Key takeaways:

• Cutaneous T-cell lymphoma cases in adults tied to dupilumab are likely an unmasking of undiagnosed cancers.
• Data show dupilumab is safe for children with eczema who do not respond to topical therapies.

The dermatology community has long debated whether dupilumab treatment for atopic dermatitis is associated with the development of cutaneous T-cell lymphoma — a concern that becomes more urgent when children are involved.

In 2024, a retrospective cohort study suggested that dupilumab (Dupixent; Sanofi, Regeneron) was associated with an increased risk for cutaneous T-cell lymphoma in patients taking the drug for AD. However, it remained unclear whether dupilumab caused the disease or simply unmasked existing cases, Healio previously reported.

“Dupilumab has been a tremendous breakthrough treatment for AD; however, questions have arisen about whether dupilumab is associated with the development of lymphoma,” Lawrence F. Eichenfield, MD, a Healio Dermatology Peer Perspective Board Member and chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego, said during an interview. “To understand this issue better, we must understand the long history of issues associated with atopic dermatitis and lymphoma.”

Healio spoke with Eichenfield, who investigated the prevalence of this connection among children in a study published in Pediatric Dermatology, about how to interpret the data on this topic and counsel families accordingly.

Healio: Why has previous literature found a link between dupilumab treatment and lymphoma?

Eichenfield: The answer to this is twofold. First, cutaneous T-cell lymphoma is often misdiagnosed as eczematous dermatitis. It can take years for people to recognize the differentiation between these conditions. The nature of cutaneous T-cell lymphoma itself is tremendously variable in terms of its presentation. It can be just a patchy eczematous dermatitis or it can be this full-blown, systemic disease called mycosis fungoides with Sézary syndrome, where you have tumors present on the skin that look very different from AD.

Second, there are good data sets that have shown that having AD is associated with a higher risk for the development of cutaneous T-cell lymphoma. However, with that data comes several questions: Is the association independent of therapy? Is this population at risk for developing cutaneous T-cell lymphoma from an immunological standpoint? Was this a misdiagnosis that was later corrected?

Healio: Based on your evaluation of the literature, is dupilumab associated with an increased risk for lymphoma development among pediatric patients with atopic dermatitis?

Eichenfield: In our review article, we looked at this long history and found that the literature is highly reassuring about dupilumab not being associated with lymphoma in this population. The cases seen in adults have created a controversial back and forth between oncologists, cutaneous T-cell lymphoma experts and some epidemiologists, but we are very reassured from a pediatric perspective that dupilumab does not cause this disease in children.

Cutaneous T-cell lymphoma is predominantly an adult disease, but we do see children who have it very rarely. When it is present in children, cutaneous findings are often a patchy, hypopigmented form of typical presentations. Many times, people can have cutaneous T-cell lymphoma as a kid, independent of AD. The prognosis, however, may not change in their life because it is effectively managed and does not typically accelerate into a phase that acts more like lymphoma.

The populations that we see are very different between AD and cutaneous T-cell lymphoma in the sense that the former is usually younger while the latter is older. The literature supports the idea that the risk for developing lymphoma from dupilumab is no greater than the risk for developing lymphoma if not taking dupilumab.

Healio: How can dermatologists and primary care physicians distinguish between AD and cutaneous T-cell lymphoma early on to avoid misdiagnosis later?

Eichenfield: Clinicians should be aware that clinical findings, such as well-demarcated patches and plaques, occasionally with a poikiloderma-type pattern, lesions that come back looking exactly the same and a distribution that is not the classic antecubital or popliteal fossa eczema, along with an incomplete response to conventional therapy and an atypical age of presentation, should all be flags to consider cutaneous T-cell lymphoma.

This can be confirmed histologically when looking at the T-cell rearrangement of the lymphocytes in the skin. These days, high-input sequencing of the T-cell receptors on beta cells is the way to show that there is a clonal lymphoma population and not just this mixed inflammation that we see with AD.

When we were going through the development program for dupilumab, some of which I was involved in, people worked hard to make sure patients with cutaneous T-cell lymphoma were not enrolled in those studies. Every investigator was told to be very careful and that if they saw any atypical presentations of AD to not enroll that patient in the study unless they had undergone a workup. The reason for this instruction was that we did not want to complicate the issue. If a patient with undiagnosed cutaneous T-cell lymphoma had been enrolled and it emerged during the clinical study, the question immediately became, “Did dupilumab cause it?”

This is why you should always have your antennae up, particularly with late-onset disease. A later presentation of what appears to be AD, especially outside the pediatric age group, should raise the possibility of cutaneous T-cell lymphoma.

Healio: What safety precautions, if any, should dermatologists take when prescribing dupilumab to children?

Eichenfield: The main safety precaution I would emphasize when using dupilumab across all age groups is to make sure the patient truly has AD. If you are uncertain, stop and think before you use it, because these concerns have been raised in relation to dupilumab, even though the data do not support that dupilumab causes them. Be smart and make sure patients clearly have AD before prescribing dupilumab.

Of course, we are always going to counsel our patients carefully about the potential side effects we see. We are aware that the label for dupilumab has changed concerning eye findings, as it now includes blindness. However, no one goes from having no eye findings to blindness, and we do not have all the details behind those reports.

Overall, I do think it is always better to be proactive in counseling patients. Although, in real-life practice, counseling does not take very long because we are sharing the decision with parents.

Healio: Should parents be hesitant to allow their children to take dupilumab?

Eichenfield: We are comfortable reassuring families that they should not be hesitant to use dupilumab in a patient who otherwise warrants systemic therapy for AD because of an inadequate response to topicals. We know how significant AD can be. It affects the whole family as well as the child’s development, neuropsychological effects and sleep. That is why I hate to see people become reluctant to use the drug based on reports that make it seem as though a subset of patients developed lymphoma because of dupilumab. At least in the pediatric data set, the message is very positive that people do not need to be concerned about that.

Healio: How can dermatologists reassure worried parents in the clinic?

Eichenfield: This comes down to style. If people raise the issue about dupilumab’s association with lymphoma, you should validate the concern and not blow it off. After that, explain the history we discussed and how rare cutaneous T-cell lymphoma is, making sure to speak in an understandable way. Emphasize that cases in adults that have been tied to dupilumab are believed to be an unmasking of undiagnosed cutaneous T-cell lymphoma. State that there is a risk-benefit to all decisions, but that we feel comfortable that the actual risk for cutaneous T-cell lymphoma in kids with this drug is incredibly low. In fact, according to survey reports from the companies behind dupilumab, there is not a single report of a child developing cutaneous T-cell lymphoma with use of the drug.

Healio: Is there anything else you would like to add?

Eichenfield: Anytime a child or teenager goes on systemic medicine for AD, there is going to be shared decision-making and a risk-benefit analysis. With our biologic agents in AD, we have a lot of extended safety data, as well as experience, supporting their use. As we work with the patient and family to make the best decision for the patient, we must accept that this will be part of the discussion.

For more information:

Lawrence F. Eichenfield, MD, is chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego, vice chair of the department of dermatology at University of California San Diego and a Healio Dermatology Peer Perspective Board Member. Eichenfield can be reached at dermatology@healio.com.