Cutaneous T-cell lymphoma (CTCL) is a rare and often chronic form of non-Hodgkin lymphoma that can profoundly affect patients’ daily lives. While early disease may initially resemble eczema or benign skin patches, CTCL can progress through the skin and, in some patients, involve lymph nodes, blood, or internal organs. In this interview, Myron Czuczman, MD, a physician-scientist, academic oncologist, and Chief Medical Officer at Citius Oncology, discusses the evolving CTCL treatment landscape, the approval of denileukin diftitox-cxdl, and the importance of balancing disease control with quality of life.

Understanding CTCL and Its Clinical Burden

CTCL arises from malignant T lymphocytes, a type of immune cell. It represents an estimated 4% of non-Hodgkin lymphomas, with approximately 3,000 new cases diagnosed annually in the United States. Dr. Czuczman estimated that roughly 25,000 people in the United States are living with the disease.

Early-stage CTCL may be managed with skin-directed approaches, including topical therapies. But when disease becomes more extensive or spreads beyond the skin, patients generally need systemic treatment. “Once it internalizes or spreads to a more significant percentage of the body, it has to be treated from the inside,” Dr. Czuczman said. “Therefore, patients need systemic therapies that are able to treat more than one area of disease.”

For many patients, CTCL is not curable with currently available systemic therapies. Allogeneic stem cell transplantation may offer curative potential for a small subset of younger, otherwise healthy individuals with a suitable donor. However, CTCL often affects older adults, many of whom have comorbidities that make transplant impractical.

Historical Treatment Challenges

Historically, chemotherapy was one of the principal systemic treatment options for advanced CTCL. While it can provide disease control, chemotherapy may also cause substantial toxicity.

More recently, targeted treatments have expanded the options for patients. These include mogamulizumab, a CCR4-directed antibody with particular relevance in Sézary syndrome, and brentuximab vedotin, a CD30-directed antibody-drug conjugate used in appropriately selected patients.

However, these therapies also present limitations. Brentuximab vedotin is active in CTCL, but Dr. Czuczman noted that its use may be limited by cumulative toxicity, particularly peripheral neuropathy. “Peripheral neuropathy, tingling in the fingers and toes and the feet, can be irreversible if the agent is continued for too long,” he said.

Histone deacetylase inhibitors have also been used, but they can suppress blood counts and increase susceptibility to infection. These constraints reinforce the need for additional effective therapies with distinct mechanisms and manageable safety profiles.

A New Option: Denileukin Diftitox

Denileukin diftitox, marketed as Lymphir^®, was approved by the US Food and Drug Administration in 2024 for adults with relapsed or refractory CTCL after at least one prior systemic therapy. Dr. Czuczman described the treatment as an immunotoxin that targets the interleukin-2 (IL-2) receptor. The therapy consists of an IL-2 protein combined with diphtheria toxin. After binding to the IL-2 receptor and entering the cell, the diphtheria toxin component disrupts protein synthesis and kills the targeted cell.

The mechanism may have a dual effect. In addition to targeting malignant T cells that express IL-2 receptors, denileukin diftitox can target regulatory T cells, commonly called Tregs. “Tregs cause suppression of our immune system,” Dr. Czuczman said. “When we use denileukin diftitox, we’re getting direct killing of the cancer cell, but also an improvement with the patient’s own immune system—to kill the cancer.”

This dual mechanism distinguishes the therapy from other available treatments, according to Dr. Czuczman. He also noted that IL-2 receptor expression is broadly present in CTCL and that treatment selection does not require clinicians to identify a specific threshold of target expression.

Clinical Activity in Previously Treated Disease

Approval was supported by a multicenter pivotal trial in patients with relapsed or refractory CTCL. Patients were heavily pretreated, having received a median of four prior therapies. In the study, denileukin diftitox demonstrated an objective response rate of 36%, including complete responses in 9% of patients. Responses were often observed quickly, with a median time to response of 1.4 months among patients who responded.

For individuals living with CTCL, the potential for relatively rapid disease control may be particularly meaningful because of the substantial symptom burden associated with the disease. “These patients suffer from very itchy, pruritic skin that is present 24/7,” Dr. Czuczman said. “It can be very debilitating and negatively impact their quality of life.”

CTCL lesions may also be painful, visible, and disfiguring, particularly when they involve the face, scalp, or extremities. For this reason, improvement in symptoms and visible lesions can be meaningful even when a patient does not achieve a complete response.

Managing Treatment-Related Toxicities

Like other systemic cancer therapies, denileukin diftitox is associated with potential adverse events. Dr. Czuczman highlighted infusion reactions and capillary leak syndrome as key considerations.

Infusion reactions can generally be managed with premedication, such as an antihistamine and acetaminophen. Corticosteroids may be used if symptoms occur despite premedication.

