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Treatment of Cutaneous T-Cell Lymphomas J. Marcus Muche, Sylke Gellrich, and Wolfram Sterry Primary cutaneous T-cell lymphomas (CTCL), rep- resenting a heterogeneous group of non-Hodgkin's lymphomas (NHL), can be defined as clonal prolif- eration of skin-infiltrating T lymphocytes primarily presenting in the cutaneous compartment. They show a considerable variation in clinical presenta- tion, histology, immunophenotype, and prognosis, which is best reflected by the proposal of the Cutaneous Lymphoma Study Group of the Euro- pean Organization for Research and Treatment of Cancer (EORTC). Due to the heterogeneity of CTCL and the lack of curative therapy regimens, mul- tiple strategies have been proposed for the man- agement of the different CTCL entities. This in- cludes topical application of corticosterolds, nitrogen mustard or carmustine (BCNU), radio- therapy, including total skin electron beam irradia- tion, photo(chemo)therapy, biological response modifiers, cytostatic chemotherapy, and com- bined regimens. More recently, fusion proteins and peptide vaccines have been introduced in the management of CTCL. Classification, staging, and treatment modalities are discussed in detail and summarized In a stage-adapted therapy regimen for CTCL. Copyright 2000 by W.B. Saunders Company p RIMARY CUTANEOUS T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL), which show a considerable varia- tion in clinical presentation, histology, immunopheno- type, and prognosis. Following the group of primary gastrointestinal lymphomas, they represent, along ~vith the primary cutaneous B-cell lymphomas, the second most common group of extranodal NHL. l The annual incidence is estimated between 0.5 and 1/100,000. 2 Despite their heterogeneity, CTCL can be defined as clonal proliferation of skin-infiltrating T lymphocytes primarily (no extracutaneous involvement for at least 6 months after complete staging procedures) presenting in the cutaneous compartment. 3 From the Department of Dermatology and Allergy, Charitd Berlin, Berlin, Germany. Address reprint requests to J. Marcus Muche, MD, Department of Dermatology and Allergy, CharitE Berlin, Schumannstra~e 20/21, 1 O117Berlin, Germany. Copyright 2000 by W.B. Saunders Company 1085-5629/00/1902-0012510.00/0 doi:I O. 1053/sder.2000.8328 Until recently, CTCL were classified according to schemes developed for nodal lymphomas, as the Kiel classification 4 in Europe and Asia and the Working Formulation 5 in the United States. However, it has become obvious that extranodal lymphomas are dis- tinct, and not simply extranodal manifestations of their lymph node-based counterparts. Concerning the clini- cal behavior and histologic features as well as the prognosis, differentiation of these 2 groups of NHL becomes very important to clinicians as well as histopa- thologists. 6 Differences in the expression of oncogenes, viral sequences, and adhesions molecules as well as in the presence of specific translocations further support the view that primary CTCL represent a clinically and biologically distinct group of NHL. In addition, several new CTCL entities, such as follicular mucinosis, lym- phomatoid papulosis, or pagetoid reticulosis have been delineated, which were not included in classification systems thus far/ Today, the heterogeneity of CTCL is best reflected by the proposal of the Cutaneous Lymphoma Study Group of the European Organization for Research and Treat- ment of Cancer (EORTC). 3 This classification princi- pally includes distinct disease entities xvith predictable clinical course, response to therapy, and prognosis. Therefore, the terms low-grade and high-grade malig- nant lymphoma originally referring to the cell size, but not to the clinical outcome were replaced by the distinction of indolent, intermediate, and aggressive lymphoma types. In addition, some provisional entities were included, which display characteristic histologic features, but of which no distinct clinical presentation and/or outcome was defined thus far. Only some of these entities are listed in the Revised European- American Lymphoma (REAL) classification. STAGING Staging of CTCL includes examination of the entire integument, chest x-ray, and uhrasonography of ab- dominal organs and superficial lymph nodes (cervical, axillary, and inguinal). In case of pathologic findings it is completed by computed tomography scan and/or histologic investigation of suspect lymph nodes and/or visceral organs. Staging examination should be re- peated at relapse and every 12 months (chest x-ray every 2-3 years). Determination of the involvement of slain, lymph nodes, and visceral organs enables the assignment to 142 Seminars in Cutaneous Mediclne and Surgery,Vo119, No 2 (Juno), 2000: pp 142-148
