Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Primary cutaneous lymphomas (PCLs) are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After gastrointestinal lymphomas, PCLs are the second most common group of extranodal non-Hodgkin lymphomas, with an estimated annual incidence of 1/100 000 in Western countries. PCLs must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily, which often have another clinical behaviour, have a different prognosis and require a different therapeutic approach. In recent lymphoma classifications, PCLs are therefore included as separate entities. Within the group of PCLs, distinct types of cutaneous T cell lymphoma (CTCL) and cutaneous B cell lymphoma (CBCL) can be distinguished [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar, 2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar]. In the Western world, CTCLs constitute ∼75%–80% of all PCLs [with mycosis fungoides (MF) as the most common type of CTCL] and CBCL ∼20%–25% [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar]. However, different distributions have been observed in other parts of the world. In Southeast Asian countries, CTCLs other than MF [in particular Epstein–Barr virus-associated natural killer (NK)/T cell lymphomas] are much more common than in Western countries, while CBCLs are much more uncommon [3.Tan S.H. Sim C.S. Ong B.H. Cutaneous lymphomas other than mycosis fungoides in Singapore: a clinicopathological analysis using recent classification systems.Br J Dermatol. 2003; 149: 542-553Crossref PubMed Scopus (30) Google Scholar, 4.Park J.H. Shin H.T. Lee D.Y. et al.World Health Organization–European Organization for research and treatment of cancer classification of cutaneous lymphoma in Korea: a retrospective study at a single tertiary institution.J Am Acad Dermatol. 2012; 67: 1200-1209Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. PCLs are rare diseases and patients should ideally be seen by a multidisciplinary team of dermatologists, pathologists, haematologists and radiation oncologists. The diagnosis and classification of PCLs should always be based on a combination of clinical, histological, immunophenotypical and genetic data. Demonstration of clonal T cell receptor or immunoglobulin gene rearrangements in lesional skin or peripheral blood may be a valuable adjunct in selected cases. However, clinical and histopathological features are, in most cases, the most important deciding factors for therapeutic planning. PCLs should be classified according to the criteria of the revised 2017 World Health Organization (WHO) classification ( see Table 1) [2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar].Table 1WHO-EORTC classification for cutaneous lymphomasCutaneous T cell lymphomaMycosis fungoides (MF)Variants of MF•Folliculotropic MF•Pagetoid reticulosis•Granulomatous slack skinSézary syndromePrimary cutaneous CD30+ lymphoproliferative disorders•Primary cutaneous anaplastic large cell lymphoma•Lymphomatoid papulosisSubcutaneous panniculitis-like T cell lymphomaExtranodal NK/T cell lymphoma, nasal-typePrimary cutaneous peripheral T cell lymphoma-not otherwise specified•Primary cutaneous γ/δ T cell lymphoma•Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphomaaProvisional entities.•Primary cutaneous acral CD8+ T cell lymphomabNew provisional entity in the revised 2017 WHO classification [2].•Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorderaProvisional entities.Cutaneous B cell lymphomaPrimary cutaneous marginal zone lymphomaPrimary cutaneous follicle centre lymphomaPrimary cutaneous diffuse large B cell lymphoma, leg typeEORTC, European Organization of Research and Treatment of Cancer; NK, natural killer; WHO, World Health Organization.Adapted from [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar] with permission.a Provisional entities.b New provisional entity in the revised 2017 WHO classification [2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar]. Open table in a new tab EORTC, European Organization of Research and Treatment of Cancer; NK, natural killer; WHO, World Health Organization. Adapted from [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar] with permission. In all cases, adequate staging should be carried out to exclude the presence of extracutaneous disease. Recommendations for the initial staging of patients with MF/Sézary syndrome (SS) are presented in Table 2. Flow cytometry of the peripheral blood is usually recommended for all stages of MF. However, it is debatable whether this test is justified in patients who are not suspected to have SS. Computed tomography (CT) and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) scans are optional in early-stage MF. Bone marrow examination is usually not indicated