A New Era in CTCL: The Dual-Action Potential of Denileukin Diftitox

The therapeutic landscape for cutaneous T-cell lymphoma (CTCL) is undergoing a significant shift with the emergence of denileukin diftitox (Lymphir), the first systemic treatment option available in the US since 2018. Unlike traditional histone deacetylase (HDAC) inhibitors or monoclonal antibodies, denileukin diftitox operates as a unique immunotoxin fusion protein. By combining human IL-2 with a diphtheria toxin fragment, the agent specifically targets IL-2 receptors on both malignant T cells and host regulatory T cells (Tregs). Once bound and internalized, the diphtheria toxin induces direct cell death, offering a precision strike against the cancer.

What truly differentiates this therapy is its dual-action mechanism. Beyond direct tumor depletion, it transiently reduces the presence of suppressive Tregs, effectively unmasking the cancer and allowing the host's own immune system to mount a more robust attack. According to Myron Czuczman, MD, this differentiated approach not only addresses the primary malignancy but also holds immense promise for combination therapies. Preliminary research suggests that by clearing the path of inhibitory Tregs, denileukin diftitox could enhance the efficacy of chimeric antigen receptor (CAR) T-cell infusions and checkpoint inhibitors such as pembrolizumab (Keytruda), potentially expanding its utility far beyond its current indication for relapsed or refractory (R/R) CTCL.

Citius Oncology, a subsidiary of Citius Pharmaceuticals, announced a distribution agreement with Uniphar, a Dublin, Ireland–based international health care services company, to provide denileukin diftitox to patients with R/R CTCL across Western and Eastern Europe.

In an interview with Targeted Oncology, Czuczman, chief medical officer and executive vice president at Citius Pharmaceuticals and former chief of the Lymphoma/Myeloma Service at Roswell Park Comprehensive Cancer Center, and Michael McGuire, MBA, vice president, commercial, at Citius Pharmaceuticals, discuss what sets denileukin diftitox apart from other agents, and how its expansion into the European Union (EU) will benefit both oncologists and patients.

Targeted Oncology: How does denileukin diftitox’s mechanism of action differ from traditional HDAC inhibitors or monoclonal antibodies currently used in the CTCL paradigm?

Myron Czuczman, MD: Denileukin diftitox’s mechanism of action is quite unique and differentiated from those other agents that are currently used for systemic therapy of CTCL, since it is an immunotoxin fusion protein that's composed of human [IL-2], which is coupled with diphtheria toxin fragment. Denileukin diftitox targets surface IL-2 receptors on malignant T lymphoma cells, as well as on host Tregs, which, once they bind, it internalizes, and then the diphtheria toxin ends up causing cell death. This unique mechanism of action leads to both a direct tumor cell death of T cell lymphoma cells [and] also transiently depletes suppressive Tregs, which results in an increase in the ability of the host immune response to attack cancer cells as well.

Where do you see it fitting into the long-term sequencing of care?

Czuczman: With respect to sequencing in long-term care, we have to keep in mind that, unfortunately, patients who have [R/R] CTCL are incurable, so any active agent that potentially benefits the patient will be utilized in the care of the patient. We should make a note that denileukin diftitox, based on the pivotal registrational study [phase 3; NCT01871727],¹ was evaluated in a heavily pretreated group of patients [median of 4 prior therapies]. It demonstrated good efficacy, a 36% objective response rate, with a small percentage of complete remissions, plus an additional 13% of patients who derived clinical benefit, as defined by having at least 6 months or greater control of their disease.

Patients often [experience] very pruritic or painful skin lesions; the median time to response to denileukin diftitox is only 1.4 months. There are some patients who are responding with the first and/or second cycle of therapy already. The median duration of response was about 9 months, but some patients received therapy for over a year or longer.

