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Topical imiquimod as treatment for different kinds of cutaneous lymphoma

European Journal of Dermatology. Volume 16, Numéro 4, 391-3, July-August 2006, Therapy

Summary

Auteur(s) : Esther A Coors, Gerold Schuler, Peter Von Den Driesch , Department of Dermatology, University of Hamburg, Martinistraße 52, 20246 Hamburg, Germany, Department of Dermatology, University of Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany, Center of Dermatology, Klinikum Stuttgart, Prießnitzweg 24, 70374 Stuttgart, GermanyFax: (+49) 40 428036492.

Illustrations

ARTICLE

Auteur(s) : Esther A Coors¹, Gerold Schuler², Peter Von Den Driesch³

¹Department of Dermatology, University of Hamburg, Martinistraße 52, 20246 Hamburg, Germany
²Department of Dermatology, University of Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany
³Center of Dermatology, Klinikum Stuttgart, Prießnitzweg 24, 70374 Stuttgart, GermanyFax: (+49) 40 428036492

accepté le 29 Mars 2006

Imiquimod is a topical immune response modifier that has been approved for the treatment of genital warts. It has been shown that imiquimod induces different cytokines via toll-like receptors on dendritic cells and leads to a localized production of interferon-alpha [1]. Therefore, imiquimod has not only been used for genital warts but also as a treatment for different cutaneous neoplasms [2-4]. It has recently been approved for the therapy of superficial basal cell carcinomas [5, 6].A Th2-dominated phenotype could be shown in mycosis fungoides, Sézary Syndrome and CD30+ lymphoproliferative disorders [7-9]. Therefore, immunomodulating therapies such as interferon-alpha are effective in the treatment of cutaneous T-cell lymphoma [10]. As one of the major cytokines induced by imiquimod is interferon-alpha, it was a tempting idea to try imiquimod as a treatment for cutaneous T-cell lymphoma. Concerning cutaneous T-cell lymphoma, only a few case reports exist where patients with mycosis fungoides or CD30+ anaplastic large cell lymphoma were treated successfully with imiquimod [11-16]. We therefore wanted to evaluate the efficacy and safety of imiquimod in some patients with therapy resistant lesions of cutaneous T-cell lymphoma. In the treatment of cutaneous B-cell lymphoma, interferon alpha is used much less than for cutaneous T-cell lymphoma, but successful use has been described as well [17]. That is the reason why we also included patients with cutaneous B-cell lymphoma.

Patients and methods

Between February 2002 and August 2005, 8 patients at our departments in Hamburg and Erlangen with an overall total of 20 lesions were treated with topical imiquimod 5% cream. 4 suffered from mycosis fungoides (MF), one had a CD30+ anaplastic large cell lymphoma (ALCL) and 3 had primary cutaneous B-cell lymphomas (CBCL). All of them had therapy resistant lesions under different treatment modalities or had refused more aggressive therapies. Patients’ characteristics, stage and treatment data are summarized in table 1( Table 1 ). All patients were informed about the off-label use and the records were analyzed retrospectively. A complete response was determined by clinical criteria.

All patients started therapy with imiquimod three times per week, in cases without response the frequency was increased to daily application. Total weeks of therapy ranged from 8 weeks up to 52 weeks (table 1). None of the patients had an interruption of treatment during this time.
Table 1

Case	Sex	Age	Diagnosis	Stage	No. of treated lesions	Previous Treatment	Concommittant Treatment	Duration of Treatment (weeks)	Outcome	Follow-up (months)
1	M	78	MF	IA	1	PUVA	None	16	CR	6
2	M	43	MF	IB	2	PUVA, IFN, Retinoids	Chlorambucil, Prednisolone	24	No change	6
3	M	76	MF	IA	2	PUVA	None	8	PD	7
4	M	56	MF	IA	2	PUVA, IFN	PUVA	8	CR	45
5	F	63	CD30+ ALCL	–	2	Excision, PUVA, IFN	None	12	CR	5
6	M	61	FCBCL	–	1	Excision, radiation, IFN	None	52	PR	42
7	M	22	FCBCL	–	3	Excision	None	12	No change	39
8	M	70	CBCL	–	7	Excision, Doxycyclin	None	12	PR	19

Results

Of the four patients with MF, two reached a complete clinical remission of the treated lesions after 8 and 16 weeks respectively ( (figure 1) ). One patient showed no reaction to imiquimod although we had increased the frequency of application up to once a day. We therefore stopped therapy after 20 weeks. The fourth patient developed new lesions after 8 weeks of therapy so that we stopped imiquimod and changed to PUVA therapy. The treated lesions had not shown a significant response until then. The patient with the CD30+ ALCL showed a marked improvement of the lesions after 8 weeks, with only a slight erythema left. After 12 weeks of treatment a complete clinical remission was achieved.

