Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sezary syndrome variants of cutaneous T-cell lymphoma

doi:10.1016/j.ctrv.2006.08.006

Cancer Treatment Reviews

Volume 33, Issue 2, April 2007, Pages 146-160

https://doi.org/10.1016/j.ctrv.2006.08.006 Get rights and content

Summary

Primary cutaneous T-cell lymphomas are a heterogenous group of non-Hodgkin lymphomas. The characteristic clinicopathologic and immunophenotypic features and prognoses of the various cutaneous lymphomas have been recently described by the World Health Organization and European Organization for Research and Treatment of Cancer. Cutaneous T-cell lymphoma variants include mycosis fungoides and Sezary syndrome, which are generally associated, respectively, with indolent and aggressive clinical courses and are the subject of this review. Currently utilized treatments for cutaneous T-cell lymphoma include skin-directed therapies (topical agents such as corticosteroids, mechlorethamine, carmustine, and retinoids, phototherapy, superficial radiotherapy, and total skin electron beam therapy), systemic therapies (photophoresis, retinoids, denileukin diftitox, interferons, and chemotherapy), and stem cell transplantation (autologous and allogeneic). This review will describe recent advances in our understanding of the biology (immunologic, cytogenetic, and genetic) of cutaneous T-cell lymphomas and discuss the efficacy and tolerability of the current therapeutic options for cutaneous T-cell lymphomas. Disease progression in over 20% of patients with early stages of disease and the current lack of a definitive treatment which produces durable responses in advanced stages of disease indicates a critical unmet need in CTCL. New insights into the molecular and immunologic changes associated with cutaneous T-cell lymphomas should ultimately lead to the identification of novel therapeutic targets and the development of improved therapeutic options for patients with these malignancies.

Introduction

Primary cutaneous T-cell lymphomas (CTCL) are an uncommon subtype of non-Hodgkin lymphoma with an annual incidence of 0.6 per 100,000.1, 2 There has been considerable progress in defining different clinicopathologic subtypes of primary CTCL and clarification of prognosis as well as a wealth of data confirming a wide range of molecular and immunologic changes. This progress is reflected in the recent consensus World Health Organization and European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas (Table 1) which also provides the basis for distinguishing extranodal primary cutaneous lymphomas from their nodal counterparts with a similar morphology and immunophenotype and crucially explains the different prognosis for lymphomas with a similar pathology arising in specific extra-nodal sites.²

Section snippets

Classification of the mycosis fungoides (MF) and Sezary syndrome (SS) CTCL variants

MF is the commonest variant of primary CTCL and is generally associated with an indolent clinical course. It is characterised by cutaneous atrophic patches and plaques which are polymorphic in terms of scale, degrees of erythema, induration and margins. MF can present with involvement of less than 10% of the body surface area (stage T1/IA) or more than 10% (stage T2/IB), tumours (stage T3/IIB) and erythrodermic disease (stage T3/III).³ The prognosis for those with stage IA and 1B disease is

Pathogenetic mechanisms

The majority of primary CTCL are clonal proliferations of mature CD4+ CD45RO+ T cells with a marked homing capacity for the papillary dermis and epidermis. Some CTCL variants are CD8+ and different subtypes have distinct prognoses. The homing to skin by CTCL cells appears to be mediated in part by expression of the surface glycoprotein cutaneous lymphoid antigen which mediates binding to E-selectin on endothelial cells of cutaneous venules, thereby facilitating their exit from the circulation

Skin directed therapy

Class I to III (potent/moderate potency) topical corticosteroids can produce complete clinical remission in early-stage disease (25–63%) but the duration of benefit may be short and prolonged use can cause cutaneous atrophy.⁴⁶

Topical mechlorethamine (nitrogen mustard), either as an ointment or aqueous solution, has been shown to produce CR rates of 26–76% in stage I (although response differs between those with stage IA compared to IB) and 22–49% in stage III disease but relapses are frequent

Biological therapy for CTCL

Cytokine based therapies have been explored in CTCL based on the observations that the malignant Sezary cells inhibited the production of Th1 cytokines and thus suppressed a cell mediated anti-tumour response.⁷³ Interferon alpha has been shown in a number of studies to be a highly active agent in CTCL with ORRs ranging from 40% to 80%.74, 75 Doses range from 1 to 18 mU administered subcutaneously on a number of schedules, the most common being three times a week. Interferon gamma has been used

Cytotoxic chemotherapy in CTCL

A number of agents have demonstrated activity in CTCL. These include alkylating therapies, such as cyclophosphamide, chlorambucil and prednisone, etoposide, and methotrexate.⁹⁹ While combination chemotherapy regimens have produced higher responses in patients with advanced refractory CTCL, these responses have not been durable. A study of infusional EPOCH (etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone) in advanced refractory CTCL demonstrated an ORR of 80% (12

Retinoids

Oral bexarotene is a synthetic RXR retinoid analogue that has shown significant clinical efficacy in patients with relapsed or refractory CTCL. ORRs of 54% have been reported in refractory early-stage CTCL and 45% in refractory advanced-stage patients treated with 300 mg/m² of oral bexarotene daily.123, 124 The median DOR was 299 days, but several patients remain in complete remission up to 5 years later. Responses occurred in patients with large cell transformation and with erythrodermic SS who

Vaccine strategies

The development of vaccines for patients with CTCL is being explored for anti-idiotype, peptide mimotope, dendritic cell, and DNA based vaccines. Anti-idiotype vaccines are being prepared from involved skin lesions. Vaccination with peptide mimotopes of tumour associated T-cell epitopes has led to responses in 2 refractory CTCL patients,¹⁴² and 5 of 10 refractory CTCL patients achieved a response following vaccination with monocyte-derived dendritic cells pulsed with tumour lysates.¹⁴³ The use

Bone marrow transplantation

Allogeneic stem cell transplantation as been shown to induce complete and durable remissions in a small number of patients with CTCL, with disappearance of the malignant clone from the peripheral blood.145, 146 Molina and colleagues reported successful outcomes with donor transplants in 6 of 8 refractory CTCL patients. All achieved a complete remission, however, 2 died from transplantation-related complications.¹⁴⁷ Guitart et al. reported that 3 young patients with refractory MF successfully

Conclusions

The risk of disease progression at 5 and 10 years in early stages of MF are 21% and 39%, respectively, with a disease-specific survival of 96% and 83% at 5 and 10 years, respectively, for stage IB patients. Although skin-directed therapies are associated with a high response rate in early stage disease, these are invariably of short duration and there is a high relapse rate. The response rates and duration of responses in late stages of disease are very poor and the palliative needs of these