Can dupilumab (Dupixent) be used in a patient with atopic dermatitis who has active or a prior diagnosis of cutaneous T‑cell lymphoma (CTCL)?

Dupilumab Should Be Avoided in Patients with Active or Prior CTCL

Dupilumab is contraindicated in patients with active cutaneous T-cell lymphoma and should be used with extreme caution—if at all—in those with a prior CTCL diagnosis, as emerging evidence demonstrates it can unmask, accelerate, or exacerbate lymphoproliferative disorders. 1, 2, 3

Critical Safety Concerns

Unmasking and Progression of CTCL

• Dupilumab has been associated with unmasking previously undiagnosed CTCL or accelerating disease progression in multiple case series, with the median time from dupilumab initiation to biopsy-confirmed lymphoproliferative disorders being approximately 5 months (range 3-12 months). 2, 3, 4

• In systematic reviews, 39% of dupilumab-associated CTCL cases presented at advanced stages (III or IV), and 100% of patients with documented body surface area had >50% BSA involvement at diagnosis. 4

• Dermatitis persisted or worsened in all reported lymphoma cases following dupilumab treatment, which should serve as a critical red flag that the underlying diagnosis may be CTCL rather than atopic dermatitis. 5

Diagnostic Pitfalls

The relationship between dupilumab and CTCL creates several dangerous diagnostic scenarios:

• Early-stage CTCL can be misdiagnosed as atopic dermatitis, leading to inappropriate dupilumab initiation that may accelerate malignant transformation. 2, 3

• Post-dupilumab biopsies reveal greater lymphoid cell density and predominantly lichenoid patterns, compared to pre-dupilumab biopsies which showed various histologic patterns with less cell density. 4

• TCR gene rearrangement studies were equivocal (20%) or negative (60%) in the majority of dupilumab-associated cases, creating a significant diagnostic pitfall that may delay recognition. 4

• 31% of lymphoma cases required multiple biopsies for definitive diagnosis, emphasizing the difficulty in distinguishing dupilumab-treated atopic dermatitis from emerging CTCL. 5

Proposed Mechanisms

While causation remains unproven, several mechanisms have been proposed:

• Upregulation of IL-13RA2 signaling pathways may promote malignant transformation, as both Hodgkin lymphoma and peripheral T-cell lymphomas are known to overexpress IL-13. 5, 3

• Dupilumab-induced changes in immune signaling through IL-4 receptor blockade may alter the tumor microenvironment and promote prolonged persistence of malignant immune cell populations. 2, 3

• The distribution of type 2 inflammatory cytokine receptors and patterns of cellular infiltration within the microenvironment may impact disease progression following dupilumab treatment. 3

Clinical Recommendations for Patients with Prior CTCL

Absolute Contraindications

• Active CTCL of any stage is an absolute contraindication to dupilumab therapy. 1, 2, 3

Relative Contraindications and High-Risk Scenarios

For patients with a history of treated CTCL in remission:

• The risk-benefit ratio strongly favors avoiding dupilumab given the potential for disease reactivation or progression, even in patients with documented remission. 2, 3

• If dupilumab is considered despite prior CTCL history (which should be exceptional), mandatory requirements include:

  • Baseline skin biopsy with histology, immunophenotyping (CD3, CD4, CD8, CD7, CD26), and TCR gene rearrangement analysis 6, 7
  • Comprehensive staging with CT chest/abdomen/pelvis and peripheral blood flow cytometry 6, 7
  • Multidisciplinary team review including dermatologist, oncologist, and dermatopathologist with CTCL expertise 8, 7

Monitoring Protocol if Dupilumab is Used (Not Recommended)

• Repeat skin biopsy at 3-4 months if no clinical improvement, disease progression, or morphologic changes occur, as this timeframe precedes the median 5-month interval to lymphoproliferative disorder diagnosis. 4

• Immediate discontinuation is recommended when lymphoid infiltration increases on biopsy, even without typical lymphoma features. 3

Red Flags Suggesting CTCL Rather Than Atopic Dermatitis

Clinicians should maintain high suspicion for CTCL in the following scenarios:

• Adult-onset "atopic dermatitis" without prior atopy history, particularly in patients over age 50 3

• Atypical skin lesions including patches, plaques, or poikiloderma that don't respond to conventional atopic dermatitis therapy 3

• Short-term exacerbation or worsening despite dupilumab treatment 5, 3

• Palpable lymphadenopathy (any node ≥1.5 cm or firm/irregular nodes) 6, 7

• Associated patches or plaques with induration 6

Dupilumab-Associated Ocular Surface Disease Note

While the ophthalmology guidelines mention dupilumab-associated ocular surface disease as typically mild to moderate and often manageable, this should not diminish concern about the more serious risk of lymphoproliferative disorders in patients with CTCL risk factors. 8