R. Mark Bickerton

21 August 2014

Online Submission To the Senate Legal & Constitutional Affairs Legislation Committee Medical Services (Dying with Dignity) Exposure Draft Bill

Dear Senators

Rare Cancers Such As Mycosis Fungoides

At the outset I would like to thank the Senate for considering this Bill, and offer my profound support of it. Please consider my submission as a public document, if warranted.

In 2009, at age 50, I was diagnosed with a rare cancer that is known as mycosis fungoides. I have used the abbreviation “MF” extensively in this submission. I am at a very early stage of MF and am not presently in any pain.

I thought it worthwhile to make a submission for the following reasons:

 Rare cancers can progress in unusual ways, and some of these cancers are not necessarily rapidly terminal – death may take many years to occur. Often death may instead come from infections, and a prediction of ‘terminal illness’ may not be easy for a specialist to make.

 The late Janet Mills, who was the second person to use the Northern Territory’s Rights of the Terminally Ill Act 1995, had an advanced stage of MF. I expect that Janet Mills’ case may be mentioned in other submissions, and as I have some knowledge of this rare cancer, I thought that my observations, and the attached medical literature, may be of assistance.

 To convey my thoughts on how the Bill, if enacted, may affect my situation.

What is Mycosis Fungoides (MF)?

The following explanation from Wikipedia explains why the name mycosis fungoides is a misnomer http://en.wikipedia.org/wiki/Mycosis_fungoides:

Mycosis fungoides was first described in 1806 by French dermatologist Jean-Louis- Marc Alibert.[2][3] The name mycosis fungoides is very misleading—it loosely means "mushroom-like fungal disease". The disease, however, is not a fungal infection but rather a type of non-Hodgkin's lymphoma. It was so named because Alibert described the skin tumors of a severe case as having a mushroom-like appearance.[4]

MF is one of a group of lymphomas known as Cutaneous Lymphomas. More specifically MF is a Cutaneous T-Cell Lymphoma. T-Cells are “white blood cells” and are therefore part of the blood and lymphatic system, and accordingly MF can also be described as a cancer of the blood and immune system.

MF is quite rare, with an incidence of about 0.3 persons per 100,000 persons per annum. As a consequence of this rarity, the average GP, with 2,000 patients “on the books”, would expect to see a patient with MF about once about every 150 years.

In early stages of MF, discoloured areas of skin appear – these are called patches.

Patients with less than 10% of the skin area covered in patches are at Stage 1A. Persons with greater than 10% are Stage 1B.

Patches can progress to plaques, which are raised patches, perhaps 1cm high.

Plaques can progress to tumours on the skin, and in later stages within the body. Involvement in lymph nodes and the blood can occur.

Three articles of medical literature are appended to this submission. The first of these appendices is from the American Society of Hematology and is titled ‘How I treat mycosis fungoides and sezary syndrome’ authored by three eminent specialists. The remaining two others are clinical practice guidelines. These appendices provide further details of MF, and other forms of Cutaneous Lymphoma. Each form has unique pathways of progression, and some are more aggressive than others.

The “mechanics” of MF are worth explaining. Any person who has cut themselves and bled during shaving will appreciate that a thin layer of skin encapsulates tissue containing blood.

In MF, a certain type of T-Cell becomes malignant. In my case, T-helper cells, known as CD4 lymphocytes periodically become lymphoprofilerative – which is to say that they multiply in an uncontrolled manner.

The malignant CD4 lymphocytes proliferate and do not die – instead they migrate from the blood and lymphatic system, to the surface of the skin. In my case the malignant CD4 cells tend to migrate to areas of the skin that do not receive direct sunlight, such as my buttocks, and lower legs.

Treatment for Stage 1A MF can involve exposure to Ultra Violet light and steroid cream to induce apoptosis in malignant CD4 lymphocytes.

Treatments for more advanced stages include a barrage of chemotherapeutic drugs, radiotherapy and novel new medicines and clinical trials.

Progression of MF

The early stages of MF are characteristically indolent. In later stages the cancer may be much more aggressive.

A dermatologist treats my early stage MF, and he has mentioned that he had another patient with more aggressive MF. This patient had large MF tumours on the soles of his feet such that he could not stand up. He also had large tumours on his buttocks such that he could not sit down. This other patient is now deceased.

Causes of Death

Even in advanced stages, MF does not necessarily cause death. The body can bear a great tumour burden without killing the patient outright. This prospect terrifies me. However, plaques and tumours on the surface of the skin often lead to patients dying of hospital acquired infections, and sepsis - bacterial infections.

Diagnosis of early stage MF is not a terminal disease. If the disease progresses, as it does in about 20% of patients, progression to advanced stages can lead to a miserable, disfiguring, painful, and incredibly itchy existence, which may not be quickly and directly terminal.

Relevant Specialists

MF, and other forms of Cutaneous Lymphoma, are usually treated by dermatologists, haematologists, radiologists, and oncologists. In the event my disease progresses I have a file open at Sir Charles Gairdner Hospital's Haematology Department.

The rarity of MF, and other Cutaneous Lymphmas, is such that there are few medical specialists capable of making a reliable prognosis.

My Personal Views

Thankfully, in the 5 years since diagnosis, my MF has not progressed. It is merely a periodic nuisance. I had concluded that if my MF progressed, and became refractory (which is to say resistant to standard treatments), that I would consider suicide.

My personal preference for self-termination using Nembutal. However, if my disease were to progress I may not be able to personally make a trip to Mexico to procure such. In that event, one would rely on another family member making the trip, which would cause moral dilemmas and potentially expose a family member to committing a criminal act.

If the Bill were to be enacted in its present form, it would affect me as follows:

1. I would have the comfort of knowing that in a worst-case situation, I could apply to die with dignity, at a time of my choosing, having said goodbye close to those close to me. 2. I would also tend to "hang on" for as long as I could. 3. If the Bill were not enacted, and my MF starts to progress, then I would start to make arrangements to obtain the necessary drugs for self-termination at the earliest opportunity. 4. I would also be concerned at the Bill's present definition of 'terminal illness', as MF does not always directly progress to death. One could literally become a walking tumour for some considerable time, until a hospital acquired infection carried me away.

Yours sincerely

Richard Mark bickerton From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

2009 114: 4337-4353 Prepublished online August 20, 2009; doi:10.1182/blood-2009-07-202895 How I treat mycosis fungoides and Sézary syndrome

H. Miles Prince, Sean Whittaker and Richard T. Hoppe

Updated information and services can be found at: http://bloodjournal.hematologylibrary.org/content/114/20/4337.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (2202 articles) How I Treat (121 articles) Lymphoid Neoplasia (1612 articles)

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Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

How I treat

How I treat mycosis fungoides and Se´zary syndrome

H. Miles Prince,1 Sean Whittaker,2 and Richard T. Hoppe3

1Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia; 2St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and Division of Genetics and Molecular Medicine, King’s College London, London, United Kingdom; and 3Department of Radiation Oncology, Stanford University, CA

The most common subtypes of primary roids, phototherapy (psoralen plus ultra- topheresis. Examples of drugs under ac- cutaneous T-cell lymphomas are mycosis violet A radiation or ultraviolet B radia- tive investigation include new histone fungoides (MF) and Se´zary syndrome tion), topical chemotherapy, topical or deacetylase inhibitors, forodesine, mono- (SS). The majority of patients have indo- systemic bexarotene, and radiotherapy. clonal antibodies, proteasome inhibitors, lent disease; and given the incurable na- Systemic approaches are used for recalci- and immunomodulatory agents, such as ture of MF/SS, management should focus trant early-stage disease, advanced-stage lenalidomide. It is appropriate to consider on improving symptoms and cosmesis disease (IIB-IV), and transformed disease patients for novel agents within clinical while limiting toxicity. Management of and include retinoids, such as bexaro- trials if they have failed front-line therapy MF/SS should use a “stage-based” ap- tene, interferon-␣, histone deacetylase in- and before chemotherapy is used. (Blood. proach; treatment of early-stage disease hibitors, the fusion toxin denileukin difti- 2009;114:4337-4353) (IA-IIA) typically involves skin directed tox, systemic chemotherapy including therapies that include topical corticoste- transplantation, and extracorporeal pho- Introduction

Primary cutaneous lymphomas are composed of both T-cell (75%ϩ) consider are outlined in Table 2 and, in this review, we aim to address the and B-cell lymphomas and are rare conditions representing 2% of all most common clinical scenarios the clinician faces. lymphomas with an annual incidence of 0.3 to 1 per 100 000.1,2 There are a variety of different types of cutaneous T-cell lymphoma (CTCL); Investigations and until relatively recently, there were 2 classifications for CTCL, the World Health Organization (WHO)3 and the European Organization for It cannot be overemphasized that the diagnosis of CTCL requires Research and Treatment of Cancer (EORTC),4 the latter characterized clinicopathologic correlation, and review by a pathologist col- by dividing the entities into aggressive or indolent conditions based on league experienced in these disorders is strongly recommended. clinicopathologic criteria. In 2005, the 2 classification systems were A consensus approach to diagnosis of early-stage MF has been combined (Table 1). In this review, we focus on the most common forms recently reported by the International Society of Cutaneous Lym- of CTCL, mycosis fungoides (MF) and its leukemic variant, Se´zary phoma (ISCL) with the majority of cases of CTCL diagnosed on syndrome (SS). hematoxylin-and-eosin sections with appropriate immunophenotyp- The wide array of clinical presentations and possible treatment ing, most commonly by immunohistochemistry and in some cases modalities makes the treatment of MF/SS complex, and there are by flow cytometry and clonal T-cell receptor gene rearrangement by polymerase chain reaction on fresh and formalin-fixed tissue.8 no simple treatment algorithms. There are several published guidelines, The approach to diagnosis is summarized in Table 3 and uses an which we recommend the reader review, that provide more detail around algorithm integrating clinical and laboratory assessments. the rationale of our management approaches to the various presentations It is also important to recognize that it is not uncommon for the of MF/SS. These include the National Cancer Center Network guide- diagnosis of MF to remain elusive for many years, often requiring 5 lines (www.nccn.org) and those by the European Society of Medical observation and repeated biopsies.9,10 Such an approach avoids 6 7 Oncology and the EORTC, with our approach most closely reflecting embarking on numerous investigations in a disease that is generally the latter. It is, however, very important to recognize that these indolent and where outcome is not altered by aggressive early guidelines are based on a somewhat restricted evidence base as intervention. CTCLs are very rare diseases with very few randomized trials performed to date. Moreover, when planning treatment, individual patient factors need to be considered, such as age and comorbidi- Non-MF cutaneous T-cell lymphoma ties, especially the risk of infection for which patients with MF/SS A key aspect of the management of CTCL is to distinguish the rare are particularly prone. The management approach is truly multidis- non-MF CTCL entities from MF.1 Clinical presentation will often ciplinary; and, as such, we hope to provide the combined perspec- help distinguish them from MF, and clinicopathologic correlation is tives of a dermatologist, radiation oncologist, and hematologist- critical to distinguish MF from other rarer CTCL subtypes, oncologist. A summary of the various treatment options we generally transformed disease, peripheral T-cell lymphoma or perhaps even a

Submitted July 5, 2009; accepted August 5, 2009. Prepublished online as © 2009 by The American Society of Hematology Blood First Edition paper, August 20, 2009; DOI 10.1182/blood-2009- 07-202895.

BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 4337 From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4338 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

Table 1. WHO-EORTC classification of cutaneous lymphomas with rare variant of MF. The approach to management of non-MF CTCL primary cutaneous manifestations1 is highly variable ranging from a conservative approach with Classification CD30ϩ CTCL, such as lymphomatoid papulosis (LyP), to a very Cutaneous T-cell and NK-cell lymphomas aggressive approach in such conditions as cutaneous ␥/␦ T-cell ϩ MF lymphoma or primary cutaneous aggressive epidermotropic CD8 MF variants and subtypes cytotoxic T-cell lymphoma. It is beyond the scope of this review to Folliculotropic MF discuss the non-MF CTCL entities in detail, and we refer the reader Pagetoid reticulosis to the WHO-EORTC manuscript for an overview of the clinical Granulomatous slack skin presentation and treatment strategies.1 Sézary syndrome Adult T-cell leukemia/lymphoma Stage Primary cutaneous CD30ϩ lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma The management of MF/SS is centered on a “stage-based” Lymphomatoid papulosis approach, and MF is classified into 4 clinical stages based on the Subcutaneous panniculitis-like T-cell lymphoma TNM classification (Table 4), which then is synthesized into a Extranodal NK-/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified clinically based staging system broadly divided into early- and 11 Primary cutaneous aggressive epidermotropic CD8ϩ T-cell lymphoma advanced-stage disease (Table 5). Skin patches and plaques occur (provisional) in stage I, which is divided into IA (Ͻ 10% body surface area Cutaneous ␥/␦ T-cell lymphoma (provisional) [BSA]) or IB (Ն 10% BSA). The presence of clinically evident Primary cutaneous CD4ϩ small-/medium-sized pleomorphic T-cell lymphoma lymphadenopathy without pathologic nodal infiltration represents (provisional) stage IIA, cutaneous tumors characterize stage IIB, generalized Cutaneous B-cell lymphomas erythroderma characterizes stage III, and pathologically positive Primary cutaneous marginal zone B-cell lymphoma lymph nodes (IVA) and visceral disease characterizing stage IVB. Primary cutaneous follicle center lymphoma Patients with staged IA, IB, and IIA disease are considered to have Primary cutaneous diffuse large B-cell lymphoma, leg type “limited-stage” disease, and those with stages IIB (tumor), III Primary cutaneous diffuse large B-cell lymphoma, other intravascular large B-cell lymphoma (erythroderma), and IV (pathologic nodes with or without viscera) Precursor hematologic neoplasm have “advanced-stage” disease. CD4ϩ/CD56ϩ hematodermic neoplasm (blastic NK-cell lymphoma) Prognosis

Although MF/SS are generally considered incurable conditions, it is important to recognize that the majority of patients have an

Table 2. Summary of treatment options for MF/SS MF Early-stage Advanced-stage Sézary syndrome/ Therapy disease disease erythrodermic MF Comments

Topical corticosteroids ϩϩϩϩ ϩϩ ϩϩϩ Symptomatic control PUVA ϩϩϩϩ ϩ ϩϩϩ Availability may be restricted in nonmetropolitan areas UVB ϩϩϩ ϩ ϩϩ More readily accessible than PUVA Topical chemotherapy ϩ If limited number of lesions Imiquimod ϩ If small lesions and limited number of lesions Photodynamic therapy ϩ If limited number of lesions; limited availability Retinoids ϩϩ ϩUsually second line; less used since bexarotene became available Bexarotene ϩϩ ϩϩϩ ϩϩϩ Usually second line; can be used in combination with PUVA or IFN-␣ Interferon-␣ ϩϩ ϩϩϩ ϩϩϩϩ Second line HDACi ϩ ϩϩϩ ϩϩϩϩ Beyond second line Oral MTX ϩ ϩϩϩ ϩϩ Low dose weekly Localized radiotherapy ϩ ϩϩϩ If localized or large/plaques and tumor nodules TSEB ϩϩϩ ϩFor widespread disease Systemic chemotherapy ϩϩ ϩϩ Beyond second line ECP ϩϩϩϩ If circulating clone detectable Autologous transplantation ϩϩVery selected cases Allogeneic transplantation ϩϩVery selected cases Denileukin diftitox ϩϩ ϩϩ Beyond second line Alemtuzamab ϩϩBeyond second line; immunosuppressive Proteasome inhibitors ϩ Under investigation Immunomodulatory agents ϩ Under investigation (lenalidomide)

MF indicates mycosis fungoides; SS, Sézary syndrome; PUVA, psoralan ultraviolet A; UVB, ultraviolet B; ECP, extracorporeal photopheresis; HDACi, histone deacetylase inhibitors; and TSEB, total skin electron beam. Crosses indicate frequency of use: ϩϩϩϩ, almost always; ϩϩϩ, very frequently; ϩϩ, moderately frequently; and ϩ, occasionally. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 HOW I TREAT CUTANEOUS T-CELL LYMPHOMAS 4339

Table 3. Algorithm of diagnosing early MF developed by the ISCL8 Criteria Scoring system Basic Additional Other 2 points 1 point

Clinical Persistent and/or progressive (1) Non–sun-exposed 2 points for basic criteria 1 point for basic criteria patches/thin plaques location and 2 additional and 1 additional (2) Size/shape variation criteria criteria (3) Poikiloderma Histopathologic Superficial lymphoid infiltrate (1) Epidermotropism without 2 points for basic criteria 1 point for basic criteria spongiosis and 2 additional and 1 additional (2) Lymphoid atypia* criteria criteria Molecular biologic Clonal T-cell receptor gene 1 point for clonality rearrangement Immunopathologic Ͻ 50% CD2ϩ, CD3ϩ, 1 point for 1 or more and/or CD5ϩ cells criteria Ͻ 10% CD7ϩ cells Epidermal/dermal discordance of CD2, CD3, CD5, or CD7†

A total of 4 points is required for the diagnosis of MF based on any combination of points from the clinical, histopathologic, molecular biologic, and immunopathologic criteria. *Lymphoid atypical is defined as cells with enlarged hyperchromatic nuclei and irregular or cerebriform nuclear contours. †T-cell antigen deficiency confined to the epidermis.

