Cutaneous T-Cell Lymphoma Guidelines

Updated: Apr 20, 2020
  • Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines

Guidelines Summary

Guidelines contributors:  Priyank P Patel, MD , Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo;  Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

NHL Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF) [128]

  • Revised European-American Classification of Lymphoid Neoplasms (REAL) [129]

  • World Health Organization (WHO) classification [130]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J. [128] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [129]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. [130]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons. [128]

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following [1, 2] :

  • Mycosis fungoides

  • Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)

  • Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)

  • Subcutaneous panniculitis-like T-cell lymphoma (provisional)

  • Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (provisional)

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Mycosis Fungoides/Sezary Syndrome

In addition to the guidelines from the National Comprehensive Cancer Network (NCCN) [131] , the European Organization for Research and Treatment of Cancer (EORTC) released consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2017. [132]  In 2018, the European Society for Medical Oncology (ESMO) updated its guidelines for primary cutaneous lymphoma. [133]

Diagnosis

The NCCN considers the following studies essential for establishing a diagnosis of MF/SS [131] :

  • Biopsy of suspicious skin sites (multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis)

  • Dermatopathology review of slides (including evaluation for presence of transformation or areas of folliculotropism)

  • Immunohistochemistry (IHC) panel of skin biopsy: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30; an additional panel of CD25, CD56, TIA1, granzyme B, ßF1, TCR-CγM1 may be useful

  • Molecular analysis to detect clonal T-cell antigen receptor (TCR) gene rearrangements or other assessment of clonality

Staging

In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease. [6]  See Table 4, below.

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Skin

Involvement

Node

Involvement

Viscera

Involvement

T1

Patchy or plaquelike skin disease involving ≤10% of the skin surface area

N0

No abnormal lymph nodes

M0

No visceral organ involvement

T2

Patchy or plaquelike skin disease involving ≥10% of the skin surface area

N1

Histopathology Dutch Gr 1 or NCI LN 0-2

M1

Visceral organ involvement

T3

Tumors are present ≥1 cm in diameter

N2

Histopathology Dutch Gr 2 or NCI LN 3

MX

Abnormal visceral site; no histologic confirmation

T4

Erythroderma ≥80% of body area

N3

Histopathology Dutch Gr 3-4 or NCI LN 4

Blood

Involvement

   

Nx

Abnormal lymph nodes; no histologic confirmation

B0

≤5% of peripheral blood lymphocytes are Sezary cells

       

B1

>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria

       

B2

≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

The ISCL/EORTC system was further modified to update clinical staging classifications. [6]  See Table 5, below.

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Clinical Stage

5-Year Survival  [132]

TNM (B) Stage

IA

98%

T1N0M0B0

T1N0M0B1

     

IB

89%

T2N0M0B0

T2N0M0B1

     

IIA

89%

T1N1M0B0

T1N1M0B1

T1N2M0B0

T1N2M0B1

 

 

T2N1M0B0

T2N1M0B1

T2N2M0B0

T2N2M0B1

 

IIB

56%

T3N0M0B0

T3N0M0B1

T3N1M0B0

T3N1M0B1

 

 

T3N2M0B0

T3N2M0B1

     

IIIA

54%

T4N0M0B0

T4N1M0B0

T4N2M0B0

   

IIIB

48%

T4N0M0B1

T4N1M0B1

T4N2M0B1

   

IVA1

 

41%

T1N0M0B2

T2N0M0B2

T3N0M0B2

T4N0M0B2

 

T1N1M0B2

T2N1M0B2

T3N1M0B2

T4N1M0B2

 

T1N2M0B2

T2N2M0B2

T3N2M0B2

T4N2M0B2

 
IVA2

23%

T1N3M0B0

T2N3M0B0

T3N3M0B0

T4N3M0B0

 

T1N3M0B1

T2N3M0B1

T3N3M0B1

T4N3M0B1

 

T1N3M0B2

T2N3M0B2

T3N3M0B2

T4N3M0B2

 

IVB

18%

T1N0M1B0

T2N0M1B0

T3N0M1B0

T4N0M1B0

 

T1N1M1B1

T2N1M1B1

T3N1M1B1

T4N1M1B1

 

T1N2M1B2

T2N2M1B2

T3N2M1B2

T4N2M1B2

 

T1N3M1B3

T2N3M1B3

T3N3M1B3

T4N3M1B3

 

Treatment

The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis. [131]

All three guidelines recommend treatment selection based on clinical stage. [131, 132, 133]

