To the Editor:
Cases of dupilumab treatment followed by cutaneous T-cell lymphoma (CTCL) diagnosis have been reported since dupilumab was approved for moderate-to-severe atopic dermatitis (AD) in 2017.1 The nature of this association is controversial: it may reflect dupilumab unmasking an underlying CTCL, dupilumab promoting lymphoid-reaction/CTCL under IL-13/IL-4 blockade, or CTCL developing in patients with advanced long-standing AD, regardless of treatment. Tralokinumab, an anti-IL13 antibody, was approved for moderate-to-severe AD in 2021 and there are no reports in the literature of CTCL diagnosis associated with treatment. Janus kinase inhibitors (JAKi) were approved for both malignant and inflammatory medical conditions, including moderate-to-severe AD in 2022, with only sparse cases of CTCL following JAKi treatment since its approval in 2011.2
To investigate the associations between biologic therapies in AD and CTCL, we identified all cases who presented to our cutaneous lymphoma clinic with a new clinicopathologically confirmed diagnosis of CTCL following exposure to dupilumab, tralokinumab, or JAKi. We searched for records from the years of initial drug approval for any indication (2011 for JAKi, 2017 for dupilumab, 2021 for tralokinumab) through 2024.
We identified 30 patients with dupilumab exposure followed by confirmed CTCL. Two patients were treated with both an oral JAKi (upadacitinib) and subsequent dupilumab prior to CTCL diagnosis (Table I). We identified no patients diagnosed with CTCL following treatment with JAKi alone or with tralokinumab. Dupilumab and upadacitinib were given for AD (n = 30) or eczematous rash (n = 2), with no patient receiving either therapy for a non-cutaneous or non-AD/eczema indication. In 22 of 32 total cases, an initial diagnosis of AD/eczema was confirmed by an outside dermatologist via skin biopsy. Of those 22 initial biopsies, 5 were re-evaluated at our institution and in only one case, biopsy read was changed from AD to mycosis fungoides. Median time from dupilumab or JAKi use to CTCL diagnosis was 12 or 10.5 months, respectively.
Table I.
Patients with CTCL following dupilumab and/or JAK-inhibitor exposure presenting to the cutaneous lymphoma clinic at Memorial Sloan Kettering Cancer Center (MSKCC)
| Characteristic | Dupilumab | JAK-inhibitor* |
|---|---|---|
| Search period | 2017–2024 | 2011–2024 |
| Number of cases | 30 | 2 |
| Age, median (range) | 55 (28–84) | 72 (62–82) |
| Sex | ||
| Male | 13 | 1 |
| Female | 17 | 1 |
| Ethnicity | ||
| Non-Hispanic, White | 15 (50.0%) | 1 (50.0%) |
| Non-Hispanic, Black | 4 (13.3%) | 1 (50.0%) |
| Hispanic, White | 5 (16.7%) | 0 (0.0%) |
| Hispanic, Black | 1 (3.3%) | 0 (0.0%) |
| Asian | 1 (3.3%) | 0 (0.0%) |
| Missing/prefer not to answer | 4 (13.3%) | 0 (0.0%) |
| CTCL stage at diagnosis | ||
| IA | 2 (6.7%) | 0 (0.0%) |
| IB | 16 (51.7%) | 1 (50.0%) |
| IIA | 0 (0.0%) | 1 (50.0%) |
| IIB | 4 (13.3%) | 0 (0.0%) |
| IIIA | 2 (6.7%) | 0 (0.0%) |
| IVA1 | 6 (20.0%) | 0 (0.0%) |
| T-cell monoclonality | ||
| No | 7 (23.3%) | 0 (0.0%) |
| Yes | 21 (70.0%) | 2 (100.0%) |
| Not tested | 2 (6.7%) | 0 (0.0%) |
| Indication for dupilumab/Upadacitinib | ||
| Atopic dermatitis | 29 (96.7%) | 1 (50.0%) |
| Other | 1 (3.3%) | 1 (50.0%) |
| Diagnosis of atopic dermatitis | ||
| Pathology based | 20 (66.7%) | 2 (100.0%) |
| Clinically based (no pathology performed) | 10 (33.3%) | 0 (0.0%) |
| Review of initial biopsy at MSK pathology (N = 5) | ||
| Atopic dermatitis | 4 (13.3%) | 0 (0.0%) |
| Mycosis fungoides | 1 (3.3%) | 0 (0.0%) |
| Time from dupilumab/upadacitinib to CTCL diagnosis (mo, median, range) | 12 (1.5–24) | 10.5 (9–12) |
CTCL, Cutaneous T-cell lymphoma; JAK, janus kinase.
Both cases were exposed to both upadacitinib and dupilumab.
National database studies have demonstrated a possible association between dupilumab and subsequent CTCL diagnosis.3,4 Our recent study using the Food and Drug Administration (FDA) Adverse Event Reporting System showed an increased reporting odds ratio 8.8, (confidence interval, CI 7.1–10.9) of CTCL following dupilumab use,4 with no increase in reported cases following JAKi-use (reporting odds ratio 1.01, [CI, 0.6–1.8]) (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/gm52hwmb2f/1). Such large database studies may be difficult to interpret due to reporting biases and lack of histopathologic confirmation of the diagnosis. Of note, skin biopsy confirmed AD in 69% of our current cohort prior to initiating a biologic therapy for AD.
Our study is limited in its retrospective, single-center nature. The lack of any cases at our institution who were diagnosed with CTCL following exposure to JAKi or IL-13 blockade for AD; however, challenge the hypothesis that severe chronic AD is the cause of CTCL in patients exposed to dupilumab. One possible explanation for this difference in incidences between AD biologic treatments, however may be that JAKi and IL-13 blockade are effective treatments in controlling CTCL,5 unlike dupilumab. This possibility and the delineation of the molecular mechanisms by which these drugs may worsen or improve CTCL, require further prospective investigation.
Funding sources:
Funding provided by the National Institute of Health/National Cancer Institute Cancer Center (Support Grant P30 CA008748).
Footnotes
Patient consent: Not applicable.
IRB approval status: Approved.
Conflicts of interest
None disclosed.
REFERENCES
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