Table 4. ISCL/EORTC revision to the classification of MF and SS11 TNMB classification Characteristics

Skin T1 Limited patches,* papules, and/or plaques† covering Ͻ 10% of the skin surface; may further stratify into T1a (patch only) versus T1b (plaque Ϯ patch) T2 Patches, papules, or plaques covering Ն 10% of the skin surface; may further stratify into T2a (patch only) versus T2b (plaque Ϯ patch) T3 One or more tumors‡ (Ն 1 cm diameter) T4 Confluence of erythema covering Ն 80% BSA Node N0 No clinically abnormal peripheral lymph nodes§; biopsy not required N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 N1a Clone negativeʈ N1b Clone positiveʈ N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3 N2a Clone negativeʈ N2b Clone positiveʈ N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3-4 or NCI LN4; clone positive or negative Nx Clinically abnormal peripheral lymph nodes; no histologic confirmation Visceral M0 No visceral organ involvement M1 Visceral involvement (must have pathology confirmation¶ and organ involved should be specified) Blood B0 Absence of significant blood involvement: Յ 5% of peripheral blood lymphocytes are atypical (Sézary) cells# B0a Clone negativeʈ B0b Clone positiveʈ

B1 Low blood tumor burden: Ͼ 5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria of B2 B1a Clone negativeʈ B1b Clone positiveʈ B2 High blood tumor burden: Ն 1000/␮L Sézary cells# with positive cloneʈ

*For skin, patch indicates any size skin lesion without significant elevation or induration. Presence/absence of hypopigmentation or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted. †For skin, plaque indicates any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features, such as folliculotropism or large-cell transformation (Ͼ 25% large cells), CD30ϩ or CD30Ϫ, and clinical features, such as ulceration, are important to document. ‡For skin, tumor indicates at least one 1-cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of large-cell transformation has occurred. Phenotyping for CD30 is encouraged. §For node, abnormal peripheral lymph node(s) indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed, or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically. ʈA T-cell clone is defined by polymerase chain reaction or Southern blot analysis of the T-cell receptor gene. ¶For viscera, spleen and liver may be diagnosed by imaging criteria. #For blood, SCs are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If SCs are not able to be used to determine tumor burden for B2, then one of the following modified ISCL criteria along with a positive clonal rearrangement of the TCR may be used instead: (1) expanded CD4ϩ or CD3ϩ cells with CD4/CD8 ratio of 10 or more; or (2) expanded CD4ϩ cells with abnormal immunophenotype including loss of CD7 or CD26. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4340 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

Table 5. ISCL/EORTC revision to the staging of mycosis fungoides and Sézary syndrome Managing early-stage (IA-IIA) MF TNMB

IA 1 0 0 0, 1 Overview IB 2 0 0 0, 1 IIA 1, 2 1, 2 0 0, 1 As mentioned, the majority of patients present with early-stage Advanced-stage disease11 disease (Table 7). As the use of early application of therapy does 16 IIB 3 0-2 0 0, 1 not impact on survival, a nonaggressive approach to therapy is III 4 0-2 0 0, 1 warranted with treatment aimed at improving symptoms and IIIA 4 0-2 0 0 cosmesis while limiting toxicity. As patients with stage IA disease IIIB 4 0-2 0 1 have a long life expectancy, an “Expectant Policy” may be a IVA1 1-4 0-2 0 2 legitimate management option in selected patients, provided that it IVA2 1-4 3 0 0-2 incorporates careful monitoring. Given that multiple skin sites are IVB 1-4 0-3 1 0-2 often involved, the initial treatment is primarily SDT, which aims to control skin lesions while minimizing morbidity. The key choices for SDT are topical or intralesional corticosteroids or indolent form of the disease and will live for many years. Indeed, it psoralen plus ultraviolet A radiation (PUVA) or ultraviolet B is estimated that 65% to 85% of patients with MF have stage IA or (UVB). Indeed, for patients with limited patch disease, topical IB disease.9,12 The most important factor in planning management steroids often control the disease for many years, and often this is and determining prognosis is the stage of the disease. Indeed, the the only form of therapy required for such patients. Patch and thin majority of patients with early-stage disease (stages IA, IB, and plaque MF can be treated with topical corticosteroids. Class I IIA) do not progress to more advanced-stage disease, and patients (potent) topical corticosteroids, such as betamethasone dipropi- presenting with isolated patch or plaque disease (T1-T2) have a onate 0.05% or mometasone furoate 0.1%, are the most effective at median survival of more than 12 years12-14 (Figure 1). Moreover, obtaining objective disease regression. Patients with stage T1 patients with stage IA disease do not appear to have a decreased disease have an approximately 60% to 65% complete response survival compared with an age-, sex-, and race-matched (CR) rate and a 30% partial response (PR) rate with topical population.13 steroids. Patients with T2 disease (generalized patch/plaque Patients with advanced-stage disease (stages IIB, III, and IVA) with Ͼ 10% of skin surface involved) have a 25% CR rate and a with tumors, erythroderma, and lymph node or blood involvement 57% PR rate. Topical corticosteroids have CR rates similar to other but no visceral involvement have a median survival of 5 years from forms of SDTs.22 Intralesional corticosteroids can be effective in time of presentation. Of note, patients with tumors (T3) have an treating thicker MF lesions, such as plaques or tumor deposits. inferior outcome to those with erythroderma (T4). Patients with For more widespread disease, phototherapy with PUVAor UVB visceral involvement are rare (stage IVB) and have a median is recommended. Response rates to PUVA therapy in patients with survival of only 2.5 years or less.9,12,13,15,16 patch disease are high with CR rates of approximately 58% to 83% 23,24 Investigations. The approach to staging the patient is summa- and overall response rates of up to 95%. Furthermore, remis- rized in Table 6 and based on the recommendations of the ISCL.11 sion is often prolonged with a reported mean duration of 23 For patients with clinically very limited-stage disease with skin 43 months. Maintenance treatment with weekly or fortnightly patches and/or plaques with no palpable lymphadenopathy, exten- therapy can be effective in maintaining remission. PUVAtherapy is sive staging investigations are not generally required. Occasional generally well tolerated; however, acute side effects include nausea patients will present with locoregional lymphadenopathy, which (from the oral psoralens) or photosensitivity. Long-term side may reflect dermatopathic changes in the node rather than true effects are acceleration of actinic damage and an increased rate of nodal involvement with MF. Thus, it is not always necessary to skin malignancies, including squamous cell carcinoma and melanoma.25-27 biopsy every patient with mildly enlarged nodes. In general, we UVB is also effective for MF, especially for patch and thin recommend biopsy of nodes larger than 1.5 cm as nodal involve- plaque disease. Broadband UVB (300-320 nm) was initially used, ment has substantial prognostic impact (Table 4). The relative hesitancy in performing node biopsies relates to the high incidence of skin colonization with pathogenic organisms in patients with MF/SS, which increases the risk of infection after surgery. Prognostic characteristics beyond stage. Clinical stage is by far the most important predictor of outcome. However, within early-stage MF, there is some prognostic heterogeneity. Indeed, we recognize an “intermediate-risk” group between early- and ad- vanced-stage disease. This includes patients with stage IIA/IB folliculotropic variant of MF and patients with very thick plaques.17,18 The relatively inferior outcomes in these groups are thought to be the result of its reduced responsiveness to skin- directed therapy (SDT).19 For advanced-stage disease, patients with stage IIB disease with multiple tumor nodules (a higher tumor burden) and large-cell transformation of MF have a substantially Figure 1. Actuarial disease-specific survival of 525 patients with MF and SS poorer prognosis (see “Transformed disease”).9 Low numbers of according to their clinical stage at diagnosis (stages IA-IV).12 For stage IA versus ϭ ϭ ϩ IB disease, P .007; for stage IB versus IIA disease, P .006; for stage IIA versus CD8 T cells in the dermal infiltrate and/or the blood have also IIB disease, P Ͻ .001; for stage IIA versus III disease, P ϭ .03; for stage IIB versus III been independently associated with reduced survival.14,20,21 disease, P ϭ .09; and for stage IA-III versus IV disease, P Ͻ .001. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 HOW I TREAT CUTANEOUS T-CELL LYMPHOMAS 4341 and more recently narrow band UVB (311 nm) has also been shown always considered before the use of chemotherapy. Radio- to be effective in MF, although remission duration with the latter therapy is a highly effective therapy in MF/SS and can be used may be inferior. The advantage of UVB over PUVA is that it is for both early- and advanced-stage disease, as first-line or more readily available (more community-based dermatology prac- relapsed/progressive disease. tices have UVB equipment) and avoids the need for protective sunglasses and the side effects, albeit modest, of psoralen. The Radiotherapy disadvantage of UVB is its somewhat lower response rate and Cutaneous lymphomas are usually highly radiosensitive, and duration of remission and less effective than PUVA with thicker radiation therapy may play a major role in the management of 28,29 lesions. PUVAhas been reported to achieve improved response many patients with MF.35 Partial regression of disease may be rates when combined with interferon-␣-2b (IFN-␣)30,31 or retinoids observed with single doses as low as 1.0 Gy.36 However, permanent such as acitretin.32 PUVAtherapy has also been used as a salvage or eradication of all disease using radiotherapy alone is an elusive maintenance therapy after total skin electron beam (TSEB) therapy.33 goal. Thus, treatment is usually aimed at improving symptoms and For even thicker plaques, particularly if localized, radiotherapy is cosmesis. Nonetheless, there is the very occasional patient who effective as the disease is highly radiosensitive (see “Radiotherapy”). presents with truly localized MF (single lesion) often around the Other choices for first-line therapy are topical chemotherapy “bathing trunk” distribution or breast. Whether this is curable is using mechlorethamine (nitrogen mustard [NM]) or carmustine. unknown, but our approach is similar to the management of other However, the use of these agents can be impractical if lesions are extensive and, with long-term use, carry a risk of secondary low-grade lymphomas: to treat such patients with local radio- epidermal cancer. Moreover, particular care must be taken to avoid therapy with “curative” intent to a dose of approximately 30 Gy. A 37 topical exposure to those carers assisting with the application of the large proportion of these patients may remain disease-free. solution or ointment. Drug hypersensitivity is reported to occur in The likelihood of achieving a CR and the durability of those up to 45% or more of patients treated with topical NM, particularly responses decreases with increasing stage of disease; patients with in solution form. NM ointment reduces the incidence of allergic T1 disease have a more than 80% CR rate with radiotherapy (either reactions; however, it involves considerable pharmacy preparation local field or TSEB therapy), compared with 20% to 30% CR rates and consequently is not readily available. Skin sensitivity occurs in for T4 disease. Five-year relapse-free survival rates with radiation up to 5% of patients treated with carmustine. Other localized alone are 40% to 60% for T1 disease, but less than 10% for T4 therapies include imiquimod34 and photodynamic therapy,24 but the disease.37 Irrespective of stage and curability, however, radio- latter is limited to specialized centers. therapy can provide excellent palliation of troublesome symptoms “Second-line” therapy for early-stage disease is often retin- of MF/SS, such as pruritus, scaling, and ulceration. oids or rexinoids (bexarotene), IFN-␣, low-dose oral methotrex- Target volume. For most patients, the target volume is the ate (MTX), histone deacetylase inhibitors (HDACi), or denileu- epidermis and/or dermis, that is, the maximum depth of interest is kin diftiox. Such second-line therapy can be highly effective for only a few millimeters from the skin surface unless there are disease refractory to topical therapies, and these choices are tumors or deep ulcers. Most lesions may therefore be treated with

Table 6. Recommended evaluation/initial staging of the patient with mycosis fungoides/Sézary syndrome11 Evaluation and staging

Complete physical examination, including: Determination of type(s) of skin lesions If only patch/plaque disease or erythroderma, then estimate percentage of BSA involved and note any ulceration of lesions If tumors are present, determine total number of lesions, aggregate volume, largest size lesion, and regions of the body involved Identification of any palpable lymph node, especially those Ն 1.5 cm in largest diameter or firm, irregular, clustered, or fixed Identification of any organomegaly Skin biopsy Most indurated area if only one biopsy Immunophenotyping to include at least the following markers: CD2, CD3, CD4, CD5, CD7, and CD8, and a B-cell marker, such as CD20; CD30 may also be indicated in cases where lymphomatoid papulosis, anaplastic lymphoma, or large-cell transformation is considered Evaluation for clonality of TCR gene rearrangement Blood tests CBC with manual differential, liver function tests, LDH, comprehensive chemistries TCR gene rearrangement and relatedness to any clone in skin Analysis for abnormal lymphocytes by either SC count with determination absolute number of SCs and/or flow cytometry (including CD4ϩ/CD7Ϫ or CD4ϩ/CD26Ϫ) Radiologic tests

In patients with T1N0B0 stage disease who are otherwise healthy and without complaints directed to a specific organ system; and in selected patients with T2N0B0 disease with limited skin involvement, radiologic studies may be limited to a chest x-ray or ultrasound of the peripheral nodal groups to corroborate the absence of adenopathy

In all patients with other than presumed stage IA disease, or selected patients with limited T2 disease and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis alone Ϯ FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral involvement, or abnormal laboratory tests; in patients unable to safely undergo CT scans, MRI may be substituted. Lymph node biopsy Excisional biopsy is indicated in those patients with a node that is either Ն 1.5 cm in diameter and/or is firm, irregular, clustered, or fixed Site of biopsy: preference is given to the largest lymph node draining an involved area of the skin or if FDG-PET scan data are available, the node with highest standardized uptake value; if there is no additional imaging information and multiple nodes are enlarged and otherwise equal in size or consistency, the order of preference is cervical, axillary, and inguinal areas Analysis: pathologic assessment by light microscopy, flow cytometry, and TCR gene rearrangement

TCR indicates T-cell receptor; CBC, complete blood count; and FDG-PET, 18F-fluoro-2-deoxyglucose positron emission tomography. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4342 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 very soft (low penetrance) beams: superficial x-ray therapy (50-145 course of TSEB is approximately 36 Gy, beyond which there is kvp) or 4 to 9 MeV electron beams. Higher-energy beams significant acute toxicity. (orthovoltage/megavoltage) are occasionally necessary for thicker Combined modality treatments. For patients with extensive lesions. and/or resistant disease, radiation has been used sequentially with TSEB therapy is usually reserved for patients with extensive several other treatments: PUVA, UVB, retinoids, and topical or skin involvement and can be used as first- or second-line therapy systemic chemotherapy. Occasionally, treatments may be adminis- for patients with extensive T2 or T3 disease, occasional patients tered concurrently, but doses of radiation will have to be modified if with T4 disease, and those who are no longer responding to large fields are being treated to minimize the risk for erythema or topical therapies. Even when the responses are incomplete or the desquamation. Extreme modifications to the radiation schedule and duration of complete response is brief, patients usually achieve lengthy treatment breaks may compromise the effectiveness of the significant clinical benefit. It is a complex technique and radiotherapy. TSEB followed by adjuvant PUVA, NM, photophere- requires the use of either multiple field arrangements or a sis, or other adjuvants does lead to a significant benefit in rotational technique, with “patching” or “boosting” for areas of disease-free survival, but not in overall survival (OS).39,40 One underdosing and self-shielding (eg, soles of feet, perineum) and combined modality approach for patients with extensive disease takes 6 to 10 weeks to complete. that we have found to have promising efficacy is the use of 2 or Dose. A wide range of radiation doses may be used in the 3 courses of chemotherapy, eg, high-dose MTX (Ͼ 1 g/m2)or management of these patients. For symptomatic treatment of liposomal doxorubicin to reduce disease to clinically minimal individual lesions, the dose may even be titrated to the response and levels before proceeding with TSEB. usually 15 to 20 Gy is sufficient. Although very small doses of Patient factors. Many patients with MF/SS are in good general radiation can provide effective palliation of these lesions, there health and may be working full-time. Others may be elderly or not does appear to be a dose-response relationship for complete reside close to a center that offers TSEB therapy. In either case, a remission, especially in the context of TSEB therapy. Doses of 10-week course of treatment may not be feasible and other 10 to 20 Gy are associated with a CR rate of only 55%, whereas management options will have to take precedence. Coexisting doses of 30 Gy or greater are associated with a 94% CR rate. In medical problems rarely preclude a patient from radiotherapy, but addition, the durability of responses is greater for patients treated there are some contraindications, eg, scleroderma, or inability to with higher doses.38 The maximum dose that is tolerated in a single stand for several minutes at a time during TSEB therapy.