Two of the patients with cutaneous B-cell lymphoma showed a partial remission of the treated lesions, with a clearing of more than 50% ( (figure 2) ). The maximum response was reached after 12 weeks and 24 weeks, respectively. The third patient showed no response to this treatment.

Two patients had minor local side effects with erythema, papules and pruritus. One of them was using imiquimod 5 times per week at this time; when the frequency of application was reduced to 3 times per week, the irritation disappeared. The other patient tolerated imiquimod well when he reduced the application to two times weekly. Later, frequency was increased in this patient again without any problems.

Discussion

Several topical and systemic therapies exist for cutaneous lymphomas [18]. Nevertheless, some patients have lesions that are resistant to the established therapies or they refuse certain therapies due to side effects or other reasons. Therefore, further effective and well tolerated treatment options are desirable.

Imiquimod belongs to the imidazoquinolines, a group of synthetic topical immune response modifiers. It leads to the secretion of interferon alpha, tumour necrosis factor alpha and interleukin-12, all being pro-inflammatory cytokines that create a Th1 response [19]. By now, the mechanism of action has been further elucidated. The Toll-like receptors (TLR), so far a family of 11 members, play an important role in the innate immune system [20]. They can detect distinct parts of viruses, bacteria or lipopolysaccharides and initiate the synthesis of interferon alpha. Imiquimod activates the TLR 7/MyD88-dependent signaling pathway [21]. The following production of interferon alpha is due to plasmacytoid dendritic cells (PDCs), a subset of dendritic cells that are found in the blood and secondary lymphoid organs [22, 23]. Apart from that, tumour cell apoptosis via different mechanisms is induced [5]. Thus, topical treatment with imiquimod has a potent effect on genital warts and cutaneous neoplasms [2-6].

Several investigators have found that different kinds of cutaneous T-cell lymphoma are dominated by Th2-cytokines [7-9]. Therefore, immunomodulating therapies such as interferon alpha, that enhances Th1-reactions, are a certain part in the therapy of cutaneous T-cell lymphoma [10].

So far, a few case reports and a non-randomized pilot study exist, showing the efficacy of imiquimod in patients with resistant lesions in MF or CD30 positive lymphoma [11-16].

Because of its ability to induce the production of interferon alpha, we used imiquimod for the treatment of 4 patients with cutaneous T-cell lymphoma. In a series of 6 patients, Deeths et al. [16] had a response in 5 patients and a histological clearing in 50%. We had a CR in more than 50% of our patients with cutaneous T-cell lymphoma as well. One has to keep in mind, of course, that the number of treated patients has been very small. One of the patients had a concomitant therapy, and it might as well be that the CR was due to a synergistic effect.

In contrast to other reports, we also treated three patients with cutaneous B-cell lymphomas. The background of this decision was that lesions of cutaneous B-cell lymphoma may locally persist for a long time without progress and that interferon-alpha can be successfully used in cutaneous B-cell lymphoma [17]. Therefore, a possible benefit due to the production of cytokines by imiquimod seemed to be reasonable. Two of the patients indeed achieved a partial remission with a reduction of the infiltration and complete healing of some of the lesions. On the whole, the effect of imiquimod seems to be less potent on B-cell lymphoma. It remains unclear at the moment if the lymphoma cells are less responsive to interferon or if less PDCs are recruited via the activation of the TLR by imiquimod.

Most of our patients tolerated imiquimod well, local irritation was mild and could be avoided by decreasing the frequency of application. Local skin reactions are mainly described in patients that respond to imiquimod therapy [5]. Urosevic et al. [23] found less PDCs in two treated lesions that did not show an inflammatory reaction compared to those that reacted with inflammation. As the lesions were excised after 5 days of treatment it is not known if they might have shown a clinical remission after a longer treatment period. Inflammation was seen in two of our patients who showed a response to the therapy. But there were also patients with a complete response who did not show any side effects at all. Further more, the local irritation in our patients was much less developed than has been described in patients with epithelial neoplasms [24]. The reason for this phenomenon remains unclear at the moment.

As a result of our preliminary data we suggest that imiquimod might be an additional treatment option in some cases of resistant lesions in T-cell lymphoma as well as in B-cell lymphoma, but controlled trials are needed to verify this effect.

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