SHORT REPORT

PUVA plus interferon a2b in the treatment of advanced orrefractory to PUVA early stage mycosis fungoides: a caseseries

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

AbstractBackground 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 efficacy 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 2–5 MU three times weekly was

retrospectively reviewed in 22 patients. Kaplan–Meyer 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

stage, five with erythrodermic MF and three with Sezary syndrome (SS). The overall response rate (complete or

partial response) was 68%, including 10 complete responses (CR) (45%) and five partial responses (PR) (23%).

Significantly, 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 significant. 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 five 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

early stage MF patients as well as treatment-naıve advanced stage patients. Its efficacy is more pronounced in the

former patient group.

Received: 15 December 2009; Accepted: 20 April 2010

KeywordsIFN-a2b, late stage, mycosis fungoides, PUVA

Conflict of interestNone declared.

IntroductionCutaneous 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 lym-

phocytes.1 Mycosis fungoides (MF) is the most common type of

CTCL comprising about 80–85% of CTCLs in general. It is usually

characterized by chronic, indolent progression.

Psoralen plus UVA exposure (PUVA) is one of the pre-

ferred treatment options for early stage disease. However, due

to the depth of the associated infiltrate, 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 combina-

tion of low-dose IFN-a with PUVA yielded additional benefit.

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.

ª 2010 The Authors

JEADV 2011, 25, 354–357 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

DOI: 10.1111/j.1468-3083.2010.03732.x JEADV

MethodsThis is a retrospective chart review analysis of patients with

advanced (IIB, III, Sezary syndrome) or early stage MF (IA–IIA)

refractory to first line treatment with PUVA, followed at the Pho-

todermatology 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

examination and blood smears for circulating Sezary cells. Treat-

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 defined as follows:d Complete remission (CR): complete clearance of all skin

lesions.d Partial remission (PR): >50% reduction of skin lesionsd No response (NR): any clinical result less than a PR.d 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 patient’s 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 sub-

jected to UVA light treatment three times weekly, until complete

skin clearing. All complete responders received maintenance treat-

ment at the same IFN-a dose that induced remission until pro-

gression or unacceptable toxicity.

Progression free survival (PFS) was defined 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 specific survival (CSS) was defined as the time from treat-

ment initiation until death from disease- or treatment-related

cause. Relapse free survival (RFS) was defined similarly to PES but

applied only to responders. Survival curves were plotted using the

Kaplan–Meier method. Differences between survival curves were

assessed using the log-rank test. P-values <0.05 were considered

statistically significant.

ResultsPatients’ characteristics are listed in Table 1. Twenty-two patients

were analysed (17 males and 5 females, median age 58 years, range

31–81) followed from October 2000 since July 2008. Seven patients

had early stage MF refractory to previous treatments, seven

patients had tumour stage MF, five patients had erythrodermic

MF and three patients had Sezary syndrome. The median follow-

up duration for the entire cohort of currently living patients was

32 months (range, 5–94). 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 med-

ian combination treatment period for our patients was 138 days

(range 43–204 days).

The overall response rate (CR or PR) was 68%, including 10

CR (45%) and 5 PR (23%). Significantly, 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 respec-

tively, but the difference was not statistically significant.

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. Sus-

tained remissions (>2 years) were achieved in five 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).

Table 1 Patient’s and treatment’s characteristics

Patient’s characteristics No of patients (%)

Gender

Male 17 (77.3)

Female 5 (22.7)

Age

Median 58 years

Range 31–81

Prior treatment

No 9 (40.1)

Yes 13 (59.1)

Stage of disease

IB 6 (27.4)

IIA 1 (4.5)

IIB 7 (31.8)

III 5 (22.7)

SS 3 (13.6)

Interferon a tolerated dose (MU ⁄ week)

6 2 (9.1)

9 17 (77.3)

12 2 (9.1)

15 1 (4.5)

PUVA (median sessions ⁄ joules)

All patients 36 ⁄ 148.75

Complete responders 33 ⁄ 130.125

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JEADV 2011, 25, 354–357 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

PUVA plus interferon in the treatment of MF 355

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 flue-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 with-

drawn as potentially cardiotoxic.

DiscussionTreatment 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.9–11 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% respec-

tively.12 It has also been shown that patients require fewer doses of

UVA than those patients on PUVA alone and doubles the progres-

sion free time of CTCL stages I and II.13 Our retrospective chart

review analysis aimed to assess the effectiveness of this combina-

tion in difficult to treat MF cases. We confirmed that the combi-

nation 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. Chiarion-

Sileni 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-Sileni’s 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 reduc-

tion 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 1 Progression free survival curve of the 22 mycosis

fungoides patients.

