PUVA Maintenance Therapy in Mycosis Fungoides (M_PUVA_2012)

• Quality of life [ Time Frame: Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72 ] [ Designated as safety issue: No ]
  Compared to baseline
• HADS [ Time Frame: Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72 ] [ Designated as safety issue: No ]
  Hospital anxiety depression score, compared to baseline;
• Cytokine response in serum [ Time Frame: Week -4 to 0; week 6, 12, 24, and 48 ] [ Designated as safety issue: No ]
  Compared to baseline
• Levels of regulatory T cells [ Time Frame: Week -4 to 0; week 6, 12, 24, and 48 ] [ Designated as safety issue: No ]
  Compared to baseline
• Function of regulatory T cells [ Time Frame: Week -4 to 0; week 6, 12, 24, and 48 ] [ Designated as safety issue: No ]
  Compared to baseline
• Microscopic alterations [ Time Frame: Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5 ] [ Designated as safety issue: No ]
  Quantification of histologic response in skin biopsy
• Cytokine expression in the skin [ Time Frame: Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5 ] [ Designated as safety issue: No ]
  Rt-PCR and immunohistochemical staining investigations

The purpose of the study is to determine whether psoralen plus UVA (PUVA) photochemotherapy maintenance treatment prolongs disease-free survival of cutaneous T cell lymphoma (mycosis fungoides) patients.

Background: Psoralen plus UVA (PUVA) photochemotherapy consists of the topical or oral application of psoralen, followed by exposure to UVA light. PUVA is used in various conditions, including early stages of mycosis fungoides (MF) and other primary and secondary lymphoproliferative disorders. PUVA has strong pro-apoptotic and immunomodulating properties, but the exact mechanisms by which PUVA leads to clearance of MF are not well understood. Although MF is generally a slowly progressing disease, it ultimately can spread to lymphoid tissues, peripheral blood, and other organs, leading to death.

Previous Work: PUVA therapy is a well-accepted first-line treatment option for skin-limited MF (stages IA, IB, and IIA), leading to complete remission in a high portion of patients (approximately 70 to 90%). Long-term remissions can be achieved with PUVA in a certain percentage of patients. However, in most cases MF lesions relapse after stop of PUVA after variable time intervals with a median time to relapse of 14 to 17 month, according to our own experience. Not only is little is known about the therapeutic mechanisms of PUVA in MF but as little is known about optimal duration and frequency of treatment (2, 3, or 4 times weekly), dose escalation, and maintenance therapy. Although PUVA has been introduced more than 30 years ago, there is lack of prospective controlled studies with clearly defined dose schemes and also an ongoing controversy whether PUVA maintenance therapy may prolong disease remission in MF upon initial complete clearance.

Hypothesis & Intended Work: We hypothesize that PUVA prolongs disease free survival in MF patients. In a randomized multicenter trial involving 9 centers in Austria, we plan to investigate (1) the clinical efficacy of PUVA and its maintenance therapy in MF and, (2) the mechanisms by which PUVA leads to disease clearance. In total, 82 patients will be enrolled and treated with a defined PUVA regimen with 2 exposures per week for 12 weeks. After 12 weeks of PUVA treatment, patients with complete remission will be randomized into two arms. In Arm A patients will be treated with PUVA maintenance therapy at constant single UVA doses. Maintenance treatment will be given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 months of maintenance therapy patients will discontinue therapy. Patients in Arm B will receive no therapy. Thereafter, all patients will be followed until recurrence or at least 12 months (in non-recurrent patients) when the primary study analysis will be done. In addition, the follow-up will be extended to 60 months for long-term results.

The mechanistic action of PUVA will be studied by laboratory investigations, including immune function and cytokine analysis.

Outlook: A better understanding of the optimal regimen and the therapeutic mechanisms of PUVA in MF should help improving treatment strategies for this life-threatening disease. The understanding of the mode of action of PUVA in MF may also help to develop novel treatments using PUVA-affected pathways, allowing to achieve overall better long-term response and success.

• Active Comparator: PUVA maintenance treatment
  Psoralen plus UVA (PUVA) treatment. The patients receive a standardized dose of oral 8-methoxypsoralen (Oxsoralen) 1 hour before UVA exposure
  Intervention: Drug: 8-methoxypsoralen
• No Intervention: No maintenance treatment
  observation

Inclusion Criteria:

• Histopathologically documented MF clinical stage IA-IIB (see Table1) confirmed by current or previous diagnostic lesion biopsy
• A Karnofsky performance score > 60
• No previous PUVA treatment
• Anti-ds-DNA (antinuclear antibodies) or anti-Ro/La antibodies: negative
• Acceptable organ function defined as follows:

SGOT (AST) and SGPT (ALT) < 2.5 times the upper limit of normal for the institution

• Creatinine < 2 times the upper limit of normal for the institution
• No evidence of severe cardiac insufficiency (NYHA grade III-IV)
• Women of child bearing potential must have a negative serum pregnancy test (ß-HCG) within seven (7) days prior to randomization
• Absence of any serious intercurrent illness or infection at time of entry into the study that could interfere with planned treatment
• Patients must be willing to accept limiting sun exposure on the day receiving PUVA treatment
• Written informed consent

Exclusion Criteria:

• Pregnancy and Lactation
• Photosensitive diseases such as lupus erythematosus or basal cell nevus syndrome
• Skin cancer syndromes such as xeroderma pigmentosum or basal cell nevus syndrome