Table 7. Recommendations for treatment of MF stages IA, IB, and IIA Treatment Comments*

First-line “Expectant policy” Usually suitable for those with stage IA disease in conjunction with symptomatic treatment if required; patients with single lesion may be considered for “curative therapy” with radiation therapy PUVA For patch/plaque disease; requires regular 2 or 3 times/week treatment; there may be limited availability of PUVA in nonmetropolitan areas; can be combined with retinoids/rexinoids UVB For patch stage disease as skin penetration not as deep as PUVA; requires regular 2 or 3 times/week treatment and generally more readily available than PUVA Topical corticosteroids Simple therapy; toxicities if extensive skin application for long periods Topical bexarotene For limited sites of disease; simple therapy; local reactions may occur Topical NM For limited sites of disease or generalized involvement; local reactions occasionally problematic; ointment causes fewer reactions; availability of NM worldwide has been a problem recently Topical carmustine Rarely used now; for limited sites of disease; local reactions may occur; causes telangiectasias Localized radiotherapy Especially for patients with limited number of lesions and/or thickened plaques; durable remissions achieved TSEB Patients with stage IB disease with relatively slow progression; limited availability; can take 6 to 10 weeks to complete Second-line؉ Oral bexarotene Generally well tolerated and convenient (oral capsule); some responses can be very durable; most common side effects are hypertriglyceridemia and hypothyroidism that usually require treatment; other relatively common side effects are rash and headache; can be used in conjunction with other therapies IFN-␣ monotherapy Major difficulty is tolerance and compliance; some responses can be very durable; somewhat inconvenient (daily subcutaneous injection); most common side effect is fatigue, particularly in older patients; requires moderately high doses aiming for 3 to 5ϩ MU/day; monitor FBC and thyroid function; IFN-␣ can also be combined with PUVA, retinoids, bexarotene Low-dose MTX Generally well tolerated and convenient (oral weekly); dose-response effect is common and usually starts at 20 to 30 mg/week (up to 60-70 mg/week); some responses can be very durable; most common side effects are cytopenias and long-term risk of liver disease; very effective in patients with coexistent lymphomatoid papulosis; can be used in conjunction with other therapies, such as steroids, ECP, PUVA, IFN-␣ Vorinostat Only approved HDACi currently; generally well tolerated and convenient (oral daily); there appears to be a dose-response effect in some patients; most common SEs are fatigue, lethargy, mild/moderate thrombocytopenia and elevated creatinine and taste changes; can improve itch even when skin lesions remain; some responses can be very durable; virtually no data on use in combination with other therapies, such as PUVA, IFN-␣, MTX, chemotherapy Denileukin diftitox Generally considered after trial of bexarotene and/or HDACi; inconvenient administration requiring daily dosing times 5 days every 3 weeks (6-8 courses); patient’s tumor must express CD25 (although responses are observed in patients with CD25Ϫ lesions); there can be substantial supportive care requirements for some patients during therapy who develop capillary leak syndrome; some responses can be very durable even in heavily pretreated patients Novel agents within In patients with stage IA-IIA disease, chemotherapy is not recommended and novel agents within clinical trials are generally clinical trials recommended before chemotherapy is considered (see Table 12)

*For more details and detailed references, we refer the reader to the EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.7 From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

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Retinoids and rexinoids

Retinoids belong to the family of steroid hormones, which bind to the nuclear receptors (retinoic acid receptor [RAR]; retinoid X receptor [RXR]) and subsequently interact with various transcrip- tion factors. RAR and RXR have various isoforms (␣, ␤, and ␥), which are differentially expressed in tissues. The skin contains both RAR and RXR. Non–RXR-selective retinoids, such as oral etreti- nate, arotinoid, acitretin, and isotretinoin (13-cis-retinoic acid), have been used alone or in combination with PUVA, IFN-␣,or even chemotherapy and are reported to have response rates in the range of 5% to 65%.31,32,41-45 Bexarotene is a new synthetic rexinoid that selectively binds to the RXR subfamily and is formulated as either as capsule or a topically applied gel.46,47 In our experience, oral bexarotene can achieve responses in chemoradio- therapy refractory patients within 2 to 4 months, and those patients may have a sustained benefit provided that the RXR-induced hyperlipidemia is manageable, allowing an optimal therapeutic dose. Bexarotene may also be useful in maintaining responses after SDT.46,48-50 Topical bexarotene is particularly useful for patients who have a limited number of patches or plaques, and we recommend its use before topical chemotherapy.47 In general terms, bexarotene is being used more frequently in MF/SS, often in place of the earlier generation retinoids.

IFN-␣ and related biologic response modifiers

IFN-␣, a biologic response modifier, should generally be consid- ered as second-line therapy for stage IA-IB disease and a first-line therapy for IIB, III, and SS and is effective at moderately high doses of 3 million to 10 million units (MU) daily or 3 times/ week.51-53 Time to response is in the order of weeks, and it can be combined with PUVA, chemotherapy, retinoids, and bexaro- tene.30,31,41,42,46,50,54,55 In advanced-stage disease, our preference is to use single-agent IFN-␣ first, adding PUVA if there is more widespread pruritus and adding bexarotene if the response is suboptimal. Prolonged responses have also been observed with ␥-interferon.56 Recombinant interleukin-12 (IL-12) has efficacy in

MF, but limited availability does not make it a realistic treatment Figure 2. Patient with stage IB disease with patches and thin plaques. option at present.57

Low-dose MTX that time, the patient had moved 140 miles from the city. PUVAwas There are few published reports on the use of MTX in MF,58,59 with not used because of inconvenience and a limited extent of the largest series of 60 patients with patch/plaque MF (T2) cutaneous disease. Topical corticosteroids were used initially with achieving a 12% CR and 22% PR rate with a median time to good response for 3 years. When more extensive lesions with ␣ treatment failure of 15 months.58 In this study, the median weekly plaques developed, the patient was treated successfully with IFN- dose was 25 mg with maximum doses up to 75 mg. Low-dose MTX 3 MU daily with complete resolution of symptoms. At the time of has been successfully combined with IFN-␣.60 next progression, we will consider retreatment with PUVA (if convenient) with or without oral bexarotene or IFN-␣.

Comment Clinical case 1: early-stage disease and SDT This case highlights the durable effect of SDT and how therapy Scenario options need to be individualized. A 42-year-old woman living in large metropolitan city presented with stage IB MF with predominantly cutaneous patches on the trunk involving 40% of the BSA (Figure 2). Clinical case 2: early-stage disease and SDT Management for “intermediate-prognosis” disease

The patient commenced PUVA therapy 3 times/week for 6 months Scenario with complete resolution of lesions. PUVA was continued for a further 3 months, twice a week and then discontinued. Localized A 65-year-old patient presented with multiple patches and plaques lesions returned (ϳ 5% of BSA) on her trunk 40 months later. By (Ͼ 50% of BSA), some showing clinical and histologic evidence of From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4344 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

Comment

This case illustrates what we could consider an intermediate prognostic disease in a patient with folliculotropic disease and dermatopathic nodal disease. Patients who are partially resistant to SDT often do well with combined modality treatment, especially PUVA plus IFN-␣/bexarotene combinations with additional use of local skin radiotherapy for resistant plaques. The response duration to TSEB will be critical as extensive subsequent relapse, even with early cutaneous stages of disease, will represent a difficult manage- ment issue.

Advanced-stage (IIB-IVB) MF

Overview

Treatment of advanced-stage disease, or indeed refractory early- stage disease, is more problematic and always requires a multidisci- plinary approach. Although systemic multiagent chemotherapy is often considered in patients with advanced-stage disease, the randomized National Cancer Institute study demonstrated that combination chemoradiotherapy offered no survival benefit over “conservative” sequential therapy.16 Moreover, relatively rapid relapses are observed after chemotherapy; consequently, SDT or biologic response-modifying agents should be used first where practicable and systemic chemotherapy considered in patients progressing after these treatments. Critically, these patients will often have resistant or relapsed disease characterized by only cutaneous patches and plaques, which will require SDT rather than a traditional escalation of systemic therapy. The choice of systemic Figure 3. Patient with stage IB disease with folliculotropic plaques on the trunk. therapy depends largely on age, performance status of patient, tempo of the disease, risks of myelosuppression, and most impor- tantly, stage. Thus, our approach is to separately consider treatment folliculotropism. Peripheral nodes in the inguinal and axillary areas options of patients with stage IIB (Table 8), stage III/SS (Table 9), were palpable with CT scan confirming that the largest axillary stage IV (Table 10), and transformed disease. In general, IFN-␣, node measured 2.5 cm. A nodal biopsy revealed dermatopathic bexarotene, vorinostat, and the fusion toxin denileukin diftitox are features confirming stage IIA disease (Figure 3). generally considered before embarking on systemic chemotherapy. Conversely, for the relatively rare patient with stage IVB disease of Management suitable performance status, aggressive chemotherapy, including The patient was treated with PUVA phototherapy twice weekly for transplantation strategies, should be considered early. Novel agents 4 months with only a limited partial clinical response. IFN-␣ was within clinical trials should always be considered in these patients. The single-agent or multiagent chemotherapy regimens described started (initially 3 MU 3 times/week, increasing to 6 MU 3 times/ in Table 11 are selected depending on disease characteristics and week) while the patient continued PUVA for a further 3 months. side-effect profile of the agents. The value of extracorporeal Prominent thick plaques involving facial areas and the inner thighs photopheresis (ECP) is generally limited to patients with erythroder- were treated with local superficial radiotherapy with complete mic disease and circulating malignant cells (see “SS”). resolution. The patient’s disease responded with a good PR and resolution of peripheral lymphadenopathy after a further 3 months Denileukin diftitox of therapy. Further superficial radiotherapy was used successfully Denileukin diftitox is a recombinant targeted fusion protein that to treat residual disease in the inguinal areas (shielded from combines the receptor-binding sequence of IL-2 with the PUVA). PUVA was discontinued after further maintenance weekly cytotoxic A-chain and translocation B-chain of diphtheria toxin therapy for 2 months (cumulative UVAdose [550 J/cm2]). Unfortu- (DAB IL-2).69-71 This drug has recently been approved by the ␣ 389 nately, despite continuing IFN- (3 MU 3 times per week) as Food and Drug Administration in the United States for patients maintenance therapy, the patient’s disease relapsed within 4 months. with relapsed CTCL whose tumors express the IL-2 receptor Therefore, PUVAwas restarted with bexarotene; but after a further subunit (CD25). This approval is based on superior outcomes in 6 months of therapy, only a PR was achieved. Higher doses of the first placebo-controlled randomized trial of systemic therapy bexarotene were not tolerated, and the cumulative dose of PUVA in MF/SS.72 The response rate was 49.1% at the 18 ␮g/kg dose (Ͼ 850 J/cm2) was considered a relative contraindication to with no statistically significant difference in RR in patients with maintenance PUVA therapy in view of the known carcinogenic early- or advanced-stage disease. Moreover, some patients had potential with high cumulative doses (Ͼ 1200 J/cm2). Therefore, prolonged remissions with the median progression-free survival the patient was treated with TSEB with a sustained complete beyond 971 days in the 18 ␮g/kg arm. This benefit needs to be remission. balanced against a toxicity profile that includes capillary leak From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

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Table 8. Recommendations for treatment of MF stage IIB Treatment Comments*

First-line IFN-␣ Can be effective even in patients with tumor and/or ulcerated lesions; see Table 7 for other comments; IFN-␣ can also be combined with PUVA, retinoids, bexarotene, MTX TSEB and superficial X-irradiation “Boosts” needed to site of thickened plaques/tumors; limited availability; can take 6 to 10 weeks to complete PUVA For patch/plaque disease; requires regular 2 or 3 times/week treatment; there may be limited availability of PUVA in nonmetropolitan areas; can be combined with retinoids/rexinoids, bexarotene, IFN-␣ Second-line Bexarotene See Table 7 for comments Vorinostat See Table 7 for comments Denileukin diftitox See Table 7 for comments Novel agents within clinical trials In patients with stage IIB disease, chemotherapy is recommended after bexarotene and/or and HDACi and/or DD; it is very acceptable to consider novel agents within clinical trials before chemotherapy is considered (see Table 12) Chemotherapy Choice of chemotherapy regimens is extensive (see Table 11), and choice depends on patient tolerance, risk of infection versus the relatively short duration of remission observed with most chemotherapy regimens; transplantation may be considered in highly selected persons

*For more details and detailed references, we refer the reader to the EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.7 syndrome, fever, and fluid retention, and so this is likely to with stage IIB or higher disease.79 The most common toxicities are remain a second- or third-line therapy. Recent evidence indi- gastrointestinal or constitutional symptoms, hematologic abnormali- cates that durable responses are also seen in patients with ties, or taste disorders, and are usually of mild to moderate severity CD25Ϫ disease.73 It has been successfully combined with and typically manageable.80 Other HDACi in development, such as bexarotene.74 romidedpsin (depsipeptide),81 panobinostat,82 and belinostat,83 have demonstrated responses in MF/SS. HDACi Monoclonal antibodies Histone deacetylase inhibitors have activity in various hematologic malignancies, including myeloid malignancies, Hodgkin lym- Alemtuzumab, the humanized monoclonal antibody targeted against phoma, peripheral T-cell lymphoma, and CTCL.75,76 Vorinostat CD52w (a pan-lymphocyte antigen) has demonstrated efficacy in (suberoylanilide hydroxamic acid) is an orally available hydrox- MF/SS; however, patients on trials to date have generally been very amic acid derivative that inhibits both class I and II histone heavily pretreated, which have probably impacted on the relatively deacetylases and has been approved in the United States by the short duration of response and the substantial cytomegalovirus Food and Drug Administration for the treatment of relapsed and reactivation and hematologic toxicity observed.84-88 Trials of refractory CTCL.77 In the initial phase 2 study, there was an overall combination strategies in less-heavily pretreated patients are war- response rate of 24%, with a reduction in pruritus seen in 58% of ranted. In general, outside the clinical trial setting, it has a very patients.78 In a subsequent trial, a 30% RR was observed in patients limited place in the treatment of MF/SS. Hopefully, more T cell–

Table 9. Recommendations for treatment of stage III or SS (stages III or IVa) Treatment Comments*

First-line ECP Well tolerated with limited toxicities; circulating T-cell clone should be detectable in blood by morphology, flow cytometry, or molecular studies; should not be considered in patients with SS who have extensive nodal (IVa) or visceral (IVb) disease; side effects to methoxsalen is rare; requires good venous access with the associated risk of infection; often combined with oral steroids (short-term), IFN-␣, bexarotene, or low-dose MTX; improvement with ECP alone can take some weeks and maximum improvement may not be seen for many months; durable responses are not uncommon IFN-␣ Major difficulty is tolerance and compliance; some responses can be very durable; somewhat inconvenient (daily subcutaneous injection); most common side effect is fatigue, particularly in older patients; requires moderately high doses aiming for 3 to 5ϩ MU/day; monitor FBC and thyroid function; IFN-␣ can also be combined with PUVA, retinoids, bexarotene, and ECP PUVA ϩ IFN-␣ For stage III disease; would not generally recommend PUVA alone; requires regular 2 or 3 times/week treatment and limited number of sites in nonmetropolitan areas MTX See Table 7 for comments Second-line Bexarotene See Table 7 for comments; can consider adding to ECP or IFN-␣ Vorinostat See Table 7 for comments; no data available of adding to ECP or IFN-␣ Denileukin diftitox See Table 7 for comments Alemtuzumab See Table 10 for comments Novel agents within clinical In patients with SS, chemotherapy is recommended after bexarotene and/or and HDACi and/or DD; it is very acceptable to consider novel trials agents within clinical trials before chemotherapy is considered (see Table 12) Chemotherapy Choice of chemotherapy regimens is extensive (see Table 11), and choice depends on patient tolerance, risk of infection versus the relatively short duration of remission observed with most chemotherapy regimens; transplantation may be considered in highly selected individuals

FBC indicates fludarabine, busulphan, and alemtuzumab. *For more details and detailed references, we refer the reader to the EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.7 From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4346 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

Table 10. Recommendations for treatment of MF stages IVA-IVB: first-line Treatment Comments*

Chemotherapy Choice of chemotherapy regimens is extensive (see Table 11), and choice depends on patient tolerance, risk of infection versus the relatively short duration of remission observed with most chemotherapy regimens; autologous or allogeneic transplantation should be considered early in treatment paradigm for selected persons TSEB and/or X-irradiation Patients with advanced-stage disease may benefit from TSEB; “boosts” to site of thickened plaques/tumors; TSEB has limited availability; can take 6 to 10 weeks to complete; conventional radiation therapy can be valuable for local control of tumors or localized/bulky nodal disease Bexarotene See Table 7 for comments; few patients on clinical trials had stage IVB disease; thus, response rate and response durations are not well described Denileukin diftitox See Table 7 for comments; few patients on clinical trials had stage IVB disease; thus, response rate and response durations are not well described IFN-␣ See Table 7 for comments; less used in this stage of disease but may be helpful in patients unable to tolerate chemotherapy Alemtuzumab Major toxicity is immune suppression with infection; requires surveillance for cytomegalovirus and antimicrobial prophylaxis; short responses if used in multirelapsed disease so should consider early Vorinostat See Table 7 for comments; few patients on clinical trials had stage IVB disease; thus, response rate and response durations are not well described Novel agents within clinical trials Given poor prognosis and incurable nature of advanced-stage disease, it is very acceptable to consider novel agents within clinical trials before chemotherapy is considered (see Table 12) Low-dose MTX Generally well tolerated and convenient (oral weekly); dose-response effect is common and usually starts at 20 to 30 mg/week (up to 60-70 mg/week); some responses can be very durable; most common side effects are cytopenias and long-term risk of liver disease; very effective in patients with coexistent lymphomatoid papulosis; anecdotal experience that can be very useful in CD30ϩ MF or CD30ϩ transformed disease; can be used in conjunction with other therapies, such as steroids, ECP, and PUVA

*For more details and detailed references, we refer the reader to the EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.7 specific antibodies will be developed with less immunosuppressive chemotherapy in CTCL (Table 11).90 In brief, systemic agents include effects. For example, zanolimumab (HuMax-CD4) is a fully alkylating agents (cyclophosphamide, chlorambucil), anthracyclines, humanized anti-CD4 monoclonal antibody and is specific for the purine analogs, and etoposide. Whereas single-agent or combination CD4 receptor expressed on most T lymphocytes. Although the chemotherapy regimens have produced moderately high response rates antibody interferes with T-cell activation, infections are uncom- in patients with advanced-stage MF/SS, these responses are typically not mon. Single-agent response rates are more than or equal to 50%, durable. There is no recognized superior multiagent chemotherapy but remission duration is relatively short.89 Combination studies regimen for MF, and regimens that are typically associated with the would be interesting but, to our knowledge, are currently not being treatment of B-cell lymphoma or Hodgkin lymphoma, such as those investigated in CTCL. using cyclophosphamide, vincristine, vinblastine, prednisolone, MTX, doxorubicin, or mechlorethamine, have a disappointing track record in Systemic chemotherapy MF/SS. For example, a study of infusional EPOCH (etoposide, vincris- Several chemotherapy agents have demonstrated activity in MF/SS. We tine, doxorubicin, bolus cyclophosphamide, and oral prednisone) in refer the reader to a detailed and comprehensive review of systemic advanced refractory MF/SS demonstrated an overall response rate of

Table 11. Key clinical studies of systemic chemotherapy in cutaneous T-cell lymphoma Therapy examples* Efficacy Comments

