Case report
Effectiveness of interferon α in mycosis fungoides therapy

Introduction

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and is characterized by the malignant proliferation of mature helper T lymphocytes [1]. It is usually associated with an indolent clinical course with episodes of remissions and subsequent relapses. Skin manifestations are generally the first signs of the disease. Patients present erythematous, sometimes poikilodermatous and scaly, long-standing patches, plaques, or tumoral lesions with an occasional itch. In patients with early disease stages, life expectancy is normal, however follicular MF has a worse prognosis than the classic type of MF. In approximately 30% of patients there is extracutaneous involvement, which is associated with a poor prognosis [2].

There are two therapeutic modalities in mycosis fungoides: skin-directed and systemic treatments. Most patients respond well to skin-targeted therapy, which may include topical chemotherapy (nitrogen mustard or carmustine), topical corticosteroids, topical retinoids, phototherapy including ultraviolet A and B radiation, oral psoralen plus ultraviolet light (PUVA), radiotherapy, excimer laser, photodynamic therapy, and total skin electron beam therapy [3-5]. Systemic therapy, generally reserved for more extensive, advanced or refractory disease, is often used in combination with skin-directed treatments [4]. A number of systemic treatment options, such as cytotoxic chemotherapy and biologic agents, enhance the host immune system response to neoplastic T cells. The most commonly used biologic response modifiers are interferon- and bexarotene, which is a novel retinoid-X-selective retinoid [6, 7]. At present, any type of available therapy (with the exception of hematopoietic cell transplantation) for MF is curative [4].

Skin-targeted therapies are first-line agents in early-stage disease but they are also useful in patients with advanced-stage disease. Systemic chemotherapy is not the treatment of choice in early-stage MF, because it does not improve survival as compared with skin-targeted therapy [8]. For some patients with early stages of the disease only careful observation is recommended. Complete responses have rarely been obtained in patients with heavily pretreated and advanced disease [9].

Case reports

Two patients suffering from MF have been treated at the Department of Dermatology, Venereology and Allergology of Medical University in Gdansk including IFN therapy with very satisfactory results. One of them, a 36-year-old man was admitted to hospital with erythroderma, very high fever and in poor general condition. The stage of MF was assessed as III (T4N0M0). Treatment has started with prednisone and cyclosporine obtaining a partial recovery followed by progression before admission to hospital, because of suspicion of adverse drug reaction (chlorprothixene taken because of depression); erythroderma and palmoplantar hyperkeratosis. Another medication was methotrexate (20 mg per week), which was discontinued after 4 weeks due to staphylococcal sepsis. Finally IFN- was included (Roferon) at a dose of 3 MU 3 times weekly obtaining a partial improvement after 2 months of therapy, while hyperkeratosis persisted. The complete treatment schedule included IFN- to which the patient responded after 84 days. During this therapy the patient also received 5 sessions of soak PUVA and 2 treatments of UVB 311 in accordance with the second skin phototype, what has allowed to achieve CR (Figures 1 A-B, 2 A-B). During the interferon (IFN) therapy, the patient complained of weakness and night sweats, but only at the beginning of the treatment. The treatment has been continued thanks to kind cooperation of the Regional Oncological Center in Gdansk and Dermatological Department of Elblag Regional Hospital (due to the patient’s place of residence).

The second patient was a 58-year-old woman, diagnosed with folliculotropic MF based on clinical features and histopathological examination of the skin slice, with widespread pruritic papules with concomitant characteristic perifollicular collocation on the trunk and buttocks (Figure 3). There were no mucin deposits in histopathological examination. We initially applied PUVA plus acitretin at a dose of 25 mg daily for 1 year. However, because of persistent itching and just partial remission, methotrexate was added at a dose of 15 mg per week. The patient received seven rounds of MTX and prednisone was given because of arthralgia diagnosed by the rheumatologist, at an initial dose of 30 mg daily, reduced to 10 mg, without improvement of skin lesions. Finally, IFN treatment was started at a dose of 3 MU 3 times weekly. After 2 weeks of IFN therapy, UVB 311 irradiation was added, yielding, after 6 doses of UVB 311 exposure, a spectacular remission, especially resolving the problem of severe pruritus. But because of influenza-like syndrome, weakness, malaise, anorexia symptoms, arthralgia, leucopenia and neutropenia, which occurred during the second week of IFN therapy, the agent was discontinued for 7 days, after which blood parameters returned to normal. The dose of IFN was reduced to 1.5 MU 3 times a week, thanks to kind cooperation of the Regional Oncological Center in Gdansk, and UVB311 was continued with better tolerance and good response (Figures 4 A-B).

