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Mycosis Fungoides

1. GENERAL INFORMATION

1.1 Definition

Mycosis fungoides (MF) constitutes the most frequent cutaneous T-cell lymphoma. Sézary syndrome is considered an erythrodermic leukemic variant of MF. Its postulated normal counterpart is a peripheral epidermotropic CD4+ T cell. Mycosis fungoides is included in the new WHO-EORTC classification of primary cutaneous lymphomas (Willemze 2005).

1.2 Incidence

Mycosis fungoides (MF) is an uncommon lymphoma; however, it is the most common of the primary cutaneous lymphomas. MF constitutes 50% of all primary NHL of the skin (Willemze 2005). Annual incidence is 0.29/100.000, being about 0.5% of all new cases of NHL diagnosed in the USA each year (Weinstock 1991).

1.3 Risk factors

The cause and risk factors of MF and Sézary syndrome are unclear. Although environmental and occupational exposures, such as exposure to solvents and chemical, have been implicated in the etiology of the disease, the most recent large case-controlled study failed to support this hypothesis (Whittemore 1989). A viral etiology for MF has been also suggested. There are some reports that have found human T-lymphotrophic virus-1 (HTLV-1) either in the peripheral blood or cutaneous lesions of some patients with MF or Sézary syndrome (Hall 1991). However, many studies have revealed evidence against a role of HTLV-1 (Wood 1996). At present, HTLV-1 is not considered to play any role in the etiology of MF. The role of other viruses such as cytomegalovirus is still unclear (Herne 2003). A few studies have demonstrated histocompatibility antigen associations with MF and Sézary syndrome, specifically Aw31, Aw32, B8, Bw38, and DR5 (Nisce 1981). Chromosomal abnormalities have been identified in tumor cells, mostly deletions and translocations in chromosome 1 or 6 (Johnson 1985). Recently, new molecular studies revealed alterations of NAV3 in MF and Sezary syndrome (Karenko 2005). The significance of these features is yet unclear.

2. PATHOLOGY AND BIOLOGY

2.1 Morphology

The tumor cells of mycosis fungoides are predominantly small cells with cerebriform nuclei, with a minority of larger cells with similar nuclei, which infiltrate the epidermis, circulate in the blood and involve the paracortex of lymph nodes. Atypical cells may be completely absent in early lesions (Massone 2005). The infiltrate is variable accompanied by interdigitating and Langerhans’ cells. The bone marrow is usually normal. Although MF presents usually with band-like, epidermotropic infiltrates, several clinicopathologic variants have been described (e.g., follicular MF, etc.).

2.2 Immunophenotype

The cells of mycosis fungoides express T-cell-associated antigens (CD2+, CD3+, CD5+), approximately one third are CD7+; most cases are CD4+, but rare CD8+ and/or CD56+ cases have been reported. CD25 is usually negative, but positive cases have been reported. S-100+ CD1a+ interdigitating and Langerhans’ cells are present (Ralfkiaer 1993). Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7- population reflective of circulating atypical lymphocytes of Sézary type (Harmon 1996).

2.3 Genetic features

TCR genes are clonally rearranged, but detection of a monoclonal population of T lymphocytes may be difficult in early lesions (Massone 2005). TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sézary syndrome (Muche 1997). Several chromosomal aberrations have been described using different molecular methods, but at present a repeatable pattern has not been identified.