CHOP-based67 ORR stage IIB: 66% Myelosuppression with risk of infection; very short remission duration EPOCH61 ORR stage IIB-IV: 80% Myelosuppression with risk of infection; short remission duration CMED/ABV42,62 ORR stage III-IV: 81% Myelosuppression with risk of infection; median DFS of 7 months and 27% 5-year DFS Pegylated liposomal doxorubicin65 ORR stage IA-IV: 88% Single agent; well tolerated; infusion-related events; no comparisons with standard anthracyclines Pentostatin64 ORR stage IIB: 75% Numerous trials and regimens used; activity in PTCL; perhaps best Stage III: 58% activity in SS; prolonged therapy needed in some cases; Stage IV: 50% lymphopenia Fludarabine plus IFN-␣55 ORR stage IIA-IVA: 58% Neutropenia common stage IVB: 40% Fludarabine plus ORR stage IIB-III: 55% Appears higher RR to fludarabine-alone; lymphopenia and prolonged cyclophosphamide66 myelosuppression in some patients; stem cell collection yields are lower Gemcitabine63 ORR stage IIB-III: 70% Neutropenia; recent evidence that toxicities (rash, infection) may be higher in patients with CTCL (see “Systemic chemotherapy”) 2-Chlorodeoxyadensine68 ORR stage IIA-IV: 28% Median duration or response of 4.5 months; bone marrow suppression and infections in 62%

CR indicates complete response; CRR, complete response rate; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone; ORR, overall response rate; PR, partial response; PUVA, ultraviolet A light with oral methoxypsoralen; and DFS, disease-free survival. *See “Systemic chemotherapy” for more details and other trial results. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

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Table 12. Selected novel drugs being evaluated in current clinical trials for MF/SS Drug class Examples Comments

HDACi Romidepsin81 Vorinostat is approved for relapsed, refractory CTCL, which has led to investigation Panobinostat110 to other HDACi in CTCL and PTCL; a number are undergoing regulatory Belinostat83 approval process; response rates and toxicities are similar Monoclonal antibodies Zanolimumab89 ORR of 50%ϩ as single agent in early studies but of relatively short duration; well tolerated with little infection risk; combination studies planned Alemtuzumab84-86,88 Single-agent studies with ORR of 40%ϩ but short duration; immunosuppressive; combination studies underway Purine nucleoside phosphorylase inhibitor Forodesine (BCX-1777)111 Single-agent activity of 30%ϩ with durable remissions observed; well tolerated and convenient (oral) Proteasome inhibitors Bortezomib112 Single-agent activity observed in heavily pretreated patients; generally well tolerated with minimal myelosuppression; combination studies planned IMiDs Lenalidomide113 Single-agent activity observed in heavily pretreated patients; generally well tolerated, but fatigue appears dose-limiting; maintenance studies being considered Synthetic oligodeoxynucleotides containing PF-3512676 CpG-ODN have potent immunostimulatory effects and activate professional unmethylated CG dinucleotides (CpG-ODN) antigen-presenting cells that express the target receptor, Toll-like receptor 9114 Retinoids Tazarotene115 Novel synthetic retinoid Fusion toxins Anti-Tac(Fv)-PE38 (LMB-2)116 Fusion toxins, which combines a target cell binding domain linked to a bacterial toxin Antifolate Pralatrexate117 Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1

IMiDs indicates immunomodulatory drugs; and CpG-ODN, cytosine-phosphate-guanosine oligodeoxynucleotide.

80% with 27% CRs61; however, the median duration of response was Transplantation just 8 months (range, 3-22 months). This study also highlighted the Interpretation of the transplantation data are difficult because the problem of infectious complications in the delivery of chemotherapy in number of patients with MF/SS treated to date with stem cell patients whose disease renders them inherently immune-suppressed and transplantation is very small. A review of this subject has recently who are frequently colonized with potentially pathogenic bacteria.91,92 been published.103 In brief, standard-intensity allogeneic stem cell The combination therapy of cyclophosphamide, MTX, etoposide, transplantation has been shown to induce complete and durable dexamethasone alternating with doxorubicin, bleomycin, and vinblas- remissions in patients with CTCL; however, infection rates are tine is suitable for selected younger patients and has demonstrated a high.104-106 Investigators have been evaluating reduced-intensity 5-year disease-free survival of 27%.42,62 conditioning for MF/SS and transplantation-related mortality is Because of the high risk of infection and myelosuppression and low, time to relapse is variable, and durable remissions are modest response durations with combination chemotherapy, single- observed.107,108 We recommend that allogeneic transplantation be agent therapies are preferred, except in patients who are refractory considered in younger patients with advanced-stage disease if not or who present with extensive adenopathy and/or visceral involve- responding to agents such as IFN-␣, bexarotene, HDACi, or ment or constitutional symptoms and require rapid tumor reduc- denileukin diftitox. tion. Thus, in patients with relatively slowly progressive disease Results with autologous stem cell transplantation have not been who have failed other treatments, we would consider low-dose oral particularly promising.103,109 However, despite the limited data, in MTX, chlorambucil, cyclophosphamide, or etoposide. For patients younger patients with stage IIB, stage IV, or transformed disease with more rapidly progressive disease and of reasonable perfor- who are refractory/relapsed after IFN-␣, bexarotene, or HDACi, mance status, our preference is to use single-agent gemcitab- their outcome is extremely poor and aggressive approaches seem ine,63,93-95 pentostatin,54,64,96-100 or liposomal doxorubicin65,101,102 as warranted.5 High-dose therapy has the potential to increase re- these agents have been investigated the most thoroughly. Gemcitab- sponse, and it has been our observation that, although virtually all ine has a high response rate, but myelosuppression can be patients relapse, some patients relapse with somewhat more problematic with dose-reduction frequently required. A recent indolent disease that in turn is more easily managed with nonche- report suggests that patients with CTCL may be more prone to motherapy agents. Clearly, more investigation is required for this 95 other nonhematopoietic toxicities of this drug. Overall response group of patients. rates as high as 70% have been reported for pentostatin with a variety of regimens used. However, such high response rates are Novel agents within clinical trials generally observed in patients with SS with lower response rates expected in patients with tumor stage or nodal disease. Infectious In the last few years, several new agents have become available for complications can be reduced with prophylactic trimethoprim and the treatment of MF. These include bexarotene, denileukin diftitox, antiviral therapies.64 It has been combined with IFN-␣ with and vorinostat. For patients who are not suitable or fail these drugs, improvement in progression-free survival. Single-agent fludara- novel agents within clinical trials should always be considered. bine has a poor response rate of less than 20%, but one combination Indeed, it is our belief that patients should be considered for clinical strategy that appears promising is fludarabine with cyclophospha- trials as an alternative strategy to systemic chemotherapy. Novel mide (Table 11). However, short- and long-term hematologic agents that are being investigated in the context of clinical trials are toxicity can be problematic.66 listed in Table 12. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4348 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

sized tumors every 18 months, which responded to further radiotherapy. However, a recurrence of extensive cutaneous patches and plaques was noted to have gradually developed at routine clinic review, and examination revealed a bulky axillary node (3 cm), which histologically showed partial effacement with malignant lymphocytes. A CT scan showed no other abnormality and the patient (with now “stage IVA disease”) was treated with CHOP chemotherapy (cyclophosphamide, doxoru- bicin, vincristine, prednisone). An initial complete response after 2 cycles was followed by a recurrence of extensive cutaneous disease (characterized by patches/plaques and scat- tered tumors) after 4 cycles despite complete resolution of the nodal disease. Chemotherapy was discontinued, the patient was entered into a clinical trial, and a donor search for reduced- intensity conditioning allogeneic transplantation was initiated.

Comment

This case emphasizes the clinical heterogeneity of MF and the challenge of deciding when to escalate therapy as some patients with advanced but limited disease (stage IIB) can be successfully managed with SDT, including radiotherapy, whereas extensive skin tumors (stage IIB) or nodal disease (stage IVA) invariably require aggressive therapies, including chemotherapy and consideration of high-dose therapies, including allogeneic transplantation if the patient’s performance status is satisfactory.

Transformed disease

Although most patients with early-stage disease (patches or plaques confined to the skin) have an indolent course, progression to cutaneous tumors, nodal, or visceral disease can occur. Cutane- ous tumors can develop either as increasing depth of the small atypical lymphocytes of MF or as a result of large-cell transforma- Figure 4. Patient with stage IIB disease with large tumor on the left calf. tion. Thus, when a patient presents with a tumor nodule, it is critical to biopsy the lesion as treatment and outcomes for advanced-stage disease versus transformed disease are quite different (Figure 5). Large-cell transformation is currently defined as large cells Clinical case 3: progressive disease despite (Ն 4 times the size of a small lymphocyte) in more than 25% of the SDT infiltrate or if these cells formed microscopic nodules.118,119 There is a variable incidence of transformation from MF of 8% to 39% Scenario reported, and it is associated with a very poor prognosis with a median survival of less than 2 years with particularly short survival A 52-year-old male patient presented with an 18-month history of in those patients who transform early after diagnosis. The risk of polymorphic patches and plaques involving the limbs and pelvic transformation is associated with advanced-stage, elevated ␤2- girdle area, which had been partially controlled with topical microglobulin and elevated lactate dehydrogenase9,118 (Table 13). steroids and attributed to “psoriasis.” A diagnosis of MF was made Treatment of transformed disease is a major challenge as these on the basis of diagnostic clinical and pathologic features (stage IB; patients generally have a poor outcome. Prognosis is particularly Figure 4). poor when patients have multiple sites of large-cell transformation. There are limited preliminary data to indicate that some patients Management with advanced-stage disease in whom the large cells express CD30 Phototherapy was initiated with initial success, but the patient may have a more indolent course.9,120 For the younger patient, developed an ulcerated tumor on the right calf, which histologi- systemic chemotherapy is initiated early and consideration should cally showed scattered large blastlike cells (CD30Ϫ). A staging be made for autologous or allogeneic transplantation. Consolida- CT scan was normal. The tumor responded to radiotherapy and tive radiation therapy should be considered in young patients with PUVA was continued with an excellent response, allowing unifocal transformation. In elderly or frail patients with unifocal withdrawal of therapy after 5 months. The patient remained well disease, local radiation therapy should be used and occasionally for 5 years despite developing on average 2 small- to medium- may result in durable remissions. From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 HOW I TREAT CUTANEOUS T-CELL LYMPHOMAS 4349

Figure 5. Patient with MF with transformed disease. (A) On limbs. (B) On trunk. (C) OS of patients with advanced-stage disease according to the presence (n ϭ 22) or absence (n ϭ 70) of large-cell transformation in the advanced-stage population.9 Median OS in the transformed group was 2.2 years, compared with 5.2 years in the nontransformed group.

Comment

Clinical case 4: transformed disease—is it or This case illustrates the critical need for expert clinical and is it not? pathologic correlation to make the correct diagnosis and avoid inappropriate aggressive therapy. MF is often associated with LyP, Scenario and treatment/prognosis is based on the stage of MF. Such patients This 40-year-old woman presented with a 2-year history of have to be distinguished from those patients with MF who develop erythematous patches and plaques over the pelvic girdle area and disease progression characterized by tumors with large-cell trans- formation (dermal sheeted nodules of large pleomorphic or anaplas- limbs, which was initially considered to be eczema by her local ϩ medical officer. She then presented with a 2-month history of small tic blast-like cells, which may or may not be CD30 ). Moreover, tumors on the trunk. A diagnostic biopsy showed an infiltrate of we think that the current pathologic criteria for large-cell transfor- large CD30ϩ anaplastic cells and staging investigations were mation in MF are inadequate and need to be further clarified to aid in distinguishing the various entities. normal, suggesting a diagnosis of primary cutaneous CD30ϩ anaplastic lymphoma. However, a biopsy of the “eczematous” rash showed an epidermotropic infiltrate of CD4ϩ T cells consistent with MF. In addition, closer discussion with the patient revealed a Se´zary syndrome history of recurrent nodules and small tumors, which always resolved to leave varioliform scars. The diagnosis was changed to SS is currently defined by the ISCL as a distinctive erythrodermic MF (stage IB) with LyP. Identical T-cell clones were detected in CTCL with hematologic evidence of leukemic involvement121 biopsies from the patches/plaques and the tumor (Figure 6). (Figure 7). The WHO-EORTC considers SS to be a separate entity from cases that otherwise meet the criteria for SS but have been Management preceded by clinically typical MF.1,122 Such latter cases have been The presenting tumor was treated with local radiotherapy, and the designated as “SS preceded by MF” and also as “secondary” SS.123 patient achieved a complete response to PUVA phototherapy after Patients with SS can be classified either as stage III or IV. The 4 months of therapy. Subsequently, she remained off therapy with median survival of classic SS in one report of 62 patients was 124 only topical emollients, but frequent recurrences of self-healing 31 months with a 5-year survival of 34%. It appears that the papules and nodules prompted successful maintenance treatment overall prognosis of SS/erythrodermic MF (E-CTCL) is improving; with low-dose oral MTX. and in a recent report of 124 patients with E-CTCL, there was a median OS of 5.1 years (range, 0.4-18.6 years).125 When patients were stratified according to Se´zary cell (SC) counts, the median OS Table 13. Distribution of patients with large-cell transformation, was 7.6 years for patients with less than 1000 SC/L versus 2.4 years according to stage of MF/SS9 for those with more than 10 000 SC/L. In multivariate analysis, Transformed Transformed advanced age and elevated lactate dehydrogenase were the stron- Stage/subtype Patients, n patients, n patients, % gest predictors of a poor prognosis.125 In another study of 106 pa- IA/IB/IIA 208 3 1.4 tients with erythrodermic MF, median survival ranged from 1.5 to IIB 41 11 26.8 10.2 years depending on the presence of 3 independent adverse III 36 1 2.8 factors: patient age, presence of lymph node disease, and peripheral IVA 9 5 55.6 blood involvement.126 IVB 3 2 66.7 Patients with E-CTCL present a difficult management problem Total 297 22 7.4 because they often have severe itch and a high risk of infection From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

4350 PRINCE et al BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20

Figure 7. Patient with SS with erythrodermic disease.

criteria, patient selection, and intervals between diagnosis and treatment. No phase 3 (randomized) trials have been performed. In line with the United Kingdom consensus guidelines, we recommend that patients with E-CTCL with circulating lympho- cytes (molecular, flow, or morphology) have an initial trial with ECP.130 The regimens used are variable131 but in general require an intense induction and then maintenance phase.130 Responses may

Figure 6. Patient with patches and plaques of MF (stage IB) on the limbs and take 6 months or more. Improved RR has been reported when used self-healing papules and nodules of lymphomatoid papulosis on the trunk. in combination with bexarotene, PUVA, and IFN-␣. In general, we recommend combining ECP with bexarotene or IFN-␣. Second-line therapy for E-CTCL is detailed in Table 9. Patients complicating therapy, and remission durations after therapy are with E-CTCL have been well represented in clinical trials of frequently short. In general terms, the treatment is similar to that of bexarotene, denileukin diftitox, HDACi, and alemtuzumab; and advanced-stage MF. Systemic therapy or TSEB is often required if indeed, in several trials patients with erythroderma appear to have a PUVA therapy fails. However, patients with erythroderma are better outcome than nodal or tumor-stage disease with such exquisitely sensitive to radiation therapy, and planned doses may strategies. Chemotherapy, including transplantation strategies, have to be reduced. In patients with E-CTCL, it is always important should be considered in younger patients. Single-agent chemo- to consider underlying staphylococcal infection “driving” disease therapy regimens, such as gemcitabine or pentostatin, are our exacerbation. Indeed, it is well recognized that recognition and preferred chemotherapy choices (Table 11). treatment of underlying infection (which is often not clinically evident) will result in clinical improvement in the patient’s erythroderma.92,127 Summary One treatment that is more effective in E-CTCL compared with other stages of MF is ECP. The efficacy of ECP in E-CTCL has The first step in managing MF/SS is obtaining an accurate been reviewed elsewhere, and these reviews are highly recom- diagnosis, which always requires good communication between the mended.128-130 In brief, phase 2 studies have reported a therapeutic clinician and pathologist. In some instances, close observation and benefit of ECP in CTCL, although the response data have been repeated biopsies may be needed. Treatment requires an individual- variable, ranging from 30% to 80% depending on study entry ized approach largely depending on the stage of disease and From bloodjournal.hematologylibrary.org by guest on February 19, 2014. For personal use only.

