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A phase II trial of miltefosine in patients with cutaneous T-cell lymphoma

Bulletin du Cancer. Volume 93, Number 11, 10115-8, Novembre 2006, Electronic Journal of Oncology

DOI : 10.1684/bdc.2006.0148

Summary

Author(s) : Charles Dumontet, Luc Thomas, Frédéric Bérard, Jean François Gimonet, Bertrand Coiffier , Service d’Hématologie, CH Lyon-Sud, Pierre-Bénite, Laboratoire d’Hématologie, Pavillon E, Hôpital Edouard-Herriot, 5 place d’Arsonval, 69003 Lyon Cedex 03, France, Service de Dermatologie, Hôtel-Dieu, Lyon, France, Baxter Oncologie, France.

Summary : A phase II trial evaluating 6% topical miltefosine solution was performed in 12 pretreated patients with cutaneous T-cell lymphoma. Miltefosine (Miltex ^®) was administered for 8 weeks, once per day during the first week then twice every day for seven weeks. Main side effects consisted in moderate to mild pruritus or desquamation in 57 % and 50 % of patients, respectively. No systemic nor biological toxicity was observed. This treatment was administered on an outpatient basis exclusively. The overall response rate was 58 % with a median duration of response of 12 months. Miltefosine is a safe, simple and effective treatment in certain patients with cutaneous T-cell lymphoma.

Keywords : miltefosine, cutaneous T-cell lymphoma

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ARTICLE

Auteur(s) : Charles Dumontet¹, Luc Thomas², Frédéric Bérard², Jean François Gimonet³, Bertrand Coiffier¹

¹Service d’Hématologie, CH Lyon-Sud, Pierre-Bénite, Laboratoire d’Hématologie, Pavillon E, Hôpital Edouard-Herriot, 5 place d’Arsonval, 69003 Lyon Cedex 03, France
²Service de Dermatologie, Hôtel-Dieu, Lyon, France
³Baxter Oncologie, France

Cutaneous T-cell lymphoma (CTCL) represents less than 2 % of all non-Hodgkin’s lymphoma (NHL). The major subtypes of CTCL are mycosis fungoides and Sezary syndrome [1, 2]. Diagnosis of CTCL is often difficult and is often performed months or years after the initial manifestations of the disease [3]. Current diagnostic methods include clonality assays demonstrating the presence of a clonal T cell population in a skin biopsy [4]. The natural history of CTCL involves two phases. The first phase corresponds to an indolent, essentially cutaneous disease during which there are no general symptoms, and a low level of infiltration of blood and/or bone marrow can be found. This phase can last for several years during which the patient can benefit from local or systemic therapy when the disease is symptomatic. The second phase corresponds to an enhanced aggressivity of disease with the development of cutaneous tumors, lymphadenopathy and general symptoms. This second phase develops over a period of a few weeks to a few months and currently carries a very poor prognosis.The choice of treatment of CTCL is currently determined by the phase at which the patient is treated. Cutaneous manifestations occurring during the first phase can be addressed by locally administered agents when the lesional surface is restricted. Systemic therapy such as PUVAtherapy is commonly used for diffuse disease [5]. Total electron beam therapy has shown activity in a majority of patients [6]. Interferon is often used, alone or in combination with other treatments [7, 8]. More recently, bexarotene has demonstrated significant activity in this disease [9]. During the second phase of disease, combination chemotherapy is the treatment of choice, although disease is globally refractory to treatment at this stage.Miltefosine is an ether lipid which represents the first agent in its class, targetting the membrane of tumor cells. It is an alkylphosphocholine with a long-chain fatty acid-like backbone which mimics normal membrane phospholipids and is thought to interfere in signal transduction pathways such as the phospholipase/protein kinase C pathway [10, 11]. Miltefosine is currently approved for the palliative treatment of cutaneous metastases of breast cancer. Response rates are in the order of 22 to 33 % [12, 13] with good local tolerance.Given the lack of novel topical therapies in CTCL we chose to perform a phase II trial evaluating the efficacy and tolerance of miltefosine in patients with relapsing CTCL. The results obtained in twelve patients treated for eight weeks with topical 6% miltefosine are presented in this report.

