JEADV

DOI: 10.1111/jdv.12684

ORIGINAL ARTICLE

Treatment of cutaneous T-cell lymphoma with oral alitretinoin C. Kapser,† T. Herzinger,† T. Ruzicka, M. Flaig,‡ S. Molin‡,* Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany *Correspondence: S.C. Molin. E-mail: [email protected]

Abstract Background Cutaneous T-cell lymphoma (CTCL) is a potentially life-limiting malignant disease. Treatment strategies in CTCL aim at disease control and remission with the lowest possible side-effects. Objective Recent reports suggest that the new vitamin A derivative alitretinoin might be a well-tolerated treatment option. zary syndrome (n = 1), who Methods We analysed the files of 11 CTCL patients with mycosis fungoides (n = 10) or Se were treated with oral alitretinoin alone or in combination with standard treatment based on individual off-label treatment decisions. Patients had been monitored every 4–8 weeks with skin examination and laboratory analyses. Results Ten of 11 patients (90.9%) showed a marked improvement of their CTCL skin lesions and no progress of the disease during treatment with alitretinoin, one patient showed no response to the treatment (9.1%). Four of the responding patients (40.0%) had a complete response and 6 (60.0%) had a partial response. Average time to response was 2.5 months. Duration of treatment varied depending on whether patients had reached complete or partial remission. In general, alitretinoin was well tolerated. One of 11 patients developed high non-fasting average serum cholesterol (>300 mg/dL) and 1/11 a mean non-fasting triglyceride value >500 mg/dL. In 3/11 patients, thyroid-stimulating hormone declined without clinical symptoms during treatment, with one of the patients also showing a decreased thyroxin level. Conclusion In our group of CTCL patients we noticed a low rate of side-effects and an overall good clinical response to treatment with alitretinoin. Further studies are required to substantiate this early clinical observation. Received: 30 April 2014; Accepted: 15 July 2014

Conflicts of interest Claudia Kapser has received a travel grant from Basilea Pharmaceutica. Thomas Herzinger has received travel grants from Basilea Pharmaceutica and Almirall. Michael Flaig has no conflict of interest. Thomas Ruzicka has acted as a principal investigator, speaker and consultant for Basilea Pharmaceutica. Sonja Molin has acted as speaker, subinvestigator and consultant for and received travel grants and author honoraria from Basilea Pharmaceutica, Almirall, Actelion and GlaxoSmithKline.

Funding sources None.

Introduction Primary cutaneous lymphomas are a group of lymphoproliferative disorders that are, by definition, limited to the skin at the time of diagnosis. In contrast to nodal lymphomas, the majority of them are of T-cell origin.1 The most common types of cutaneous T-cell lymphoma (CTCL) are mycosis fungoides (MF) and Sezary syndrome (SS).2 Males are more often affected than females, and the disease’s onset is mostly in the mid-50s. The †

The first two authors contributed equally to this work The last two authors contributed equally to this work



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incidence, which is about 6.4 per million, is rising with age. 72% of CTCL are classified as MF. In the beginning, typical skin lesions are erythematous, asymmetric patches and plaques, sometimes associated with atrophy, appearing as superficial wrinkling and scaling on sun-protected areas. The burden of disease is usually low at this early stage. MF may progress within years to a tumourous form and eventually to systemic involvement. Sezary syndrome accounts for about 2.5% of all cutaneous lymphomas. Its typical clinical presentation is characterized by erythroderma, lymphadenopathy, palmoplantar hyperkeratosis, alopecia, nail dystrophy, eye involvement and pruritus. Besides