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Treatment of Cutaneous T-Cell Lymphomas

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PII: S1085-5629(00)80012-7Treatment of Cutaneous T-Cell Lymphomas J. Marcus Muche, Sylke Gellrich, and Wolfram Sterry
Primary cutaneous T-cell lymphomas (CTCL), rep- resenting a heterogeneous group of non-Hodgkin's lymphomas (NHL), can be defined as clonal prolif- eration of skin-infiltrating T lymphocytes primarily presenting in the cutaneous compartment. They show a considerable variation in clinical presenta- tion, histology, immunophenotype, and prognosis, which is best reflected by the proposal of the Cutaneous Lymphoma Study Group of the Euro- pean Organization for Research and Treatment of Cancer (EORTC). Due to the heterogeneity of CTCL and the lack of curative therapy regimens, mul- tiple strategies have been proposed for the man- agement of the different CTCL entities. This in- cludes topical application of corticosterolds, nitrogen mustard or carmustine (BCNU), radio- therapy, including total skin electron beam irradia- tion, photo(chemo)therapy, biological response modifiers, cytostatic chemotherapy, and com- bined regimens. More recently, fusion proteins and peptide vaccines have been introduced in the management of CTCL. Classification, staging, and treatment modalities are discussed in detail and summarized In a stage-adapted therapy regimen for CTCL. Copyright 9 2000 by W.B. Saunders Company
p RIMARY CUTANEOUS T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin's
lymphomas (NHL), which show a considerable varia- tion in clinical presentation, histology, immunopheno- type, and prognosis. Following the group of primary gastrointestinal lymphomas, they represent, along ~vith the primary cutaneous B-cell lymphomas, the second most common group of extranodal NHL. l The annual incidence is estimated between 0.5 and 1/100,000. 2 Despite their heterogeneity, CTCL can be defined as clonal proliferation of skin-infiltrating T lymphocytes primarily (no extracutaneous involvement for at least 6 months after complete staging procedures) presenting in the cutaneous compartment. 3
From the Department of Dermatology and Allergy, Charitd Berlin, Berlin, Germany.
Address reprint requests to J. Marcus Muche, MD, Department of Dermatology and Allergy, CharitE Berlin, Schumannstra~e 20/21, 1 O117 Berlin, Germany.
Copyright 9 2000 by W.B. Saunders Company 1085-5629/00/1902-0012510.00/0 doi: I O. 1053/sder.2000.8328
Until recently, CTCL were classified according to schemes developed for nodal lymphomas, as the Kiel classification 4 in Europe and Asia and the Working Formulation 5 in the United States. However, it has become obvious that extranodal lymphomas are dis- tinct, and not simply extranodal manifestations of their lymph node-based counterparts. Concerning the clini- cal behavior and histologic features as well as the prognosis, differentiation of these 2 groups of NHL becomes very important to clinicians as well as histopa- thologists. 6 Differences in the expression of oncogenes, viral sequences, and adhesions molecules as well as in the presence of specific translocations further support the view that primary CTCL represent a clinically and biologically distinct group of NHL. In addition, several new CTCL entities, such as follicular mucinosis, lym- phomatoid papulosis, or pagetoid reticulosis have been delineated, which were not included in classification systems thus far/
Today, the heterogeneity of CTCL is best reflected by the proposal of the Cutaneous Lymphoma Study Group of the European Organization for Research and Treat- ment of Cancer (EORTC). 3 This classification princi- pally includes distinct disease entities xvith predictable clinical course, response to therapy, and prognosis. Therefore, the terms low-grade and high-grade malig- nant lymphoma originally referring to the cell size, but not to the clinical outcome were replaced by the distinction of indolent, intermediate, and aggressive lymphoma types. In addition, some provisional entities were included, which display characteristic histologic features, but of which no distinct clinical presentation and/or outcome was defined thus far. Only some of these entities are listed in the Revised European- American Lymphoma (REAL) classification.
STAGING
Staging of CTCL includes examination of the entire integument, chest x-ray, and uhrasonography of ab- dominal organs and superficial lymph nodes (cervical, axillary, and inguinal). In case of pathologic findings it is completed by computed tomography scan and/or histologic investigation of suspect lymph nodes and/or visceral organs. Staging examination should be re- peated at relapse and every 12 months (chest x-ray every 2-3 years).
