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

Cancer Treatment Reviews (2007) 33, 146– 160

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctrv

ANTI-TUMOUR TREATMENT

Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sezary syndrome variants of cutaneous T-cell lymphoma Sean J. Whittaker a b

a,c

, Francine M. Foss

b,*

St. John’s Institute of Dermatology, Guys and St. Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK Department of Medical Oncology, Yale University Cancer Center, 800 Howard Avenue, New Haven, CT 06519, United States

Received 28 February 2006; revised 30 August 2006; accepted 31 August 2006

KEYWORDS

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. c 2006 Elsevier Ltd. All rights reserved.

Cutaneous T-cell lymphoma; CTCL; Mycosis fungoides; Sezary syndrome; Bexarotene; Carmustine; PUVA; TSEB; Denileukin diftitox; Allogeneic transplant



* Corresponding author. Tel.: +1 203 737 5312; fax: +1 203 785 3788. E-mail addresses: [email protected] (S.J. Whittaker), [email protected] (F.M. Foss). c Tel.: +44 207 1886410; fax: +44 207 1886257.



0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2006.08.006

Current therapies for CTCL

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

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 excellent with 5-year

147 survival rates of 100% and 96%, respectively, but diseasespecific survival at 10 years for stage IB is 83%.4,5 The presence of tumour stage disease is associated with a worse prognosis (5- and 10-year survival rates of 80% and 42%, respectively).6,7 While patients can present with tumours or erythroderma, approximately 20% of patients with early-stage IB disease will develop disease progression. SS is characterized by erythroderma, peripheral lymphadenopathy and the presence of atypical peripheral blood Sezary cells comprising more than 5% of total leukocytes or more than 20% of the total lymphocyte count with a detectable molecular or cytogenetic clone. Most cases of MF/SS are not curable. Independent prognostic features in MF include the cutaneous and lymph node stage of disease and age of onset (>60 years). The lymph-node status and tumour burden within peripheral blood determine the prognosis in SS.8–11 Serum lactate dehydrogenase, folliculotropic disease (36% disease-specific survival at 10 years) and the thickness of the infiltrate in plaque-stage MF are also markers of a poor prognosis.12,13 Multivariate analysis indicates that an initial complete response (CR) to various therapies is an independent favourable prognostic feature, particularly in early stages of disease. For MF, two staging systems are in regular use including a TNM system and a clinical staging specifically designed for CTCL.14 These staging systems can also be applied to SS, but neither system provides a quantitative method for assessing peripheral blood disease other than an additional B0 and B1 in the TNM system and this has prompted alternative approaches for SS.15 Specifically, the development of peripheral lymphadenopathy in MF/SS alters the staging regardless of the cutaneous

Table 1 World Health Organization–European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas with primary cutaneous manifestations Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides Mycosis fungoides variants and subtypes Folliculotropic mycosis fungoides Pagetoid reticulosis Granulomatous slack skin Sezary syndrome Adult T-cell leukaemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders Primary cutaneous anaplastic large-cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) Cutaneous c/d T-cell lymphoma (provisional) Primary cutaneous pleomorphic CD4+ small/medium T-cell lymphoma (provisional) Cutaneous B-cell lymphomas Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center B-cell lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other intravascular large B-cell lymphoma Precursor haematologic neoplasm CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)

148 stage of disease10 and histopathologic involvement of lymph nodes and other organs is a very poor prognostic sign (stage IVA 5-year survival is 40%, median survival 13 months). Any systemic organ can be involved and this is associated with rapid deterioration (stage IVB 5-year survival is 0%, median survival 13 months). Large cell transformation in skin or lymph nodes is associated with a poor prognosis but this has not been assessed in multivariate analysis. While there are clinical markers of disease progression and poor prognosis in early stage MF such as thick plaques and folliculotropic disease, there is an urgent need for potential biomolecular markers of prognosis and treatment response. There is also a need to produce durable remissions as both currently available skin directed and systemic therapies are associated with a high relapse rate at all stages of disease. Both MF and SS show a high frequency of chemoresistance and are associated with T-cell immunosuppression, which increases the risk of life threatening infection particularly in the elderly population.

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 and into the skin. Tumour cells express Th2 cytokines at least for the common clinical variants of MF and SS. Recent in vitro studies have suggested that CTCL represents a neoplastic proliferation of regulatory T-cells16 and there is also evidence for a striking restriction of the normal non-tumour peripheral blood T-cell population even in patients with early stages of disease.17 Tumour cells may be induced to have the phenotype and function of regulatory T-cells in vitro,16 but ex vivo do not function as normal regulatory T-cells in SS.18 Whether tumour cells function as regulatory T-cells in early MF, where they may receive the correct signals, has yet to be proven. In CTCL, no disease specific balanced translocations have yet been identified but molecular cytogenetic studies do indicate that MF and SS have a closely related pattern of chromosomal abnormalities suggesting that the two conditions share a similar if not identical pathogenesis.19,20 Numerical rather than structural abnormalities predominate with losses on 1p, 10q, 13q, 17p and gains of 4, 17q and 18 common.20–23 Recent studies have shown a high prevalence of deletions or translocations involving a gene, NAV3, at 12q2, which has helicase-like activity and might therefore contribute to genomic instability.24 In addition the gene may have a putative role in interleukin-2 (IL-2) induced T-cell signalling. As for other hematologic malignancies, inactivation of cell cycle and apoptosis genes is common in MF/SS and is probably partly due to a ‘‘mutator phenotype’’ associated with microsatellite instability due to hypermethylation of mismatch repair gene promoter sequences.25–29 Promotor hypermethylation and repression of gene transcription ap-