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these in the peripheral blood Sezary cells, abnormal lymphocytes with hyperconvoluted, cerebriform nuclei, are mandatory for diagnosis. Early stage CTCL patients have an excellent prognosis, while patients with advanced disease and systemic involvement have a median survival of less than 2 years. No curative therapy is available for CTCL up to now. The therapeutic management depends on the stage of disease and aims at disease control and remission with the lowest possible side-effects.1,2 In MF, firstline therapy encompasses topical corticosteroids, narrow band UVB or psoralen plus UVA (PUVA). Single lesions may be treated by local radiation therapy. From stage IIB, PUVA may be administered together with interferon-alpha (IFN-a), radiation therapy or bexarotene. In more advanced stages, these treatment options might be combined with low-dose methotrexate, extracorporeal photopheresis or chlorambucil. Second-line therapies include doxorubicin, chlorambucil, total skin electron beam therapy, denileukin diftitox, gemcitabine and other systemic agents. In SS, extracorporeal photopheresis and/or PUVA is complemented by INF-a and/or bexarotene initially.3 Because of unpredictable and variable treatment outcomes and side-effects, there is a need for effective and tolerable alternatives. A number of case reports suggest that the retinoid alitretinoin (formerly Basilea Pharmaceutica, now GlaxoSmithKline) might be a welltolerated alternative in the systemic therapy of retinoid-responsive skin diseases including CTCL.4–6 Earlier, the retinoids isotretinoin, etretinate and acitretin, that all bind to retinoic acid receptors (RAR), had been tested for efficacy in CTCL, when it became clear, that retinoid X receptor (RXR) mediated efficacy might be of additional benefit. Bexarotene was developed as a specific RXR agonist for treatment of CTCL.7 RAR and RXR belong to a family of intracellular receptors acting as transcription factors.8 RARs play a role in cellular differentiation as well as proliferation, whereas RXRs regulate apoptosis.9 Alitretinoin (9-cis-retinoic acid) is a new vitamin A derivative. It uniquely binds both, RAR and RXR.10 The substance is licensed for therapy of severe chronic hand eczema (CHE) in some European countries and Canada.4 Several large studies in patients with CHE documented a lower incidence of typical retinoid adverse effects like mucocutaneous dryness or dyslipidaemia or hypothyroidism.11,12 All these properties encouraged us to try off-label treatment with alitretinoin in several of our patients with CTCL between 2009 and 2012. Here, we present a retrospective analysis of individual clinical responses and sideeffects in these patients.

Materials and methods We carried out a retrospective analysis of patients with CTCL who were treated with oral alitretinoin between 2009 and 2012 at the Department of Dermatology of the Ludwig-Maximilian University in Munich. In all patients the diagnosis had been established by a synoptical state of the art approach considering clinical presentation, histology, immunohistochemistry, molecular

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analysis and, in case of Sezary syndrome, additionally by immunophenotyping of the peripheral blood. Staging was made according to the TNMB system 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) for mycosis fungoides and Sezary syndrome based on the clinical examination, lymph node palpation and further diagnostics where necessary.2,13 All patients had been monitored at intervals of 4-8 weeks with skin examination and routine blood control including cholesterol, triglycerides and thyroid parameters. High serum cholesterol was defined on the basis of data from previous trials on alitretinoin in CHE12 by values above 300 mg/dL (7.77 mmol/L), high serum triglyceride values above 500 mg/dL (5.66 mmol/L). We calculated mean values of cholesterol and triglycerides. Fasting lipid parameters were not available for all patients and all visits. No response (NR), partial response (PR) and complete response (CR) were set as possible outcomes of treatment in our data analysis. We included stage I - III CTCL, response scores refer solely to the skin. No response was defined as progressive or stable disease, partial response as reduction of skin lesions compared to the baseline and complete response as full clinical remission of the skin lesions. Duration of remission was defined as relapse-free follow-up after reaching partial or complete response. Due to the small sample size the statistical analysis was confined to descriptive percentage rates only to estimate a trend.

