Denileukin diftitox

Summary

Denileukin diftitox (Ontak; REZUROCK predecessor context, later Lymphir) is an IL-2-diphtheria toxin fusion protein approved for treatment of CD25-positive cutaneous T-cell lymphoma (CTCL). It selectively targets and destroys malignant T-cells expressing the IL-2 receptor alpha subunit (CD25). Originally approved by the FDA in 1999 (Ontak), a reformulated version (Lymphir) received FDA approval in 2023.

Mechanism of Action

Denileukin diftitox is a recombinant fusion protein combining the active domains of diphtheria toxin (fragments A and B) with human interleukin-2 (IL-2). It binds to the high-affinity IL-2 receptor (CD25) expressed on malignant T-cells, is internalized, and the diphtheria toxin fragment inhibits protein synthesis via ADP-ribosylation of elongation factor-2, leading to cell death.

Routes of Administration

Goals & Uses

• Treatment of CD25+ cutaneous T-cell lymphoma (CTCL)OncologyHigh
• Treatment of peripheral T-cell lymphoma (PTCL)OncologyModerate
• Immunosuppression in graft-versus-host diseaseImmunologyLow

Contraindications

• Hypersensitivity to diphtheria toxin or IL-2Allergy/ImmunologyHigh
• Severe hepatic impairmentOrganModerateLiver function concerns
• Active uncontrolled infectionInfectious DiseaseModerate

Adverse Effects

• HepatotoxicityHepaticCommonLiver injury or dysfunction
• Capillary leak syndromeVascularUncommonLeakage of fluid from blood vessels into tissues
• HypoalbuminemiaMetabolicCommon
• Nausea/vomiting/fatigueGastrointestinal/GeneralCommon
• Visual loss / decreased visual acuityOphthalmologicUncommon
• Infusion-related reactionsHypersensitivityCommon

Drug Interactions

• Nephrotoxic agentsModerate
• CorticosteroidsModerate
• ImmunosuppressantsModeratePotential interaction with immune pathways or infection risk

Population Constraints

• Pediatric patientsAgeRelative
• Breastfeeding womenReproductiveRelative
• Patients with serum albumin <3 g/dLLaboratoryRelative
• Pregnant womenReproductiveRelative

Regulatory Status

• European UnionUnknownNot currently approved by EMA as of 2024; not marketed in the EU.
• United StatesApprovedApproved: Relapsed or refractory CD25-positive cutaneous T-cell lymphoma (CTCL) in adultsOriginal Ontak approved 1999; withdrawn from market. Reformulated E7777 (Lymphir, Citius Oncology) FDA-approved August 2023 for relapsed/refractory CTCL. Orphan Drug designation.
• United KingdomUnknownNot approved by MHRA as of 2024.

Originally approved by FDA in 1999 as Ontak (Ligand/Eisai); original formulation discontinued. Reformulated version (E7777, Lymphir) approved by FDA in August 2023 for relapsed/refractory CTCL. Carries black box warning for serious adverse reactions including capillary leak syndrome, loss of visual acuity, and infusion reactions.

Evidence & Sources

No sources recorded yet.