Determination of the involvement of slain, lymph nodes, and visceral organs enables the assignment to
142 Seminars in Cutaneous Mediclne and Surgery, Vo119, No 2 (Juno), 2000: pp 142-148
TREATMENT OF CUTANEOUS T-CELL LYMPHOMAS 143
the tumor, (lymph) nodes, metastases (TNM) system. Although prognostic value and applicability of the TNM staging in CTCL have been controversial, the alternative TNM scheme of the International Consen- sus Conference on CTCLs 9 facilitates the decision process towards an adapted therapy regimen in most CTCL. Therefore, it is summarized in Table 1 and a discussion follows.
THERAPY
Multiple strategies have been proposed to treat the different CTCL entities. This first includes topical application of corticosteroids, nitrogen mustard or carmustine (BCNU), radiotherapy, including total skin electron beam irradiation, photo(chemo)therapy (psor- alen plus UVA [PUVAI, extracorporeal photopheresis), biological response modifiers, and combined regimens. Surgical excision may be preferred in solitary or local- ized skin lesions. Oral chemotherapy is effective in cases of lymphomatoid papulosis, erythrodermic CTCL, and tumor stage of mycosis fungoides (MF). In case of unequivocal lymph node or secondary visceral involve- ment as well as in case of CD30- large cell CTCL or ~vide spread cutaneous involvement, multiagent chemo- therapy is indicated.
The treatment modalities are detailed in the follow- ing text, and a stage adapted therapy regimen for CTCL is given in Table 2.
T O P I C A L THERAPY
Topical treatment modalities in CTCL encompass topical ointments (cortieosteroids, meehlorethamine, carmustine) and radiotherapy (x-ray, electron beam).
Corticosteroids (class II-IV) qualify for primary therapy in stage IA disease, where complete remissions (CR) in up to 60% of the cases have been observed. 1~ In more advanced stages, they should exclusively be applied in an adjuvant manner.
Topical administration of the cytostatic drugs meeh- lorethamine (nitrogen mustard) and BCNU (carmus- tine) raises considerable responses in CTCL stages I-III. The alkylating agent nitrogen mustard induces CR in 80% to 60% of stage I-III disease (except stage lIB: 49%). With sparing of head and intertrigines, it is administered daily as 0.5% solution in H20 until CR is
reached. Thereafter, the therapy should be maintained for 1 to 3 years. Side effects include erythema, xerosis cutis, hyperpigmentation and, in 35% to 67% of the cases, delayed-type hypersensitivity. The latter can be overcome by treatment continuation with a reduced nitrogen mustard concentration. Long-term adverse effects encompass enlarged risks for spinalioma (8 times), basal cell carcinoma, Hodgkin's disease, and colon carcinoma. II BCNU generates CR rates of 86% to 47% in CTCL stage I-IIA. Patients with T3 or T4 disease show considerably lesser response xvith CR rates of 17% and 21%, respectively. Until CR is reached, it is applied daily as 0.2% solution in ethanol (96% vol) with sparing of head and intertrigines. Adverse effects include erythema, hyperpigmentation, delayed-type hypersensitivity (7% of the cases), and bone marrow suppression (3%). 12 Although both agents show notice- able response rates, the complex treatment procedure (daily application to total skin, short shelf life of the solution) and adverse side effects (delayed-t))pe hyper- sensitivity in up to 67% of the eases, high risk for secondary malignancies) limit the use of these drugs.
Localized radiotherapy by x-ray or electron beam is preferentially applied in T3 (tumor) disease. In combi- nation xvith other regimens (ie, PUVA), local radio- therapy is successfully applied to single tumor lesions in patients with extended plaque and/or limited tumor disease. However, locoregional relapses outside the radiation field might be observed. In case of unilesional MF, actuarial relapse-free and overall survival at 10 years were, respectively, 86.2% and 100%. 13 For local irradiation, a total dose of 30 to 40 Gy is administered in single fractions of 2 to 4 Gy given 3 to 4 times per week. Voltage should be adapted to the tumor depth as determined by uhrasonography.