S.J. Whittaker, F.M. Foss pears to be a common mechanism of gene inactivation in CTCL.30 Chromosomal amplification of JunB at 19p12 has also been detected in MF/SS.31 JunB is part of the AP1 transcription factor complex involved in control of cell proliferation, differentiation and apoptosis. Over-expression of JunB is likely to be the explanation for the TH2 cytokine profile commonly seen in CTCL. Constitutive or cytokine stimulated JunD expression may also play a role in CTCL progression.32 cDNA array studies in SS have identified a gene signature which appears to confer a worse prognosis and have also shown over-expression of a tyrosine kinase receptor, EphA4.33,34 Similar studies in MF have shown evidence for dysregulation of TNF signalling pathways.35 The signal transducer and activator of transcription (STAT) family of transcription factors are critically involved in regulating T-cell activation and STAT1 downregulation may play a role in interferon resistance of CTCL.36 As for other solid and hematologic malignancies, constitutive expression of STAT3 protein has been found in MF/SS.37 Interestingly it has been shown that EphA4 activates the JAK/STAT downstream signalling pathway which might explain the constitutive expression of STAT3 in CTCL, but this has yet to be confirmed.38 There is also evidence for expression of a truncated STAT5 protein in SS due to the presence of a serine protease, a situation mirrored in unactivated T-cells.39 Both early and late stages of T-cell activation may be further perturbed as there is evidence for hypermethylation of the phosphotyrosine phosphatase (SHP-1) promoter.40 These varied and complex abnormalities have a wide variety of potential consequences, but a unifying hypothesis would be that there is dysregulation of T-cell activation in MF/SS, which prevents activation induced T-cell death. In primary cutaneous CD30+ lymphoproliferative disorders such as anaplastic large cell lymphoma (ALCL)/lymphomatoid papulosis the t(2;5) translocation described in a majority of systemic CD30+ ALCL is not present.41,42 The lack of a translocation involving a fusion protein nucleophosmin NPM (2p23) and the anaplastic lymphoma kinase ALK gene (5q35) is reflected in the lack of nuclear expression of ALK protein by tumour cells. Recent studies suggest that primary cutaneous CD30+ ALCL cases also show overexpression of JunB at the genomic and protein level, suggesting that this gene may be amplified as has been shown in MF/SS.43 Intriguingly, JunB over-expression has been detected in both Hodgkin’s disease and systemic CD30+ ALCL and recent studies suggest that this is due to constitutive expression of an upstream ERK1/2/MAPK signalling pathway.44 JunB binds to the CD30 promotor and induces upregulation of CD30 which in turn induces ERK1/2/MAPK expression therefore creating an autoregulatory loop.45 Therefore it appears that both primary cutaneous and systemic CD30+ ALCL show distinct differences in pathogenesis as well as sharing certain molecular abnormalities.

Current therapies Skin directed therapy Class I to III (potent/moderate potency) topical corticosteroids can produce complete clinical remission in early-stage

Current therapies for CTCL

149

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 even if therapy is continued after remission (Tables 2 and 3).47–49 Mechlorethamine may cause an irritant reaction and up to 40% of patients develop contact hypersensitivity. This is less common with the ointment (0.01–0.02%). The aqueous solution (10–20 mg in 40–60 ml water) is less stable than the ointment. Mechlorethamine is carcinogenic and secondary cutaneous malignancies (non-melanoma skin cancer) have been attributed to long-term use (8.6-fold and 1.8-fold increased risk for squamous cell and basal-cell carcinoma, respectively).50 Mechlorethamine is an effective topical therapy for early-stage (patches/thin plaques) MF. However, interpretation of the studies is confounded by the use of other therapeutic modalities for most patients and the retrospective nature of the studies. Duration of response (DOR) varies, and the efficacy of maintenance therapy (6–18 months) and whole-body application remains unclear, but some patients with stage IA disease may be cured. Topical carmustine (BCNU – 10 mg in dilute (95%) alcohol (60 ml) or 20–40% ointment) has been shown retrospectively to induce CRs in 86% of stage IA, 47% of stage IB, 55% of stage IIA and 21% of stage III patients.51 The median time to CR in this retrospective study was 11.5 weeks. Contact hypersensitivity is uncommon (10%), but bone marrow suppression is common (30%). The risk of secondary cutane-

Table 2

ous malignancies may be lower than with mechlorethamine. There are no comparative trials of mechlorethamine and carmustine. A topical RXR retinoid has recently been approved by the FDA for patients with stage IA/IB disease resistant to other topical therapies. A phase I/II open study of 0.1–1% bexarotene (Targretin, Ligand Pharmaceuticals, San Diego, CA) gel as incremental doses in 67 patients with stage IA/IB/ IIA disease showed an overall response rate (ORR) of 63%, with 21% of patients showing a CR.52 Median time to response and DOR were 20 and 99 weeks, respectively. Bexarotene 1% gel twice daily was well tolerated and adverse events included mild/moderate pruritus, burning pain and rash (12% irritant contact dermatitis). As with other topical therapies the lack of a placebo control makes interpretation difficult. Another novel topical therapy is peldesine (BCX-34). Peldesine is an inhibitor of the purine nucleoside phosphorylase, an enzyme involved in purine degradation within lymphocytes. A randomised controlled trial compared topical application of peldesine twice daily to the entire skin surface for 24 weeks with a placebo (vehicle control) in 90 patients with stage IA/IB MF.53 PR or CR occurred in 28% of patients treated with peldesine and 24% of patients treated with placebo (P = 0.677). Treatment was well tolerated and only a minority of patients noted minor pruritus and rash. This is the only published placebo-controlled trial in CTCL. This trial demonstrated a significant placebo therapeutic response and thus no significant difference between the two arms. This study demonstrates the potential difficulties in interpretation of single arm trials of different topical therapies in early-stage MF.