Mycosis fungoides

In general, topical skin-directed therapies (SDTs) are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments. [131, 132, 133]

Both the ESMO and EORTC guidelines include an expectant 'watch and wait' policy as a recommended management option for patients with stage IA disease. [132, 133] EORTC guidelines note that in patients with stage 1A disease, only an estimated 10% of cases progress within 10 years, and life expectancy does not appear to be affected. [132]

Localized therapies endorsed by the guidelines include the following [131, 132, 133]

  • Psoralens + ultraviolet A (PUVA)—For thick plaquesNarrow-band ultraviolet B (UVB)—For patch or thin plaques
  • Topical corticosteroids
  • Localized radiation therapy (12-36 Gy)
  • Topical mechlorethamine (nitrogen mustard)
  • Topical retinoids (ie, bexarotene, tazarotene)

The guidelines diverge on the use of total skin electron beam therapy (TSEBT). EORTC recommends a standard treatment course consisting of a total dose of 30–36 Gy applied over a period of 8–10 weeks, particularly in T2 and T3 disease. While acknowledging that toxicity is dose-related, the guidelines find lack of evidence that low-dose regimens (in the range of 10–12 Gy) with shorter treatment times (2–3 weeks) will be equally effective in inducing remissions. [132]

The ESMO guidelines prefer the lower-dose TSEBT regimen (10–12 Gy) noting the shorter duration of treatment, fewer adverse effects, and the advantage of allowing multiple retreatments. [133]  NCCN recommends TSEBT (12–36 Gy) for generalized skin involvement followed by systemic therapies such as interferon or bexarotene to maintain response. [131]

Systemic therapies recommended by NCCN are divided into two categories. Agents considered category A include the following [131] :

  • Retinoids: bexarotene
  • Interferons: IFN-alpha, IFN-gamma
  • Histone deacetylase (HDAC)-inhibitors: vorinostat, romidenpsin—not approved in Europe
  • Extracorporeal photopheresis (ECP)
  • Chemotheapy: methotrexate
  • Targeted immunotherapies: brentuximab vedotin, mogamulizumab 

NCCN-recommended second-line treatments for localized disease (stage I and IIA) include category A systemic therapies with or without localized therapies, or the following combination therapies [131] :

  • PUVA/UVA with ECP
  • PUVA/UVA with Interferons
  • PUVA/UVA with retinoid
  • TSEBT with ECP
  • ECP with Interferon
  • ECP with retinoid
  • ECP with retinoid and Interferon
  • Retinoid with Interferon

The EORTC recommends retinoids, IFN-alpha, TSEBT or low-dose methotrexate for second-line treatment of localized disease. [132]  ESMO also recommends retinoids, IFN-alpha, and TSEBT along with the following combination therapies [133] :

  • Localized skin-directed therapies (SDTs) with retinoids
  • SDTs with IFN-alpha
  • Retinoids and IFN-alpha

NCCN catagory B systemic agents include:

  • Targeted immunotherapies: brentuximab vedotin
  • Chemotherapies: gemicitabine, liposomal doxorubicin,  pralatrexate

NCCN recommendations for the treatment of stage IIB disease with limited lesions include localized radiation therapy with or without other localized therapies and category A systemic therapies with or without localized radiation therapy. For stage IIB generalized lesions, the recommendation include the following [131] :

  • TSEBT
  • Category A systemic therapy with or without localized therapies
  • Category B systemic therapy with or without localized therapies
  • Combination therapy with or without localized therapies

EORTC recommends retinoids, IFN-alpha, TSEBT, gemcitabine, pegylated liposomal doxorubinine, low-dose methotrexate and localized radiation therapy for the first-line treatment of stage IIB.  For second-line treatment, EORTC recommends combination chemotherapy and allogeneic hematopoietic cell transplantation (HCT). [132]

ESMO recommends a combination of SDT with local radiation therapy, retinoids or IFN-alpha, or TSEBT for first-line treatment of stage IIB. For second-line treatment, gemcitabine, liposomal doxorubinine, brentuximab vedotin, combination chemotherapy, and allogeneic HCT are recommended. [133]

Sezary syndrome and erythrodermic mycosis fungoides

The NCCN's preferred regimens for treatment of low- to intermediate-burden Sézary syndrome or stage III advanced (erythrodermic) mycosis fungoides include the following [131] :

  • Combination therapies (listed above)
  • Category A systemic therapy with or without localized therapies

Other recommended treatments include the following [131] :