3. DIAGNOSIS

3.1 Clinical presentations

Mycosis fungoides (MF) usually occurs in old adults, with a median age between 55 and 60 years and a 2:1 male to female ratio, presenting with multiple cutaneous plaques or nodules, or with generalized erythroderma. Cases in children have been well documented. MF presents as an indolent cutaneous eruption with erythematosus scaly patches or plaques that often resemble common skin disorders such as atopic dermatitis or psoriasis. The initial lesions are often confined to sun-protected areas, although any skin site may be affected. There may be prominent poikiloderma (skin atrophy with telangiectasia) or associated alopecia or with follicular mucinosis. In addition, several other clinical variants have been described (e.g., hypopigmented MF among others). Especially in the past, a definitive diagnosis is was often preceded by a variably long period (often referred to as the “premycotic” stage) that could range from several months to several years (Hoppe 1990). However, the identification of precise histopathologic criteria for diagnosis of early MF allows a specific diagnosis in most cases (Sanchez 1979; Massone 2005). As the disease progresses, patches may evolve into infiltrated plaques with a more generalized distribution, and patients may subsequently develop ulcerated or exophytic tumors.nt Tumors, however, develop only in a minority of the patients (Kim 1996; Willemze 2005). Another phase of skin involvement is generalized erythroderma. The erythema may be accompanied by either very atrophic or lichenified skin, and plaques or tumors may also be present. These patients are almost always affected by intense pruritus. If peripheral blood involvement is present, these patients are considered to have Sézary syndrome. It is controversial as to how many or what percentage of Sézary cells constitute a significant level to define Sézary syndrome. Although the original NCI classification used the criterion of greater than 5% lymphocytes for significant blood involvement (Bunn 1979), the current practice by many MF referral centers is to use a criterion of at least 20% lymphocytes or an absolute count of at least 1.000/mm3 to define peripheral blood involvement. Precise criteria for definition of Sezary syndrome have been proposed in the new WHO-EORT classification of cutaneous lymphomas (Willemze 2005). Sézary syndrome is considered by some authors to be an erythrodermic leukemic variant of MF, but is classified separately in the new WHO-EORT classification of cutaneous lymphomas (Willemze 2005). Patients present with generalized erythroderma, lymphadenopathy and circulating atypical T cells (Sézary cells) in the peripheral blood. Peripheral blood involvement may be subtle in MF or prominent in Sézary syndrome. Patients may present with all components of Sézary syndrome or may present initially with only one component and subsequently progress to develop other clinical features of this syndrome (Wieselthier 1990). Patients with Sézary syndrome have a worse prognosis than patients with erythrodermic MF (Kim 1995). Extracutaneous involvement is directly correlated to the extent of cutaneous disease. Cutaneous dissemination is observed in less than 10% of patients with patch or plaque disease and in 30% – 40% of patients with tumors or generalized erythrodermatous involvement (Hoppe 1990). Lymphadenopathy is usually a late occurrence, being an initial manifestation of extracutaneous dissemination. Regional lymphadenopathies especially in areas draining extensive skin involvement are the most common presentation. Visceral dissemination may develop subsequently, and the most commonly involved organs are the lungs, spleen, liver, and gastrointestinal tract (Epstein 1972). In advanced stages, transformation into a large cell lymphoma may occur, with predominance of either immunoblasts, large pleomorphic, or large anaplastic cells. Some of these cases are CD30+, thus being similar to anaplastic large cell lymphoma. An association with Hodgkin’s disease and lymphomatoid papulosis has also been reported.

3.2 Diagnostic criteria

Clinical criteria for early diagnosis of MF include presence of asymmetrical, irregular, persistent erythematous lesions on sun-protected areas, that don’t improve with or recur after conventional treatments. Histopathologic criteria for diagnosis of early MF include the following: presence of a patchy-lichenoid or band-like lymphocytic infiltrate within an expanded, partly fibrotic papillary dermis; epidermotropism of lymphocytes (arranged either as solitary units or in small collection defined as “Pautrier’s microabscesses” or aligned along the dermo-epidermal junction); presence of atypical lymphocytes (lymphocytes larger than normal and with indented – cerebriform nuclei); presence of intraepidermal lymphocytes larger than the dermal ones; intraepidermal lymphocytes surrounded by a clear halo (“haloed lymphocytes”). It should be underlined that in some cases histopathologic features alone are non-diagnostic, and only a careful clinicopathologic corelation allows a precise diagnosis. Flow cytometric studies of the peripheral blood may show expansion of the CD4+ CD7- population reflective of circulating atypical lymphocytes of Sézary type (Harmon 1996). Detection of monoclonality of the T lymphoytes by molecular techniques is a useful additional diagnostic criterion. TCR gene-rearrangement studies may show evidence of clonal expansion in peripheral blood in patients with Sézary syndrome (Muche 1997).