Staging and treatment of mycosis fungoides or Sezary syndrome

Disease stage

Manifestation

Treatment

<10% BSA patch/plaque (T1) P10% BSA patch/plaque (T2) T1–T2, palpable adenopathy (node biopsy negative)

Topical (nitrogen mustard, carmustine, bexarotene) PUVA or narrow- or broad-band UV-B Electron beam radiation Oral bexarotene Immunomodulatory therapies

Intermediate  IIB  III  IVA

Cutaneous tumours (T3) Erythroderma (T4) T1–T4, node biopsy positive

Radiation therapy, including total skin electron beam irradiation Single-agent or combination chemotherapy (methotrexate, alkylating agents, fludarabine, gemcitabine, pentostatin, denileukin diftitox, bexarotene, liposomal doxorubicin) Photopheresis with or without adjuvant agents (interferons, bexarotene) for erythroderma PUVA with interferon Monoclonal antibodies (alemtuzumab) Investigational agents Stem cell transplantation

Advanced IVB

T1–T4, visceral involvement

Single-agent or combination chemotherapy Monoclonal antibodies Investigational agents Stem cell transplantation

Early  IA  IB  IIA

BSA, body surface area; PUVA, ultraviolet A light with oral methoxypsoralen.

150 Table 3

S.J. Whittaker, F.M. Foss Clinical studies in cutaneous T-cell lymphoma

Therapy Topical agents Mechlorethamine

Study type

Efficacy

Safety

Reference

RA NR

CRR Stage I: 26–76% Stage III: 22–49% CRR Stage IA: 86% Stage IB: 47% Stage IIA: 55% Stage III: 21% Stage IA–IIA: 21% CR, 42% PR ORR Stage IA/IB: 28% vs. 24% with placebo

Contact dermatitis, secondary cutaneous malignancies

[47–50]

Bone marrow suppression, telangiectasia

51

Contact dermatitis

52

Pruritus

53

CRR Stage IA/IB: 75–83% CRR Stage IA: 79–88% Stage IB: 52–59% Stage IIA: 83% Stage III: 46% CRR Stage I/II: 70% (1) vs. 38% (2)

Erythema, pruritus

54,55

Nausea, phototoxic reactions, secondary cutaneous malignancies

57,58

Flu-like symptoms

62

Carmustine

RA

Bexarotene

NR

Peldesine

R

Phototherapy UVB PUVA

PUVA plus alpha interferon (1) vs. acitretin plus alpha interferon (2)

RA NR NR

R

Radiotherapy Total skin electron beam therapy

MA

CRR Stage IA–IIA: 96% Stage IIB: 36% Stage III: 60%

Secondary cutaneous malignancies, pigmentation, anhydrosis,pruritus, alopecia, xerosis, telangectasia

65

Cytotoxic chemotherapy EPOCH

NR

ORR Stage ORR Stage Stage Stage ORR Stage Stage ORR Stage ORR Stage

Myelosuppression

100

Lymphopenia

108

Neutropenia

111

Neutropenia

115

Infusion-related events

122

Hypertriglyceridemia hyperlipidemia, hypothyroidism

123,124

Diarrhea, nausea, vomiting, fatigue

130,131

Flu-like symptoms, infusion-related events, vascular leak syndrome

133

Pentostatin

Fludarabine plus alpha interferon

Gemcitabine Pegylated liposomal doxorubicin Novel targeted strategies Bexarotene

HDAC inhibitors

Denileukin diftitox

NR

NR

NR RA

R NR NR

R

ORR Stage Stage ORR Stage Stage ORR Stage Stage

IIB–IV: 80% IIB: 75% III: 58% IV: 50% IIA–IVA: 58% IVB: 40% IIB/III: 70% IA–IV: 88%

IA/IIA: 20–67% IIB–IV: 49% IA/IIA: 20–31% IIB–IV: 25–30% I/IIA: 37% IIB–IV: 24%

CR, complete response; CRR, complete response rate; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone; MA, meta-analysis; NR, non-randomised; ORR, overall response rate; PR, partial response; PUVA, ultraviolet A light with oral methoxypsoralen; R, randomised; RA, retrospective analysis.