Figure 2 Progression free survival curves according to stage.

Figure 3 A 45-year-old female patient with early stage

mycosis fungoides refractory to PUVA, before (a) and after

(b) combination treatment.

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JEADV 2011, 25, 354–357 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

356 Nikolaou et al.

maintenance treatment. However, fatigue was very commonly

reported and making the dose escalation difficult to achieve.

It is not clear from the literature whether a prolonged adminis-

tration of IFN-a could prolong the duration of CR or not. How-

ever, we observed sustained remission in five out of six early stage

patients who achieved complete remission after PUVA–IFN-acombination. All of those patients received maintenance treatment

for a median of 13 months after remission.

Our results are in concordance with Ross’s 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,

responders to treatment were all treatment-naıve patients. Larger

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 supe-

rior 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

difficult to treat cases of MF and is well tolerated. Further studies

should focus to the identification of prognostic factors in order to

select those patients who would be suitable for IFN-a treatment in

advanced stages of CTCL.

References1 Murphy GF. Cutaneous T cell lymphoma. Adv Pathol 1988; 1: 131–156.

2 Muche JM, Lukowsky A, Asadullah K et al. Demonstration of frequent

occurrence of clonal T cells in the peripheral blood of patients with

primary cutaneous T-cell lymphoma. Blood 1997; 90: 1636–1642.

3 Bunn PA Jr, Ihde DC, Foon KA. The role of recombinant interferon

alfa-2a in the therapy of cutaneous T-cell lymphomas. Cancer 1986; 57:

1689–1695.

4 Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell

lymphoma. Hematol Oncol Clin North Am 1995; 9: 1089–1107.

5 Ross C, Tingsgaard P, Jorgensen H, Vejlsgaard GL. Interferon treatment

of cutaneous T-cell lymphoma. Eur J Haematol 1993; 51: 63–72.

6 Mostow EN, Neckel SL, Oberhelman L et al. Complete remissions in

psoralen and UV-A (PUVA)-refractory mycosis fungoides-type cutane-

ous T-cell lymphoma with combined interferon alfa and PUVA. Arch

Dermatol 1993; 129: 747–752.

7 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of

cancer treatment. Cancer 1981; 1: 207–214.

8 Olsen E, Vonderheid E, Pimpinelli N et al. Revisions to the staging and

classification of mycosis fungoides and Sezary syndrome: a proposal of

the International Society for Cutaneous Lymphomas (ISCL) and the

cutaneous lymphoma task force of the European Organization of

Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713–

1722.

9 Oguz O, Engin B, Aydemir EH. The influence of psoralen + ultraviolet

A treatment on the duration of remission and prognosis in mycosis

fungoides. J Eur Acad Dermatol Venereol 2003; 17: 483–485.

10 Herrmann JJ, Roenigk HH, Hurria A et al. Treatment of mycosis

fungoides with photochemotherapy (PUVA): long–term follow-up.

J Am Acad Dermatol 1995; 33: 234–242.

11 Roupe G, Sandstrom MH, Kjellstrom C. PUVA in early mycosis fungo-

ides may give long-term remission and delay extracutaneous spread.

Acta Derm Venereol 1996; 76: 475–478.

12 Rupoli S, Goteri G, Pulini S et al. Long-term experience with low-dose

interferon-a and PUVA in the management of early mycosis fungoides.

Eur J Haematol 2005; 75: 136–145.

13 Stadler R, Kremer A, Luger T, Sterry W. Prospective, randomized

multicentre clinical trial on the use of interferon a 2a plus pUVA versus

PUVA monotherapy in patients with cutaneous T-cell lymphoma, stages

I and II. J Clin Oncol 2006; 24: 7541.

14 Chiarion - Sileni V, Bononi A, Fornasa CV et al. Phase II trial of Inter-

feron-a-2a plus Psoralen with Ultraviolet light A in patients with cuta-

neous T-cell lymphoma. Cancer 2002; 95: 569–575.

15 Roenigk HH Jr, Kuzel TM, Skoutelis AP et al. Photochemotherapy

alone or combined with interferon alpha-2a in the treatment of cutane-

ous T-cell lymphoma. J Invest Dermatol 1990; 95: 198S–205S.

16 Kuzel TM, Roenigk HH Jr, Samuelson E et al. Effectiveness of inter-

feron alfa-2a combined with phototherapy for mycosis fungoides and

the Sezary syndrome. J Clin Oncol 1995; 13: 257–263.

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