3.3 Additional useful tests

DNA microarray studies revealed a specific “gene signature” of MF as compared to inflammatory skin disorders (Tracey 2003). These results, if confimed by larger studies, may provide valuable additional diagnostic criteria in the near future.

4. STAGING

4.1 Staging procedures

Complete staging work-up for mycosis fungoides (MF) includes an accurate physical examination, with a careful description of all cutaneous lesions (especially including the scalp, palms, soles and anogenital region) and complete hematological and biochemical exams with Sézary cells analysis. Even if the “blood” classification does not modify clinical stage, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease (Hoppe 1990). Routine imaging studies in patients with early stages (I to IIA) in the absence of peripheral lymphadenopathy is unproductive (Kulin 1990). Lymph node biopsies must be obtained if lymphadenopathy is present, since the presence of lymph node involvement affects both the stage and prognosis. Appropriate imaging studies and histologic evaluation must confirm suspected sites of visceral involvement when possible. Significant bone marrow involvement with an infiltrative histologic pattern is never found as a rule in patients with limited skin disease, and can be observed in patients with advanced MF or with Sézary syndrome (Salhany 1989). Significant bone marrow disease is usually reflected by the presence of readily detectable Sézary cells in the peripheral blood. Therefore, bone marrow biopsy is not routinely used as part of the initial staging procedure for patients with MF.

4.2 Staging system

The standard staging classification system for mycosis fungoides (MF) is the tumor, node, metastasis, blood (TNMB) system first proposed at the NCI-sponsored Workshop on cutaneous T-cell lymphomas in 1978 (Bunn 1979), and is summarized as follows:

T (skin)
T1: limited patch/plaque (< 10% of total skin surface)
T2: generalized patch/plaque (≥10% of total body surface)
T3: tumors
T4: generalized erythroderma

N (lymph node)
N0: lymph nodes clinically uninvolved
N1: lymph nodes enlarged, histologically uninvolved
(reactive and dermatopathic nodes)
N2: lymph nodes clinically uninvolved, histologically involved
N3: lymph nodes enlarged and histologically involved

M (viscera)
M0: no visceral involvement
M1: visceral involvement

B (blood)
B0: no circulating atypical Sézary cells (< 5% of lymphocytes)
B1: circulating atypical Sézary cells (≥5% of lymphocytes)

The overall clinical stage is defined by the TNMB criteria as follows:
Stage IA: T1 N0 M0
Stage IB: T2 N0 M0
Stage IIA: T1-2 N1 M0
Stage IIB: T3 N0-1 M0
Stage IIIA: T4 N0 M0
Stage IIIB: T4 N1 M0
Stage IVA: T1-4 N2-3 M0
Stage IVB: T1-4 N0-3 M1
The “blood” classification does not modify clinical stage.

4.3 Molecular analysis of minimal residual diseaseMolecular analyses by PCR have been used for detection of minimal residual disease and of early recurrences in some study, but their reliability and repeatability are yet controversial.

4.4 Restaging proceduresRestaging should include all diagnostic procedures positive at time of diagnosis and initial staging.