Results Investigation sample

A total of 11 patients with mycosis fungoides (n = 10) or Sezary syndrome (n = 1) had been treated with oral alitretinoin alone or in combination with standard treatment based on individual off-label decisions. Five (45.5%) of them were women and 6 (54.5%) men with a mean age of 73 years (range 45–85) at the initiation of treatment. The mean disease duration of CTCL before therapy with alitretinoin was 6.1 years (73.5 months; range 5–324 months). The largest proportion (90.9%) of patients was classified as early stage disease (IA: n = 5, IB: n = 4, IIB: n = 1) at the initiation of alitretinoin therapy. Only 1/11 (9.1%) had already a progressed disease stage (IIIA: n = 1). Previous treatment courses had included topical steroids (n = 9), topical calcineurin inhibitors (n = 1), PUVA (n = 7), UVB 311 nm (n = 6), IFN-a (n = 2), methotrexate (n = 1), systemic steroids (n = 3), extracorporeal photopheresis (n = 4) and chemotherapy with chlorambucil (n = 1), but had not resulted in sufficient response (Table 1). Three of the patients (27.3%) had pre-existing coronary heart disease. In all of them the blood lipids were well controlled with anti-hyperlipidaemic agents. One patient had depressive episodes in her history, but was currently stable, and one had

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Table 1 Clinical data of the patients ID

Gender

Age in years

Type of lymphoma

ISCL/ECORT stage

History of disease in months

Previous treatments

1

F

54

MF

IA

36

2

F

65

MF

IA

24

3

M

45

MF

IA

324

4

M

77

MF

IA

7

5

M

66

MF

IA

7

6

F

63

MF

IB

72

oS, sS

7

F

66

MF

IB

92

tS, UVB, P

8

M

85

MF

IB

48

tS, P, UVB

9

M

57

MF

IB

8

10

F

84

SS

IIIA*

95

tS, oS, ECP

11

M

78

MF

IIB

36

tS, P, UVB, ECP

tS tS, tCNI, UVB, P, ECP tS, P, INFa oS, P, UVB, INFa, MTX, C tS, P

tS, UVB, ECP

*Patient was categorized as SS on account of erythroderma and atypical lymphocytes in the blood. However, the criteria for B2 were not met. Therefore, we classified the patient as IIIA. C, chemotherapy; ECP, extracorporeal photopheresis; F, female; INFa, interferon-a; M, male; MF, mycosis fungoides; MTX, methotrexate; oS, oral stezary syndrome; tS, topical steroids; tCNI, topical calcineurin inhibitor; UVB, UVB 311 nm. roids; P, PUVA; R, radiotherapys; S, systemic steroids; SS, Se

Figure 1 Patient 8 in week 0. Figure 2 Patient 8 in week 10. Complete response.

known hypothyroidism, which was well controlled by thyroid hormone substitution. In some cases a specialist in internal medicine was consulted before starting alitretinoin to exclude contraindications and to optimize the co-medication. Response

Ten of 11 patients (90.9%) showed a marked improvement of their CTCL skin lesions with no progression of the disease, only one patient showed no response to the treatment (9.1%). Four

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of the responders (40.0%) achieved a complete remission (Figs. 1–4), 6 (60.0%) experienced a partial response. Average time to PR was 2.5 months, average time to CR was 5.3 months. Duration of treatment varied depending on whether patients had reached complete remission or partial response. The mean duration of treatment was 19.2 months. The daily dose of oral alitretinoin (10 or 30 mg) was chosen individually for each patient depending on his/her medical history. The individual

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All patients had a therapy concomitant to alitretinoin: topical steroids (n = 11), topical calcineurin inhibitors (n = 3), PUVA (n = 2), UVB 311 nm (n = 1), IFN-a (n = 1), systemic steroids (n = 3) or extracorporeal photopheresis (n = 6). Safety assessment/side-effects

In general, alitretinoin was well tolerated by our patients (Table 3). A high average level of (non-fasting) serum cholesterol (>300 mg/dL) and a mean (non-fasting) high triglyceride value (>500 mg/dL) developed in respectively 1/11 patients. In 3/11 patients (27.3%), thyroid-stimulating hormone (TSH) declined without clinical significance during treatment with alitretinoin (500 mg/dL (5.66 mmol/L). †

Treatment of cutaneous T-cell lymphoma with oral alitretinoin.

Cutaneous T-cell lymphoma (CTCL) is a potentially life-limiting malignant disease. Treatment strategies in CTCL aim at disease control and remission w...
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