Current therapies for CTCL

Phototherapy Phototherapy remains a very effective skin directed therapy for early-stage CTCL, but there have been no comparative studies comparing different phototherapy modalities. Broadband UVB (290–320 nm) phototherapy with maintenance therapy produced CRs in 83% of 35 patients with early-stage disease (IA/IB) with a median response time of 5 months and median DOR of 22 months in one study.54 Narrowband UVB (TL-01; 311–313 nm) also produced CRs in 75% of patients with a mean DOR of 20 months.55 High-dose UVA1 phototherapy (340–400 nm; 100 J/cm2 on a 5 day per week basis) has been used in 13 patients (8 stage IB, four stage IIB and one stage III) until maximal response. Eleven of the 13 patients showed a CR (mean number of sessions 22; cumulative dose 2149 J/cm2) and seven patients had sustained the CR after a mean follow up of 7.2 months.56 PUVA (ultraviolet A light with oral methoxypsoralen) is the most commonly used phototherapy in CTCL. There have been no randomised controlled trials of PUVA monotherapy except those comparing PUVA alone with PUVA and different systemic therapies. An open study of 82 patients treated with PUVA and followed for up to 15 years reported an overall CR rate of 65% (79% for stage IA, 59% for stage IB and 83% for stage IIA disease) with mean cumulative doses of 134 J/cm2 (IA), 140 J/cm2 (IB) and 240 J/cm2 (IIA), and median time to CR of 3 months.57 In this study, 67% of stage IA, 41% of stage IB and 67% of stage IIA patients were free of disease at 2 years but maintenance PUVA was given to most patients.Survival rates at 5 and 10 years were 89% for stage IA, 78% for stage IB and, surprisingly, 100% for stage IIA. A further open study of PUVA in 82 patients with CTCL showed CR in 62% of patients, with 88% CR in stage IA (mean cumulative PUVA dose 160 J/cm2), 52% in stage IB (498 J/cm2) and 46% in stage III disease (178 J/cm2). No responses were seen in stage IIB patients.58 The maximum DOR was 68 months; 38% of the complete responders relapsed despite maintenance PUVA. Although maintenance therapy has been recommended for responders, a further open study has shown that 56% of stage IA and 39% of stage IB patients with CR had no recurrence of CTCL during a maximum period of 44 months follow up without maintenance therapy.59 A recent retrospective study has shown that of stage IA/IIA MF patients who achieve a CR, 50% will be sustained and 50% will relapse regardless of maintenance therapy.60 Importantly, the patients who did not relapse had a higher cumulative UVA dose and there was no difference in disease-specific survival at 5 and 10 years in patients who relapsed compared to those who did not. PUVA can cause nausea and phototoxic reactions. High cumulative UVA doses are also known to contribute to a higher risk of non-melanoma skin cancer. Ultraviolet B (UVB) phototherapy is an effective option for early patch and thin plaques but duration of disease-free remission varies and treatment probably does not affect long-term survival rates. UVA1 penetrates more deeply than UVB and PUVA but whether this is clinically relevant has not yet been established. Despite the lack of controlled trials, PUVA remains one of the most useful skin-directed therapies for early stages of MF. Randomised controlled trials comparing PUVA with narrow-band UVB (TL-01) and topical mechlorethamine would be helpful in early-stage disease (IA/

151 IB). DOR and disease-free and overall survival (DFS/OS) have also not been well defined. The role of maintenance therapy is unclear but high cumulative doses entail a significant risk of secondary skin cancers.

Combination regimens involving PUVA photochemotherapy Several well conducted trials have assessed the role of PUVA in combination with various systemic agents, notably interferon alpha and retinoids. Phase I and II studies of PUVA (three times weekly) combined with variable doses of alpha interferon (maximum tolerated dose of 12 MU/m2 three times weekly) in 39 patients with MF (all stages) and SS have reported an ORR of 100%: 62% showing CR and 28% PR. (CR rates were 79% in stage IB patients, 80% in stage IIA patients, 33% in stage IIB patients, 63% in stage III patients and 40% in stage IVA patients.)61 PUVA was continued as a maintenance therapy indefinitely while alpha interferon was continued for 2 years or until disease progression or withdrawal due to adverse effects. The median DOR was 28 months, with a median survival of 62 months.61 A randomised controlled trial compared PUVA (2–5 times weekly) plus alpha interferon (9 MU three times weekly) with alpha interferon plus an RAR retinoid, acitretin (25– 50 mg/day), in 98 patients with a maximum duration of treatment in both groups of 48 weeks.62 In 82 patients with stage I/II diseases, CR rates were 70% in the PUVA/interferon group compared with 38% in the interferon/acitretin group (P < 0.05). Time to response was 18.6 weeks in the PUVA/interferon group, compared with 21.8 weeks in the interferon/acitretin group (P = 0.026) but no data on DOR was reported. Total cumulative doses of alpha interferon were similar in both groups. An open study of 69 patients compared PUVA and acitretin with PUVA alone in MF.63 This showed that the cumulative dose of PUVA to achieve a CR was lower in the combined treatment group, although the overall CR rate was similar in the two groups (73% and 72%, respectively). No data on DOR was documented. These studies suggest that combined PUVA and interferon alpha are more effective than a combination of interferon alpha and acitretin in early-stage I/II disease. The trial comparing PUVA alone with PUVA plus acitretin suggests a reduction in mean cumulative dose of PUVA to achieve a CR, which would be helpful; disappointingly, however, there is no evidence for improved overall efficacy using combined retinoid and PUVA or alpha interferon and PUVA as ORRs are similar to those for PUVA alone. There are a number of weaknesses of these studies including the lack of a validated scoring system to assess tumour burden and lack of evidence that outcome was assessed blind to allocation status. In addition, data regarding the DOR and DFS/OS are urgently required. A randomised controlled trial comparing PUVA alone with PUVA plus alpha interferon has recently closed and the results are awaited.

