What is the treatment for Sezary syndrome?

Treatment of Sézary Syndrome

The primary treatment for Sézary syndrome should begin with extracorporeal photopheresis (ECP), interferon alfa, bexarotene, low-dose methotrexate, or denileukin diftitox as first-line systemic monotherapies, with skin-directed therapies like PUVA or potent topical steroids as adjuvant therapy. 1

Understanding Sézary Syndrome

Sézary syndrome (SS) is defined by a triad of:

• Erythroderma (affecting ≥80% of body surface)
• Generalized lymphadenopathy
• Presence of clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in skin, lymph nodes, and peripheral blood

As a systemic disease (leukemia) by definition, SS requires systemic treatment rather than skin-directed therapies alone.

First-Line Treatment Options

Category A Systemic Therapies (Primary Treatment)

• Extracorporeal photopheresis (ECP): Either alone or in combination with other modalities

  • Overall response rates range from 30% to 80%
  • Complete response rates range from 14% to 25% 1
  • Often considered the treatment of choice for SS 1

• Interferon alfa: Can be used as monotherapy or in combination with ECP

  • Dosing typically ranges from 3-9 MU three times weekly 1

• Bexarotene: Oral retinoid specifically approved for cutaneous T-cell lymphomas

  • Can be used as monotherapy or in combination 1

• Low-dose methotrexate: ≤100 mg/week 1

• Denileukin diftitox: Usually administered with corticosteroids 1

Adjuvant Skin-Directed Therapies

• PUVA (psoralen plus ultraviolet A)
• Potent topical corticosteroids

Second-Line Treatment Options

For patients with inadequate response, refractory disease, or progression despite primary treatments:

Category B Systemic Therapies

• Alemtuzumab: Low-dose regimen (10 mg subcutaneous, 3 times weekly for 12 weeks) 1
• Chlorambucil + corticosteroid: Often effective for disease control but unlikely to yield complete responses 1
• Liposomal doxorubicin
• HDAC inhibitors:
  • Vorinostat
  • Romidepsin
• Gemcitabine
• Deoxycoformycin
• High-dose methotrexate (≥100 mg/week)
• Fludarabine + cyclophosphamide
• Mechlorethamine
• Allogeneic stem cell transplantation: Consider in relatively young patients with refractory, progressive disease 1, 2

Treatment Selection Considerations

When selecting therapy, consider:

1. Blood tumor burden
2. Patient age and overall health status
3. Prior therapies and response
4. Comorbidities

Combination Approaches

Combination therapies may be more effective than monotherapy:

• ECP + interferon alfa
• ECP + retinoids
• ECP + PUVA
• Interferon alfa + retinoids

Prognostic Factors and Monitoring

• Median survival historically around 2.9 years 1
• Complete remissions are rare, occurring in only about 8.3% of patients 2
• Regular monitoring of:
  • Skin involvement (erythroderma)
  • Peripheral blood Sézary cell counts
  • Lymph node status

Emerging Therapies

Promising newer agents:

• Mogamulizumab: A phase III study showed significantly better overall response rate (28% vs 5%) and progression-free survival (7.7 months vs 3.1 months) compared to vorinostat 1

Pitfalls and Caveats

1. Diagnostic challenges: Histopathology may be nonspecific in SS; diagnosis requires correlation with clinical presentation and blood evaluation 3

2. Treatment comparison difficulties: Comparison of treatment results across studies is challenging due to differences in diagnostic criteria used for SS 1

3. Immunosuppression concerns: Treatments that preserve rather than compromise the immune system are preferred to reduce infection risk 3

4. Delayed diagnosis: SS can mimic common benign skin conditions like psoriasis or atopic dermatitis, potentially delaying diagnosis until later stages 4

5. Limited evidence base: Due to the rarity of SS, there are few randomized controlled trials comparing treatment efficacy