Patients and methods

This study was conducted between August 1998 and December 2001 in the Service d’Hématologie of the Center Hospitalier Lyon-Sud in Pierre-Bénite, France. This was a open-label phase II trial with endpoints incorporating parameters both of efficacy and tolerance. This protocol was approved by the Ethical Committee of Centre Léon-Bérard, Lyon, France and patients were requested to provide a signed informed consent.

Patient selection

Patients 18 years of age or older with histologically confirmed pretreated cutaneous T-cell lymphoma were considered for entry onto this study. All patients were required to have received at least one prior systemic or topical treatment for CTCL. Othe eligibility criteria included adequate bone marrow status (absolute neutrophil count > 1.0 x 10⁹/L, platelet count > 100 x 10⁹/L), adequate renal and hepatic function (creatinine < 120 μmol/L, bilirubin < 30 μmol/L, ALT and alkaline phosphatase less than 2.5 times the upper limit of normal ranges). Patients were excluded if any of the lesions were deeply penetrating, infected, ulcerated, formed palpable tumors or if the total lesional area was greater than 200 cm². Patients were required to have interrupted all therapy for CTCL for at least 4 weeks prior to study entry.

Treatment

6 % miltefosine was provided by Asta Medica (Frankfurt, Germany) as a clear, colorless and odourless, slightly viscous liquid, in 10-mL glass vials with a dropper allowing the delivery of the solution in drops of approximately 0.025 ml (38 to 40 drops/mL). Miltefosine was applied on the lesional surface(s) as well as to a 3 cm margin around each lesion, at a standard dose of 2 drops/10 cm² of skin area per application. After washing the amount of solution was dropped onto the skin to be treated and gently massaged with a glove-protected hand. Miltefosine was applied once daily during the first week then, if no intolerable skin reactions were observed, twice daily during the next seven weeks.

All other topical or systemic treatments were prohibited during the period of the study. Patients were allowed to apply an aqueous paraffin emulsion for treatment of cutaneous reactions but local steroids were prohibited.

Patient follow-up

After patient screening patients or their families were shown how to administer topical miltefosine and were given enough miltefosine for a 4-week period. Patients were then assessed at 4 weeks and given additional miltefosine to complete the protocol. Patients were then seen every 4 weeks for three months then every three months. Biological analyses including blood count, serum chemistry, creatinin, ALT and AST, alkaline phosphatase were performed at 4 weeks and 8 weeks.

Endpoints

Skin lesions were assessed (description, size, symptoms) at baseline then at 4-week intervals during the first three months then every three months. Complete response was defined as the complete disappearance of all lesions treated for at least 4 weeks without the appearance of any new lesions within the treated area. Partial response (PR) was defined as a decrease by at least 50 % of the sum of the products of two perpendicular diameters without the appearance of new lesions within the treated area. Stable disease (SD) was defined as a decrease in size of less than 50 % or an increase of less than 25 %. Progressive disease (PD) was defined by an increase in size of 25 % of any measurable lesions within the treated area. A remission had to be confirmed by a second measurement after 4 weeks. TTP was defined as the time from the start of treatment to the time of progression of disease defined by the appearance or increase in size in any adequately treated area.

Results and discussion

Patient characteristics

Twelve patients were included between August 1998 and December 2001 in the Service d’Hématologie of the Center Hospitalier Lyon-Sud in Pierre-Bénite, France after referral by the collaborating Dermatology centers. The main characteristics are shown in table 1( Table 1 ). Two thirds of the patients were male, and the median age was 57 years (range 28-78). All patients had good performance status, and had received at least one prior treatment for their CTCL (median number of prior treatments: 2). A total of twenty lesions was treated in the twelve patients. The median size of the lesions was 9 cm².
Table 1 Main patient characteristics