Radiotherapy CTCL is a highly radiosensitive malignancy, and localised superficial radiotherapy is an invaluable palliative therapy for patients with all stages of MF. Dose response studies

152 have clearly established that localised superficial radiotherapy is an effective therapy for individual lesions in MF.64 A retrospective study of palliative superficial radiotherapy showed a CR rate of 95% for plaques and small (<3 cm) tumours and a CR rate of 93% for large tumours (>3 cm), irrespective of dose. Use of low-dose/energy (4 Gy in 200 cGy fractions at 80–150 kV) allows treatment of overlapping fields and lower limb sites. Total skin electron beam therapy (TSEB) has been an effective therapy for selected patients with advanced or cutaneously disseminated CTCL. There have been a number of large studies of TSEB in CTCL and higher dosage regimens are more effective (32–40 Gy with 4–6 MeV). A systematic review (meta-analysis) of open uncontrolled and mostly retrospective studies of TSEB as monotherapy for 952 patients with all stages of CTCL indicates that the rate of CR is dependent on stage of disease, skin surface dose and energy, with CR rates of 96% in stage IA/IB/IIA disease, 36% in stage IIB disease and 60% in stage III disease.65 Greater skin surface dose (32–36 Gy) and higher energy (4–6 MeV electrons) are associated with a significantly higher rate of CR (5-year relapse-free survivals of 10–23%). A retrospective study of 66 CTCL patients (1978–96) treated with 30 Gy in fewer fractions (12 fractions over 40 days) showed a CR rate of 65% with progression-free survival (PFS) of 30% at 5 years and 18% at 10 years.66 Responses and specifically 5-year OS were highest in those with early-stage disease (79–93% for IA/IB/III compared with 44% for IIB/IVA/B). Adverse effects of TSEB include radiation-induced secondary cutaneous malignancies, telangiectasia, pigmentation, anhidrosis, pruritus, alopecia and xerosis. A randomised controlled trial comparing TSEB with topical mechlorethamine in 42 patients, showed similar rates of CR and DOR in both groups in early stages of disease but better overall responses in later stages of disease with TSEB.67 This study clearly indicates a lack of a long-term response in early-stage disease and suggests that TSEB should be reserved for later stages of disease. A retrospective study of TSEB (median dose 32 Gy; median treatment time 21 days) as monotherapy for 45 patients with erythrodermic CTCL showed a 60% CR rate, with 26% DFS at 5 years.68 Median OS was 3.4 years and was best in those without peripheral blood involvement. Higher rates of CR (74%) and disease-free progression (36%) were noted in those patients receiving a more intense regimen (32– 40 Gy and 4–6 MeV). A retrospective non-randomised study comparing TSEB (32–40 Gy) alone with TSEB followed by extracorporeal photopheresis (ECP) (given 2 days monthly for a median of 6 months) in 44 patients with erythrodermic CTCL (59% had haematological involvement B1) reported an overall CR rate of 73% after TSEB, with a 3-year DFS of 49% for 17 patients who received only TSEB and 81% for 15 patients who received TSEB followed by ECP.69 This data in erythrodermic CTCL suggest that TSEB is effective, particularly if combined with ECP. Although it has been recommended that TSEB can only be given once in a lifetime, several reports have described multiple courses in CTCL.70,71 A retrospective analysis of 15 patients (1968–90) with MF who received two courses of TSEB reported a mean dose of 32.6 Gy for the first course and 23.4 Gy for the second, with a mean interval of 41.3

S.J. Whittaker, F.M. Foss months.70 No additional toxicities were noted but the CR rate for the second course was lower (40% compared with 73%). A further retrospective study of 14 patients with CTCL revealed a mean dose of 36 Gy for the first (93% CR) and 18 Gy for the second course (86% CR).71 In this series five patients received a third course. The median DOR was 20 months for the first and 11.5 months for the second course. No additional toxicities were reported. In both of these studies the fractionation regimens employed may have been critical for tolerability (1 Gy per day at 6 MeV over 9–12 weeks). A randomised controlled trial in 103 CTCL patients comparing TSEB and multi-agent chemotherapy (CAVE) with sequential topical therapy including superficial radiotherapy and phototherapy was conducted at the National Cancer Institute. In this study, a higher CR rate was reported in the TSEB/chemotherapy group (38% compared with 18%; P = 0.032) but after a median follow up of 75 months DFS and OS did not differ significantly.72 Although this randomised controlled trial indicates that combined TSEB and chemotherapy is no more effective than sequential skindirected therapy in CTCL, a further trial comparing TSEB alone with TSEB and chemotherapy in late stages of disease (stage IIB) would be helpful.

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 as a monotherapy in 16 patients with refractory disease, with an ORR of 30% and a DOR of 10 months.76 Constitutional symptoms and bone marrow suppression have limited aggressive and long term use of interferons for many patients. Early studies with high dose IL-2 has demonstrated activity in relapsed CTCL but with significant toxicity.77–87 In a recent study of intermediatedose IL-2, 11 patients (median age, 60 years) with advanced or refractory CTCL underwent 8-week cycles of daily subcutaneous injections of 11 MIU, 4 days per week for 6 weeks, followed by 2 weeks off therapy. This dose was well-tolerated, and there were four partial responses, three of which were sustained.88 IL-12 has also demonstrated activity in relapsed CTCL. In phase I and II studies, nearly half of the 32 evaluable patients achieved a response, and toxicities included myalgias, fatigue, and chills.89,90 ECP is an immunomodulatory apheresis-based therapy that works directly on both subsets of T cells and on the precursors of maturing dendritic cells77–84,86,91 ECP involves the collection of approximately 1010 peripheral blood mononuclear cells from a patient, exposure of the cells to PUVA, and then reinfusion of the treated cells. The mechanism of action of ECP is believed to be related to the induction of apoptosis in clonal Sezary T-cells, leading to uptake and processing of tumour antigens by immature dendritic cells

