5661

e-mail: Lebwohl@aol.com

COPYRIGHT 2005 Journal of Drugs in Dermatology, Inc.
COPYRIGHT 2005 Gale Group