Discussion

Recombinant interferon- (IFN-) is named type I IFN as it binds to IFN cell surface receptors type 1. There are two major forms of IFN-: IFN--2a (Roferon) and IFN--2b (Intron), which are differently purified and have different amino acid substitution at position 23. There are also the pegylated forms of IFN--2a, IFN--2b and con-1, but neither of them has been reported to be used in clinical trials in MF [10]. Elimination half-life is 3-8 h for IFN--2a and 2-3 h for IFN--2b for both subcutaneous and intramuscular injections [11]. Interferons are cytokines with immunoregulatory, antiproliferative, antiangiogenic, and antiviral effects [12]. The mechanism of IFN- action is not completely understood. However, studies have shown inhibition of IL-4 and IL-5 production by T cells and SCs, under the influence of IFN [13]. In combination with radiation, IFN- has been reported to have a potential effect on radiation enhancing blockage at the G2-M phase of the cell cycle [14].

The first report on the effectiveness and toxicity of IFN in the treatment of patients with advanced cutaneous T-cell lymphomas was published in 1984. The maximal tolerated dose of IFN- (50 × 106 U/m² body surface area), used intramuscularly 3 times weekly, was highly effective in treatment of disease refractory to at least two standard therapies. However, none of 20 patients had complete response (CR). Almost half of the patients had partial response in the first 4 weeks of therapy. Both cutaneous and extracutaneous lesions, including the size of palpable lymph nodes and the number of circulating malignant cells, definitely improved [15].

Interferon- was used at doses ranging from about 3 million units (MU) three times weekly to 9 or 12 MU daily [16]. In spite of short periods of IFN therapy at high doses, it showed a dose-related toxicity. A strong correlation between dose and efficacy has never been confirmed [7, 17].

Interferon- has been reported to be effective at each stage of MF. Clinical response rates have been reported for 45-74% and complete response rates for 10-27% of treated patients [18, 19]. Significantly, the highest complete response was achieved in patients of the early-stage group compared with the advanced-stage group [20]. The efficacy of IFN was higher than that of chemotherapy (high-dose methotrexate, etoposide) and serotherapy such as TlOl monoclonal antibody and antithymocyte globulin.

To improve effectiveness of IFN monotherapy, combinations with other agents were introduced into the treatment of MF. Some very encouraging results have been observed using the combination of IFN- and PUVA [21], retinoids [17, 22] or extracorporeal photopheresis [23]. Kuzel et al. [24] reported the results of combined treatment of IFN-2a (6-30 MU TIW) and PUVA. Complete response was achieved in 80% of patients, with a median duration that approached 2 years. The combination of PUVA and IFN-2b of 2-5 MU 3 times weekly demonstrated higher response rates (a median of overall response rate – 98%, CR rate – 84%) and longer duration of response than PUVA or IFN- alone [18, 19, 21, 25, 26]. They have been shown to be effective in patients with refractory to PUVA early-stage MF and less in advanced-stage patients. A 2-year progression free survival was observed in 100% of patients with early-stage disease and 27% of patients in the advanced-stage group. In each case the number of PUVA treatments and the dose of IFN-2b necessary to produce response were reduced [18, 27]. This combination was more effective than IFN- plus acitretin [28].

The lack of complete responses was probably the cause of the rapid dose reductions in some cases. Initially, when interferon was administered in very high doses, all patients required dose reductions to 50% of the initial dose, during the initial 3 months of therapy [15]. This approach always alleviated a toxicity within several weeks after dose reduction [20]. Major complications associated with the use of IFN include influenza-like syndrome with myalgia, chills, mild fever, malaise and fatigue. Moreover, anorexia, weight loss, depression, rashes and hypotension were often observed. Hematologic toxicity was mild, including neutropenia and thrombocytopenia; not dose limiting [29]. Febrile responses were most severe in the first week of therapy. Subsequently re-escalated doses of interferon causedtachyphylaxis to the major dose-limiting influenza-like syndrome. Perhaps escalating doses should be applied, however the optimal IFN dose and schedule is still an unresolved issue.

We used low doses of IFN- in our patients, because such proceeding minimizes the risk of side effects. According to world literature, time to response is in the order of weeks and the treatment should be carried out at least for 1 year, if the tolerance is good.

In conclusion, IFN is a treatment of choice for patients with MF helping to delay the introduction of chemotherapy, especially in erythroderma, as a single agent or as a part of combined therapy with phototherapy. It has been shown that the use of chemotherapy in patients with MF did not lead to prolongation of their survival, therefore recommending drugs with different mechanism of action, such as IFN. According to the Polish guidelines, the section of skin lymphomas of the Polish Lymphoma Research Group established last year, treatment of choice in early stages of MF (IA-IIA) is a therapy being possibly the least aggressive one, as at this stage of disease patients have normal life expectancy [30]. Interferon- is recommended as second-line in monotherapy at doses of 3 to 5 MU daily, or in combination with PUVA, retinoids, bexarotene and methotrexate. For advanced-stage disease (IIB-IV) IFN- should generally be considered as first-line therapy. To increase the effectiveness of IFN-, it can be combined with PUVA, retinoids, bexarotene and additionally methotrexate (IIB) or extracorporeal photopheresis (III-IV). In folliculotropic MF, because of the depth of infiltration, phototherapy should be used only in combination with IFN and retinoids or bexarotene [31]. Psoralen plus ultraviolet light should be added in the case of more widespread pruritus and bexarotene if the response is suboptimal [9].