Current therapies for CTCL generated from the effects of the ECP process on circulating monocytoid precursors.92 The process of ECP has been shown to induce a cell-mediated anti-tumour response. Clinical improvement with ECP has been demonstrated in both patients with the SS and in patients with tumour and plaque stage CTCL. Other biomodulatory agents have been combined with photophoresis, including retinoids, interferons, and cytokine growth factors. Richardson and colleagues have reported high response rates in patients with the SS whenECP therapy was administration with immune adjuvant therapies, including interferon alpha and bexarotene.93 In some cases, granulocyte-macrophage colony-stimulating factor (GM-CSF) was also administered following each ECP treatment to enhance antigen-presenting cell function. In one patient, administration of GM-CSF 3 times per week for 6 months resulted in the persistent normalization of dendritic cell numbers. This finding may indicate that the long-term use of GM-CSF may augment the functions of antigen-presenting cells in patients with SS. A modification of ECP known as transimmunisation may improve tumour-targeted response. Researchers at Yale University have devised an immunotherapy for treatment of T-cell malignancies and T-cell–mediated immunologic disorders.94–97 Transimmunisation involves co-incubating the apoptotic malignant T cells and the newly formed dendritic cells prior to reinfusion in order to optimize antigen processing and stimulate a more efficient induction of tumour-targeted immunity. The goal of treatment is to transfer the disease-associated antigens to antigen-presenting dendritic cells, thus initiating immunisation against these antigens. A phase I trial of transimmunisation in advanced CTCL has been completed. Another novel immunomodulatory therapy is the use of CpG oligonucleotides, a new class of immunomodulators that targets multiple immune effector cells. The Toll-like receptor 9 agonist CPG7909 belongs to this new class of immunomodulators. In a phase 1 study of 28 patients with recurrent or advanced CTCL who received CPG7909 in weekly subcutaneous doses of 0.08, 0.16, 0.24, or 0.28 mg/kg for 24 weeks, the ORR was 25%.98 Five patients (18%) achieved PRs and 2 (7%) achieved CRs. Studies combining CPG7909 with other immunomodulatory therapies are planned.

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 patients), with 4 (27%) CRs.100 However, the median DOR was just 8 months (range 3–22 months). At a median follow-up of 11.4 months (range from 2 to P56 months), median survival was 13.5 months. Treatment-related toxicity was significant, with 61% of the patients experiencing grade 3/4 myel-

153 osuppression. Because of the high risk of infection and myelosuppression and modest response durations with combination chemotherapy, single-agent therapies are preferred except in patients who are refractory or who present with extensive adenopathy and/or visceral involvement and require immediate palliation.

Purine analogs One class of agents which has demonstrated significant activity is the nucleoside analogs. ORRs as high as 70% have been reported for pentostatin.101–107 Investigators at the MD Anderson Cancer Center reported an ORR of 56% for dose escalated pentostatin (3–5 mg/m2/day for 3 days on a 21day schedule) in 42 patients with CTCL.108 The median OS was 18 months with a median failure-free survival of 2.1 months. Grade 3/4 neutropenia occurred in 21% of patients. The incidence of infectious complications with pentostatin was initially high but was subsequently reduced by prophylactic trimethoprim and anti-viral therapies. In a combination study of pentostatin at 4 mg/m2/day · 3 with intermediate dose interferon alpha, the ORR was similar, but the median PFS was improved to 13.1 months.109 Fludarabine and cladrabine have demonstrated more modest single-agent activity with an ORR of 16% in refractory patients.110 The combination of fludarabine with interferon alpha had greater efficacy with an ORR of 51% (4 CR, 14 PR) with a median PFS of 5.9 months and an OS of 19.6 months; however, haematologic toxicity was significant, with 62% of patients experiencing grade 3/4 neutropenia.111 Similarly, a combination of fludarabine (18 mg/m2) and cyclophosphamide (250 mg/m2) for 3 days monthly was associated with a DOR of 10 months but with significant hematologic toxicity.112 Quaglino et al.113 reported results from a non-randomised study comparing fludarabine monotherapy to the sequential use of fludarabine with ECP in 44 patients with advanced CTCL. The ORR was 29.5% with a higher response rate in patients with the SS (35.3%) than with MF (25.9%). The ORR for the combination therapy was 63.2% compared to 29% with fludarabine alone, but there was not a significant difference in time to progression (13 months vs. 7 months). A decrease in the CD4+CD26 subset was reported in patients who were responders, which paralleled a reduction in circulating Sezary cells. Gemcitabine, a pyrimidine antimetabolite, has also demonstrated activity in advanced and refractory CTCL. Zinzani and colleagues observed a 70% ORR (31 patients), including 8 (11%) CRs, in 44 patients treated on Days 1, 8, and 15 of a 28-day schedule at a dose of 1200 mg/m2 for a total of 3 courses. For complete and partial responders, the median DORs were 15 months (range 6–22 months) and 10 months (range 2–15 months), respectively.114,115 Talpur et al. reported similar results with an ORR of 68% (3 CR, 19 PR) in 32 patients.116 Tumours improved or resolved in 10 of 13 patients with stage IIB disease. The incidence of grade 3 neutropenia was 25%. The use of gemcitabine as first line therapy in advanced CTCL has recently been explored. A dose of 1200 mg/m2 of gemcitabine was administered on Days 1, 8, and 15 of a 28-day schedule for a total of 6 courses to 20 patients, 19 with stage IIB/IV MF or SS.117 These patients had all been treated previously with local radiation or PUVA,