The total skin electron beam therapy (TSEBT) in- duces long-term remission particularly in stage IA disease xvith CR rates of 90% (50% relapse-free survival at 10 years). Considerable responses are also observed in stage IB and III (T4NOM0 only) ~vith CR rates of 71% and 64%, respectively. 14 For TSEBT, a total dose of 30 to 36 Gy is given in fractions of 2 Gy administered 2 to 3 times per week. Unfortunately, TSEBT, in particular single-field TSEBT, which prevents sparing of skin
Table I . TNM-Staging Adapted From the International Consensus Conference on CTCL Treatment ReCOmmendations TM
Stage T (Tumor) N (Lymph nodes) M (Metastasis)
I A Patches and plaques <10% of the skin surface 0.1) No lymphadenopothy, nonspecific lymph node pathology No visceral involvement I B Patches and plaques >10% of lhe skin surface 0"2) No lymphadenopathy, nonspecific lymph node pathology No visceral involvement II A Patches and plaques lymphadenopathy, nonspecific lymph node pathology No visceral Involvement II B Tumor > 1 03) Nonspecific lymph node pathology No visceral involvement III Erythroderma 0.4) Nonspecific lymph node pathology No visceral involvement IV A Independent Specific lymph node pathology No visceral involvement IV B Independent Independent Visceral involvement
144 MUCHE, GELLRICH, AND STERRY
Table 2. Therapy Scheme for CTCL
Entity Stage Initial Therapy Atiernative Adjuvant Therapy of Relapse Maintenance
MF/FM I-IIA PUVA + IFH-ot PUVA Topical cortlcosteroids PUVA PUVA PUVA + Ret PUVA + Ret IFN-et PLIVA + IFN-et + Ret PLIVA + IFN-ct + Ret
TSEBT
lib PUVA + IFH-c= + Rot PUVA + Ret Local irradiation PUVA + IFH-c= + Rot IFN-a Multiogent chemotherapy
III ECP + IFN-et ECP Topical corticosteroids Chlorambucile + prednisone IFH-a Chlorombucile + prednisone TSEBT Chlorabucile
IV Multiagent chemotherapy
PR PUVA + IFH-a PUVA Local irradiation
LP PUVA + IFN-r Methotrexate CD30+ IA Excision + local irradiation Local irradiation
IB-IIB PUVA + IFH-o~ + Rot
Local irradiation Multiagent chemotherapy Topical corticosteroids Topical cort[costerolds PUVA + IFH-a
+ prednisone
Multiagent chemotherapy Local irradiation Multiogent chemotherapy
ECP Topical corticosteroids Chlorambucile + prednisone IFH-ct Chlorambucile + prednisone TSEBT Chlorambucile
+ prednisone CD30- IA Excision + local irradiation Multiagent chemotherapy Mulfiogent chemotherapy
IBM Multiagentchemotherapy Multiagentchemotherapy S/M Plea Excision + local Irradiation Local Irradiation Topical corticosterolds PUVA + IFN-a + Rot PUVA
PUVA + IFH-et + Rel IFH-c= GSS PUVA + IFN-ct PUVA Topical corticosteroids PUVA + IFN-a
Local Irradiation SO CTCL Mulfiagent chemotherapy Multiogent chemotherapy
Abbreviations: FM, follicular muclnosis; PIL pagetoid reticulosis; LP, lymphomotold populosis; CD30 +, CD30-positive large cell CTCIj SS, S&ary's syndrome; CD30-, CD30-negotive large cell CTCL; S/M Plea, small 1o medium-sized pleomorphlc CTCL; GSS, granulomotous slack skin; $C CTCL subcutaneous ponniculitis-like CTCL.
areas or overlapping irradiation fields, is technically complex and application should be reserved to experi- enced centers. In addition, some considerable adverse effects as total alopecia (transient in case of total doses <25 Gy), loss of perspiration, and severe xerosis cuffs limit the application of TSEBT. Therefore, it should be reserved to stage 1/111 cases that are refractory to, or relapsing after, standard regimens (see Table 3).
Table 3. Mulflagent Chemotherapy of CTCL
Median Relapse-Free
BAM (bleomycine, adriamycine, metho- trexate) 8/10 7/10 41
CAVE (cyclophosphamide, addamycine, vincristine, etoposide) 47152 20/52
CBP + Rot (cyclophosphasmide, hIeomy- cine, prednisone, retinoid) 25/32 19132 8
CHOP (cyclophosphamide, adriomycine, vincfistine, prednisone) 16117 7117 5
COPPIMOPP (cyclophosphamlde/mechlor- ethamine, vincrisfine, procarbacine, prednisone) 19/21 11121 14
ULTRAVIOLET I R R A D I A T I O N
Because ultraviolet (UV) irradiation, particularly in combination with photosensitizers (so-called photoche- motherapy), causes systemic immunologic changes in addition to local effects, this treatment modality should be differentiated from topical therapies.