5. PROGNOSIS

 5.1 Natural history

The prognosis of mycosis fungoides (MF) is variable and strongly conditioned by the extent and type of skin involvement and presence of extracutaneous disease. Patients with stage IA-disease have an excellent prognosis with an overall long-term life expectancy that is similar to an age-, sex-, and race-matched control population (Kim 1996 ; Willemze 2005). Almost all patients with stage IA MF who die will die from causes other than MF, with a median survival longer than 33 years. Only 9% of these patients will progress to more extended disease. The latter group of patients had a lower complete remission rate to initial therapy and an older mean age than the rest of stage IA patients. Patients with stage IB or IIA have a median survival greater than 11 years (Kim 1999b). These patients with T2 disease have a likelihood of disease progression of 24% and nearly 20% die of causes related to MF. Subgroups with stage IB or IIA have similar prognosis. Patients with cutaneous tumors (stage IIB) or generalized erythroderma (stage III) have a median survival of 3 and 4.5 years, respectively. The majority of these patients will die of MF. The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (65 years), overall stage (III vs. IV), and peripheral blood involvement (B0 vs. B1) (Kim 1995). The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. Patients with extracutaneous disease at presentation involving either lymph nodes (stage IVA) or viscera (stage IVB) have a median survival of less than 1.5 years. Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology, often expressing CD30. CD30+ lymphomas arising in these patients share a common clonal origin as observed in their preexisting MF (Wood 1993). These patients usually have rapid disease progression and require more intensive local or systemic therapy. Thus, transformation of MF to a large cell lymphoma is associated with an aggressive clinical course and less favorable outcome.

5.2 Prognostic factors

The extent and type of skin involvement, that is T-stage, and presence of extracutaneous disease arethe most important indicators of survival in patients with mycosis fungoides (MF). The long-term outcome in patients with erythroderma is quite variable and is dependent on patient age at presentation (65 years), overall stage (III vs. IV), and peripheral blood involvement (B0 vs. B1) (Kim 1995). The median survival can vary widely depending on the combinations of these independent prognostic factors, and three distinct prognostic subgroups have been identified, with a median survival of 10, 3.5 and 1.5 years. The presence of a significant number of Sézary cells in the peripheral blood (B1 condition) is not factored into the overall clinical stage; however, it usually correlates with a more advanced T-stage (usually T4) and the presence of extracutaneous disease (stage IV) (Hoppe 1990). The lymph node histologic grade seems to correlate with survival. Dermatopathic changes or the presence of just a small number of atypical cells (histologic grade LN-1 or LN-2) have a 5-year survival of 80%. Patients with large clusters of paracortical atypical cells (LN-3) have a 5-yr survival of 30%, and those with effaced nodes (LN-4) have a 5-yr survival of 15% (Sausville 1988). Actual lymph node involvement with MF (N2-3, stage IVA) correlates with the histologic grade of LN-3 or -4. Some genetic features have been linked to worse prognosis, including among others the finding of an identical clone in the blood and the skin (Beylot-Barry 2001 ; Fraser-Andrews 2000).

