DOI: 10.1111/j.1468-3083.2010.03732.

JEADV

SHORT REPORT

PUVA plus interferon a2b in the treatment of advanced or refractory to PUVA early stage mycosis fungoides: a case series
V Nikolaou,,* MP Siakantaris, TP Vassilakopoulos, E Papadavid, A Stratigos, A Economidi, L Marinos, T Papadaki, C Antoniou

Department of Dermatology, University of Athens Medical School, A. Sygros Hospital, First Department of Internal Medicine, Haematology Clinic, University of Athens, Laikon General Hospital, Department of Dermatology, University of Athens Medical School, Attikon Hospital, and Hematopathology Department, Evagelismos Hospital, Athens, Greece *Correspondence: V Nikolaou. E-mail: drviknik@yahoo.com

Abstract
Background The combination of PUVA with variable doses of systemically administered interferon a2b (IFN-a2b) reduces the number of PUVA treatments and the dose of IFN-a2b required to produce remission in all mycosis fungoides (MF) stages. Objectives To evaluate the efcacy of the combination of PUVA and IFN-a2b in patients with late stage or refractory to treatment early stage MF. Methods The combination of PUVA three times weekly and IFN-a2b 25 MU three times weekly was retrospectively reviewed in 22 patients. KaplanMeyer method and log-rank test was used for statistical analysis. Results Twenty-two patients were analysed, seven with refractory to PUVA early stage MF, seven with tumour zary syndrome (SS). The overall response rate (complete or stage, ve with erythrodermic MF and three with Se partial response) was 68%, including 10 complete responses (CR) (45%) and ve partial responses (PR) (23%). Signicantly, more patients of the early stage group achieved CR compared with the advanced stage group (86% vs. 27%, P = 0.03). Within the advanced stage group, CR rates were 14% vs. 37% in stage IIB and III SS patients respectively, but the difference was not statistically signicant. Patients with early stage disease had a 2-year PFS of 100% vs. 27% for the advanced stage group (P < 0.001). Sustained remissions (>2 years) were achieved in ve out of six complete responders in the early stage group of patients. Conclusion This combination of IFN-a2b and PUVA is an effective and safe treatment for refractory to treatment ve advanced stage patients. Its efcacy is more pronounced in the early stage MF patients as well as treatment-na former patient group. Received: 15 December 2009; Accepted: 20 April 2010

Keywords
IFN-a2b, late stage, mycosis fungoides, PUVA

Conict of interest
None declared.

Introduction
Cutaneous T-cell lymphomas (CTCL) is a group of low-grade non-Hodgkin lymphomas with initial presentation in the skin, characterized by malignant proliferation of mainly T-helper lymphocytes.1 Mycosis fungoides (MF) is the most common type of CTCL comprising about 8085% of CTCLs in general. It is usually characterized by chronic, indolent progression. Psoralen plus UVA exposure (PUVA) is one of the preferred treatment options for early stage disease. However, due to the depth of the associated inltrate, treatment with PUVA

irradiation is often ineffective.2 Interferon alpha (IFN-a) has been shown to be a highly active agent in CTCL with response rates ranging from 40% to 80%.3,4 In the late 1993, Ross et al.5 reported that IFN-a monotherapy was effective even at low doses. Mostow et al.6 suggested that the combination of low-dose IFN-a with PUVA yielded additional benet. The aims of our study were to evaluate the effectiveness of the combination treatment of PUVA plus low-dose IFN-a2b in patients with refractory to PUVA early stage disease or late stage MF.

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Methods
This is a retrospective chart review analysis of patients with zary syndrome) or early stage MF (IAIIA) advanced (IIB, III, Se refractory to rst line treatment with PUVA, followed at the Photodermatology department of A.Sygros Hospital for skin diseases. In all cases, a skin biopsy was performed for histological and immunohistochemical examination. Staging procedures included history and physical examination, complete blood cell count with differential, routine laboratory tests, LDH and thoraco-abdomical CT scans. All MF patients were followed for lymphadenopathy, at 8- to 12-week intervals during the treatment period with physical zary cells. Treatexamination and blood smears for circulating Se ment toxicity was graded according to World Health Organization (WHO) criteria.7 Disease was staged according to the TNM system for CTCL.8 Response to treatment was dened as follows: Complete remission (CR): complete clearance of all skin lesions. Partial remission (PR): >50% reduction of skin lesions No response (NR): any clinical result less than a PR. Progressive disease (PD): lesion size increasing more than 25% or appearance of new lesions, tumours or change of histology. To avoid treatment discrepancies, we strictly included patients treated with combination of low-dose IFN-a and PUVA according to the following protocol: Patients were started with 3 MU of IFN-a2b three times weekly s.c. The dose was increased according to patients tolerance up to 5 MU three times weekly. For PUVA treatment, 0.6 mg kg 8-methoxypsoralen was given 2 h before therapy and the whole body, apart from the genital area, was subjected to UVA light treatment three times weekly, until complete skin clearing. All complete responders received maintenance treatment at the same IFN-a dose that induced remission until progression or unacceptable toxicity. Progression free survival (PFS) was dened as the time from treatment initiation until progressive disease, relapse after CR or last follow-up. Patients, who required a change in treatment approach, were also considered as failures in the analysis of PFS. Cause specic survival (CSS) was dened as the time from treatment initiation until death from disease- or treatment-related cause. Relapse free survival (RFS) was dened similarly to PES but applied only to responders. Survival curves were plotted using the KaplanMeier method. Differences between survival curves were assessed using the log-rank test. P-values <0.05 were considered statistically signicant.
d d d d