Denileukin diftitox has a tolerable safety profile; patients treated on the pivotal registrational study had primarily grade 1 or 2 adverse events. They do have something unique that I should mention. It's called capillary leak syndrome [CLS], where the patients can gain weight and have fluid accumulation. However, in these patients, [the majority were] grade 1 or 2. Of note, denileukin diftitox appears to demonstrate noncumulative toxicity and does not demonstrate evidence of cross-resistance to other systemic therapies being utilized.

….Patients who we believe would best benefit from our therapy are patients who have a good [ECOG] performance status and good nutritional balance. One thing that increases the risk of [CLS] is a low albumin [less than 3 g/dL]. Therefore, using this agent in patients who have exhausted other options, or prior to a patient being referred to hospice or end-stage comfort care, [these] are not patients who would benefit from our therapy, or from any other systemic therapy for that matter.

Regarding the managed access programs, this agreement facilitates access through managed access programs, rather than a full commercial launch in the EU. How do these programs typically work for a clinician trying to prescribe a drug that is not yet locally approved?

Michael McGuire, MBA: First, the drugs must be approved by the FDA to participate in this program. The managed access programs are designed so physicians can treat individual patients with serious or life-threatening conditions before approval is in place in the EU and other countries.

The managed access program starts with the treating clinician submitting the name [of the] patient requiring denileukin diftitox. Under the country's regulatory framework, the clinician will need to document the medical necessity [and] lack of satisfactory alternatives.  There is no cure for CTCL, so these patients eligible for denileukin diftitox may have been through many types of therapies. Denileukin diftitox is a new treatment option, the first systemic treatment in the US since 2018, for patients who have tried other current treatments. Once approved, the product would be supplied in full compliance with all the local importation of the pharmacovigilance requirements to our distribution partner, Uniphar. From the physician’s perspective, this is a medically driven, patient-specific process. It's reserved for high unmet cases of care.

There is ongoing research into using denileukin diftitox to deplete Tregs before CAR T-cell therapy or in combination with pembrolizumab. Based on the mechanism of action, what is your professional intuition regarding its potential in these combination settings?

Czuczman: Prior to joining the pharmaceutical sector, I spent 23 years in academia at the Roswell Park Comprehensive Cancer Center [in Buffalo, New York], where I not only treated a number of these patients but also did translational research in the immunology department. And what I can tell you, I'm very excited about its combination potential. As you stated, the mechanism of action, outside of the T-cell lymphoma space, is in its ability to transiently deplete the suppressive Tregs in patients, and therefore, it has the potential of activating the host immune system and increasing the antitumor activity of biological agents being utilized to treat cancer. For example, with CAR T–based therapy, the CAR T cells will be inhibited by these Tregs. By depletion of Tregs prior to receiving CAR T infusion, we allow not only CAR T cells, but also the patient’s own immune system to work more effectively and potentially increase efficacy outcomes.

In addition to evaluating denileukin diftitox in CAR T therapy, it can be combined with anti–PD1 checkpoint inhibitors; we have preliminary translational published research that demonstrated increased antitumor activity when used in combination in an in vivo model of liver and colon cancer. In other words, single agents have limited activity, but for some reason, that combination is quite unique, and it gives a significant boost to the immune response against tumors. In addition, I envision the possibility that denileukin diftitox could be used with other biologically active agents such as bispecific antibodies. By transiently depleting immunosuppressive host Tregs, I can envision that our agent, hypothetically, could benefit efficacy outcomes when combined with multiple different agents.

As we go through and we look at unique combinations in the future, because our agent has noncumulative toxicity and does not suppress a patient's blood counter cause significant immunosuppression, I believe that denileukin diftitox has significant potential to be safely added to biologically active cancer agents and be utilized in the future in other cancers beyond its current FDA-approved² use in [R/R] CTCL.

REFERENCES

1. A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma. ClinicalTrials.gov. Updated November 13, 2024. Accessed February 24, 2026. https://clinicaltrials.gov/study/NCT01871727

2. FDA approves immunotherapy for relapsed or refractory CTCL. News release. The ASCO Post. August 25, 2024. Accessed February 24, 2026. https://tinyurl.com/mtxzr65x