BLOOD, 12 NOVEMBER 2009 ⅐ VOLUME 114, NUMBER 20 HOW I TREAT CUTANEOUS T-CELL LYMPHOMAS 4351 performance status of the patient. Overaggressive therapy with Conflict-of-interest disclosure: H.M.P. is a consultant to Merck, multiagent chemotherapy should be avoided, particularly in pa- Novartis, Gloucester Pharmaceuticals, Eisai, and has received tients with early-stage MF/SS. Exciting novel targeted therapies are research funding from Merck, Novartis, and Gloucester Pharmaceu- under investigation, which will add to the armamentarium of ticals. S.W. is a consultant for Gloucester Pharmaceuticals, Eisai, treatments for this challenging group of diseases. and Merck. R.T.H. declares no competing financial interests. Correspondence: H. Miles Prince, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Authorship Bag 1, A’Beckett St, Melbourne 8006, Victoria, Australia; e-mail: Contribution: H.M.P., S.W., and R.T.H. wrote the paper. [email protected]. References

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Kurzrock R, Pilat S, Duvic M. Pentostatin therapy nisone in patients with refractory cutaneous T-cell treatment of cutaneous manifestations of ad- of T-cell lymphomas with cutaneous manifesta- lymphoma. Cancer. 1999;86(7):1368-1376. vanced primary cutaneous T-cell lymphoma. Clin tions. J Clin Oncol. 1999;17(10):3117-3121. 62. Duvic M, Apisarnthanarax N, Cohen DS, Smith Cancer Res. 2007;13(8):2318-2322. 100. Mercieca J, Matutes E, Dearden C, MacLennan TL, Ha CS, Kurzrock R. Analysis of long-term out- 81. Piekarz R, Frye R, Turner M, et al. A multi- K, Catovsky D. The role of pentostatin in the comes of combined modality therapy for cutane- institutional phase II trial of the HDAC inhibitor treatment of T-cell malignancies: analysis of re- ous T-cell lymphoma. J Am Acad Dermatol. 2003; romidepsin as monotherapy for patients with cu- sponse rate in 145 patients according to disease 49(1):35-49. taneous T-cell lymphoma. J Clin Oncol. In press. subtype. J Clin Oncol. 1994;12(12):2588-2593. 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Soligo D, Ibatici A, Berti E, et al. Treatment of ad- 117. O’Connor OA. Pralatrexate: an emerging new mic cutaneous T-cell lymphoma, superantigen- vanced mycosis fungoides by allogeneic stem- agent with activity in T-cell lymphomas. Curr Opin positive Staphylococcus aureus, and oligoclonal cell transplantation with a nonmyeloablative regi- Oncol. 2006;18(6):591-597. T-cell receptor V beta gene expansion. Blood. men. Bone Marrow Transplant. 2003;31(8):663- 118. Diamandidou E, Colome-Grimmer M, Fayad L, 1997;89(1):32-40. 666. Duvic M, Kurzrock R. Transformation of mycosis 128. Oliven A, Shechter Y. Extracorporeal photophere- 108. Herbert KE, Spencer A, Grigg A, Ryan G, fungoides/Sezary syndrome: clinical characteris- sis: a review. Blood Rev. 2001;15(2):103-108. McCormack C, Prince HM. Graft-versus- tics and prognosis. Blood. 1998;92(4):1150-1159. 129. Dani T, Knobler R. Extracorporeal photoimmuno- lymphoma effect in refractory cutaneous T-cell 119. Vergier B, de Muret A, Beylot-Barry M, et al. therapy-photopheresis. Front Biosci. 2009;14: lymphoma after reduced-intensity HLA-matched Transformation of mycosis fungoides: clinico- 4769-4777. sibling allogeneic stem cell transplantation. Bone pathological and prognostic features of 45 cases. 130. Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. con- Marrow Transplant. 2004;34(6):521-525. French Study Group of Cutaneous Lymphomas. sensus statement on the use of extracorporeal 109. Olavarria E, Child F, Woolford A, et al. T-cell Blood. 2000;95(7):2212-2218. photopheresis for treatment of cutaneous T-cell depletion and autologous stem cell transplanta- 120. Barberio E, Thomas L, Skowron F, Balme B, lymphoma and chronic graft-versus-host disease. tion in the management of tumour stage mycosis Dalle S. Transformed mycosis fungoides: clinico- Br J Dermatol. 2008;158(4):659-678. fungoides with peripheral blood involvement. Br J pathological features and outcome. Br J Derma- 131. Arulogun S, Prince HM, Gambell P, et al. Extra- Haematol. 2001;114(3):624-631. tol. 2007;157(2):284-289. corporeal photopheresis for the treatment of 110. Ellis L, Pan Y, Smyth GK, et al. Histone deacety- 121. Vonderheid EC, Bernengo MG, Burg G, et al. Up- Sezary syndrome using a novel treatment proto- lase inhibitor panobinostat induces clinical re- date on erythrodermic cutaneous T-cell lym- col. J Am Acad Dermatol. 2008;59(4):589-595. Annals of Oncology 24 (Supplement 6): vi149–vi154, 2013 clinical practice guidelines doi:10.1093/annonc/mdt242 Published online 17 July 2013

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† R. Willemze1, E. Hodak2, P. L. Zinzani3, L. Specht4 & M. Ladetto5, on behalf of the ESMO Guidelines Working Group* 1Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands; 2Department of Dermatology, Rabin Medical Centre, Beilinson Hospital, Petach Tikva, Israel; 3Institute of Haematology and Medical Oncology, University of Bologna, Bologna, Italy; 4Department of Oncology and Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 5Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy,

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) Downloaded from epidemiology skin or peripheral blood may be a valuable adjunct in selected cases. However, clinical and histopathological features are, in fi Primary cutaneous lymphomas (PCLs) are de ned as non- most cases, the most important deciding factors for therapeutic ’ Hodgkin slymphomasthatpresentintheskinwithno planning. PCLs should be classified according to the criteria of evidence of extracutaneous disease at the time of diagnosis. the World Health Organisation–European Organisation for http://annonc.oxfordjournals.org/ After the gastrointestinal lymphomas, PCLs are the second Research and Treatment of Cancer (WHO–EORTC) ’ most common group of extranodal non-Hodgkin s classification (Table 1)[1]. 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 staging skin secondarily, which often have another clinical In all cases, adequate staging should be carried out to exclude behaviour, have a different prognosis and require a different the presence of extracutaneous disease. Staging includes fi guidelines therapeutic approach. In recent lymphoma classi cations, complete physical examination, complete and differential clinical practice PCLs are therefore included as separate entities. Within the blood cell count and serum biochemistry and appropriate by guest on October 17, 2013 group of PCLs, distinct types of cutaneous T-cell lymphoma imaging studies (computed tomography scans ± [18F]2-fluoro- (CTCL) and cutaneous B-cell lymphoma (CBCL) can be 2-deoxy-D-glucose–positron emission tomography scans in all distinguished [1, 2]. In the western world, CTCL constitutes but stage IA), although they are not required in patients with ∼ – 75% 80% of all PCLs, with mycosis fungoides (MF) as the lymphomatoid papulosis (LyP) [5, 6]. Flow cytometry of the ∼ – most common type of CTCL, and CBCL 20% 25% [1]. peripheral blood should only be carried out in selected cases, However, different distributions have been observed in other but is mandatory in patients with (suspected) Sézary syndrome parts of the world. In southeast Asian countries, CTCLs (SS). Bone marrow biopsy and aspiration should be carried out other than MF, in particular Epstein-Barr virus-associated in cutaneous lymphomas with an intermediate or aggressive natural killer/T-cell lymphomas, are much more common clinical behaviour, but is not required in cutaneous than in Western countries, while CBCLs are much more lymphomas with an indolent clinical behaviour (MF, uncommon [3, 4]. cutaneous anaplastic large-cell lymphoma and cutaneous marginal zone lymphoma), unless indicated by other staging diagnosis assessments [5, 6]. The significanceofbonemarrow examination in primary cutaneous follicle centre lymphoma fi The diagnosis and classi cation of PCLs should always be based (PCFCL) is controversial [6, 7]. Prognosis is extremely variable on a combination of clinical, histological and depending on the type of PCL and the stage of disease. For immunophenotypical data. Demonstration of clonal T-cell clinical staging of MF and SS, the revised International Society receptor or immunoglobulin gene rearrangements in lesional for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) TNMB (tumour–node–metastasis-blood) staging system should be *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; used (Tables 2 and 3)[5].ForPCLotherthanMF/SS,a E-mail: [email protected] separate ISCL/EORTC TNM classification system has been published [6]. This staging system is primarily intended to †Approved by the ESMO Guidelines Working Group: December 2006, last update June 2013. This publication supersedes the previously published version. Ann Oncol 2010; 21 document the extent of disease and cannot be used as a (Suppl. 5): v177–v180. prognostic guide.

© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. clinical practice guidelines Annals of Oncology

Table 1. World Health Organisation–European Organisation for Table 2. Revised TNMB classification of mycosis fungoides (MF) and Research and Treatment of Cancer (WHO–EORTC) classification Sézary syndrome (SS)

Cutaneous T-cell lymphoma (CTCL) T (skin)

Mycosis fungoides (MF) T1 Limited patch/plaque (involving <10% of total skin surface) ≥ Variants of MF T2 Generalised patch/plaque (involving 10% of total skin surface)

Folliculotropic MF T3 Tumour(s)

Pagetoid reticulosis T4 Erythroderma Granulomatous slack skin N (lymph node) Sézary syndrome (SS) N0 No clinically abnormal peripheral lymph nodes Primary cutaneous CD30-positive lymphoproliferative disorders N1 Clinically abnormal peripheral lymph nodes; histologically Primary cutaneous anaplastic large-cell lymphoma uninvolved Lymphomatoid papulosis N2 Clinically abnormal peripheral lymph nodes; histologically involved Subcutaneous panniculitis-like T-cell lymphoma (nodal architecture uneffaced) Extranodal natural killer (NK)/T-cell lymphoma, nasal-type N3 Clinically abnormal peripheral lymph nodes; histologically involved Primary cutaneous peripheral T-cell lymphoma-not otherwise specified (nodal architecture (partially) effaced) Aggressive epidermotropic CD8+ CTCLa Nx Clinically abnormal peripheral lymph nodes; no histological Cutaneous γ/δ T-cell lymphomaa confirmation CD4+ small/medium-sized pleomorphic CTCLa Cutaneous B-cell lymphoma (CBCL) M (viscera) Primary cutaneous marginal zone B-cell lymphoma M0 No visceral involvement Primary cutaneous follicle centre lymphoma M1 Visceral involvement Primary cutaneous diffuse large B-cell lymphoma, leg type B (blood) aProvisional entities. B0 No circulating atypical (Sézary) cells (or <5% of lymphocytes) ≥ Republished with permission of the American Society of Hematology, B1 Low blood tumour burden ( 5% of lymphocytes are Sézary cells, from Willemze R, Jaffe ES, Burg G et al., WHO/EORTC classification but not B2) ≥ for cutaneous lymphomas Blood 2005; 105: 3768–3785; permission B2 High blood tumour burden ( 1000/µl Sézary cells and positive conveyed through Copyright Clearance Center, Inc. clone) Republished with permission of American Society of Hematology, from Olsen E, Vonderheid E, Pimpinelli N et al., Revisions to the staging and therapy classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous The choice of treatment depends on the type of PCL and the Lymphoma Task Force of the European Organization of Research and stage of disease. Due to their heterogeneity and rarity, controlled Treatment of Cancer (EORTC), Blood 2007; 110: 1713–1722; permission clinical trials in PCLs are almost non-existent, with a few conveyed through Copyright Clearance Center, Inc. exceptions mainly concerning recently marketed drugs. Recommendations are therefore largely based on (retrospective) cohort studies and expert opinions discussed during consensus meetings of the EORTC Cutaneous Lymphoma Group, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and Table 3. Revised clinical staging system for mycosis fungoides (MF) and the International Lymphoma Radiation Oncology Group. Sézary syndrome (SS) Consensus recommendations for clinical end points and response criteria in MF/SS and in PCLs other than MF/SS have Clinical stage recently been published (Olsen EA, Willemze R, Wood GS et al. IA T1 N0 M0 B0-1

Clinical endpoints and response criteria in primary cutaneous IB T2 N0 M0 B0-1 lymphomas other than mycosis fungoides and Sézary IIA T1–2 N1-2 M0 B0-1 syndrome: a Consensus Statement of the International Society IIB T3 N0-2 M0 B0-1 for Cutaneous Lymphomas (ISCL), the United States III T4 N0-2 M0 B0-1

Cutaneous Lymphoma Consortium (USCLC) and the IVA1 T1-4 N0-2 M0 B2 Cutaneous Lymphoma Task Force of the European IVA2 T1-4 N3 M0 B0-2 Organization for the Research and Treatment of Cancer IVB T1-4 N0-3 M1 B0-2 (EORTC). Blood. In preparation.) [8]. Republished with permission of American Society of Hematology, from Olsen E, Vonderheid E, Pimpinelli N et al., Revisions to the staging and mycosis fungoides and variants classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Since early aggressive chemotherapy is associated with Lymphoma Task Force of the European Organization of Research and considerable side-effects but does not improve survival, a stage- Treatment of Cancer (EORTC), Blood 2007; 110: 1713–1722; permission adapted conservative therapeutic approach is recommended for conveyed through Copyright Clearance Center, Inc.

vi | Willemze et al. Volume 24 | Supplement 6 | October 2013 Annals of Oncology clinical practice guidelines

MF and its variants [9–12]. Patients with only patches and/or suggested as the treatment of choice in SS and erythrodermic plaques covering <10% (stage IA) or ≥10% of the skin surface MF [10–12]. Overall response rates range from 30% to 80% with (stage IB) should be treated with skin-directed therapies, complete response rates ranging from 14% to 25%, depending including topical steroids, psoralens + ultraviolet A (PUVA), on the ECP regimen and the type of combination used. narrow-band ultraviolet B (UVB) and topical cytostatic agents, However, the suggested superiority of ECP over the traditional such as mechlorethamine or carmustine (BCNU). Narrow-band low-dose chemotherapy regimens has not yet been substantiated UVB should only be used in patients with patches or very thin by randomised, controlled trials [21]. Prolonged treatment with plaques. Topical steroids can be recommended as monotherapy a combination of low-dose chlorambucil and prednisone is for patches/flat plaques stage IA disease. In stage IB, topical often effective in controlling the disease, but is unlikely to yield steroids can be used as adjuvant therapy for selected skin complete responses. Low-dose methotrexate, bexarotene, lesions. In patients developing one or few infiltrated plaques or denileukin diftitox, alemtuzumab (low-dose) and multiagent tumours (stage IIB), additional local radiotherapy may suffice. chemotherapy have been recommended as second-line Local radiotherapy can be curative in patients with early treatment of SS [10–12, 22]. It should be emphasised that localised disease, particularly in patients with unilesional MF comparison of treatment results in the different studies is almost and pagetoid reticulosis. Local radiotherapy is most commonly impossible due to differences in diagnostic criteria used for SS. 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 24–36 Gy. For patients with more primary cutaneous CD30-positive extensive infiltrated plaques and tumours or patients refractory lymphoproliferative disorders (LPDs) to skin-directed therapies, a combination of PUVA and The group of primary cutaneous CD30-positive LPDs includes interferon alpha or PUVA and retinoids (including bexarotene), primary cutaneous anaplastic large lymphoma (C-ALCL) and a combination of interferon alpha and retinoids or total skin LyP, which form a spectrum of disease. Both C-ALCL and LyP electron beam irradiation can be considered. However, these have an excellent prognosis, with a 10-year survival of 90% and treatments are not curative, although remission may last for almost 100%, respectively [23, 24]. Patients with C-ALCL several years. Total skin electron beam irradiation was often generally present with solitary or localised (ulcerating) tumours given to total doses of 30–36 Gy, but recently lower doses or nodules and should be treated with radiotherapy or surgical (10–12 Gy) have been employed with the advantages of shorter excision. Patients with C-ALCL presenting with multifocal skin duration of the treatment period, fewer side-effects and lesions can be best treated with low-dose methotrexate, as in opportunity for re-treatment [13]. In patients with advanced LyP, or radiotherapy in case of only a few lesions. Radiotherapy and refractory disease, gemcitabine or liposomal doxorubicin is commonly administered with electrons, with bolus, a margin may be considered [14, 15]. Other agents like the fusion toxin of ≥2 cm and a total dose of 40 Gy [25]. This dose is effective denileukin diftitox and histone deacetylase (HDAC) inhibitors, and well-tolerated. Lower doses may achieve the same result, but such as vorinostat and romidepsin, have been approved in the data have not been published. In patients with multiple lesions, United States by the Food and Drug Administration (FDA) for lower doses of radiation may be used for palliation. In cases not patients with relapsed and refractory CTCL, but have not yet responsive to these treatments, systemic retinoids including been registered for CTCL in Europe [16–18]. Multiagent bexarotene or interferon alpha can be used [24]. Recent chemotherapy is only indicated in patients with effaced lymph preliminary studies report high response rates of brentuximab nodes or visceral involvement (stage IV), or in patients with vedotin (anti-CD30 monoclonal antibody coupled to the anti- widespread tumour stage MF which cannot be controlled with tubulin agent monomethyl auristatin E) in patients with C- skin-targeted and immunomodulating therapies. Local ALCL as well as patients with MF expressing CD30, but palliation of cutaneous as well as extracutaneous lesions may be controlled clinical trials have just started [26, 27]. Multiagent achieved with local radiotherapy to doses ≥8Gy[19]. In chemotherapy is only indicated in patients presenting with or relatively young patients with refractory, progressive MF or with developing extracutaneous disease and in rare patients with SS, allogeneic stem cell transplantation may be considered. rapidly progressive skin disease. Durable responses have been reported, but experience is still limited, and the optimal conditioning regimen and the optimal timing for an allogeneic transplant are currently unknown [20]. subcutaneous panniculitis-like T-cell Results with autologous stem cell transplantation in MF and SS lymphoma (SPTCL) have been disappointing. The term SPTCL is only used for cases with an α/β T-cell phenotype, which have a favourable prognosis, particularly if Sézary syndrome not associated with a haemophagocytic syndrome (HPS), which is frequently an extremely aggressive clinical syndrome Being a systemic disease (i.e. leukaemia) by definition, systemic requiring immediate intervention. One study reported 5-year treatment is required. Skin-directed therapies like PUVA or overall survival rates of 91% and 46% in SPTCL patients without potent topical steroids may be used as adjuvant therapy. and with an HPS, respectively [28]. In SPTCL without Extracorporeal photopheresis (ECP), either alone or in associated HPS, systemic steroids or other immunosuppressive combination with other treatment modalities such as interferon agents should be considered first, whereas in cases of solitary or alpha, retinoids, total skin electron beam and PUVA, has been localised skin lesions, radiotherapy with electrons is advised.

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Table 4. Recommendations for the initial management of CBCL

Extent First-line therapy Alternative therapies PCMZL Solitary/localised Local radiotherapy IFN alpha i.l. Excision Rituximab i.l. (Antibiotics)a Intralesional steroids Multifocal Wait and see IFN alpha i.l. Local radiotherapy Rituximab i.l. Chlorambucilb Topical or intralesional steroids Rituximab i.v. (Antibiotics)a

PCFCL Solitary/localised Local radiotherapy IFN alpha i.l. Excision Rituximab i.l.

Multifocal Wait and see R-CVP/CHOPc Local radiotherapy Rituximab i.v.

PCLBCL, LT Solitary/localised R-CHOP ± IFRT Local radiotherapy Rituximab i.v.