154 but were chemotherapy-naive. The ORR was 70%, with 5 complete responders and a median DOR of 8 months. Forodesine (BCX-1777) is a novel nucleoside analog which inhibits purine nucleoside phosphorylase, resulting in accumulation of deoxyguanosine and dGTP and apoptosis in Tlymphocytes.118 A phase I/II study of intravenous forodesine enrolled 13 patients with CTCL or the SS who received at least 1 course of forodesine. Nine of the 13 patients had a skin improvement and/or a pharmacodynamic response—as measured by a decrease in the absolute numbers of Sezary cells and/or a decrease in the CD4/CD8 ratio. One patient achieved CR and 2 achieved PRs. A study of oral forodesine is underway in patients with relapsed or refractory CTCL at doses of 40, 80, 160, and 320 mg/day for 28 days. Thus far, responses have been seen in a small number of patients treated. Toxicities associated with forodesine have been mild and include nausea and reversible lymphopenia. ARAG, a prodrug of deoxyguanosine, has been explored in 19 patients, 11 with CTCL previously untreated with systemic therapy and 8 with relapsed or refractory PTCL.119 A daily intravenous infusion of 1.5 g/m2 was administered on Days 1, 3, and 5, for a 21-day cycle. Efficacy results were disappointing, with 2 PRs in each patient group for an ORR of 10.5%. Median event-free survival was 1.2 months, median OS was 3 months, and 2 patients died of treatment-related causes. There was significant neurologic toxicity, with 33% of patients experiencing grade 3/4 ataxia, vertigo, peripheral neuropathy, confusion, and/or depressed consciousness.

Liposomal doxorubicin Pegylated liposomal doxorubicin is an active agent in Kaposi’s sarcoma and has been shown to accumulate in involved skin lesions.120 Rupoli et al. evaluated liposomal doxorubicin at a dose of 20 mg/m2 every 28 days for 2–8 cycles in 7 patients with CTCL, including 2 with transformed histology.121 All patients had been previously treated with interferon alpha, PUVA, single-agent gemcitabine, fludarabine, or combination chemotherapy. The ORR was 88%, including 4 CRs. Wollina et al. reported similar results using lower doses of liposomal doxorubicin in a larger study of 34 patients with CTCL or PTCL.122 In this retrospective multicenter study, all patients received at least 1 cycle of liposomal doxorubicin, intravenously administered in a 20 mg/m2 dose every 2 weeks (n = 6), every 2–3 weeks (n = 4), or every 4 weeks (n = 23). There were 15 CRs and 15 PRs, with a median event-free survival of 12.0 months. With the exception of infusion related events, liposomal doxorubicin was well-tolerated.

Novel targeted strategies 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

S.J. Whittaker, F.M. Foss years later. Responses occurred in patients with large cell transformation and with erythrodermic SS who were refractory to other systemic therapies. The dose limiting toxicities of bexarotene are related to hypertriglyceridemia, hyperlipidemia, and hypothyroidism. Administration of lipid-lowering agents and thyroid replacement therapies has significantly improved the therapeutic index of bexarotene. The effects of bexarotene on immune response to CTCL have recently been described by Porcu et al. He reported an overall increase in CD8+ T cells with a concordant decrease in the CD4/CD8 ratio after 6 weeks of therapy; of interest, a decrease in CD8+ cells preceded relapse in 21 patients. Bexarotene has been studied in combination with interferon alpha in patients with refractory CTCL in a phase 2 trial. Responses were comparable when bexarotene was used as a single-agent or in combination.125

HDAC inhibitors Histone deacetylase (HDAC) inhibitors modulate gene expression by inhibiting the deacetylation of histone proteins associated with DNA, thereby permitting expression of a number of genes.126 Numerous HDAC defects have been identified in vitro, and HDAC inhibition has been shown to induce histone acetylation, cell cycle arrest, and apoptosis in leukaemia and lymphoma cell lines.127,128 Depsipeptide was the first HDAC inhibitor tested in clinical trials at the National Cancer Institute. Piekarz et al. conducted a phase II study of depsipeptide administered at a dose of 14 mg/m2 on Days 1, 8, and 15. Of 27 patients, three with the SS had a CR and 5 had a PR, including 3 with tumour stage MF.129 The DOR ranged from 8 to 14 months. Toxicities included nausea, thrombocytopenia, leucopenia, and reversible ST-T segment changes and QT prolongation on electrocardiograms. Vorinostat (suberoylanilide hydroxamic acid, SAHA), an orally bioavailable HDAC inhibitor, demonstrated responses in patients who received daily dosing. In a phase 2 single-agent study, oral vorinostat was administered (400 mg daily, 300 mg twice daily for 3 days with 4 days rest, or 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily) to 33 patients with relapsed or refractory CTCL.130 The ORR in this heavily pretreated population was 24% (8 patients), and responses were observed in 7 of 28 patients (25%) with advanced disease and 4 of 11 patients (36%) with SS. The median time on therapy of the responders was 7 months. Adverse events included nausea, vomiting, and fatigue. The 400 mg daily schedule had the most favourable profile and was further evaluated in a multicenter, phase 2b trial.131 In this study, 22 of 74 patients (30%) with relapsed or refractory CTCL achieved a response, including 18 of 61 patients (30%) with advanced disease and 10 of 30 patients (33%) with SS. The median time to progression for responders with stage IIB or higher disease was not reached but estimated to be at least 9.8 months. The most common adverse events included diarrhea, fatigue, and nausea.