Capillary leak syndrome can manifest as weight gain, edema, and fluid shifts. However, Dr. Czuczman emphasized that clinicians can monitor for and manage this risk, particularly by assessing patients’ clinical condition and nutritional status. “It is important for patients to have good nutritional status,” he said. “When we look at their albumin levels , if it’s at least 3.0 or greater, then these patients tend to have a lower incidence of significant capillary leak syndrome.”

Another consideration is the therapy’s non-cumulative toxicity profile. Unlike treatments in which adverse effects may progressively intensify over time, certain treatment-related effects with denileukin diftitox tend to occur early and decrease/resolve over subsequent cycles. Dr. Czuczman also noted that liver enzyme elevations may occur, but they often resolve within the first one or two treatment cycles without specific intervention.

Quality of Life Is a Core Treatment Goal

For CTCL, response rates tell only part of the story. The disease can affect sleep, function, emotional well-being, and social interactions through persistent itching, painful lesions, and visible skin changes. Dr. Czuczman emphasized that relieving pruritus should be considered a meaningful clinical outcome. “I think that’s critical,” he said. “That itch is intolerable. It’s basically 24/7.”

He added that even partial improvement may matter if it makes the disease more manageable for the patient. “If the disease and its effects become tolerable, there’s also a potential benefit in the patient’s quality of life,” he said. For clinicians, this underscores the importance of discussing symptom burden directly with patients and considering patient-reported outcomes alongside conventional measures such as objective response.

Combination Strategies and Emerging Research

The distinct biology of denileukin diftitox may also make it a candidate for combination strategies. Its temporary reduction of immunosuppressive Tregs could potentially complement other anticancer treatments, including checkpoint inhibitors.

Dr. Czuczman cautioned that sustained depletion of Tregs or poorly designed combinations could raise concerns about autoimmune toxicity. However, he noted that denileukin diftitox has a short half-life, and significant autoimmune toxicity has not been observed with the agent to date in the settings discussed. “There seems to be a signal and activity when the therapy is evaluated in combination with an anti–PD-1 checkpoint inhibitor,” he said, referring to preliminary early-phase research.

Other areas of CTCL investigation include novel antibody targets, such as KIR3DL2, as well as PD-1 and PD-L1 checkpoint inhibition. Researchers are also exploring whether cellular therapies, including CAR T-cell or natural killer cell–based approaches, could eventually play a role.

Developing cell therapies for CTCL presents a particular challenge, however. Unlike malignant B cells, malignant T cells closely resemble normal T cells that are essential to immune function. “It’s a little bit tricky to attack a cancerous T cell,” Dr. Czuczman said, “because if you’re knocking out normal T cells as well, those patients could have significant toxicities.”

The Importance of Clinical Trials

Because CTCL is rare, research advances often come from studies involving relatively limited numbers of patients. Dr. Czuczman stressed the importance of clinical trial participation to expand the evidence base and evaluate new therapeutic strategies. “The important thing is that patients go on clinical trials,” he said. Continued research will be needed to identify additional disease-specific targets, determine the best sequencing and combination strategies, and develop therapies that control CTCL while preserving immune function and quality of life.

The Bottom Line

CTCL remains a challenging disease, particularly for patients with relapsed or refractory disease who have limited durable treatment options. The approval of denileukin diftitox adds a therapy with a distinct immunotoxin mechanism, clinically meaningful activity in previously treated patients, and the potential to address both tumor cells and immunosuppressive regulatory T cells.

For Dr. Czuczman, the central goal remains clear: improving disease control while reducing the symptoms that can dominate patients’ lives. As novel targets, immunotherapies, and cellular approaches continue to move through clinical development, the field is steadily building toward more personalized and effective care for people living with CTCL.

Key Takeaways

CTCL is a complex lymphoma of the T-cells that primarily manifests in the skin.
Non-curative systemic therapies currently dominate the treatment landscape.
Targeted therapies have replaced traditional chemotherapy to improve patient outcomes.
Denileukin diftitox-cxdl offers a unique "dual" mechanism of action.
Clinical trial data shows rapid and meaningful responses in heavily pretreated patients.
The therapy features a non-cumulative toxicity profile compared to other agents.
Patient nutritional status is a key predictor for managing capillary leak syndrome.
Alleviating persistent pruritus is the most critical factor for patient quality of life.
Short half-life makes this immunotoxin a promising candidate for future combinations.
Future research is focused on novel combinations of active agents, identification of new targets and development of cellular therapies.

About Dr. Czuczman

Myron Czuczman, MD, is a physician-scientist and academic oncologist currently serving as Chief Medical Officer and Executive Vice President of Citius Oncology. He has decades of experience in strategic design, implementation, and oversight of the global development of novel therapies for hematologic malignancies. Prior to transitioning to the pharmaceutical industry, Dr. Czuczman practiced medicine for over two decades at Roswell Park Cancer Institute, where he served as Chief of the Lymphoma/Myeloma Service and Head of the Lymphoma Translational Research Laboratory. He has held numerous leadership roles in national and international research organizations and has an extensive publication record in hematologic malignancy research.

New Paths Forward in Cutaneous T-Cell Lymphoma