Multifocal R-CHOP Rituximab i.v.

aIn case of evidence for Borrelia burgdorferi infection, bor other single or combination regimens appropriate for low-grade B-cell lymphomas, cin exceptional cases or for patients developing extracutaneous disease i.l. intralesional; i.v.: intravenous; IFRT: involved field radiotherapy. Republished with permission of American Society of Hematology, from Senff NJ, Noordijk EM, Kim YH et al., European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas, Blood 2008; 112: 1600–1609; permission conveyed through Copyright Clearance Center, Inc.

Little information on radiation dose is available, but a dose of more advanced disease, these lymphomas show an aggressive 40 Gy has been used. Bexarotene may be also effective in SPTCL clinical behaviour and are often resistant to chemotherapy. [29]. Multiagent chemotherapy is required only in cases with Recently, an intensive chemotherapy regimen including progressive disease not responding to immunosuppressive L-asparaginase (the SMILE regimen) was shown to be therapy or in cases with HPS. effective [31].

primary cutaneous peripheral T-cell extranodal natural killer (NK)/T-cell fi lymphoma, nasal type lymphoma-not otherwise speci ed (PTCL-NOS) Extranodal NK/T-cell lymphoma, nasal type is a rare, nearly always Epstein-Barr virus-positive lymphoma, which is more Within the group of primary cutaneous PTCL-NOS, three fi common in Asia and Central and South America. The skin is somewhat better de ned subgroups have been included as the second most common site of involvement after the nasal provisional entities (see Table 1). However, most of the cases cavity/nasopharynx. Patients generally present with multiple have in common a generally aggressive clinical course and poor (ulcerating) plaques and tumours, or in the case of nasal survival, and should therefore be treated as systemic PTCL-NOS NK/T-cell lymphoma with a midfacial destructive tumour. Skin with multiagent chemotherapy. Since the results are often involvement may be a primary or secondary manifestation of disappointing, early allogeneic stem cell transplantation may be the disease. One study reported a median survival of 27 months considered. The only exception is the group of CD4-positive for patients presenting with only skin lesions, compared with small-medium pleomorphic CTCL. These patients often present 5 months for patients presenting with cutaneous and with a solitary tumour, most commonly on the head, should be extracutaneous diseases [30]. Since both groups have an treated with local radiotherapy or excision, and have an aggressive clinical behaviour, distinction between primary and excellent prognosis. secondary cutaneous involvement seems not to be useful for this category. In patients with stage I disease, radiotherapy is the cutaneous B-cell lymphoma first choice of treatment. Recommended radiation doses are higher than for other lymphomas, with 50 Gy to the initial In the WHO–EORTC classification, three main types of CBCL lesion and a boost of 5–10 Gy to residual disease. In the case of are distinguished: primary cutaneous marginal zone lymphoma

vi | Willemze et al. Volume 24 | Supplement 6 | October 2013 Annals of Oncology clinical practice guidelines

Table 5. Levels of evidence and grades of recommendation (adapted from (histology, blood examination, imaging, etc.) should only be the Infectious Diseases Society of America-United States Public Health carried out if required. Service Grading Systema) note Levels of evidence I Evidence from at least one large randomised, controlled trial of good According to the levels of evidence and grades of methodological quality (low potential for bias) or meta-analyses of recommendation shown in Table 5, the levels of evidence in well-conducted, randomised trials without heterogeneity these guidelines are mostly level IV and the recommendations II Small randomised trials or large randomised trials with a suspicion are grade B. This is due to the heterogeneity and rarity of the of bias (lower methodological quality) or meta-analyses of such diseases. trials or of trials with demonstrated heterogeneity III Prospective cohort studies IV Retrospective cohort studies or case–control studies conflict of interest V Studies without control group, case reports, experts opinions Dr Ladetto has reported speaker’s bureau from Celgene, Grades of recommendation Janssen-Cilag, Roche, Bayer, Amgen, Mundipharma; research A Strong evidence for efficacy with a substantial clinical benefit, contracts from Celgene, Pfizer, Mundipharma, Roche; funds strongly recommended received from Amgen, Roche, Italfarmaco. The other authors fi B Strong or moderate evidence for ef cacy but with a limited clinical have declared no potential conflicts of interest. benefit, generally recommended C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, ...), optional references D Moderate evidence against efficacy or for adverse outcome, generally 1. Willemze R, Jaffe ES, Burg G et al. WHO–EORTC classification for cutaneous not recommended lymphomas. Blood 2005; 105: 3768–3785. E Strong evidence against efficacy or for adverse outcome, never 2. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours recommended Haematopoietic and Lymphoid Tissues, 4th Edition, Geneva: WHO Press, 2008. aDykewicz CA. Summary of the guidelines for preventing opportunistic 3. Tan SH, Sim CS, Ong BH. Cutaneous lymphomas other than mycosis fungoides in infections among hematopoietic stem cell transplant recipients. Clin Infect Singapore: a clinicopathological analysis using recent classification systems. Br J Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of Dermatol 2003; 149: 542–553. America. 4. Park JH, Shin HT, Lee DY 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: 1200–1209. (PCMZL), PCFCL and primary cutaneous diffuse large B-cell 5. Olsen EA, Vonderheid E, Pimpinelli N et al. Revisions to the staging and lymphoma, leg type (PCLBCL-LT). PCMZL and PCFCL are classification of mycosis fungoides and Sézary syndrome: a proposal of the indolent types of CBCL with a disease-related 10-year survival International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous rate of 90%, while PCLBCL-LT has a more unfavourable Lymphoma Task Force of the European Organization of Research and Treatment of prognosis (disease-related 5-year survival, ∼50%). EORTC/ISCL Cancer (EORTC). Blood 2007; 110: 1713–1722. fi consensus recommendations for the management of these three 6. Kim YH, Willemze R, Pimpinelli N et al. TNM classi cation system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a types of CBCL have been formulated and are summarised in proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Table 4 [32]. Recommended radiation doses for localised Cutaneous Lymphoma Task Force of the European Organization of Research and PCMZL and PCFCL are 24–36 Gy, whereas for palliative Treatment of Cancer (EORTC). Blood 2007; 110: 479–484. treatment of multifocal disease, low-dose radiation (4 Gy) is 7. Senff NJ, Kluin-Nelemans HC, Willemze R. Results of bone marrow examination in often sufficient [19]. For the more aggressive PCLBCL-LT, a 275 patients with histological features that suggest an indolent type of cutaneous radiation dose of 40 Gy is recommended. B-cell lymphoma. Br J Haematol 2008; 142: 52–56. 8. Olsen EA, Whittaker S, Kim YH et al. Clinical endpoints and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the personalised medicine International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and the Cutaneous Lymphoma Task In this disease setting, more research is needed to identify Force of the European Organization for Research and Treatment of Cancer molecular markers which could lead to advances in (EORTC). J Clin Oncol 2011; 29: 2598–2607. personalised medicine. 9. Kaye FJ, Bunn PA Jr., Steinberg SM et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Eng J Med 1989; 321: follow-up 1784–1790. The frequency of follow-up visits depends on the type of PCL 10. Whittaker SJ, Marsden JR, Spittle M et al. Joint British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines for the and the stage of disease. It may vary from every 6 or 12 months management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003; in patients with indolent types of PCL and stable disease or 149: 1095–1107. – patients in complete remission to every 4 6 weeks in patients 11. Trautinger F, Knobler R, Willemze R et al. EORTC consensus recommendations for with active or progressive disease. Follow-up visits should focus the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 2006; 42: on history and physical examination, and additional testing 1014–1030.

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12. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sézary Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and syndrome. Blood 2009; 114: 4337–4353. guidelines for diagnosis and treatment. Blood 2000; 95: 3653–3661. 13. Kamstrup MR, Lindahl LM, Gniadecki R et al. Low-dose total skin electron beam 24. Kempf W, Pfaltz K, Vermeer MH et al. EORTC, ISCL, USCLC consensus therapy as a debulking agent for cutaneous T-cell lymphoma: an open-label recommendations for the treatment of primary cutaneous CD30-positive prospective phase II study. Br J Dermatol 2012; 166: 399–404. lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous 14. Marchi E, Alinari L, Tani M et al. Gemcitabine as frontline treatment for cutaneous anaplastic large-cell lymphoma. Blood 2011; 118: 4024–4035. T-cell lymphoma: phase II study of 32 patients. Cancer 2005; 104: 2437–2441. 25. Yu JB, McNiff JM, Lund MW, Wilson LD. Treatment of primary cutaneous CD30+ 15. Dummer R, Quaglino P, Becker JC et al. Prospective international multicenter anaplastic large-cell lymphoma with radiation therapy. Int J Radiat Oncol Biol Phys phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in 2008; 70: 1542–1545. patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from 26. Pro B, Advani R, Brice P et al. Brentuximab vedotin (SGN-35) in patients with EORTC 21012. J Clin Oncol 2012; 30: 4091–4097. relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase 16. Prince HM, Duvic M, Martin A et al. Phase III placebo-controlled trial of denileukin II study. J Clin Oncol 2012; 30: 2190–2196. diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol 2010; 28: 27. Krathen M, Sundram U, Bashey S et al. Brentuximab vedotin demonstrates 1870–1877. significant clinical activity in relapsed or refractory mycosis fungoides with 17. Olsen EA, Kim YH, Kuzel TM et al. Phase IIb multicenter trial of vorinostat in variable CD30 expression. Blood ASH Annual Meeting Abstracts 2012; patients with persistent, progressive, or treatment refractory cutaneous T-cell 120: 797. lymphoma. J Clin Oncol 2007; 25: 3109–3115. 28. Willemze R, Jansen PM, Cerroni L et al. Subcutaneous panniculitis-like 18. Whittaker SJ, Demierre MF, Kim EJ et al. Final results from a multicenter, T-cell lymphoma: definition, classification and prognostic factors. An international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. EORTC Cutaneous Lymphoma Group study of 83 cases. Blood 2008; 111: J Clin Oncol 2010; 28: 4485–4491. 838–845. 19. Neelis KJ, Schimmel EC, Vermeer MH et al. Low-dose palliative radiotherapy for 29. Mehta N, Wayne AS, Kim YH et al. Bexarotene is active against subcutaneous cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009; 74: panniculitis-like T-cell lymphoma in adult and pediatric populations. Clin 154–158. Lymphoma Myeloma Leuk 2012; 12: 20–25. 20. Duarte RF, Schmitz N, Servitje O, Sureda A. Haematopoietic stem cell 30. Bekkenk MW, Jansen PM, Meijer CJ et al. CD56+ hematological neoplasms transplantation for patients with primary cutaneous T-cell lymphoma. Bone Marrow presenting in the skin: a retrospective analysis of 23 new cases and 130 cases Transplant 2008; 41: 597–604. from the literature. Ann Oncol 2004; 15: 1097–1108. 21. Russell-Jones R. Extracorporeal photopheresis in cutaneous T-cell lymphoma. 31. Yamaguchi M, Kwong YL, Kim WS et al. Phase II study of SMILE chemotherapy Inconsistent data underline the need for randomized studies. Br J Dermatol 2000; for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer 142: 16–21. (NK)/T-cell lymphoma, nasal type: the NK-cell Tumor Study Group study. J Clin 22. Bernengo MG, Quaglino P, Comessatti A et al. Low-dose intermittent alemtuzumab Oncol 2011; 29: 4410–4416. in the treatment of Sézary syndrome: clinical and immunologic findings in 14 32. Senff NJ, Noordijk EM, Kim YH et al. European Organization for Research patients. Haematologica 2007; 92: 784–794. and Treatment of Cancer and International Society for Cutaneous 23. Bekkenk MW, Geelen FA, van Voorst Vader PC et al. Primary and secondary Lymphoma consensus recommendations for the management of cutaneous B-cell cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch lymphomas. Blood 2008; 112: 1600–1609.

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Annals of Oncology 00: 1–12, 2014 review doi:10.1093/annonc/mdu152

SIE-SIES-GITMO Guidelines for the management of adult peripheral T- and NK-cell lymphomas, excluding mature T-cell leukaemias P. Corradini1, M. Marchetti2, G. Barosi3*, A. Billio4, A. Gallamini5, S. Pileri6, N. Pimpinelli7, G. Rossi8, P. L. Zinzani9 & S. Tura10 1Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milano, Milan; 2Unit of Hematology, Hospital C. Massaia, Asti; 3Biotechnology Research Area, Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia; 4Unit of Hematology, Ospedale Civile di Bolzano, Bolzano; 5 Department of Hematology and BMT Unit, Azienda Ospedaliera S. Croce e Carle, Cuneo; 6Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Bologna; 7Department of Dermatology, Department of Specialised, Experimental and Diagnostic Medicine, University of Bologna, Bologna; 8Department of Hematology, Spedali Civili, Brescia; 9Institute of Hematology ‘Seragnoli’; 10University of Bologna, Bologna, Italy Downloaded from

Received 3 October 2013; revised 10 March 2014; accepted 7 April 2014

Background: In order to promote widespread adoption of appropriate clinical practice, the Italian Society of http://annonc.oxfordjournals.org/ Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. In this article, we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukaemias. Design: By using the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) system, we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical

appraisal of evidence. The consensus methodology was applied to evidence-orphan issues. review Results: Six courses of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, doxo- rubicin, vincristine, etoposide and prednisone (CHOEP) chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ ana- by guest on June 24, 2014 plastic large-cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extra- nodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while L-asparaginase-containing chemo- therapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong). Conclusion: In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus meth- odology. Key words: T/NK-cell lymphoma, clinical practice guidelines, hematopoietic stem cell transplantation introduction PTCLs account for about 12% of lymphoid malignancies [1]. PTCLs are rare disorders with a dismal prognosis and for which fi The Italian Society of Hematology (SIE), and the af liate soci- few treatment options are available [2]. The WHO classification eties SIES (Società Italiana di Ematologia Sperimentale) and has divided this group of disorders into those with predomin- GITMO (Gruppo Italiano Trapianto Midollo Osseo) have estab- antly leukemic from those with nodal, extranodal or cutaneous lished to produce guidelines for the most relevant hematological presentation [1]. The present guidelines address specifically to issues. In this article, we report the results of the project of prac- the management of non-leukemic adult PTCLs (Table 1). tice guidelines for the management of adult peripheral T- and NK-cell lymphomas (PTCLs). methods guidelines development process fi *Correspondence to: Dr Giovanni Barosi, Center for the Study of Myelo brosis. Fondazione The Advisory Council (AC), composed of three members with IRCCS Policlinico S. Matteo, Viale Golgi 19, 27100 Pavia, Italy. Tel: +39-0382-503636; Fax: +39-0382-503917; E-mail: [email protected] expertise in clinical epidemiology, haematology and critical

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. review Annals of Oncology

Table 1. Peripheral T- and NK cell neoplasms (excluding mature results T-cell leukaemias) issue 1: diagnostic requirements (consensus-based Nodal peripheral T-cell lymphomas (PTCL) recommendations) Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) The characterization of pathological subtypes of PTCL is manda- Angio-immunoblastic T-cell lymphoma (AITCL) tory in order to optimize prognosis and therapy. The antibodies Anaplastic large-cell lymphoma (ALCL), anaplastic lymphoma raised against T-cell receptor (TCR) β and γ chains, are useful kinase (ALK) positive for the differential diagnosis between αβ and γδ PTCLs. CD30 Anaplastic large-cell lymphoma (ALCL), ALK negative plays a basic role in the recognition of anaplastic large-cell lymph- (provisional) omas (ALCLs), CD30+ cutaneous lymphoproliferative disorder Extranodal PTCL (CTLPD) and the rare CD30+ PTCLs–NOS. ALCLs are further Extranodal NK-/T-cell lymphoma, nasal type distinguished in ALK+ and ALK− depending on the occurrence Enteropathy-associated T-cell lymphoma (EATL) − or not of the t(2;5) translocation and variants. ALK ALCL is Hepatospleinic T-cell lymphoma (HSTL) morphologically and phenotypically indistinguishable from the αβ Subcutaneous panniculitis-like T-cell lymphoma ( only) ALK+ form; however, the distinction between the two entities is (SPTCL) of practical relevance, since the former behaves much better Cutaneous T-cell lymphoma (CTCL) than the latter [6]. CD16, CD56 and CD57 in variable combina- Mycosis fungoides (MF) tions and often in association with cytotoxic markers assist Sezary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disease in diagnosing NK-cutaneous lymphoma, hepatosplenic T-cell Downloaded from Primary cutaneous PTCLs lymphoma (HSTL), entheropathy-associated T-cell lymphoma (EATL) type II and entheropathy-associated NK-cell lymphoma WHO classification 2008 [1]. (ENKTCL/NT). Some other markers specifically have a prognostic values, such as Ki-67 rate. Also the T-cell or NK-cell lymphomas http://annonc.oxfordjournals.org/ showing positivity of neoplastic cells for Epstein-Barr virus (EBV) are characterized by a very aggressive behaviour. A vari- able proportion of PTCLs–NOS, in fact, show positivity of appraisal, oversaw the process. An Expert Panel (EP) was neoplastic cells for EBV. In 23 patients with PTCL nasal type selected according to the conceptual framework elements of the who underwent bone marrow (BM) biopsy for EBV, search NIH Consensus Development Program [3]. for EBV, especially by EBER in situ hybridization, was positive in 10 [7]. A lower survival rate was seen in patients with BM producing and grading evidence-based positive for EBER, suggesting that EBER positivity in BM is the major determinant of a poor prognosis. Some markers, recommendations fi by guest on June 24, 2014 such as t(6;7) andTP63 abnormalities, speci cally allow to strat- The AC selected the clinical questions that needed to be ify the prognosis of ALK− ALCL [8, 9]. addressed by a critical appraisal of evidence. The EP chose the critical outcomes for each clinical query. Literature search was limited to publications edited after 2005. The search included Recommendations proceedings 2010 through 2012 of the American Society of The pathological diagnosis of NK/T-cell lymphomas requires the Hematology, the European Hematology Association and the integration of clinical data, morphology, immunohistochemistry, flow 11th International Conference on Malignant Lymphoma. cytometry, cytogenetics and molecular biology. This complex multi- ‘ According to GRADE methodology [4], the AC prepared evi- criteria diagnostic pathway translates into a high risk of misdiagnosis. ’ ‘ ’ dence tables and quality-of-evidence tables for each critical ap- The referral of tissue specimens to national reference centres with high fi praisal. The EP drafted recommendations based on the bene t expertise in the field is highly recommended. to risk profile of each compared intervention. Definite agree- The first diagnostic target is the assessment of the neoplastic nature of ment of the recommendations and their strength (weak or a given T-cell population. Even though CD5 and CD7 are the most strong) was made through subsequent face-to-face meetings. frequently defective markers, the application of a larger panel from CD2 Even though the recommendations were issued on the basis of to CD8 antibodies is recommended (Table 2). systematic review of literature published up to December 2012, In cases with documented T-cell lymphoma, a subtype pathological analysis of data published since that date up to September 2013 characterization is mandatory for prognostic and therapeutic reasons. was carried out before publication of the present paper. Such characterization is based on immunohistochemical and molecular characterization. Antibodies against the β and γ chains of the T-cell receptor (TCR) can producing consensus-based recommendations be usefully applied for the distinction of tumours derived from αβ and γδ T-lymphocytes, respectively. The usage of antibodies against the ALK The consensus methodology was applied by the EP for all the protein is pivotal for the differential diagnosis between ALK+ and ALK− issues not addressable by a critical appraisal. During three con- anaplastic large-cell lymphomas (ALCL). secutive consensus conferences, the issues were analysed and Besides immunohistochemical staining, the detection of clonal discussed according to the nominal group technique, as previ- rearrangement of the genes encoding for the TCR is pivotal for the ously described [5].