In CTCL, photochemotherapy has been proven to be superior to single UV irradiation using UV-B or UV-A. Most frequently, PUVA and extracorporeal photopher- esis (ECP) are administered. Both involve the therapeu- tic use of UV-A irradiation after photosensitization using 8-methoxypsoralene (8-MOP). Whereas in PUVA the patient is UV-A irradiated after systemic or topical application of the photosensitizer, ECP is based on separation of a leukocyte/lymphocyte-enriched cell fraction from the peripheral blood, extracorporeal treatment of the cells with 8-MOP and UV-A, and subsequent reinfusion of the cells.
For PUVA, the 8-MOP is administered orally (0.6 mg/kg body weight) or in bath solu!ion. Regarding the UV dosage, CTCL patients frequently show an in- creased sensibility that requires careful dose adjust-
TREATMENT OF CUTANEOUS T-CELL LYMPHOMAS
ment during the treatment course. Until the first response, treatment should be administered 4 times weekly, thereafter it is continued 3 times weekly until CR is reached. Maintenance therapy by scheduling PUVA 1 to 2 times/mo might be applied. Taken orally, 8-MOP might cause transient increases of liver transam- inases and gastrointestinal side effects. Side effects of long-term PUVA include increased risk for spinalioma, cataracts, and amyloid deposits in the skin. An in- creased occurrence of melanoma has also been dis- CUssed.
PUVA has become a standard therapy regimen in early stage CTCL. Applied in stage IA-IIA, PUVA induces CR in 80% to 90% of the cases. Even in stage IIB, simuhaneous administration of PUVA and local 'electron beam irradiation results in CR rates of approxi- mately 60%. Although long-term remissions have been described, 30% to 70% of the CTCL patients experience a relapse after 11 to 44 months and require repetitive PUVA cycles, l~ ' ECP is administered on 2 consecutive days at 2-week intervals for the first 3 months and thereafter every 4 weeks. Response is evaluated after 6 months, and a ECP maintenance therapy might be started 4 to 6 months after CR is reached. Therefore, treatment intervals are extended every 3 cycles until an interval of 8 weeks is reached. Besides transient fever, no relevant side effects of ECP have been described.
ECP represents the therapy of choice in erythroder- mic CTCL. In these cases, CR has been observed in up to 80% of the treated cases. 16 However, successful treatment depends on some pretherapeutical condi- tions: Initial lymphocyte count ~15,000/mL, normal frequencies of CD8+ T lymphocytes in the peripheral blood, and primary occurrence of T4 disease ensures response to that therapy. ECP might also be adminis- tered as maintenance therapy in patients with plaque or tumor lesions that have reached CR after radiation treatment.
Currently, the underlying mechanisms of action of photochemotherapy are not entirely understood. Be- sides direct lymphocytotoxic effects, mediated by DNA damage, subsequent poly adenosine diphosphate- ribosylation and adenine nucleotide depletion, 17 at least ECP appears to induce a highly specific immune response against the malignant T cells, resulting in the removal of both the photo-damaged and the untreated neoplastic cells in experimental systems, is This re- sponse seems to be mediated by changes in the immunogeneity of the neoplastic cells as well as by activation of the immune system, in particular of cytotoxic lymphocytes and monocytes.
BIOLOGIOAL RESPONSE MODIFIERS
lnterferons (lFIq), interleukins (IL) as well as mem- bers of the tumor necrosis factor family are considered
145
to be potent biological response modifiers. Activities associated with these substances include inhibition of viral replication, influence on cellular protein produc- tion, direct antiproliferative effects, and a variety of modulatory effects on the immune response. 19
In most cases of CTCL, the neoplastic T cells express a type 2 cytokine pattern and are attacked by cytotoxic, type 1 cytokine expressing T lknnphocytes in major histocompatibility complex (MHC) class I. In vitro observations suggest that the production of type 2 cytokines and the addition of type i cytokines as IFN-~/ or IL-12 exerts cytolytic effects on CTCL tumor cells. 2~ Consequently, biological response modifiers, which normalize the type 2-skewing state, are potent candi- dates for the treatment of CTCL.
Although improvement of CTCL under IFN-'y or IL-12 treatment has been reported, 21,22 both substances can not yet fulfill the expectations regarding treatment response and applicability.