6. TREATMENT

6.1 Treatment of stage IA disease

For patients with T1 without extracutaneous involvement (stage IA), standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total skin topical mechlorethamine hydrochloride (HN2), phototherapy ultraviolet B (UVB), psoralen and ultraviolet A (PUVA), or localized electron-beam radiotherapy (EBRT). There is no evidence that early aggressive systemic therapy is preferable to conservative strategy in the management of limited disease (Kaye 1989). Patients treated with topical HN2 had a similar long-term survival than those treated with total-skin EBRT, with a complete remission rate of 70% – 80% and a median time to skin clearance of 6 to 8 months. When treatment is discontinued, more than half of the patients will relapse locally, but most will respond to a resumption of therapy. Twenty percent of patients treated with topic HN2 have a durable remission (>10 years). Topical HN2 with 10 to 20 mg/dL strength, either in ointment base or in water, can be applied to the entire skin once daily (Kim 1996). Treatment is continued on a daily basis until complete skin clearance, which is followed by a variable duration of maintenance therapy. By this way, HN2 seems to exert its cytotoxic activity mediated by immunostimulation. Topical BCNU produces similar outcome to those obtained with HN2 (Zackheim 1994); however, because of its systemic absorption, the potential hematologic complications are greater and the maximum duration of treatment is limited. Local EBRT is useful for the rare patients with a single lesion. EBRT is followed by a topical HN2 maintenance regimen. The total-skin EBRT should be reserved for patients with progressive skin disease. In spite of a higher remission rate, there are no difference in survival between patients treated with topical HN2 or with EBRT (Kim 1996). UVB or PUVA are also used a standard treatment in T1 disease. After 1.5 to 2 hours of oral psoralen, patients receive a timed exposure to UVA light in a phototherapy unit. Only the eyes are shielded routinely, however selected areas can be shielded to minimize undesired photodamage. Certain areas like scalp, perineum, and axillae may result shadowed and not receive adequate exposure. PUVA treatment is initiated thrice weekly until skin clearance is achieved, after which the frequency is gradually decreased to as infrequently as once every 2 weeks. Maintenance should be discontinued within one year to reduce the risk of skin carcinogenesis. With this strategy, complete remission rate is 90%, with a median time to skin clearance of 2 to 6 months (Abel 1987; Herrmann 1995; Ramsay 1992; Resnik 1993; Roenigk 1990). An alternative to PUVA is represented by narrow-band (311nm) UV-B phototherapy (Boztepe 2005; Gathers 2002 ; Diederen 2003; El-Mofty 2005;Ghodsi 2005). Erythema, pruritus, skin dryness, nausea, cataracts, and carcinogenesis are the main complications related to phototherapy (Wood 1986). Chronic complications are more common in patients treated with more topical strategies. The long-wave UVA has an advantage over UVB in its greater depth of penetration into the dermal infiltrates of MF. Other topical treatment possibilities for which experience in large, controlled studies is lacking include topical steroids, bexarotene gel, topical methotrexate, imiquimod cream, and photodynamic therapy (Breneman 2002 ; Coors 2004; de Quatrebarbes 2005; Deeths 2005; Demierre 2003 ; Heald 2003). Several aspects other than clinical stage strongly influence therapeutic decision. Among others, the assessment of prognostic factors, the accessibility of different approaches, the patient’s age, social problems, and the cost-benefit ratio should be taken into consideration. This is equally important for all other stage-disease in MF. Nonspecific symptomatic treatment is an integral component of the overall therapeutic regimen. Supportive measures such as aggressive emolliation, topical steroids, and oral antipruritics should be used as necessary. Hoppe 1991; Quiros 1997).

6.2 Treatment of stage IB – IIA disease

For patients with T2 without extracutaneous involvement (stage IB – IIA), the standard treatment plan is limited to topical therapeutic measures. The main therapeutic options for these patients are local or total skin topical mechlorethamine hydrochloride (HN2), psoralen and ultraviolet A (PUVA), or total-skin electron-beam radiotherapy (EBRT). The latter should be considered as initial therapy for patients with very thickened plaques, since the effective depth of treatment of total-skin EBRT is more substantial than with either topical HN2 or PUVA. It should also be considered for patients with rapid progression and patients who failed to respond to the other strategies. A total dose of 36 Gy administered over a 10-week period, with a 1-week split after 18 – 20 Gy is suggested .

Some areas like the top of the scalp, the perineum, the soles of the feet, underneath of the breasts or of the panniculus of obese individuals could receive relatively lower doses. Thus, these areas should be supplemented with 6 MeV electrons to a total dose of 20 Gy (Hoppe 1991). Following completion of total-skin EBRT, adjuvant topical HN2 is appropriate and may be continued for at least 6 months. Total-skin EBRT produces a complete remission rate of 80% to 90% in these patients (Jones 1994;Quiros 1997). In spite of a higher complete remission rate, patients treated with total-skin EBRT do not have an improved survival compared with those treated with topical HN2 (Kim 1999b). HN2 and PUVA are used with the same modalities as for stage IA patients . Complete remission rate with topical HN2 or with PUVA are 50% to 70% (Kim 1999b) and 50% to 80% (Abel 1987; Herrmann 1995; Ramsay 1992; Resnik 1993 ; Roenigk 1990), respectively. Patients who fail to respond to one topical therapy or who progress after an initial response may be treated with an alternative topical strategy. There is no evidence that development of resistance to one modality affects the subsequent response to an alternative topical modality (Kim 1996; Kim 1999b). Patients who failed to respond to a single-agent topical regimen can receive combined-modality therapy as appropriate for individual clinical use on a type 3 level evidence. This can be done by combining topical HN2 with total-skin EBRT or with PUVA; or adding interferon- (IFN-) or retinoids to those treatments (Duvic 1996; Jones 1992 ; Kuzel 1995).