 | Corradini et al. Annals of Oncology review

distinction between partial lymph node involvement by peripheral T-cell Table 2. List of markers applicable to formalin-fixed, paraffin- lymphoma (PTCL) and paracortical T-cell hyperplasia. embedded tissue sections for the diagnosis of peripheral NK/T-cell Immunohistological markers of aggressiveness are mandatory to better lymphomas characterize the prognostic classification of these lymphomas. The Ki-67 Markers marking is included in the modified prognostic index for peripheral T-cell lymphoma unspecified (PIT) (prognostic index for PTCL, not otherwise T cell CD2, CD 3, CD 4, CD5, CD7, CD8, specified) in which BM involved is substituted by a Ki-67 rate >80%. CD52, βF1, TCRγ The search for EBV is recommended. EBER should be carried out on Cytotoxic TIA1, granzyme B, perforin BM specimens of patients with nasal PTCL to identify the presence of FTH (follicular helper CD10, Bcl6, PD1, CXCL13, SAP, ICOS, EBER positive cells, which appears to carry a poor prognosis. T cell) CCR5 Treg FoxP3 NK CD16, CD56, CD57 Activation CD25, CD30 Proliferation MIB1/Ki67 issue 2: pre-treatment evaluation and staging B cell CD20, BSAP/PAX5 requirements (consensus-based EBV EBER ISH (in situ hybridization), LMP1, EBNA2 recommendations) Follicular dendritic cells CD21 The International Prognostic Index (IPI) predicts the outcomes Histiocytes and epiteliod CD68/PG-M1 Downloaded from in all PTCL subtypes by including age, serum lactic dehydrogen- elements ase (LDH) levels, and performance status [10]. The index was Others CCR4, ALK, EMA, CD45 further refined by the adjunct of BM involvement (PIT score) [11] or Ki-67 (modified PIT score) [12]. The recently proposed Glasgow Prognostic score [13], including C-reactive protein and albumin assessment, is potentially useful for a better stratification Table 3. Prognostic index in peripheral T-cell lymphomas http://annonc.oxfordjournals.org/ in low-risk patients, however, still waits for validation. In the NK IPI (all patients) K-IPI PIT subset of extranodal disease, high β2-microglobulin values and EBV-DNA load are all unfavourable prognostic factors; however, Factors Factors Factors the standard stratification is done according to Korean Prognostic 1) Age (≤60 versus >60 1) B symptoms 1) Age >60 years ≥ ≥ Index (KIPI), which also allows to predict CNS involvement years) 2) Stage 3 2) ECOG PS 2 [14, 15](Table3). 2) Serum LDH 3) LDH level 3) LDH level more (≤1 × normal versus >1 × upper than >1 × normal) normal limit 1 × normal Recommendations 3) Performance status 4) Regional lymph value by guest on June 24, 2014 After a diagnosis of PTCL, common clinical evaluations useful for staging (0 or 1 versus 2–4) nodes (N1–N3, 4) BM and prognostic assessment should include: physical examination and 4) Stage (I or II versus not M1) involvement performance status evaluation; complete blood count; biochemistry (liver III or IV) and kidney function tests, LDH, total serum proteins, protidogram). 5) Extranodal Bone marrow trephine biopsy, contrast-enhanced whole-body CT scan, involvement (≤1 site Waldeyer ring examination and ear-nose-throat evaluation should be versus >1 site) carried out except for early (I and IIA stages) mycosis fungoides. In nodal Index Index Index PTCL, pre-treatment evaluation should also include: serum Low = 0 or 1 Group 1: no Group 1: no immunoglobulin assay and direct anti-globlin test. adverse factors adverse factors In enteropathy-associated T-cell lymphoma (EATL), pre-treatment Low intermediate = 2 Group 2: 1 factor Group 2: 1 factor evaluation should also include: test for coeliac disease and colonoscopy High intermediate = 3 Group 3: 2 factors Group 3: 2 factors with last ileum loop examination and random biopsies. High = 4 or 5 Group 4: 3 or 4 Group 4: 3 or 4 18 F-fluorodeoxyglucose positron emission tomography/computed factors factors tomography scanning is not routinely recommended. However, in patients with nasal-type PTCL, PET is recommended since it was documented to be a valuable modality for staging and treatment planning [16]. issue 3: first-line therapy in nodal T-cell lymphoma, In erythrodermic cutaneous T-cell lymphoma (CTCL), T-cell intestinal and hepatosplenic T-cell lymphomas associated antigens (CD2, CD3, CD4, CD7, CD8, CD26) should be (evidence-based recommendations) evaluated in peripheral blood lymphocytes. The Panel devised the following key questions to be analysed In all forms of PTCL except for CTCL, Ann Arbor staging should be according to GRADE appraisal of evidence. used to define disease extension. In CTCL, the ISCL-EORTC system should instead be used. For patients with nodal, intestinal and hepatosplenic T-cell IPI prognostic index should be used for nodal PTCL. For PTCL, a lymphoma, is there a therapy better than cyclophosphamide, specific Korean-IPI (KIPI) prognostic index has been proposed. PIT doxorubicin, vincristine and prednisone (CHOP) in ameliorating prognostic index should also be used for PTCL-NOS. complete response (CR) and progression-free survival (PFS) pro- vided that an acceptable toxicity was assured?

doi:10.1093/annonc/mdu152 |  review Annals of Oncology

According to a meta-analysis of studies in patients with PTCL remission [11, 33–40], and some retrospective studies enrolling treated with anthracycline-based regimens, 2-year event-free >50 patients [41–45]. A small randomized study compared dif- survival (EFS) of 38% is expected after standard CHOP and ferent induction regimens [11], while a second one compared 5–10% toxic mortality [17]. Only two regimens proved weak chemotherapy (ACVB or NCVB) with versus without consoli- evidence of superiority to CHOP for first-line treatment: dation ASCT [38]. With the former, a higher toxicity and lower etoposide-enhanced CHOP in young or ALK+ patients, and survival with megaCHOEP when compared with cyclophospha- intensified induction with ifosfamide, vepeside and epirubicin mide, doxorubicin, vincristine, etoposide and prednisone plus methotrexate followed by upfront autologous stem cell (CHOEP) induction was found. With the latter, higher but not transplantation (ASCT) in EATL [18]. Four studies, including statistically significant survival rates were reported with ASCT two randomized trials, compared etoposide containing CHOP consolidation. A non-statistically significant trend was also versus CHOP [19–22]: no advantage in OS was ever detected. reported by a retrospective case–control study by GELA [44]. A However, amelioration of PFS by 10%–20% in patients aged <60 retrospective study addressed to EATL reporting 26 patients years and ALK+ was reported [21] versus a higher grade 3–4 treated with IVE/MTX-ASCT regimen: EFS and OS were signifi- toxicity and hospitalization in the elderly [20]. Indirectness and cantly better in patients assigned to intensive versus standard mild inconsistency in the CR and PFS outcomes caused the evi- anthracycline-based therapy [18]. One retrospective study [45] dence be judged of low quality. However, the EP judged that the reported lower relapse rate by the use of TBI. benefit-to-risk balance in young patients was favourable. The EP agreed that in young patients with nodal, intestinal The adjunct of bleomicin to CHOP (ACVBP) was judged to and hepatosplenic T-cell lymphomas, frontline ASCT was better

be inferior to CHOP due to a twice as high toxic mortality with than standard chemotherapy (evidence: very low; recommenda- Downloaded from ACVBP, especially in elderly patients and in those with a poor tion: do, weak). Results cannot be extrapolated to patients aged performance status, as reported by two phase II studies [23, 24]. over 65 years or with ALK+ ALCL. Therefore, the EP judged that the survival benefit, i.e. improved EFS and OS, reported in the 60- to 70-year subgroup could not balance the higher toxicity over CHOP, and provided recom- Recommendations http://annonc.oxfordjournals.org/ mendation against ACVBP (evidence very low). The enrolment into clinical trials with new and experimental drugs Uncertainty was reported by the EP regarding first-line should be highly recommended in patients with PTCL. CHOP14 when compared with CHOP21 [21], since EFS amelior- In patients aged 65 years or younger, with nodal, intestinal or ation was documented in both old and young low-risk patients hepatosplenic T-cell lymphoma, except for ALK + ALCL, six courses of without a relevant increase of toxicity. However, the advantage was CHOP or CHOEP (induction phase) followed by ASCT (consolidation not judged clinically relevant and the quality of evidence was low phase) is the recommended therapy. due to inconsistency, imprecision and indirectness of the unique For ALK+ ALCL patients with an IPI score < 3, the induction phase study addressing this comparison. Similarly, no evidence is avail- with CHOP or CHOEP × 6 courses without the consolidation phase is able supporting a preference for eight versus six CHOP courses. recommended. Evidence regarding the combination of CHOP with alemtu- Patients older than 65 years, CHOP or CHOP-like regimens are the by guest on June 24, 2014 fi fi zumab consists of four phase II studies [25–28]. No consistent rst therapeutic options. In patients t to intensive chemotherapy, the demonstration of improved survival could be inferred. A vari- approach used in younger patient can be considered. able CHOP14 or CHOP21 and six or eight cycles schedule were applied; therefore, the overall quality of the evidence was judged fi to be very low due to limitations and imprecision. A NCI trial issue 4: rst-line therapy in extranodal PTCL nasal with low number of patients reported a survival plateau with type (evidence-based recommendations) dose-adapted etoposide, vincristine, doxorubicin, cyclophos- For patients with disseminated extranodal PTCL nasal type, is phamide, prednisone (EPOCH) and Campath [29]. The EP there a first-line chemotherapy better than CHOP, i.e. ameliorat- could not reach a consensus on the benefit-to-risk-ratio of C- ing CR and PFS provided that an acceptable toxicity was assured? CHOP for first-line therapy. Etoposide-based regimens such as EPOCH or etoposide, ifos- Evidence was insufficient to support any recommendation famide, cisplatin, dexamethasone did not prove to increase CR regarding the adjunct of denileukin diftitox [30] or bortezomib or PFS, the critical end points selected by the EP for evidence [31] to CHOP, as well as gemcitabine to CHEOP [32]. evaluation [46]. Enhancement of CHOP/CEOP with oral nitro- In summary, the EP agreed that CHOP remains the standard sureas in limited-stage patients provided prolonged PFS in a chemotherapy for nodal, intestinal and hepatosplenic T-cell retrospective study [47], but the data were not confirmed by a lymphoma. Exception could be etoposide-containing CHOP in randomized phase II study [48]; therefore evidence was not con- young patients and those with ALK+ lymphomas (evidence: sidered conclusive. low; recommendation: do, weak). The adjunct of bleomicin to A L-asparaginase-based regimen (SMILE) was applied upfront CHOP induces a high toxicity not balanced by increased effect- to 38 advanced-stage patients enrolled in a phase II trial: short- iveness (evidence: low; recommendation: do not do, weak). term OS was 55% [49] which is promising when compared with For young patients (<65 years old) with nodal, intestinal and historical data [50–52]. hepatosplenic T-cell lymphomas is frontline autologous stem cell On the basis of the reported evidence, the EP agreed that transplantation (ASCT) better than standard chemotherapy? L-asparaginase-containing regimens such as SMILE or Aspa- We identified eight prospective studies applying consolidation Met-Dex [53] can obtain better response rates (RRs) and PFS ASCT in at least 15 PTCL patients achieving a first complete than CHOP (evidence: low; recommendation: do, strong).

 | Corradini et al. Annals of Oncology review

However, the toxicity of SMILE is so high that it should not be 50–54 Gy, and it should be given upfront and not after CT. The used without optimal supportive care. benefit of adding CT either concurrently or after RT is less For patients with limited-stage PTCL nasal type is combined proven, particularly in localized disease. chemioradiotherapy (CRT) better than CT or radiotherapy (RT) In patients with extranodal PTCL nasal type, does haemato- alone in providing a CR, provided that an acceptable toxicity was poietic stem cell transplantation (HSCT) prolong PFS or overall assured? survival (OS)? All of the studies allowing comparisons among treatments A few reports analysed high-dose CT in the subset of PTCL were retrospective. RT 50 Gy alone achieved 69% PFS in stage I nasal type [71]. Retrospective data on allogeneic stem cell trans- patients [54, 55], which corresponded to a relevant improve- plantation (allo-SCT) in refractory/relapsed patient support its ment of survival rate (from 15%–27% to 50%–83% at 5 years) feasibility and potential benefit[72–77]. when compared with CT alone [56]. The Panel agreed on claiming that ASCT carried out in RT doses >50 Gy achieved better survival rates at regression patients with bad prognostic features during complete remission analyses [57–61]. Higher doses inevitably increased toxicity [62]; may prolong survival. Allo-SCT can rescue a proportion of however, grade 3–4 adverse events are usually not reported [63]. patients with chemosensitive relapse (evidence: very low; recom- RT followed by CT significantly improved RR and survival mendation: uncertain). versus CT alone in three retrospective studies in patients with limited-stage disease [57, 58, 64]. Results from retrospective Recommendations studies are not consistent with the survival advantage of CRT The treatment of PTCL nasal type differs according to the extent of the when compared with RT alone [61, 65, 66]. However, in the disease. Patients with localized disease should receive radiotherapy as Downloaded from largest retrospective cohort [57] and recent studies [67, 68], early as possible at doses of at least 50 Gy to the tumour and adjacent fi median survival duration was signi cantly longer in patients structures treated with CRT (72 versus 42 months). Patients with CR The evidence is not sufficient to routinely support CT concurrently or achieved a survival rate of 80% at 5 years [63]: therefore, CR sequentially to RT. appears to be a robust intermediate end point in this setting. Patients with systemic disease should receive L-asparaginase- http://annonc.oxfordjournals.org/ In stage I patients, RT achieved better survival rates (90% containing regimens. The SMILE protocol proved to produce the best versus 49% at 5 years) when applied upfront rather than after CT results, although toxicity was not negligible. [58], but a recent phase II study confirmed satisfactory survival The use of autologous HSCT should be considered during first rates (75% at 5 years) with EPOCH CT followed by involved field complete remission. radiotherapy [46] in localized nasal extranodal NK lymphoma. RT should be added to areas of bulky or residual disease. Similar data (survival rates >78% at 2–3 years) were reported by two phase I/II studies applying concurrent RT [67–70]andCT with various agents including etoposide, ifosfamide, vincristine, fi L-asparaginase and platinum. Despite such favourable results, no issue 5: rst-line therapy in panniculitis comparison of schedules including concurrent or subsequent RT (consensus-based recommendations) by guest on June 24, 2014 was conducted versus CT alone. Moreover, several studies For patients with panniculitis, is chemotherapy better than local reported high rates of progression during (anthracycline-based) radiotherapy, i.e. ameliorating PFS provided that an acceptable CT not preceded by RT. Therefore, the EP favoured the classic toxicity was assured? upfront schedule. Published case series of panniculitis never exceed 20 patients, On the basis of the above reported evidence, the essential and they do not distinguish αβ from γδ entities [78]. An array of treatment modality in limited-stage NK/T-cell lymphoma nasal treatments have been successfully applied: pulse steroids [79], type is RT which is significantly more effective than CT (evi- bexarotene [80], cyclosporine [81, 82], methotrexate, anthracy- dence: very low; recommendation: do, weak). It should be used cline-based chemotherapy [83, 84], romidepsin [85]. RT was at doses higher than those usually employed in lymphoma, of judged a reliable therapeutic option for localized disease, mostly

Table 4. Novel agent response data in relapsed T-cell lymphoma

Regimen (reference) No. of patients Response PFS (months) OS

Bendamustine (Damaj et al.) [107] 38 ORR, 47%; CR, 29% NR NR Pralatrexate (O’Connor et al.) [108] 111 ORR, 29%; CR, 11% Median, 3.5 Median, 14.5 months Romidepsin (Coiffier et al.) [109] 130 ORR, 25%; CR, 15% Median, 4 DHAP–alemtuzumab plus auto-SCT (Kim et al.) [110] 24 ORR, 50%; CR, 21% NR Median, 6 months Gem–Cis–methylpred (Arkenau et al.) [111] 16 ORR, 69%; CR, 19% NR 69% at 1 year PEGS (Mahadevan et al.) [112]33a ORR, 39% 12% at 2 years 30% at 2 years Lenalidomide (Dueck et al.) [113] 23 ORR, 30% Median, 3.2 Median, 8 months Zancolimumab (D’Amore et al.) [114] 21 ORR, 24% NR NR

aSeventy-nine percent were newly diagnosed.