However, administration of IFN-a, a glycoprotein also downregulating type 2 cytokines in favor of the type 1 cytokines and suppressing the growth of malig- nant T cells, became a well-established treatment regimen in CTCL. 23 Particularly the combination of IFN-a with PUVA or ECP represents an efficient therapy for stage I-IlA/stage Ill CTCL (discussed later). In addition, 1FN-a serves for maintaining CR in CTCL stage I-III. As a single agent for initial treatment, IFN-a induces clinical responses in only 55% of CTCL patients, including a CR rate of 17%. In this case, median relapse-free survival ranges 4 to 8 months. 24
For single or combination therapy, IFN-a is adminis- tered subcutaneously in doses of 3 to 18 • 106 U, 3 times weekly. For maintenance therapy, 3 to 9 • 106 U 3 timesAvk or 3 x 106 U daily are given. Adverse events consist of reversible fever/chills, depression and, in the case of long-term application, elevation of hepatic transaminases.
FUSION PROTEINS
The knowledge of the expression of specific cell- surface markers on the malignant CTCL cells opens a further treatment modality. Proteins specifically bind- ing to these surface markers may show distinct thera- peutic capacities after fusion with other functional molecules.
DAB3891L2 represents one of these substances. It retargets the cytotoxic c~-chain of the diphtheria toxin to high-affinity IL-2-receptor expressing tumors. Ad- ministered in doses of 9 or 18 l~g/kg/d intravenously for 5 days every 3 weeks, DAB3891L2 treatment is well tolerated. Doses less than 31 llg/kg/d induced clinical responses in 37% of previously treated CTCL patients, including CR in 14%. 25 Because neoplastic .T cells express the high-affinity IL-2 receptor in approxi-
146 MUCHE, GELLRICH, AND STERRY
mately 20% of CTCL, DAB3891L2 therapy is limited to selected CTCL cases. Application of the substance is further restricted by the occurrence of a capillary leak syndrome in 10% to 20% of treated patients. More detailed data on DAB389IL2 treatment are expected from an ongoing muhicenter study for CTCL stage I-III. However, due to the reported limitations, DAB3891L2 may be reserved as treatment of refractory or relapsing T3 disease.
Fusion proteins may also be constructed as chimeric (murine/human) anti-CD4 monoclonal antibodies to induce an immune response against CD4+ cells. Those well-tolerated therapies showed clinical efficacy against MF, but additionally had immediate immunosuppres- sire effects. 26
DesPite only moderate response rates, the novel mechanism of action, in combination with the evidence of biologic activity in refractory cancer patients, will lead to the development of more active constructs for this therapeutic modality.
TUMOR-SPECIFIC PEPTIDE VACCINATION
The infiltration of early CTCL lesions by CD8+ cells reflects host immunity to the neoplasm and suggests the presence of tumor-specific cytotoxic T cells recog- nizing distinctive MHC class I associated molecules on the neoplastic cells. After characterization, the tumor- specific antigens can serve as tumor vaccines inducing a MHC class I restricted immune response. Such peptides can be identified from the third complementa- rity determining region of the clonal (malignant) T-cell receptor. Furthermore, native peptides may be eluted from MHC class I molecules.
Testing peptides developed by these techniques in a TNF-a assay already succeeded in the detection of unique idiotypic molecules specifically recognized by autologous CD8+ T cells from CTCL patients. 2r In addition, screening of random peptide libraries with cytotoxic T lymphocytes for the CTCL line Myla could identify a HLA-B8 restricted peptide, which is recog- nized by CD8+ T cells from several HLA-B8+ CTCL patients. 28
Ahhough the generation of such immunogenes is very complex, these peptides might form the basis of an antitumor vaccine for the specific immunotherapy of CTCL in the future.
COMBINED THERAPY REGIMENS
Combined regimens are often applied in CTCL therapy to obtain synergistic effects, to reduce long- term toxicity of the single agents, and to prolong relapse-free survival. Furthermore, primary skin- targeted therapies can be combined with primary systemic approaches. In particular, the latter becomes
important because recent studies showed the early occurrence of circulating clonal T cells in CTCL.
The association of PUVA with IFN-a has become a standard therapy regimen in stage I-IIA disease, when combined with local irradiation it induces considerable responses even in stage lIB CTCL. Application of PUVA + IFN-~x as described previously results in response rates…