  • Category B systemic therapy with or without localized therapies
  • Alemtuzumab
  • Pembrolizumab

Preferred regimens for treatment of high-burden Sézary syndrome or stage III advanced (erythrodermic) mycosis fungoides include [131] :

  • Combination therapies (listed above)
  • Mogamulizumab with or without localized therapies
  • Romidepsin with or without localized therapies

Other recommended treatments include the following [131] :

  • Category A systemic therapies not included in preferred regimens above
  • Category B systemic therapy 
  • Alemtuzumab
  • Pembrolizumab

EORTC and ESMO provide separate treatment recommendations for Sézary syndrome and erythrodermic mycosis fungoides (stage III) disease. The EORTC and ESMO recommendation are in agreement for Sézary syndrome and include the following first-line treatments [132] :

  • Chlorambucil with prednisone
  • Systemic therapies (retinoids or IFN-alpha) in combination with ECP or PUVA
  • Low dose methotrexate

For second-line Sézary syndrome treatments, EORTC and ESMO recommend the following [132, 133] :

  • Chemotherapy (gemcitabine, pegylated liposomal doxorubicine, CHOP and CHOP-like regimens)
  • Alemtuzumab
  • Allogeneic HCT

For erythrodermic MF (stage III) disease, the first-line EORTC recommended treatments include [132] :

  • Retinoids
  • IFN-alpha
  • ECP
  • Low dose methatrexate
  • TSEB

ESMO recommends the following first-line treatments for erythrodermic mycosis fungoides (stage III) disease [133] :

  • SDT with retinoids
  • SDT with IFN-alpha
  • ECT with or without IFN-alpha with or without retinoids
  • Low dose methatrexate

For second-line erythrodermic MF (stage III) disease treatment, EORTC recommends the following [132] :

  • Gemcitabine
  • Pegylated liposomal doxorubicine
  • Allogeneic HCT

ESMO recommends TSEBT for second-line treatment of erythrodermic mycosis fungoides (stage III) disease. [133]

NCCN recommended treatments for erythrodermic mycosis fungoides (stage IV) includes [131] :

  • Category B systemic therapy 
  • Allogeneic hematopoietic cell transplantation (HCT) 

NCCN also recommends the following, with or without radiation therapy [131] :

  • Brentuximab vedotin
  • Gemcitabine
  • Liposomal doxorubicin
  • Pralatrexate
  • Romidepsin

For erythrodermic mycosis fungoides (stage IV), EORTC recommends the following treatments [132] :

  • Chemotherapy (gemcitabine, pegylated liposomal doxorubicine, CHOP and CHOP-like regimens)
  • Localized radiotherapy or TSEBT
  • Alemtuzumab
  • Allogeneic HCT

ESMO recommends gemcitabine, lipsomal doxorubicin or brentuximab vedotin for first-line treatment of erythrodermic mycosis fungoides (stage IV) and combination chemotherapy or allogeneic HCT for second-line treatment. [133]

Participation in a clinical trial as a treatment option for all patients with disease progression or refractory Sézary syndrome or advanced-stage mycosis fungoides is recommended by both the NCCN and EOTRTC.  [131, 132]  

 

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma  (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs). [134]

Classification

Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features. [1]

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following [131] :

  • Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation

  • Mycosis fungoides can be comorbid

  • Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes

  • Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1

  • Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH

  • Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance

  • Molecular analysis of skin biopsy: TCR gene rearrangements

  • Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)

  • Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)

  • Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease

Staging

NCCN, ESMO and EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome. [28, 134, 131, 133]

Treatment

NCCN primary treatment recommendations for PC-ALCL, are as follows [131, 134] :

  • For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment

  • Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated

  • For multifocal lesions, brentuximab vedotin is the preferred treatment. Other recommended regimens with or without SDT include low dose methotrexate, retinoids, pralatrexate and observation, if asymptomatic. 

  • Interferon is an NCCN category 3 recommendation.

For PC-ALCL with regional node involvement (N1), brentuximab vedotin with or without ISRT is the preferred regimen. Other recommended treatmens include [131] :

  • Brentuximab vedotin with CHP 
  • Methotrexate with or without ISRT
  • Pralatrexate with or without ISRT
  • CHOP or CHOEP with or without ISRT, in select cases

NICE

After reviewing the clinical- and cost-effectiveness evidence for brentuximab vedotin for treating relapsed or refractory CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL), the National Institute for Health and Care Excellence (NICE) recommended brentuximab vedotin as a second-line treatment for treating CD30+ CTCL. [135]  

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