doi:10.1093/annonc/mdu152 |  review  ordn tal. et Corradini |

Table 5. Recommendations published in the last 5 years for the management of NK/T-cell lymphomas

BJH, 2011 [117] ESMO, 2013 [118] SIE, SIES, GITMO, 2014

Nodal T-cell Peripheral T-cell lymphoma, not otherwise specified First-line treatment of all TCL subtypes but NK/TCL, In patients aged 65 years or younger, with nodal, lymphoma, (PTCL-NOS): CHOP remains the standard therapy. nasal type, should be based on anthracycline- intestinal or hepatosplenic T-cell lymphomas, intestinal and Consideration should be given to consolidation with containing regimens such as CHOP/CHOEP and except for ALK+ ALCL, six courses of CHOP or hepatosplenic auto-haematopoietic stem cell transplantation (HSCT). CHOP-like regimens. An exception to this CHOEP (induction phase) followed by ASCT T-cell lymphoma Relapsed or refractory disease should be treated with assumption could probably made for EATL that has (consolidation phase) is the recommended therapy. relapse-schedule chemotherapy and considered for been treated with a specific regimen according to the For ALK+ ALCL patients with an IPI score lower than allo-HSCT. Scottish Lymphoma Group. For patients with poor- 3, the induction phase with CHOP or CHOEP × 6 CNS prophylaxis should be considered risk TCL (IPI or PIT ≥2) with a chemosensitive courses without the consolidation phase is Angioimmunoblastic T-cell lymphoma (AITL): Outside a disease (in CR or PR) after induction chemotherapy, recommended. clinical trial, CHOP or FC would be considered as autologous stem cell transplantation (ASCT) should Patients older than 65 years, CHOP or CHOP-like standard therapy. Consolidation with auto-HSCT should be delivered. regimens are the first therapeutic options. In be considered for chemosensitive diseases in first Second-line treatment of refractory/relapsed TCL should patients fit to intensive chemotherapy, the approach remission or after relapse. Routine CNS prophylaxis is contain one or more than one among the following used in younger patient can be considered. not warranted. drugs: platinum, gemcitabine. Auto-SCT should be In patients with refractory or relapsed PTCL (excluding ALCL (anaplastic large-cell lymphoma): Patients with considered for relapsed/refractory TCL-NOS as well ALC), platinum-based, ifosfamide-based, limited-stage ALCL and no adverse prognostic features as ALK-negative ALCL and AITL. gemcitabine-containing chemotherapy, pralatrexate, by IPI should be treated with three to four cycles of Allo-SCT in relapsed/refractory TCL (TCL-NOS, ALCL romidepsin or bendamustine are the recommended CHOP chemotherapy and involved field radiotherapy. ALK− and AITL) proved to be the only curative therapies. All other patients should receive six to eight cycles of treatment of this patient subset (provided by The current evidence does not allow to make a choice CHOP chemotherapy. ALK-negative patients should be retrospective studies). among these agents. treated as for PTCL-NOS. Primary cutaneous ALCL Refractory relapsed TCL should be enrolled, whenever In refractory or relapsed ALCL, anti-CD30 (ALK negative) should be managed with local possible, in phase I or II prospective clinical trials (brentuximab–vedotin) monoclonal antibody excision ± radiotherapy and chemotherapy reserved for aimed at exploring the efficacy of new drugs that have should be preferred. those patients with systemic disease. At relapse, patients shown activity in preclinical studies. Patients with chemosensitive disease should receive should receive platinum-based chemotherapy or an consolidation with allogeneic SCT. In the absence of alternative salvage regimen and patients with a donor, autologous transplantation can be used. chemosensitive disease should be considered for In non-transplant eligible patients, novel agents should transplant. be recommended, but these therapies should be Enteropathy-associated T-cell lymphoma (EATL): CHOP considered as experimental and to be done within like therapy, with or without an up-front autograft clinical trials. remains a common approach outside trial but evidence of efficacy is lacking and adoption of a more intensive approach, such as NCRI/SNLG protocol, is a reasonable option in fitter patients. Hepatosplenic T-cell lymphoma: allogeneic bone marrow Oncology of Annals transplantation could be considered but the evidence is purely anecdotal. Conventional chemotherapy approaches as for PTCL-NOS are the default, and there

are some survivors reported in the literature.

Downloaded from from Downloaded http://annonc.oxfordjournals.org/ by guest on June 24, 2014 24, June on guest by naso Oncology of Annals

Extranodal NK/T- Patients with localized disease should receive radiation with For NK/T-cell nasal-type lymphoma, the treatment Patients with localized disease should receive cell lymphoma, 50–55 Gy. The value of additional chemotherapy (CHOP, should include L-asparaginase and local radiotherapy as early as possible at doses of at least nasal type etoposide-based or asparaginase-based) remains unclear (nasopharyngeal) radiotherapy. 50 Gy to the tumour and adjacent structures. The but is considered conventional pending more evidence is not sufficient to routinely support CT information. Asparaginase-containing regimens should concurrently or sequentially to RT. Patients with be considered in relapsed or refractory disease. High-dose systemic disease should receive L-asparaginase- therapy is unproven, and there is no basis to recommend containing regimens. The SMILE protocol proved to it outside trial. produce the best results, although toxicity was not negligible. The use of ASCT should be considered during first complete remission. Radiotherapy should be added to areas of bulky or residual disease. Subcutaneous CHOP-like chemotherapy appears to be effective and In SPTCL without associated haemophagocytic Radiotherapy (20–30 Gy), possibly preceded by panniculitis-like produces survivors. syndrome (HPS), systemic steroids or other reductive surgery, should be recommended in T-cell lymphoma Relapse disease may respond to dose intensification in some immunosuppressive patients with localized lesions. Pulse steroid therapy (SPTCL) (αβ only) patients. Local radiotherapy has a place for good Agents should be considered first, whereas in cases of (0.6–0.7 mg/kg/die × 10 days every month prognosis localized symptomatic skin involvement which solitary or localized skin lesions, radiotherapy with prednisone or equivalent) should be recommended does not resolve with topical steroids. electrons is advised. Little information on radiation in patients with multiple non-contiguous lesions. dose is available, but a dose of 40 Gy has been used. Six courses of monochemotherapy with gemcitabine or Bexarotene may be also effective in SPTCL. Multi- peg-doxorubicin is an alternative option in patients agent chemotherapy is required only in cases with with high tumour load. progressive disease not responding to immunosuppressive therapy or in cases with HPS. o:019/nocmu5 | doi:10.1093/annonc/mdu152 review



Downloaded from from Downloaded http://annonc.oxfordjournals.org/ by guest on June 24, 2014 24, June on guest by review Annals of Oncology based on evidence from CTCL. The EP judged that the scant lit- Bexarotene should be recommended in patients refractory to or erature could not support evidence-based recommendations. relapsing after first-line systemic treatment, and should also be used in patients obtaining at least stabilization after TSEBI or CT first line. Recommendations Enrolment in clinical trials should be recommended whenever possible. Young patients responding to first-line treatment should be considered, Radiotherapy (20–30 Gy), possibly preceded by reductive surgery, should at least in selected cases, for HSCT procedures. be recommended in patients with localized lesions. Pulse steroid therapy (0.6–0.7 mg/kg/die ×10 days every month fi prednisone or equivalent) is recommended in patients with multiple issue 7: monitoring the response to rst-line non-contiguous lesions. therapy (consensus-based recommendations) Six courses of monochemotherapy with gemcitabine or peg- doxorubicin is an alternative option in patients with high tumour load. Recommendations In PTCL, re-evaluation should be carried out after three cycles of issue 6: first-line therapy in advanced CTCL chemotherapy to define primary refractory disease. (consensus-based recommendations) In PTCL nasal type, the re-evaluation should be done after two cycles of the SMILE regimen. EBV-DNA quantitative assay could be used Several large retrospective studies consistently documented clin- during treatment to predict therapy outcome. ical RRs with total skin electron beam irradiation (TSEBI), i.e. In CTCL, re-evaluation should be done 6 weeks after the completion of ionizing radiation to the entire skin surface. as high as 100% in TSEBI or after three cycles of monochemotherapy. T2/T3 mycosis fungoides (MF) with relevant improvement of Downloaded from – PET/CT scan has been proposed as useful tool for early response symptoms and quality of life [86 90], and short response dur- evaluation in PTCL, but it should be discouraged outside clinical trials ation in T3 MF with cosmetic adverse effects. since no validated reporting rules are available. Cytotoxic regimens has been proven to prolong OS in advanced-stage CTCL; therefore, immunomodulatory therapies are fi preferred for rst-line systemic treatment. Interferon alpha-2b issue 8: therapy for non-responding or relapsed http://annonc.oxfordjournals.org/ – – achieves 60% 100% RR in stage IIB IVA disease: higher rates are patients (consensus-based recommendations) allowed by the association with psoralens plus ultraviolet A [91]. Bexarotene did not prove to achieve better RRs than CT [92]. Relapsed/refractory disease is common for most patients with Indeed, with gemcitabine monotherapy a 68% RR has been PTCL who receive current agents with inadequate salvage reported both in untreated and in refractory patients with advanced therapy. An array of new agents have been tested with early CTCL [93]. Similar or higher rates were obtained with pegylated phase trials in non-responding or relapsed patients. A number – liposomal doxorubicin [94, 95]. Polychemotherapy never produced has been proven to be effective (Table 4)[107 114]. higher RRs than the above monochemotherapy regimens [96]. The role of allo- and auto-transplantation in patients with Extracorporeal photophoresis (ECP) produced RRs of 30%– advanced disease has been retrospectively studied in 77 and 241 by guest on June 24, 2014 70% which were greatly increased with the association with patients with PTCL [115, 116]. Three-year PFS and OS of ASCT fi interferon, bexarotene or granulocyte-macrophage-colony recipients beyond rst complete remission were 42% and 53%, stimulating factor [97–99]. However, the evidence that ECP respectively. Among allo-SCT recipients who received transplanta- fi improves both RRs and OS in the setting of refractory erythro- tions beyond rst complete remission, 31% remained progression- dermic CTCL was judged of low quality [100]; therefore, the EP free at 3 years, despite being more heavily pre-treated and with did select ECP as a first-line treatment. more refractory disease. Non-relapse mortality was 3.5-fold higher Three histone deacetylase (HDAC) inhibitors were tested: for allo-SCT. In multivariate analysis, chemotherapy sensitivity and romidepsin, vorinostat and denileukindifitox. The former two or fewer lines of pre-transplantation therapy were prognostic achieved RRs of 34% in two large phase II studies [101, 102]. of survival. These data suggest greater effectiveness of SCT earlier Both vorinostat and denileukin diftitox achieved 30%–44% in the disease course and limited utility in mutiply relapsed disease. responses in a phase III and some phase II trials [103–105]. A recent literature review retrieved scant retrospective data on allo-SCT in advanced CTCL [105] and no randomized study. Recommendations However, retrospective data consistently showed [106] survival In patients with refractory or relapsed PTCL (excluding ALC), platinum- rates >50% at 3 years with non-myeloablative conditioning. based, ifosfamide-based, gemcitabine-containing chemotherapy, pralatrexate, romidepsin or bendamustine are the recommended therapies. The current evidence does not allow to make a choice among these agents. Recommendations In refractory or relapsed ALCL, anti-CD30 (brentuximab–vedotin) Total skin electron beam irradiation (TSEBI) ± boost is highly monoclonal antibody should be preferred. recommended first-line in skin-advanced cutaneous T-cell lymphoma. Patients with chemosensitive disease should receive consolidation with Monochemotherapy is an alternative option in case TSEBI facilities are allo-SCT. In the absence of a donor, ASCT can be used. not readily available. In non-transplant eligible patients, novel agents should be Different drugs have been proposed for this indication (gemcitabine, recommended, but these therapies should be considered experimental and peg-doxorubicin, vorinostat, romidepsin, denileukindiftitox, bexarotene), to be done within clinical trials. but there is no evidence of superiority for any of them.

 | Corradini et al. Annals of Oncology review

Table 6. Recommendations published in the last 5 years for the therapy of advanced primary cutaneous T-cell lymphomas

ESMO, 2013 (119) SIE SIES, GITMO, 2014

In patients with advanced and refractory disease, gemcitabine or liposomal Total skin electron beam irradiation (TSEBI) ± boost is highly doxorubicin may be considered. Other agents like the fusion toxin recommended first-line in skin-advanced cutaneous T-cell denileukin diftitox and histone deacetylase inhibitors, such as vorinostat lymphoma. and romidepsin, have been approved in the United States, but have not Monochemotherapy is an alternative option in case TSEBI facilities are yet been registered for cutaneous T-cell lymphoma in Europe. not readily available. Multi-agent chemotherapy is only indicated in patients with effaced lymph Different drugs have been proposed for this indication (gemcitabine, nodes or visceral involvement (stage IV), or in patients with widespread peg-doxorubicin, vorinostat, romidepsin, denileukindiftitox, tumour stage MF which cannot be controlled with skin-targeted and bexarotene), but there is no evidence of superiority for any of them. immunomodulating therapies. Bexarotene should be recommended in patients refractory to or relapsing Local palliation of cutaneous as well as extracutaneous lesions may be after first-line systemic treatment, and should also be used in patients achieved with local radiotherapy to doses ≥8Gy. obtaining at least stabilization after TSEBI or chemotherapy first line. In relatively young patients with refractory, progressive mycosis fungoides Enrolment in clinical trials should be recommended whenever possible. or with Sezary syndrome allogeneic stem cell transplantation may be Young patients responding to first-line treatment should be considered, considered. Durable responses have been reported, but experience is still at least in selected cases, for HSCT procedures. limited, and the optimal conditioning regimen and the optimal timing for an allogeneic transplant are currently unknown. Downloaded from discussion 2. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin In this project, we used a rigorous appraisal of evidence for pro- Oncol 2008; 26: 4124–4130. fi viding speci c evidence-based recommendations on manage- 3. Ferguson JH. The NIH Consensus Development Program. The evolution of http://annonc.oxfordjournals.org/ ment of PTCL according to GRADE methodology. This system guidelines. Int J Technol Assess Health Care 1996; 12: 460–474. was applicable to a limited number of issues in which a prelim- 4. Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating inary judgement of the quality of evidence and a subsequent quality of evidence and strength of recommendations. Br J Med 2008; 336: 924–926. assessment of the strength of the recommendation based on a fi 5. Delbecq AL, van de Ven AH, Gustafson DH. Group Techniques for Program qualitative risk-bene t analysis was provided [4]. For the Planning: a Guide to Nominal Group and Delphi Processes. Glenview, IL, USA: remaining key issues, we adopted the group discussion method- Scott, Foresman and Co, 1975. ology and we provided consensus-based recommendations. 6. Savage KJ, Harris NL, Vose JM et al. ALK- anaplastic large-cell lymphoma is Few other guidance, projects have been published for these clinically and immunophenotypically different from both ALK+ ALCL and rare lymphomas. The British Committee for Standards in peripheral T-cell lymphoma, not otherwise specified: report from the International by guest on June 24, 2014 Haematology has produced in 2011 guidelines for the manage- Peripheral T-Cell Lymphoma Project. Blood 2008; 111: 5496–5504. ment of mature T-cell and NK-cell neoplasms, excluding CTCLs 7. Huang WT, Chang KC, Huang GC et al. Bone marrow that is positive for Epstein- [117]. In 2013, the European Society of Medical Oncology Barr virus encoded RNA-1 by in situ hybridization is related with a poor prognosis fi in patients with extranodal natural killer/T-cell lymphoma, nasal type. Haema- (ESMO) organized consensus conferences to focus on speci c tologica 2005; 90: 1063–1069. issues in different lymphomas, including PTCL [118, 119]. The 8. Feldman AL, Dogan A, Smith DI et al. Discovery of recurrent t(6;7)(p25.3;q32.3) recommendations on therapy are reported in Tables 5 and 6. translocations in ALK-negative anaplastic large cell lymphoma by massively parallel genomic sequencing. Blood 2011; 117: 915–919. 9. Vasmatzis G, Johnson SH, Knudson RA et al. Genome-wide analysis reveals funding structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood 2012; 120: 2280–2289. This work was supported by SIE, SIES and GITMO societies 10. Schmitz N, Trumper L, Ziepert M et al. Treatment and prognosis of mature T-cell and from at-arm’s-length contribution from Celgene and and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in Munipharma (Italy) provided to SIE. The SIE administered all studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418–3825. aspects of the meetings. The funding sources had no role in 11. Gallamini A, Stelitano C, Calvi R et al. Peripheral T-cell lymphoma unspecified identifying statements, abstracting data, synthesizing results, (TCL-U): a new prognostic model from a retrospective multicentric clinical study. grading evidence or preparing the manuscript or in the decision Blood 2004; 103: 2474–2479. to submit the manuscript for publication. No grant number 12. Went P, Agostinelli C, Gallamini A et al. Marker expression in peripheral T-cell applies. lymphoma: a proposed clinical-pathological prognostic score. J Clin Oncol 2006; 24: 2472–2479. 13. Li YJ, Jiang WQ, Huang JJ et al. The Glasgow Prognostic Score (GPS) as a novel and significant predictor of extranodal natural killer/T-cell lymphoma, nasal type. references Am J Hematol 2013; 88: 394–399. 1. Campo E, Swerdlow SH, Harris NL et al. The 2008 WHO classification of 14. Lee J, Suh C, Park YH et al. Extranodal natural killer T-cell lymphoma, nasal- lymphoid neoplasms and beyond: evolving concepts and practical applications. type: a prognostic model from a retrospective multicenter study. J Clin Oncol Blood 2011; 117: 5019–5032. 2006; 24: 612–618.

doi:10.1093/annonc/mdu152 |  review Annals of Oncology

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