in patients with MF/SS.Table 2Recommendations for staging evaluation in patients with MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]Complete physical examination including:•Determination of type(s) of skin lesions•Identification of any palpable lymph node, especially those ≥ 1.5 cm in largest diameter or firm, irregular, clustered or fixed•Identification of any organomegalySkin biopsy•Most indurated area if only one biopsy•Routine histology and immunophenotyping•Evaluation for clonality of TCR gene rearrangement (optional)Blood tests•CBC with manual differential, liver function tests, LDH, comprehensive chemistries•TCR gene rearrangement and relatedness to any clone in skin (optional)•Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number of Sézary cells and/or flow cytometry (including CD4+/CD7– or CD4+/CD26–) (optional)Radiological tests•CT scans of chest, abdomen and pelvis alone ± FDG-PET (optional in patients with early-stage MF)Lymph node biopsy•Excisional biopsy in patients with a node that is either ≥ 1.5 cm in diameter and/or is firm, irregular, clustered or fixed•Routine histology, immunohistochemistry and TCR gene rearrangement analysisCBC, complete blood count; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; TCR, T cell receptorAdapted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab CBC, complete blood count; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; TCR, T cell receptor Adapted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Initial work-up for patients with a PCL other than MF/SS also includes complete physical examination, representative skin biopsy, complete and differential blood cell count, routine serum biochemistry with lactate dehydrogenase (LDH) and appropriate imaging studies (CT and/or FDG-PET scans) [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar]. In PCLs with a predominantly subcutaneous presentation, such as subcutaneous panniculitis-like T cell lymphoma (SPTCL) and primary cutaneous gamma/delta T cell lymphoma (PCGD-TCL), FDG-PET is essential to evaluate the extent of disease. In patients with typical lymphomatoid papulosis (LyP) or primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder (LPD), CT and FDG-PET scans are not required. Bone marrow biopsy and aspirate should be carried out in cutaneous lymphomas with an intermediate or aggressive clinical behaviour but is not required in cutaneous lymphomas with an indolent clinical behaviour, unless indicated by other staging assessments [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar, 6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]. Bone marrow examination is not indicated in patients with primary cutaneous marginal zone lymphoma (PCMZL), but its significance in primary cutaneous follicle centre lymphomas (PCFCLs) is controversial [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar, 7.Senff N.J. Kluin-Nelemans H.C. Willemze R. Results of bone marrow examination in 275 patients with histological features that suggest an indolent type of cutaneous B-cell lymphoma.Br J Haematol. 2008; 142: 52-56Crossref PubMed Scopus (53) Google Scholar]. Prognosis is extremely variable depending on the type of PCLs and the stage of disease. For clinical staging of MF and SS, the revised tumour, node, metastasis and blood (TNMB) staging system should be used (Tables 3 and 4) [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]. Apart from clinical stage, older age, large cell transformation and increased LDH values have been identified as independent unfavourable prognostic factors in MF [8.Agar N.S. Wedgeworth E. Crichton S. et al.Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.J Clin Oncol. 2010; 28: 4730-4739Crossref PubMed Scopus (569) Google Scholar, 9.Scarisbrick J.J. Prince H.M. Vermeer M.H. et al.Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model.J Clin Oncol. 2015; 33: 3766-3773Crossref PubMed Scopus (266) Google Scholar, 10.Alberti-Violetti S. Talpur R. Schlichte M. et al.Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment.Clin Lymphoma Myeloma Leuk. 2015; 15: e105-e112Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. For PCLs other than MF/SS, a separate TNM classification system has been published [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar]. This staging system is primarily meant to document extent of disease and cannot be used as a prognostic guide.Table 3Revised TNMB classification of MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]T (skin)T1Limited patch/plaque (involving < 10% of total skin surface)T2Generalised patch/plaque (involving ≥ 10% of total skin surface)T3Tumour(s)T4ErythrodermaN (lymph node)N0No clinically abnormal peripheral lymph nodesN1Clinically abnormal peripheral lymph nodes; histologically uninvolvedN2Clinically abnormal peripheral lymph nodes; histologically involved (nodal architecture uneffaced)N3Clinically abnormal peripheral lymph nodes; histologically involved [nodal architecture (partially) effaced]NxClinically abnormal peripheral lymph nodes; no histological confirmationM (viscera)M0No visceral involvementM1Visceral involvementB (blood)B0No circulating atypical (Sézary) cells (or < 5% of lymphocytes)B1Low blood tumour burden (≥ 5% of lymphocytes are Sézary cells, but not B2)B2High blood tumour burden (≥ 1000/µl Sézary cells and positive clone)MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour, node, metastasis, blood.Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab Table 4Revised clinical staging system for MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]Clinical stageIAT1N0M0B0-1IBT2N0M0B0-1IIAT1–2N1-2M0B0-1IIBT3N0–2M0B0-1IIIT4N0–2M0B0-1IVA1T1–4N0-2M0B2IVA2T1–4N3M0B0-2IVBT1–4N0–3M1B0-2MF, mycosis fungoides; SS, Sézary syndrome. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour, node, metastasis, blood. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. MF, mycosis fungoides; SS, Sézary syndrome. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. The choice of treatment depends on the type of PCL and the stage of disease. Due to their heterogeneity and rarity, controlled clinical trials in PCLs are almost non-existent, with a few exceptions mainly concerning recently marketed drugs. Recommendations are therefore largely based on (retrospective) cohort studies and expert opinions discussed during consensus meetings of the European Organization of Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and the International Lymphoma Radiation Oncology Group (ILROG), including consensus recommendations for clinical end points and response criteria in MF/SS [11.Olsen E.A. Whittaker S. Kim Y.H. et al.Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.J Clin Oncol. 2011; 29: 2598-2607Crossref PubMed Scopus (457) Google Scholar]. Since early aggressive chemotherapy (ChT) is associated with considerable side effects but does not improve survival, a stage-adapted conservative therapeutic approach is recommended for MF and its variants [12.Kaye F.J. Bunn Jr, P.A. Steinberg S.M. et al.A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides.N Engl J Med. 1989; 321: 1784-1790Crossref PubMed Scopus (427) Google Scholar, 13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 14.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; Mycosis fungoides/Sézary syndrome (Version 2.2018 – January 2, 2018). https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf (8 January 2017, date last accessed).Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar]. Patients with only patches and/or plaques covering < 10% (stage IA) or ≥ 10% of the skin surface (stage IB) should be treated with skin-directed therapies, including topical steroids, psoralens plus ultraviolet A (PUVA), narrow-band ultraviolet B (nb-UVB) and topical cytostatic agents, such as mechlorethamine (nitrogen mustard) (Figure 1). nb-UVB is recommended for patients with patches or very thin plaques but PUVA is preferred for patients with thicker plaques [III, A] [13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar]. Topical steroids can be recommended as monotherapy for stage IA disease with patches/flat plaques. In stage IB, topical steroids can be used as adjuvant therapy for selected skin lesions. Topical application of mechlorethamine, either in aqueous solution or in an ointment-based preparation, has been used successfully for decades in the treatment of early-stage MF. A commercial 0.02% gel preparation was approved by the European Medicines Agency (EMA) as an orphan drug for the treatment of early stage MF [II, B] [16.Lessin S.R. Duvic M. Guitart J. et al.Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.JAMA Dermatol. 2013; 149: 25-32Crossref PubMed Scopus (122) Google Scholar]. In patients developing one or few infiltrated plaques or tumours (stage IIB), additional low-dose local radiotherapy (RT) may suffice [III, A] [17.Neelis K.J. Schimmel E.C. Vermeer M.H. et al.Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.Int J Radiat Oncol Biol Phys. 2009; 74: 154-158Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Local RT can be curative in patients with early localised disease, particularly in patients with unilesional MF and pagetoid reticulosis [IV, A]. In such patients, local RT is most commonly administered with electrons (energy dependent on the thickness of the lesion), with bolus to achieve full skin dose, a margin of ≥ 2 cm and a total dose of 20–24 Gy [IV, A] [18.Specht L. Dabaja B. Illidge T. et al.Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.Int J Radiat Oncol Biol Phys. 2015; 92: 32-39Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. For patients with more extensive infiltrated plaques and tumours, or patients refractory to skin-directed therapies, systemic therapy with interferon alpha (IFNα) or retinoids (including bexarotene), commonly combined with PUVA or other skin-directed therapies, or a combination of IFNα and retinoids or total skin electron beam therapy (TSEBT), can be considered [III, B] [13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar, 19.Quaglino P. Maule M. Prince H.M. et al.Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.Ann Oncol. 2017; 28: 2517-2525Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. TSEBT was often given to total doses of 30–36 Gy, but lower doses (10–12 Gy) have been employed with the advantages of shorter duration of the treatment period, fewer side effects and opportunity for re-treatment [III, A] [20.Hoppe R.T. Harrison C. Tavallaee M. et al.Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.J Am Acad Dermatol. 2015; 72: 286-292Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 21.Kamstrup M.R. Gniadecki R. Iversen L. et al.Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.Int J Radiat Oncol Biol Phys. 2015; 92: 138-143Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. In patients with advanced and refractory disease, gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived [II, B] [22.Marchi E. Alinari L. Tani M. et al.Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients.Cancer. 2005; 104: 2437-2441Crossref PubMed Scopus (153) Google Scholar, 23.Dummer R. Quaglino P. Becker J.C. et al.Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012.J Clin Oncol. 2012; 30: 4091-4097Crossref PubMed Scopus (79) Google Scholar]. Other agents like the fusion toxin denileukin diftitox and histone deacetylase (HDAC) inhibitors, such as vorinostat and romidepsin, have been approved in the United States by the Food and Drug Administration (FDA) for patients with relapsed and refractory CTCL, but have not yet been registered for CTCL in Europe [24.Prince H.M. Duvic M. Martin A. et al.Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 1870-1877Crossref PubMed Scopus (184) Google Scholar, 25.Olsen E.A. Kim Y.H. Kuzel T.M. et al.Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.J Clin Oncol. 2007; 25: 3109-3115Crossref PubMed Scopus (877) Google Scholar, 26.Whittaker S.J. Demierre M.F. Kim E.J. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar]. Multi-agent ChT is only indicated in patients with effaced lymph nodes or visceral involvement (stage IV), or in patients with widespread tumour stage MF, which cannot be controlled with skin-targeted and immunomodulating therapies or who failed single-agent ChT, but—similar to single-agent ChT—responses are generally short-lived [IV, B] [27.Hughes C.F.M. Khot A. McCormack C. et al.Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: a comparative study of systemic therapy.Blood. 2015; 125: 71-81Crossref PubMed Scopus (150) Google Scholar]. Local palliation of cutaneous as well as extracutaneous lesions may be achieved with local RT to doses ≥ 8 Gy [III, A] [17.Neelis K.J. Schimmel E.C. Vermeer M.H. et al.Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.Int J Radiat Oncol Biol Phys. 2009; 74: 154-158Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Recent studies report high response rates of brentuximab vedotin (BV; an anti-CD30 monoclonal antibody coupled to the anti-tubulin agent monomethyl auristatin E) in patients with advanced MF/SS expressing CD30 [II, B] [28.Duvic M. Tetzlaff M.T. Gangar P. et al.Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.J Clin Oncol. 2015; 33: 3759-3765Crossref PubMed Scopus (220) Google Scholar, 29.Kim Y.H. Tavallaee M. Sundram U. et al.Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.J Clin Oncol. 2015; 33: 3750-3758Crossref PubMed Scopus (208) Google Scholar, 30.Prince H.M. Kim Y.H. Horwitz S.M. et al.Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.Lancet. 2017; 390: 555-566Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar]. In a phase II trial including 28 patients with CD30+ relapsed or refractory MF, BV showed a 54% overall response rate (ORR) with a median time to response of 12 weeks and a median duration of response of 32 weeks in patients with MF, independent of the degree of CD30 expression [28.Duvic M. Tetzlaff M.T. Gangar P. et al.Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.J Clin Oncol. 2015; 33: 3759-3765Crossref PubMed Scopus (220) Google Scholar]. Another phase II study reported an ORR of 70% in a group of 32 patients with relapsed or refractory MF/SS with a wide range of CD30 expression levels [29.Kim Y.H. Tavallaee M