Denileukin diftitox Fusion proteins are recombinant molecules that combine a targeting mechanism with a cytocidal moiety. Denileukin diftitox consists of the IL-2 gene joined to the active and

Current therapies for CTCL membrane-translocating domains of diphtheria toxin. Denileukin diftitox intoxicates cells expressing both intermediate- and high-affinity IL-2 receptors by inhibiting protein synthesis.132 The pivotal trial that led to FDA approval of denileukin diftitox was a multicenter, randomized, double-blind study that administered 2 daily doses of denileukin diftitox, 9 mg/kg or 18 mg/kg, for 5 days, in 71 patients with relapsed or refractory CTCL. The ORR was 30%, with 10% CRs (7 patients) and 20% PRs (14 patients).133 The median DOR was approximately 6.9 months. A combination study of bexarotene and denileukin diftitox was initiated based on the observation that bexarotene upregulates expression of IL-2 receptor on lymphoma cells and enhances the susceptibility of these cells to undergo apoptosis in the presence of denileukin diftitox. Fourteen patients with refractory CTCL received escalating daily doses of bexarotene (75–300 mg) and denileukin diftitox (18 mcg/kg for 3 days every 21 days).134 The ORR for all evaluable patients was 70%, with 4 CRs (35%) and 4 PRs (35%). Four patients developed grade 2/3 leukopenia, and 2 developed grade 4 lymphopenia. This study demonstrated that doses of bexarotene greater than 150 mg/ day were capable of in vivo up-regulation of CD25 (IL-2) expression and may enhance the efficacy of denileukin diftitox.

Monoclonal antibodies Zanolimumab is a high-affinity, fully humanized monoclonal antibody that targets the CD4 receptor on T lymphocytes. Kim and colleagues have reported promising results with zanolimumab in 49 patients with biopsy-proven CD4+ CTCL, including 23 patients with advanced-stage disease.135 Patients were initially treated with intravenous zanolimumab at a dose of 280 mg/week, which was increased to 560 mg/week in early-stage patients and 980 mg/week in patients with advanced disease. Partial remissions were reported in 16 of 36 (44%) evaluable patients overall including 3 of 6 with advanced disease at 980 mg/week. SGN-30 is a chimeric mononclonal antibody that recognizes the CD30 antigen, expressed on subsets of activated T and B cells as well as in tumour cells of patients with Hodgkin’s disease and ALCL. Forero and colleagues reported results from an ongoing phase 2 study of SGN-30 in patients with refractory ALCL. Patients were treated with 6 weekly infusions of 6 mg/kg of SGN-30. The median age of the 8 patients with ALCL was 59 years. Among the 6 evaluable patients, there was 1 CR, 1 PR, 1 sustained remission, and 3 cases of disease progression.136 A study is underway to evaluate the efficacy of SGN-30 in patients with cutaneous CD30+ lymphomas, including CD30+ transformed MF. In this study, 5 of 6 patients have responded, and toxicity has been minimal. Alemtuzumab, a humanized monoclonal antibody that targets the CD52 antigen, has been shown to be active in relapsed or refractory T-cell lymphomas but was associated with significantly immunosuppression and a high incidence of opportunistic infections.137–140 Zinzani et al. explored the efficacy of lower doses of alemtuzumab, 10 mg three times per week, and reported responses in 6 of 10 patients, including 2 CR and 4 PR.141 Cytomegalovirus (CMV) reactivation occurred in only 1 patient (10%).

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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 of DNA vaccines was recently demonstrated by Urosevic et al., who developed a recombinant adenoviral vaccine containing the interferon gamma gene.144 Intralesional injection of this vaccine into the tumoral lesions of CTCL has led to responses in 13 patients with regression of non-injected distant lesions in some, suggesting a systemic effect. Presence of the interferon gamma gene has been confirmed in biopsied tumour tissue.

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 underwent allogeneic HLA-matched sibling transplantation.148 Reduced-intensity allogeneic transplantation has been developed to reduce the toxicity related to induction therapy and to increase graft-vs-lymphoma effect. Herbert and colleagues evaluated reduced-intensity allogeneic transplantation with bone marrow stem cells from HLA-matched siblings in 3 patients with ages ranging from 35 to 49 years who had advanced refractory MF and transformed disease.149 Transplant related mortality was low, but all experienced early relapse. One patient achieved a CR with salvage chemotherapy. The use of reduced intensity conditioning regimens in advanced CTCL patients is still undergoing investigation. Results with autologous stem cell transplantation have not been as promising. Olavarria and colleagues described their experience with autologous bone marrow transplantation in 9 patients with stage III and IV CTCL.150 These patients had been received up to 5 previous treatment regimens. Among the 9 patients who successfully underwent autologous transplantation, 7 relapsed within 2–14 months.

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

156 palliative needs of these patients are considerable. There is therefore a serious unmet therapeutic need for this group of patients. The recent development of RXR retinoids and toxin therapies have provided important alternative systemic treatment options for patients with resistant and late stages of disease, but it is clear that these approaches have not produced durable remissions at a high rate. Of the other novel therapies which show promise in CTCL, humanised antibodies may be associated with additional risks of severe immunosuppression such as CMV reactivation. In contrast therapies such as HDAC inhibitors may offer important and well tolerated therapeutic options for early stage patients with treatment resistant disease or those with frequent relapses, while patients with late stage disease may benefit from these therapies as second line or maintenance treatment. Although the underlying pathogenesis of CTCL is unknown, there are a wide range of genomic mutations and a high incidence of epigenetic abnormalities. These epigenetic changes are likely to be responsive to HDAC inhibition which therefore represents an additional form of targeted therapy in CTCL. The identification of CTCL patients who might be responsive to epigenetic therapy would be beneficial. There is also an urgent need to assess novel therapies in controlled trials although the difficulties in establishing appropriate endpoints and enrolling sufficient numbers of patients to ensure adequate statistical power for such studies should not be underestimated.

Acknowledgments This work was supported in part by funding from Merck & Co., Inc. The authors also thank Justin L. Ricker for his editorial assistance.

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