What is the latest approach to treating mycosis fungoides?

Updated Approach to Mycosis Fungoides Management

The current treatment paradigm for mycosis fungoides follows a strict stage-based approach, with skin-directed therapies as first-line for early disease (stages IA-IIA) and systemic therapies reserved for advanced or refractory cases, prioritizing quality of life and disease control over aggressive interventions that do not improve survival. 1, 2

Early Stage Disease (IA-IIA)

First-Line Skin-Directed Therapies

For patches and thin plaques, narrowband UVB is the preferred initial option, achieving response rates of 79-88% in stage IA and 52-59% in stage IB. 1, 2 For thicker plaques, PUVA (psoralen plus UVA) phototherapy is superior to UVB and should be used preferentially. 1

Topical therapies are effective alternatives or adjuncts:

• Topical corticosteroids (class 1/very potent) show 94% response in stage IA and 82% in stage IB, though responses are rarely durable 1, 2
• Topical mechlorethamine (nitrogen mustard) 0.02% demonstrates 59% response rate with the gel formulation in a large randomized trial, with no increased risk of secondary cancers in long-term follow-up 1
• Topical bexarotene gel achieves 44-63% response rates in stages IA-IIA 1, 2

For localized disease such as pagetoid reticulosis, local radiotherapy (20-24 Gy) can be curative. 1, 2

Critical Pitfall to Avoid

Do not use aggressive chemotherapy in early-stage disease—a pivotal randomized trial demonstrated that combined total skin electron beam therapy plus multiagent chemotherapy (CAVE regimen) achieved higher complete response rates (38% vs 18%) but showed no difference in disease-free or overall survival compared to palliative skin-directed therapy, while causing significantly greater morbidity. 1

Intermediate Stage Disease (IIB)

For patients developing one or few tumors (stage IIB), add local radiotherapy (24-30 Gy) to ongoing skin-directed therapy. 1, 2 This approach often suffices without requiring systemic therapy initially.

For extensive infiltrated plaques and tumors refractory to monotherapy:

• Combine PUVA with interferon-alpha 1, 2
• Combine PUVA with systemic retinoids (including bexarotene) 1
• Consider total skin electron beam therapy (TSEB) at 30-36 Gy, though lower doses (10-12 Gy) offer advantages of shorter treatment duration, fewer side effects, and opportunity for retreatment 1

Patients with stage IIB disease refractory to skin-directed therapy should be referred to supranetwork multidisciplinary teams to ensure access to clinical trials and specialized treatments like TSEB. 1

Advanced Stage Disease (III-IV)

Systemic Therapy Hierarchy

For erythrodermic disease (stage III) and stage IVA, prioritize immunomodulatory approaches over chemotherapy:

First-line systemic options:

• Extracorporeal photopheresis (ECP) shows overall responses of 35-71% in erythrodermic disease, with a reported median survival of 62 months compared to 30 months in historical controls 1, 2
• Interferon-alpha combined with PUVA or retinoids 1, 2
• Bexarotene (oral) at 300 mg/m² daily achieves 45-54% response rates with notable reduction in pruritus, though requires monitoring and treatment for hyperlipidemia and central hypothyroidism 1

Second-line targeted therapies:

• Brentuximab vedotin (anti-CD30 antibody-drug conjugate) for cases with ≥10% CD30-positive malignant cells 3
• Mogamulizumab (anti-CCR4 antibody) is highly effective for cases with blood involvement 3
• Romidepsin (histone deacetylase inhibitor) demonstrates 34-35% overall response rate with median duration of response 11-15 months in patients who failed prior systemic therapy 4

Single-agent chemotherapy options (when targeted therapies fail):

• Gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived 1, 2

When to Use Multi-Agent Chemotherapy

Multi-agent chemotherapy is ONLY indicated for:

• Effaced lymph nodes or visceral involvement (stage IV) 1
• Widespread tumor stage MF that cannot be controlled with skin-targeted and immunomodulating therapies 1

Important caveat: Multi-agent chemotherapy regimens achieve complete responses in only ~30% of cases with median duration of 3-41 months, and early aggressive chemotherapy does not improve survival. 1, 2

Transplantation Considerations

Allogeneic hematopoietic stem cell transplantation is the only potentially curative option and should be considered in relatively young patients with refractory, progressive MF/SS who have good performance status and have achieved complete or near-complete response with systemic therapy. 1, 2, 3 The optimal conditioning regimen and timing remain unknown. 1

Autologous stem cell transplantation has shown disappointing results and is not recommended. 2

Multidisciplinary Team Requirements

All patients with stage IIB or higher MF, Sézary syndrome, or rare CTCL variants must be reviewed by supranetwork multidisciplinary teams that include dermatologists, clinical oncologists, hemato-oncologists, and specialized pathologists. 1 This ensures access to clinical trials, which are often the standard of care, and facilitates appropriate use of newly approved therapies.

Key Principles

The fundamental approach prioritizes prolonging survival and preventing disease progression—goals unique to cutaneous T-cell lymphoma compared to other dermatologic conditions. 1 Treatment should achieve long-lasting remissions without long-term toxicity, recognizing that most patients are elderly with multiple comorbidities. 1 In treatment-resistant late-stage disease, palliative radiotherapy (doses as low as 4-8 Gy) can produce significant short-term benefit, with quality of life always given priority. 1