Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan - LARVOL DELTA

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma. (PubMed, J Clin Oncol) - "Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Fatigue • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Lymphoma • Mycosis Fungoides • Oncology • Sezary Syndrome • Skin Cancer • T Cell Non-Hodgkin Lymphoma • IL2

Safety and Effectiveness of Denileukin Diftitox-cxdl in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma: An All-Case Post-Marketing Study in Japan. (PubMed, Cancer Rep (Hoboken)) - P | "This is the first observational study to evaluate the safety and effectiveness of DD-cxdl in Japanese patients with relapsed or refractory PTCL and CTCL in daily clinical practice. No new safety concerns were identified. Clinicians should remain aware of the risk of capillary leak syndrome."

Journal • Observational data • P4 data • Cutaneous T-cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • IL2

Immune Correlates of Denileukin Diftitox Treatment in TFH-Type Lymphoma. (PubMed, Cancers (Basel)) - " TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8/TCR Vβ skewing in responding cases, although these findings remain exploratory and do not establish causality."

IO biomarker • Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD163 • CD4 • CD68 • CD8 • FOXP3

Denileukin diftitox (Lymphir) for cutaneous T-cell lymphoma. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Targeting Cutaneous T-cell lymphoma in non-hodgkin lymphoma: What's new for investigational agents? (PubMed, Expert Opin Investig Drugs) - "Recent years have seen a shift away from chemotherapy with the approval of targeted therapies like mogamulizumab, brentuximab vedotin, and denileukin diftitox-cxdl. Though these novel agents have improved outcomes for patients with advanced-stage CTCL, most patients will continue to experience relapses. Emerging agents, including lacutamab, resminostat, and immune checkpoint inhibitors and biomarkers including CD5, CD70, and CD47/Sirpα represent the next frontier in maintaining durable remissions and improving quality of life (QoL) for these patients."

IO biomarker • Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • CD5 • CD70 • SIRPA

Emerging Therapeutic Strategies in Cutaneous T-Cell Lymphoma: A Comprehensive Review of Clinical Trials. (PubMed, Am J Clin Dermatol) - "The 2020-2025 period brought meaningful therapeutic advances for CTCL, including new FDA approvals, breakthrough designations, and emergence of cellular therapy. Future development should prioritize patient-reported outcomes as co-primary endpoints, prospective biomarker validation, and combination strategies with non-overlapping toxicity profiles."

IO biomarker • Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Disorders • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • Skin Cancer • T Cell Non-Hodgkin Lymphoma • CD70

Current Practice and Research in T-cell and NK/T-cell Lymphoma in Japan (ICKSH 2026) - "For patients with major subtypes of peripheral T -cell lymphoma (PTCL), including PTCL not otherwise specified, angioimmunoblastic T -cell lymphoma (AITL), and anaplastic large cell lymphoma, the 2024 Japanese Society of Hematology (JSH) guidelines recommend the use of brentuximab vedotin (BV) -CHP for CD30 -positive tumors and CHOP -like regimens for CD30 -negative tumors as the first -line treatment...For patients with relapsed /refractory T-cell and NK/T -cell lymphoma, many therapeutic drugs (mogamulizumab, BV , pralatrexate, forodesine, romidepsin, alectinib, denileukin diftitox, tucidinostat, darinaparsin, and valemetostat) are approved and available in Japan...However, among immune checkpoint inhibitors, only atezolizumab was approved for the treatment of ENKL in 2025, and little experience is available with its use. Patients with ENKL in Japan account for less than 1% of all lymphoma patients, which is as low as in Western countries. To fill these gaps, an..."

Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • TNFRSF8

Bioinformatics Identification and Functional Analysis of Key Genes of Nucleotide Metabolism in Oral Squamous Cell Carcinoma. (PubMed, Oral Health Prev Dent) - "ADA, NT5E and TYMS can serve as potential diagnostic markers and therapeutic targets for OSCC. The study has reference value for early diagnosis and the development of individualised treatment strategies."

Biomarker • Journal • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • CD73 • MIR192 • MIR215 • MIR30A • MIR30B • NT5E • TYMS

Denileukin diftitox (Lymphir) for cutaneous T-cell lymphoma. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Outcomes of relapsed or refractory mature T/NK-cell lymphomas in the era of novel agents: A nationwide observational Study in Japan (ASH 2025) - P | "The median TTNT of each SA after 2nd- or later-linetherapies (mo, 95% CI) was 10.7 (3.9–17.3) for brentuximab vedotin (BV; n = 53, 21%), 5.0 (2.7–7.1) fortucidinostat (n = 36, 14%), 3.9 (2.6–4.8) for romidepsin (n = 80, 31%), 2.1 (0.4–5.2) for darinaparsin (n = 7,3%), 1.8 (1.3–2.5) for pralatrexate (n = 58, 23%), 1.5 (0.6–NE) for forodesine (n = 8, 3%), 1.1 (0.4–2.4) formogamulizumab (n = 22, 9%), 0.7 (0.4–3.5) for denileukin diftitox (n = 5, 2%), and NR (NE–NE) for alectinib(n = 1, 0.4%). In patients with TFHL, romidepsin (44%) and tucidinostat (18%) yielded median TTNTs (mo,95% CI) of 4.0 (2.6–8.7) and 5.5 (1.9–7.8), respectively... To the best of our knowledge, this study reports the most recent treatment patterns andprognoses for patients with R/R MTNKL. No standard of care has been established, as diverse treatmentpatterns have been observed. SAs resulted in similar survival outcomes to CCs in 2nd-line therapy,despite distinctive clinical Background of the groups."