6.3 Treatment of stage IIB disease

Standard therapeutic option for patients with stage IIB disease depends on the entity of tumors. Local electron-beam radiotherapy (EBRT) combined with topical mechlorethamine hydrochloride (HN2) or with psoralen and ultraviolet A (PUVA) are the first-choice treatments for patients with few discrete tumors. In patients with generalized tumors three effective combinations are available: total-skin EBRT plus topical HN2, PUVA plus interferon-alfa, and PUVA plus retinoids. Total-skin EBRT produces a complete remission rate of 45% to 75% in patients with stage IIB MF (Chinn 1999 ; Wilson 1995). In these patients the survival benefit of topical or systemic adjuvant treatment remains unclear (Chinn 1999 ; Wilson 1995). More aggressive combinations like PUVA plus interferon or retinoids are suitable for individual clinical use on a type 3 level evidence, in refractory disease or tumors relapsed after the above-mentioned strategies. The addition of interferon to PUVA improved survival respect to PUVA alone (Roenigk 1990), being associated with a complete remission rate of 33% (Kuzel 1995). To date, there is no evidence that a more aggressive combination using systemic chemotherapy offers superior survival outcome (Winkler 1986). Focal resistant tumors can be boosted with local EBRT or orthovoltage radiation.

6.4 Treatment of stage III disease

Standard therapeutic option for patients with stage III disease is low-dose psoralen and ultraviolet A (PUVA) with a low and caution increased of the UVA dose to avoid phototoxic reactions. Considering that erythrodermic MF usually presents very inflamed and itchy skin and that the skin in these patients is frequently irritated by prior topical therapies, electron-beam radiotherapy (EBRT) is usually associated with severe desquamation, even with very low doses. The combination between PUVA and interferon-alfa produces a complete remission rate of more than 60% and response duration longer than those obtained with PUVA or interferon alone (Kuzel 1995). In any way, there is no clear evidence that prolongation of the response duration leads to improvement in the overall survival. Photopheresis or extracorporeal photochemotherapy is suitable for individual clinical use as primary therapy for erythrodermic MF or Sézary syndrome on a type 3 level evidence (Holloway 1992). It can be effective in patients without visceral involvement or with limited lymph node disease, with a 60% of overall response rate (Wilson 1995). If the response to photopheresis is partial or slow, interferon alfa can be added, obtaining a significant improvement in response rate (Gottlieb 1996). Systemic retinoids are also suitable for individual clinical use as primary therapy for erythrodermic MF or Sézary syndrome on a type 3 level evidence. Retinoids can be used alone, or more often, in combination with PUVA or interferon alfa (Dreno 1991; Marschalko 1993). Single-agent chemotherapy is most effective in patients without extracutaneous disease. Methotrexate produces a complete remission rate of 41% with doses between 5 and 50 mg/wk (Zackheim 1996).

6.5 Treatment of stage IV disease

Standard therapeutic option for patients with stage IV disease is conventional-doses systemic chemotherapy. In MF, most chemotherapy regimens result in temporary palliative control only. Chemotherapy is used alone, or in combination with radiation or interferon alfa. In spite of a complete response rate of 80% to 100%, the median duration of response to chemotherapy is shorter than one year (Bunn 1994 ; Zackheim 1996). The most effective and commonly used combinations are CHOP and CVP regimens (Grozea 1979). Methotrexate, etoposide, bleomycin, vinblastine, fludarabine, and 2-deoxycoformycin are the most commonly used single-agent chemotherapy regimens in MF and Sézary syndrome (Bunn 1994; Rosen 1995 ; Quaglino 2004). Response rates and duration are lower than those reported for combination chemotherapy regimens. The purine analogs fludarabine and 2-deoxycoformycin are suitable for individual clinical use on a type R basis. In effect, these drugs seems to be active against MF with response rates as high as 50% (Kuchnio 1994; Mercieca 1994; Von Hoff 1990). Biologic therapy, interferon alfa an retinoids are suitable for individual clinical use on a type R basis, either when used alone, together or in combination with chemotherapy or topical treatment (Bunn 1994; Duvic 1996; Kuzel 1995). The combination fludarabine plus interferon produces a response rate of 46% with a median duration of 6 months (Foss 1992). Megavoltage photon irradiation can be used as a palliative treatment of lymph node masses. This can be associated with systemic chemotherapy or interferon alfa. High-dose chemotherapy supported by autologous bone marrow transplantation is an experimental strategy. Experience with this strategy in MF is very limited (Bigler 1991), and, thus, its efficacy has not been established. However, it seems that autologous or allogeneic bone marrow or stem cell transplantation represent a promising approach in tumor-stage patients; mini-allogeneic transplantation may provide the additional advantage of a “graf-versus-tumor” effect (Guitart 2002 ;Masood 2002; Molina 2005; Olavarria 2001; Soligo 2003).