Nowadays, there is no possibility of free IFN treatment of patients with cutaneous lymphoma in dermatological out-patient departments in Poland. However, those patients can receive IFN without the costs of the medicament in oncological or hematological ambulatories. That means that therapy of MF patients has required the cooperation of the dermatologist and the oncologist or the hematologist.

References

 1. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004; 350: 1978-88.  

2. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730-9.  

3. Whittaker SJ, Foss FM. Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sezary syndrome variants of cutaneous T-cell lymphoma. Cancer Treat Rev 2007; 33: 146-60.  

4. Gardner JM, Evans KG, Musiek A, et al. Update on treatment of cutaneous T-cell lymphoma. Curr Opin Oncol 2009; 21: 131-7.  

5. Olek-Hrab K, Osmola-Mańkowska A, Silny W, et al. Use of UVA1 in the treatment of mycosis fungoides – case report. Post Dermatol Alergol 2011; 28: 158-64.  

6. Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 2001; 137: 581-93.  

7. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther 2003; 16: 311-21.  

8. Kaye FJ, Bunn PA Jr, Steinberg SM, 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.  

9. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sézary syndrome. Blood 2009; 114: 4337-53.

10. Olsen EA, Rook AH, Zic J, et al. Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 2011; 64: 352-404.

11. Lai L, Hui CK, Leung N, Lau GK. Pegylated interferon alpha-2a (40 kda) in the treatment of chronic hepatitis B. Int J Nanomedicine 2006; 1: 255-62.

12. Stark GR, Kerr IM, Williams BR, et al. How cells respond to interferons. Annu Rev Biochem 1998; 67: 227-64.

13. Rook AH, Heald P. The immunopathogenesis of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 1995; 9: 997-1010.

14. Angioli R, Sevin BU, Perras JP, et al. In vitro potentiation of radiation cytotoxicity by recombinant interferons in cervical cancer cell lines. Cancer 1993; 71: 3717-25.

15. Bunn PA Jr, Foon KA, Ihde DC, et al. Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med 1984; 101: 484-7.

16. Ross C, Tingsgaard P, Jørgensen H, Vejlsgaard GL. Interferon treatment of cutaneous T-cell lymphoma. Eur J Haematol 1993; 51: 63-72.

17. Bunn PA Jr, Hoffman SJ, Norris D, et al. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome). Ann Intern Med 1994; 121: 592-602.

18. Chiarion-Sileni V, Bononi A, Fornasa CV, et al. Phase II trial of interferon-alpha-2a plus psolaren with ultraviolet light A in patients with cutaneous T-cell lymphoma. Cancer 2002; 95: 569-75.

19. Rupoli S, Goteri G, Pulini S, et al. Long-term experience with low-dose interferon-alpha and PUVA in the management of early mycosis fungoides. Eur J Haematol 2005; 75: 136-45.

20. 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: 1689-95.

21. Kuzel TM, Roenigk HH, Samuelson E, et al. Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 1995; 13: 257-63.

22. Knobler RM, Trautinger F, Radaszkiewicz T, et al. Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids. J Am Acad Dermatol 1991; 24: 247-52.

23. Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous t-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002; 138: 1054-60.

24. Kuzel TM, Gilyon K, Springer E, et al. Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst 1990; 82: 203-7.

25. Roenigk HH Jr, Kuzel TM, Skoutelis AP, et al. Photochemotherapy alone or combined with interferon alpha-2a in the treatment of cutaneous t-cell lymphoma. J Invest Dermatol 1990; 95 (6 Suppl): 198S-205S.

26. Mostow EN, Neckel SL, Oberhelman L, et al. Complete remissions in psoralen and UV-A (PUVA)-refractory mycosis fungoides-type cutaneous T-cell lymphoma with combined interferon alfa and PUVA. Arch Dermatol 1993; 129: 747-52.

27. Nikolaou V, Siakantaris MP, Vassilakopoulos TP, et al. PUVA plus interferon alpha2b in the treatment of advanced or refractory to PUVA early stage mycosis fungoides: a case series. J Eur Acad Dermatol Venereol 2011; 25: 354-7.

28. Stadler R, Otte HG, Luger T, et al. Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood 1998; 92: 3578-81.

29. Baron S, Tyring SK, Fleischmann WR Jr, et al. The interferons. Mechanisms of action and clinical applications. JAMA 1991; 266: 1375-83.

30. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 1999; 40: 418-25.

31. Małgorzata SW, Ewa LM, Waldemar P, et al. Leczenie pierwotnych chłoniaków skóry. Rekomendacje sekcji chłoniaków skóry Polskiej Grupy Badawczej Chłoniaków (PLRG). Onkol Prakt Klin 2010; 6: 29-47.