Clinical • Observational data • Bone Marrow Transplantation • Cutaneous T-cell Lymphoma • Dermatology • Extranodal Natural Killer/T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

Clinically approved immunotoxins targeting hematological cancers: "the best of both worlds". (PubMed, Front Pharmacol) - "In this review, we analyze three FDA-approved RITs, namely, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, and adult R/R cutaneous T-cell lymphoma (CTCL), respectively. We reviewed their comprehensive safety profiles, describe complications associated with these fusion proteins, and, finally, discuss potential risk management strategies that may enhance their clinical outcomes. Overall, RITs have demonstrated efficacy, and researchers continue to extend these findings to other indications."

Journal • Review • Cutaneous T-cell Lymphoma • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Clinically Approved Immunotoxins Targeting Hematological Cancers: "The Best of Both Worlds" (Front Pharmacol) - "In this review, we analyze three FDA-approved RITs, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, adult R/R cutaneous T-cell lymphoma (CTCL), respectively."

Review • Blastic Plasmacytoid Dendritic Cell Neoplasm • Cutaneous T-cell Lymphoma • Hairy Cell Leukemia

Safety and efficacy of denileukin diftitox in patients receiving (Report on the results of a survey of all patients receiving Remitro ) (JSCS 2025) - No abstract available

Clinical • Hematological Malignancies • Lymphoma • Oncology

New nonchemotherapy treatment options for cutaneous T-cell lymphomas- an update. (PubMed, Expert Rev Anticancer Ther) - "Targeted therapies including brentuximab vedotin, lacutamab, denileukin diftitox, and mogamulizumab have shown activity in registrational trials. Novel agents which modulate tumor microenvironment and upregulate tumor-specific immune responses have been in clinical trials, including bispecific antibodies recruiting immune effectors, agents eradicating suppressive microenvironments, and engineered T cells targeting tumor epitopes. Checkpoint inhibitors may play a role in MF/SS but their role has not been well defined and they may induce hyper progression."

Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

An evaluation of denileukin diftitox for the treatment of relapsed or refractory cutaneous T-cell lymphoma. (PubMed, Expert Opin Biol Ther) - "In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies."

Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Infectious Disease • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • IL2 • IL2RA

Citius Oncology Enters into Distribution Services Agreement with Cardinal Health (PRNewswire) - "This agreement is designed to help provide access to LYMPHIR (denileukin diftitox-cxdl), an innovative immunotherapy FDA-approved for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma (CTCL), in support of its anticipated U.S. commercial launch."

Commercial • Cutaneous T-cell Lymphoma

Selecting appropriate therapy for cutaneous T-cell lymphomas (CTCLs): recent advances and the unmet need. (PubMed, Expert Opin Pharmacother) - No abstract available

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer. (PubMed, Vaccines (Basel)) - "Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study."

Journal • P2 data • Breast Cancer • Infectious Disease • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • IL2 • IL2RA

Compromising the immunogenicity of diphtheria toxin-based immunotoxins through epitope engineering: An in silico approach. (PubMed, J Pharmacol Toxicol Methods) - "Pseudomonas exotoxin A and diphtheria toxin (DT) have been abundantly used in immunotoxins, with the latter applied as the toxin moiety of the FDA-approved drug Denileukin diftitox (ONTAK®)...By subtracting conserved and ligand-binding residues, K33, T111, and E112 were identified as common epitopes across all platforms...Finally, a 3D model of the mutant was generated and verified. The model was then docked with its native ligand NADH, and the complex's molecular behavior was simulated using molecular dynamics."

Journal • Infectious Disease

Denileukin diftitox therapy for relapsed refractory PTCL (JSH 2024) - "Sponsored by Eisai Co., Ltd."

Hematological Malignancies • Peripheral T-cell Lymphoma

Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer. (PubMed, Gynecol Oncol) - P1 | "Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels."

Journal • Infectious Disease • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • CXCL8 • IL2RA • TGFB1

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease. (PubMed, Adv Hematol) - "These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin...For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future."

Clinical • Journal • Review • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Transplantation • DPP4

Targeting regulatory T cells by E7777 enhances CD8 T-cell-mediated anti-tumor activity and extends survival benefit of anti-PD-1 in solid tumor models. (PubMed, Front Immunol) - "This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. Treatment with E7777 was safe and well-tolerated. Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Infectious Disease • Liver Cancer • Oncology • Solid Tumor • IL2

T cell activation is insufficient to drive SIV disease progression. (PubMed, JCI Insight) - "We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs...Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs."

Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • IL2

CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model. (PubMed, FEBS Open Bio) - "C-C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We demonstrated that CCR4-IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4-IL2 IT and brentuximab was more effective than brentuximab or CCR4-IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4-IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment."

Journal • Preclinical • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Infectious Disease • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • CCR4 • IL2 • IL2RA • TNFRSF8