In August 2024, the US Food and Drug Administration approved denileukin diftitox (Lymphir™; Citius Oncology) for the treatment of patients diagnosed with Stage I-III relapsed or refractory (r/r) cutaneous T-cell lymphoma (CTCL), a rare form of non-Hodgkin lymphoma (NHL), after at least one prior systemic therapy.[1]
Each year, approximately 2,500 to 3,000 patients are diagnosed with the disease while an estimated 40,000 patients are living with the condition.
In CTCL, T-cells, a type of lymphocyte that plays a role in the immune system, become cancerous and develop into skin lesions, leading to a decrease in the quality of life of patients with this disease due to severe pain and pruritus.
Mycosis Fungoides (MF) and Sézary Syndrome (SS) comprise the majority of CTCL cases.
Depending on the type of CTCL, the disease may progress slowly and can take anywhere from several years to upwards of ten to potentially reach tumor stage. However, once the disease reaches this stage, the cancer is highly malignant and can spread to the lymph nodes and internal organs, resulting in a poor prognosis.
Given the duration of the disease, patients typically cycle through multiple agents to control disease progression. CTCL affects men twice as often as women and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Other than allogeneic stem cell transplantation, for which only a small fraction of patients qualify, there is currently no curative therapy for advanced CTCL.
A new approach
Denileukin diftitox is a recombinant engineered fusion protein fusion protein that combines interleukin-2 (Il-2) and diphtheria toxin. The drug specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. Its unique mechanism of action targets both malignant T-cells and immunosuppressive regulatory T-cells (Tregs). Transiently eliminating Tregs has the potential of unleashing potent immune responses by the patient’s immune system against their tumors.[2]
In recent preclinical studies, denileukin diftitox has demonstrated the ability to deplete murine Tregs in-vivo and human Tregs ex vivo. In addition, the combination of denileukin diftitox with anti-m-PD1 showed improved tumor response and very significant improvement in survival in the combination groups relative to either therapy alone in a syngeneic mouse solid tumor model.
Two investigator-initiated trials designed to evaluate the potential safety and efficacy of denileukin diftitox in combination with pembrolizumab (Keytruda®; Merck & Co/MSD) in patients with recurrent or metastatic solid tumors and denileukin diftitox given prior to lymphodepletion (LD) chemotherapy and CAR-T therapies for the treatment of relapsed/refractory B-cell lymphomas (DLBCL) considered at a high risk for failure from tisagenlecleucel (Kymriah®; Novartis) alone formed the bases for Citius Oncology to seek regulatory approval for the , at that time, investigational agent.
The approval of denileukin diftitox is based on results from the phase 3 Study 302 (NCT01871727) of patients with CTCL who had previously received at least one systemic treatment
Citius plans to further explore the potential of denileukin diftitox to treat larger patient populations with additional indications in peripheral T-cell lymphoma (PTCL) and immuno-oncology.
Expanded distribution
In July 2025, Citius announced the execution of a distribution services agreement with Cencora (formerly AmerisourceBergen), designed to expands Citius Oncology’s commercial distribution network, providing additional access and product availability upon launch. The agreement with Cencora builds on a previously announced distribution services agreement to support long-term scalability and market reach of denileukin diftitox.
“As we move closer to the U.S. market introduction of denileukin diftitox, we remain focused on disciplined execution across all key commercial readiness activities,” noted Leonard Mazur, Chairman and CEO of Citius Oncology and Citius Pharmaceuticals.
“Our agreement with Cencora adds further depth to our distribution strategy and strengthens our ability to deliver denileukin diftitox to treatment centers across the country. These foundational partnerships demonstrate our ongoing commitment to building a launch platform that supports near-term revenue and long-term shareholder value.”
Under the terms of the agreement, Cencora will serve as a wholesale distributor for denileukin diftitox, providing specialty distribution services to facilitate product availability across its distribution network.
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Clinical trials
T-regulatory Cell Depletion with E7777 Combined with Pembrolizumab in Recurrent or Metastatic Solid Tumors – ClinicalTrials.gov ID NCT05200559
Ph I/II Study of E7777 Prior to CAR-T for R/R LBCL – ClinicalTrials.gov ID NCT04855253
A Trial of E7777 in Persistent and Recurrent Cutaneous T-Cell Lymphoma – ClinicalTrials.gov ID NCT01871727
Highlight of Prescribing Information
Diftitox (Lymphir™; Citius Oncology)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Tisagenlecleucel (Kymriah®; Novartis)[Prescribing Information]
Reference
[1]Goyal A, Foss FM. An evaluation of denileukin diftitox for the treatment of relapsed or refractory cutaneous T-cell lymphoma. Expert Opin Biol Ther. 2025 Jul;25(7):687-694. doi: 10.1080/14712598.2025.2517853. Epub 2025 Jun 14. PMID: 40489974.
[2] Figgitt DP, Lamb HM, Goa KL. Denileukin diftitox. Am J Clin Dermatol. 2000 Jan-Feb;1(1):67-72; discussion 73. doi: 10.2165/00128071-200001010-00008. PMID: 11702307.
Featured image: Photo by Nappy on Unsplash
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