Sex
Male	8
Female	4
Age, years
Median	57
Range	28-78
Delay between diagnosis and accrual (months)
Median	19
Range	3-198
Prior therapies
Median	2
Range	1-5
Body surface (m²)
Median	1.72
Range	1.49-2.20
ECOG performance status
0	8
1	4
>1	0
Number of lesions treated
1	7
2	2
3	3
Surface of lesions treated (cm²)
Median	9
Range	1-168
Localization of treated lesions
Lower limb	5
Upper limb	7
Thorax / abodmen	5
Face and scalp	3

Tolerance

The overall tolerance of miltefosine treatment was satisfactory. No systemic toxicity was observed. Local desquamation occurring during the first ten days was observed in 6 (50 %) of the patients and local pruritus was reported in 7 (58 %). These side effects were usually temporary and symptoms were usually controlled with the application of an aqueous paraffin emulsion.

Response and follow-up

After eight weeks of topical application of miltefosine, 5 patients were considered to be in complete response, 2 patients had partial response and 5 patients had stable disease. The overall response rate was thus 58 %. Complete responses were observed in patients with lesions of various sizes (up to 168 cm²). With a median follow-up of 26 months 2 of the complete responders and 1 patient in partial response have progressed, with a median freedom-from progression of 12 months ( (figure 1) ). Three patients (25 %) had responses lasting between 2 and 4.5 years. An example of response in a patient with extensive facial involvement is shown in ( figure 2 ).

Concluding remarks

Our results show that topical miltefosine is active and well tolerated in patients with limited cutaneous T cell lymphoma. The high response rates observed in this series are comparable to those observed with other topical therapies. Systemic and local tolerance was excellent and is compatible with an exclusively outpatient treatment. These results justify a larger trial with miltefosine both in untreated and in priorly treated patients.

Acknowledgments

This trial was supported by Asta Medica, Frankfurt, Germany.

References

1 Kashani-Sabet M, McMillan A, Zackheim HS. A modified staging classification for cutaneous T-cell lymphoma. J Am Acad Dermatol 2001; 45: 700-6.

2 Willemze R, Meijer CJ. EORTC classification for primary cutaneous lymphomas: a comparison with the R.E.A.L. Classification and the proposed WHO Classification. Ann Oncol 2000; 11(Suppl 1): 11-5.

3 Siegel RS, Pandolfino T, Guitart J, Rosen S, Kuzel TM. Primary cutaneous T-cell lymphoma: review and current concepts. J Clin Oncol 2000; 18: 2908-25.

4 Magro CM, Nuovo GJ, Crowson AN. The utility of the in situ detection of T-cell receptor Beta rearrangements in cutaneous T-cell-dominant infiltrates. Diagn Mol Pathol 2003; 12: 133-41.

5 Plettenberg H, Stege H, Megahed M, Ruzicka T, Hosokawa Y, Tsuji T, et al. Ultraviolet A1 (340-400 nm) phototherapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 1999; 41: 47-50.

6 Quiros PA, Jones GW, Kacinski BM, Braverman IM, Heald PW, Edelson RL, et al. Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 1997; 38: 1027-35.

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

8 Wollina U, Looks A, Meyer J, Knopf B, Koch HJ, Liebold K, et al. Treatment of cutaneous T cell lymphoma stage II with interferon-alpha-2a and extracorporeal photochemotherapy: a prospective controlled trial. Ann N Y Acad Sci 2001; 941: 210-3.

9 Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 2001; 19: 2456-71.

10 Jendrossek V, Handrick R. Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers. Curr Med Chem Anti-Canc Agents 2003; 3: 343-53.

11 Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ, Verheij M. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs 2003; 14: 167-73.

12 Smorenburg CH, Seynaeve C, Bontenbal M, Planting AS, Sindermann H, Verweij J. Phase II study of miltefosine 6olution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs 2000; 11: 825-8.

13 Leonard R, Hardy J, van Tienhoven G, Houston S, Simmonds P, David M, et al. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 2001; 19: 4150-9.