Table 1 Patients and treatments characteristics

Results
Patients characteristics are listed in Table 1. Twenty-two patients were analysed (17 males and 5 females, median age 58 years, range 3181) followed from October 2000 since July 2008. Seven patients had early stage MF refractory to previous treatments, seven patients had tumour stage MF, ve patients had erythrodermic

zary syndrome. The median followMF and three patients had Se up duration for the entire cohort of currently living patients was 32 months (range, 594). Seventeen patients tolerated 3 MU three times weekly, two patients 2 MU three times weekly, two patients 4 MU three times weekly and one patient 5 MU three times weekly. The median PUVA sessions for the entire group of patients was 36 and the median joules cm2 were 148.75. The median combination treatment period for our patients was 138 days (range 43204 days). The overall response rate (CR or PR) was 68%, including 10 CR (45%) and 5 PR (23%). Signicantly, more patients of the early stage group achieved CR compared with the advanced stage group (86% vs. 27%, P = 0.03). Within the advanced stage group, CR rates were 14% vs. 37% in stage IIB and III SS patients respectively, but the difference was not statistically signicant. The 2- and 5-year PFS for the entire cohort was 52% and 29% respectively (Fig. 1). Patients with early stage disease had a 2-year PFS of 100% vs. 27% for the advanced stage group (P < 0.001) (Fig. 2). The 2- and the 5-year RFS of the 15 responders was 82% and 45% respectively and the median RFS was 48 months. Sustained remissions (>2 years) were achieved in ve out of six CRs in the early stage group of patients (Fig. 3). The 2- and 5-year CSS for the entire cohort was 100% and 69% respectively. Although only two disease-related deaths were recorded, CSS of early stage patients was superior to that of advanced stage patients (P = 0.03).

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Nikolaou et al.

Figure 3 A 45-year-old female patient with early stage mycosis fungoides refractory to PUVA, before (a) and after (b) combination treatment. Figure 1 Progression free survival curve of the 22 mycosis fungoides patients.

Discussion
Treatment of MF is based on TNM clinical stage. PUVA is the gold standard of treatment in early disease reaching up to 71.4% of complete remission.911 It is well known, that combinations of therapies may work synergistically to induce sustained remissions with less adverse effects, and thereby improve both quality of life and duration of response. When PUVA is used in combination with IFN-a2b, both response rates and response duration are reported to be improved, with a recent study reporting overall response and complete response rates of 98% and 84% respectively.12 It has also been shown that patients require fewer doses of UVA than those patients on PUVA alone and doubles the progression free time of CTCL stages I and II.13 Our retrospective chart review analysis aimed to assess the effectiveness of this combination in difcult to treat MF cases. We conrmed that the combination of IFN-a2b with PUVA is an effective treatment for MF and that the best clinical responses can be achieved in the early stages of the disease, even if patients are resistant to previous PUVA treatment. Some very promising results have been reported in the literature using the combination of those treatment modalities. ChiarionSileni et al.14 showed response rates in all stages and a 75% CR rate in 63 patients treated with a median duration of 32 months. Compared with Chiarion-Silenis results the response rates of our group of patients was slightly lower. However, Chiarion-Sileni used higher doses of IFN-a reaching 12 MU three times per week. Roenigk et al. reported a 80% CR rate with a median duration that approached 2 years in 15 patients treated with a combination of IFN-a and PUVA.15 In a subsequent study including 39 patients, 87% pretreated and 36% with advanced disease, the authors16 reported a 62% CR rate with a median duration of 28 months. They reported that 48% of patients needed a reduction in IFN-a dose due to toxicity and constitutional symptoms were experienced by 85% of patients. In our study, only one patient withdrew treatment due to cardiotoxicity while he was on

Figure 2 Progression free survival curves according to stage.

Life-threatening adverse events were not observed. Mild and moderate (WHO Grade I and II) adverse events were seen in 18 out of 22 patients (81%). Fatigue was the most common side effect in 18 patients (Grade I 45.5%, Grade II 36.4%). Six patients (27.3%) reported moderate ue-like symptoms. Reduction of white blood counts was observed in eight patients (Grade I 31.8% and Grade II 4.5%) while anaemia was seen in one patient (4.5%). Elevated liver enzymes were recorded in one patient. One young male patient complained of fatigue in his usual daily activities of recent onset. The heart ultrasound demonstrated a low injection fraction (40%) without evidence of ischemia. IFN-a2b was withdrawn as potentially cardiotoxic.

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maintenance treatment. However, fatigue was very commonly reported and making the dose escalation difcult to achieve. It is not clear from the literature whether a prolonged administration of IFN-a could prolong the duration of CR or not. However, we observed sustained remission in ve out of six early stage patients who achieved complete remission after PUVAIFN-a combination. All of those patients received maintenance treatment for a median of 13 months after remission. Our results are in concordance with Rosss study that showed that clinical stage of disease before treatment is the only predictive parameter concerning the clinical response to IFN-a treatment in patients with MF.5 On the other hand, we showed that between advanced stage MF, erythrodermic MF had better response than tumour stage. Moreover, within the advanced stage group, ve patients. Larger responders to treatment were all treatment-na patient groups are needed to assess whether response rates are inferior in tumour stage MF. Limitations of our study include the small number of patients evaluated and its retrospective nature. However, we believe that IFN-a2b combined with PUVA is an effective and safe therapy for patients with all stages of MF. Randomized studies are needed to establish whether the combination of IFN-a2b plus PUVA is superior to other treatment modalities especially in patients with advanced stage disease. In conclusion, in our series of patients, the combination of PUVA with low-dose IFN-a2b gives substantial response rates in difcult to treat cases of MF and is well tolerated. Further studies should focus to the identication of prognostic factors in order to select those patients who would be suitable for IFN-a treatment in advanced stages of CTCL.

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