What is the treatment approach for cutaneous Chronic T cell lymphoma, such as mycosis fungoides and Sézary syndrome?

Cutaneous Chronic T-Cell Lymphoma: Treatment Approach

Overview and Classification

Cutaneous T-cell lymphomas (CTCLs) are the second most common extranodal non-Hodgkin lymphomas, with an annual incidence of 1/100,000, and must be distinguished from systemic lymphomas secondarily involving the skin because they have fundamentally different prognoses and require entirely different treatment strategies. 1

• CTCLs constitute 75-80% of all primary cutaneous lymphomas in Europe 1
• The most common subtypes are mycosis fungoides (MF) and Sézary syndrome (SS), which together represent the majority of CTCL cases 1, 2
• Diagnosis requires integration of clinical presentation, histology, immunophenotyping (typically CD4+, often with loss of CD7), and molecular studies showing T-cell receptor gene rearrangements 1

Critical Treatment Principle: Stage-Adapted Conservative Approach

The fundamental principle in CTCL management is that aggressive chemotherapy does not improve survival in early-stage disease and causes significant toxicity, particularly life-threatening infections which are the primary cause of death in advanced disease—therefore, a stage-adapted conservative approach prioritizing quality of life is mandatory. 1, 3, 4

• Early aggressive chemotherapy is associated with considerable side effects but does not improve survival 1
• Most patients with advanced disease die from secondary infections, which are worsened by cytotoxic drugs 3, 4
• The realistic treatment goal is achieving long-lasting remissions with drugs that can be safely used without long-term toxicity, NOT cure in most cases 4

Stage-Specific Treatment Algorithm

Early Stage Disease (IA-IB): Patches and Plaques

For stage IA (patches/plaques covering <10% body surface area) and IB (≥10% coverage), skin-directed therapies alone are first-line, with topical steroids, narrow-band UVB, PUVA, or topical mechlorethamine as the primary options. 1

First-line skin-directed therapies:

• Narrow-band UVB (311 nm): Recommended for thin patches or very thin plaques, achieving 81-86% complete response rates 1, 4
• PUVA (psoralen + UVA): Preferred for thicker plaques, with response rates of 71-88% in stage IA and 52-59% in stage IB 1, 4
• Topical corticosteroids: Can be used as monotherapy for stage IA disease with patches/flat plaques 1
• Topical mechlorethamine (nitrogen mustard): FDA-approved as 0.02% gel for stage IA and IB MF after prior skin-directed therapy, with mean daily usage of 2.8g 5

Important caveat: Chemotherapy is explicitly NOT suitable for stage IA or IB disease 1

Stage IIA: Patches/Plaques with Lymphadenopathy

Stage IIA disease should be treated with skin-directed therapies as first-line, with combination therapy (PUVA + interferon-alpha or PUVA + retinoids) or total skin electron beam therapy (TSEBT) as second-line options. 1

• First-line remains skin-directed therapy 1
• Second-line options include interferon-alpha combined with PUVA, or TSEBT 1
• Chemotherapy remains unsuitable at this stage 1

Stage IIB: Tumor Stage Disease

For patients with one or few tumors, local radiotherapy alone (20-24 Gy) may suffice, but patients with more extensive infiltrated plaques and tumors require combined modality therapy with PUVA plus interferon-alpha or systemic retinoids (including bexarotene). 1, 3

Treatment algorithm for tumor stage:

• Solitary or few tumors: Local radiotherapy 20-24 Gy is first-line and can be curative in unilesional MF and pagetoid reticulosis 1, 3
• Palliative treatment: Low-dose radiotherapy (4-8 Gy) is sufficient for palliation of specific lesions 1, 3
• Extensive disease: PUVA combined with interferon-alpha OR PUVA combined with systemic retinoids (including bexarotene) 1, 3
• Alternative: TSEBT at traditional doses of 30-36 Gy, though lower doses (10-12 Gy) have been employed recently with fewer side effects and opportunity for re-treatment 1, 3

Critical pitfall to avoid: Multi-agent chemotherapy is only indicated for stage IV disease with effaced lymph nodes or visceral involvement, or widespread tumor-stage MF that cannot be controlled with skin-targeted and immunomodulating therapies 1, 3

Stage III: Erythroderma/Sézary Syndrome

Sézary syndrome and erythrodermic MF require systemic treatment combined with skin-directed therapies, with extracorporeal photopheresis (ECP) ± interferon-alpha as the preferred first-line approach, particularly for patients with peripheral blood involvement. 1, 4

First-line systemic options:

• ECP (extracorporeal photopheresis): Ideal for patients with peripheral blood involvement, either alone or combined with interferon-alpha, retinoids, TSEBT, or PUVA 1, 4
• PUVA ± interferon-alpha: Alternative first-line option 1, 4
• Methotrexate: Can be used as first-line 1

Second-line options:

• TSEBT 1
• Bexarotene 1
• Denileukin diftitox 1
• Low-dose alemtuzumab (10 mg subcutaneous, 3 times weekly for 12 weeks) 1
• Single-agent chemotherapy (gemcitabine, PEGylated liposomal doxorubicin) 1

Important note: Mogamulizumab has shown significant clinical efficacy in MF/SS, particularly in patients with blood involvement 1