6.6 New active drugs and therapeutic options

Anti-T-cell monoclonal antibodies are an investigational alternative on a type R basis. It was studied in small series treated with chimeric anti-helper T-cell (anti-CD4) antibody (Knox 1991). The clinical response were generally modest and short-lived. Among novel targeted therapeutic approaches to CTCL are the retinoids, all-trans retinoic acid (ATRA) (Sacchi 1997) and bexarotene (Targretin) (Duvic 2001a ; Duvic 2001b). Other targeted therapies include the anti-CD52 antibody alemtuzumab (Campath) (Lundin 1998; Lundin 2003 ; Pangalis 2001; Hagberg 2002 ; Zinzani 2005), DAB389 IL-2 (denileukin diftitox, ONTAK) (Olsen 2001; Talpur 2006), tumor vaccination (Dummer 2004; Maier 2003), unmodified or 90Y-conjugated anti-Tac Pseudomonas exotoxin conjugates, and inhibitors of intracellular signal transduction factors. Further important therapeutic modalities include Gemcitabine (Zinzani 2000 ; Marchi 2005), pegylated liposomal doxorubicin (Wollina 2003), pentostatin (Tsimberidou 2004a), etanercept (Tsimberidou 2004b), immunomodulation of pro-inflammatory cytokines such as interleukin (IL)-12 (Rook 2003), and photopheresis with or without concurrent immunoadjuvant treatment. Due to the inadequacy of standard therapy, all patients with extracutaneous disease should be considered candidates for newer investigative therapies.
An emerging class of investigational agents is represented by histone deacetylase (HDAC) inhibitors, which may restore the expression of tumor suppressor or cell cycle regulatory genes by increasing the acetylation of histones. Depsipeptide and suberoylanilide hydroxamic acid are potent histone deacetylase inhibitors and have shown in-vitro and in-vivo cytotoxic activity against various tumors (Duvic 2003 ; Wysocka 2004). Vorinostat (suberoylanilide hydroxamic acid – SAHA) is the first FDA-approved HDAC inhibitor for the treatment of cutaneous manifestations of cutaneous T-cell lymphomas. Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in phase I development. In two phase II trials, vorinostat 400 mg/day was safe and effective with an overall response rate of 24 – 30% in refractory advanced patients with cutaneous T-cell lymphomas including large cell transformation and Sézary syndrome. The common side effects of vorinostat, which are similar in all studies, include gastrointestinal symptoms, fatigue and thrombocytopenia and the most common serious event was thrombosis. Many other HDAC inhibitors, such as valproic acid (Munster 2007), MS-275 (Gojo 2007), CI-994 (Undevia 2004), and FK-228 (Robey 2006) among others, are being investigated, but clinical experience on MF patients is still limited .

 

INDEX

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Prof. Lorenzo Cerroni (Reviewer)
Medical University of Graz, Austria
mail: lorenzo.cerroni@meduni-graz.at

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
mail: carlo.tondini@ospedaliriuniti.bergamo.it

Prof. Pier Luigi Zinzani (Author)
Institute of Hematology and Oncology Seragnoli, University of Bologna, Italy
mail: plzinzo@med.unibo.it