Denileukin Diftitox: Leveraging T-Cell Biology to Overcome Limitations in CTCL

For patients living with advanced cutaneous T-cell lymphoma (CTCL), the therapeutic landscape has long been defined by a challenging cycle of management rather than a definitive cure. While existing treatments offer activity, their utility is frequently curtailed by cumulative toxicity, forcing oncologists to rotate through therapies to balance efficacy with patient safety. This rotation is particularly critical as patients grapple not only with disfiguring skin lesions but also with intractable pruritus that resists standard dermatological care.

The FDA approval of denileukin diftitox (Lymphir) marked a significant shift in this paradigm. As a first-in-class immunotoxin, it employs a dual-action mechanism: directly targeting interleukin-2 (IL-2) receptors on malignant T cells to halt protein synthesis and inducing a transient knockout of immunosuppressive regulatory T cells (Tregs).

Myron Czuczman, MD, chief medical officer at Citius Pharmaceuticals, the developer of the agent, spoke with Targeted Oncology about the mechanism of action of denileukin diftitox and the effect it can have on patients with CTCL.

Targeted Oncology: Before the approval of denileukin diftitox, what were the primary limitations of the existing treatment options for patients with advanced CTCL?

Myron Czuczman, MD: With respect to limitations of existing therapies for patients with advanced CTCL would be that, unfortunately, none of the treatments available are curative. There is good activity with these agents. However, it is limited. Some of these agents are limited by cumulative toxicity.

There is the significance of rotating these therapies is because these patients are not cured by any one of these therapies, any active therapy that can work in patients will potentially be utilized by physicians to treat their patients, depending on the patient's degree of illness, the patient's oncologist, would decide in which order to give these treatments.

What is the mechanism of action of denileukin diftitox, and how does the targeted approach specifically leverage the biology of the T cells in CTCL?

The mechanism of action of denileukin diftitox is unique compared to other agents being utilized for this disease, as we consider it an immunotoxin. Actually, [denileukin diftitox] is a human IL-2 protein that has diphtheria toxin blended in as a fusion protein. Therefore, it targets IL-2 receptors. The IL-2 receptors that are present on T-cell lymphomas is the primary target, since denileukin diftitox will bind to those IL-2 receptors, it becomes internalized, where the diphtheria toxins break off inside the cell and leads to protein synthesis, and cell death. And what we've appreciated is that IL-2 receptors are also present on immunosuppressive [Tregs] within the patient, the host, within the tumor microenvironment, and an additional mechanism other than that, direct mechanism of killing by binding to the IL-2 T receptors on T cell lymphomas, is that a transient knockout.

For example, these Tregs allow a better host patient's body to attack the tumor as well, and therefore it's quite unique with respect to Tregs. There's a lot of research being done in this field. We believe that, because we have such a short half-life of this agent, that, because it's transient, we get the activity intake and tumor activity. At the same time, because if you had a prolonged exposure or half-life of that agent, that individual may be more prone to develop autoimmune immune related adverse events [AEs], and from our experience, currently, we see a minimum of those type of [AEs] at this time.

What is the safety profile of denileukin diftitox?

There are certain treatment emergent [AEs] that we would say are somewhat unique to patients receiving this agent. One of them is called capillary leak syndrome [CLS]. With respect to [CLS], patients can develop peripheral neuropathy, gain some weight while they're on the actual treatment, can have some changes in blood pressure, maybe orthostatic hypotension, and it has to be monitored.

From the study that led to the approval of denileukin diftitox [NCT01871727]¹, about 17% of patients experience [CLS], and most of them were only grade 1 or 2, and they were easily managed. Now, the other thing that was very interesting with respect to some of these [AEs], especially the [CLS], most events occurred either in cycle 1 or 2. Of interest is that if patients then went to subsequent therapy, the degree of [CLS] decreased and remained low or did not become an issue for many patients after the second cycle. It's very interesting, and it would be considered [a] noncumulative toxicity, which is quite unique when we look at the type of drugs that we utilize to treat cancer patients with today.

Of the patients that did develop CLS on the trial, 3 patients discontinued based on the doctor's decision. Two patients had a dose reduction. Six patients had a dose interruption. And out of those, for example, a dose interruption, patients would not finish the full 5 days. The cycle may be stopped after, say, 3 doses. But then, of interest, when they came in for the next cycle 3 weeks later, they often could handle the full 5 days.

Some other [AEs] that can be seen [were] infusion related reactions, and they were also primarily grade 1 or 2. We have to keep in mind, though, that patients were also given premeds, a little bit of fluids, in addition to Tylenol and Benadryl.

How does the approval of denileukin diftitox represent a step forward in the entire field of CTCL treatment and research?

Unfortunately, patients with advanced CTCL have an incurable illness. But not only is it incurable, many patients have intractable pruritus, itching of the skin, that is so severe that the standard type of agents a dermatologist might use do not work, and handling this pruritus, what works is basically treating the underlying cancer. And with respect to this, we realize that denileukin diftitox has an objective response rate of 36.2% overall in patients, but it adds another almost 14% of patients who develop clinical benefit, meaning at least 6 months of stable disease, that a significant number of these patients have significant improvement in that pruritus. In addition to that, unfortunately, these patients have skin lesions that can affect the extremities or their face or scalp, and it can be very disfiguring for these patients socially, that having an agent that can work where other agents have not been able to have a prolonged type of response. It is great that patients can have an additional agent that can help them with respect to responses to this disease.

REFERENCE

1.A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma. ClinicalTrials.gov. Updated November 13, 2024. Accessed December 19, 2025. https://clinicaltrials.gov/study/NCT01871727