Stage IV: Visceral or Nodal Involvement

Stage IV disease with effaced lymph nodes or visceral involvement requires multi-agent chemotherapy, though responses are generally short-lived, and allogeneic stem cell transplantation should be considered in relatively young patients with refractory, progressive disease. 1, 3

• Radiotherapy or TSEBT as first-line 1
• Multi-agent chemotherapy is indicated at this stage 1
• Second-line options include interferon-alpha, denileukin diftitox, alemtuzumab, bexarotene 1
• Allogeneic stem cell transplantation should be considered in relatively young patients with refractory, progressive disease, though optimal conditioning regimen and timing remain unknown 1, 3

Advanced/Refractory Disease Options

For patients with advanced and refractory disease who have failed skin-directed and combination therapies, gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived. 1, 3

• Gemcitabine: Single-agent option with short-lived responses 1, 3
• Liposomal doxorubicin: Alternative single-agent option 1, 3
• HDAC inhibitors (vorinostat, romidepsin): Approved by FDA in the United States for relapsed/refractory CTCL but not yet registered in Europe 1, 3

Special CTCL Subtypes

Primary Cutaneous CD30+ Lymphoproliferative Disorders

CD30+ disorders (lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma) have excellent prognosis (100% and 96% 5-year survival respectively) and should be treated with skin-directed therapy alone unless extensive cutaneous or systemic disease develops. 1, 4

Lymphomatoid papulosis:

• Low-dose oral methotrexate (5-20 mg/week) for cosmetically disturbing lesions 1
• PUVA therapy is effective 1
• Radiotherapy is an option 1

Primary cutaneous anaplastic large cell lymphoma (C-ALCL):

• Local radiotherapy (20 Gy) is first choice for solitary or localized lesions 1
• Low-dose methotrexate for multifocal skin lesions 1
• Brentuximab vedotin should be considered for multifocal lesions refractory to conventional therapies and patients developing extracutaneous disease 1
• Multi-agent chemotherapy only indicated for extracutaneous disease or rare rapidly progressive skin disease 1

Aggressive CD30-Negative Subtypes

CD30-negative large cell pleomorphic, anaplastic and immunoblastic variants, extranodal NK-like/T-cell lymphomas (nasal type), and subcutaneous panniculitis-like T-cell lymphomas all have poor prognosis and invariably require systemic chemotherapy—skin-directed therapy alone is not indicated. 1, 4

• These aggressive subtypes have high incidence of systemic involvement and hemophagocytosis 1
• Radiotherapy may be indicated when disease is restricted to skin, but systemic dissemination is likely 1
• Multi-agent chemotherapy is required, though responses are likely to be poor 1

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL):

• Without hemophagocytic syndrome: Systemic steroids or other immunosuppressive agents (ciclosporin, methotrexate) are first choice 1
• Solitary lesions: Radiotherapy with electrons 1
• Multi-agent chemotherapy required only with progressive disease 1

Staging and Monitoring Requirements

All patients except those with early-stage MF (IA-IB) or lymphomatoid papulosis require comprehensive staging to exclude extracutaneous disease, including physical examination, complete blood count, serum biochemistry, imaging, and consideration of bone marrow biopsy. 1

• Staging CT scans of chest, abdomen, and pelvis indicated for stage IIA/B/III/IV MF and all non-MF CTCL variants, but NOT for stage IA/IB disease or lymphomatoid papulosis 1
• Bone marrow aspirate or trephine biopsies indicated for all CTCL variants (except lymphomatoid papulosis) and should be considered in stage IIB/III/IV MF 1
• For MF/SS staging, use the revised TNM staging system 1
• Unfavorable prognostic factors include older age, large cell transformation, and increased LDH values 1

Multidisciplinary Team Approach

All patients, except possibly those with stage IA MF or lymphomatoid papulosis, should be reviewed by a multidisciplinary team including a dermatologist, clinical/medical oncologist, and dermatopathologist with considerable CTCL experience. 1

• Central pathology review is desirable, consistent with recommendations for specialized pathology services 1
• The MDT should be supported by an accredited laboratory for immunophenotypic and molecular diagnostic studies 1
• Multiple skin biopsies (ellipse rather than punch) are often required to confirm diagnosis 1

Critical Pitfalls and Caveats

Earlier therapeutic interventions may aggravate late-stage problems, as radiotherapy or phototherapy may contribute to mutations that increase tumor cell proliferative capacity—therefore, treatment intensity must be carefully calibrated to disease stage. 3, 6

• High-dose chemotherapy is not indicated in management of lymphomatoid papulosis 1
• Cyclosporin is not suitable for any stage of MF/SS 1
• Long-term cure may be achieved in localized disease such as pagetoid reticulosis, but patients with multifocal early-stage MF are only likely to achieve short-term clinical response with recurrent disease 1
• A small proportion (4%) of lymphomatoid papulosis patients will develop other lymphomas including MF, Hodgkin's disease, and large cell anaplastic lymphoma 1
• Topical mechlorethamine is flammable (alcohol-based gel)—avoid fire, flame, and smoking until gel has dried 5
• Mechlorethamine exposure to mucous membranes, especially eyes, can cause severe injury potentially leading to blindness—immediately irrigate for at least 15 minutes if exposure occurs 5