Version July 2025
Capillary leak syndrome (CLS), including life-threatening or fatal reactions, can occur in patients receiving denileukin diftitox. Monitor patients for signs and symptoms of CLS during treatment. Withhold denileukin diftitox until CLS resolves, or permanently discontinue based on severity.
Dosage guidance:
Safety: Assess serum albumin prior to each cycle; if serum albumin is <3 g/dL, delay administration until ≥3 g/dL. Administer premedications prior to each infusion in cycles 1 to 3 to reduce the risk of infusion reactions (premedications are optional after cycle 3).
Cutaneous T-cell lymphoma, stage I to III, relapsed or refractory: IV: 9 mcg/kg/day (based on actual body weight) on days 1 through 5 of a 21-day treatment cycle; continue until disease progression or unacceptable toxicity.
|
Treatment cycle |
Premedication |
Dosage |
|---|---|---|
|
a If ≥ grade 2 infusion reaction occurs, premedicate at least 30 minutes prior to each subsequent infusion with a systemic corticosteroid (eg, dexamethasone 4 mg [or equivalent] IV) for at least 3 cycles. | ||
|
Cycles 1 to 3 (optional after cycle 3) |
Antipyretic |
Acetaminophen 650 mg orally (or per local institutional protocol) at least 30 minutes prior to infusion. |
|
Antihistamine |
Diphenhydramine 25 mg IV (or other antihistamine per local institutional protocol) at least 30 minutes prior to infusion. | |
|
Antiemetic |
Per local institutional protocol at least 30 minutes prior to infusion. | |
|
Hydration |
NS 250 to 500 mL IV (or other volume of fluid considered appropriate based on patient's condition) at least 30 minutes prior to infusion. | |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Kidney function estimated using the Cockcroft-Gault equation.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant differences in denileukin diftitox pharmacokinetics were observed based on CrCl 30 to 89 mL/minute.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (effects on denileukin diftitox pharmacokinetics is unknown).
End-stage kidney disease (CrCl <15 mL/minute): There are no dosage adjustments provided in the manufacturer's labeling.
Altered liver function prior to treatment initiation:
Mild impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant differences in denileukin diftitox pharmacokinetics were observed based on mild impairment.
Moderate or severe impairment (total bilirubin >1.5 times ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling (effects on denileukin diftitox pharmacokinetics are unknown).
Acute hepatotoxicity during treatment:
Grade 2 (ALT and/or AST 3 to 5 times ULN): Maintain denileukin diftitox dose and monitor liver transaminases at least weekly until return to <3 times ULN.
Grade 3 (ALT and/or AST >5 to 20 times ULN): Withhold denileukin diftitox and monitor liver transaminases at least weekly until return to <3 times ULN; resume denileukin diftitox at the same dose (first occurrence) or with the dose reduced by 50% (for subsequent occurrences).
Restarting denileukin diftitox after a dosage delay due to toxicity:
• If ≤16 days since the last denileukin diftitox dose: Restart a new cycle no earlier than 16 days after the last dose of denileukin diftitox.
• If >16 days since the last denileukin diftitox dose: Restart a new cycle of denileukin diftitox.
• If >42 days since the last denileukin diftitox dose: Permanently discontinue denileukin diftitox.
Grade 4 (ALT and/or AST >20 times ULN): Permanently discontinue denileukin diftitox.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).
|
Adverse reaction |
Severity |
Denileukin diftitox dosage modificationa |
|---|---|---|
|
a Restarting denileukin diftitox after a dosage delay due to toxicity:
| ||
|
b CLS = capillary leak syndrome. | ||
|
CLSb |
Any |
If denileukin diftitox is withheld due to CLS, do not resume until symptoms are resolved and serum albumin is ≥3 g/dL. |
|
Grade 2 |
Withhold denileukin diftitox until CLS resolves to grade 1. | |
|
Grade 3 |
Withhold denileukin diftitox and provide supportive management until CLS resolves to grade 1. Resume denileukin diftitoxa with the dose reduced by 50%. Consider corticosteroid premedication for subsequent infusions. | |
|
Recurrent grade 3 |
Permanently discontinue denileukin diftitox. | |
|
Grade 4 |
Permanently discontinue denileukin diftitox. | |
|
Infusion reaction |
Grade 2 or 3 |
Interrupt infusion and manage signs/symptoms. For subsequent infusions, premedicate at least 30 minutes prior to each infusion with a systemic corticosteroid (eg, dexamethasone 4 mg [or equivalent] IV) for at least the next 3 cycles (premedication is optional thereafter). |
|
Recurrent grade 3 |
Permanently discontinue denileukin diftitox. Institute appropriate medical management. | |
|
Grade 4 |
Permanently discontinue denileukin diftitox. Institute appropriate medical management. | |
|
Ocular disorders (visual impairment) |
Grade 1 or 2 |
Consider withholding or discontinuing denileukin diftitox as clinically indicated. Refer for ophthalmic evaluation. |
|
Grade 3 or 4 |
Withhold denileukin diftitox until resolved to grade 1 or baseline. Refer for ophthalmic evaluation. Permanently discontinue denileukin diftitox if visual impairment does not resolve to grade 1 or baseline. | |
|
Other adverse reactions |
Grade 3 |
Withhold denileukin diftitox until toxicity is resolved to grade 1 or baseline. |
|
Grade 4 |
Permanently discontinue denileukin diftitox as appropriate. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Capillary leak syndrome (17%; serious: 10%), edema (33%)
Dermatologic: Pruritus (19%), skin infection (13%), skin rash (23%; including acute generalized exanthematous pustulosis)
Endocrine & metabolic: Decreased serum albumin (43%), weight gain (13%)
Gastrointestinal: Constipation (12%), decreased appetite (13%), diarrhea (19%), nausea (43%; grade 3: 1%), vomiting (13%)
Hematologic & oncologic: Decreased hemoglobin (34%; grades 3/4: 2%), lymphocytopenia (52%; grades 3/4: 20%)
Hepatic: Increased serum alanine aminotransferase (66%), increased serum alkaline phosphatase (18%), increased serum aspartate aminotransferase (60%)
Hypersensitivity: Infusion-related reaction (25%)
Immunologic: Antibody development (88%; neutralizing: 80%)
Nervous system: Chills (27%), dizziness (13%), fatigue (38%; including asthenia), headache (25%), mental status changes (13%; including amnesia, confusion, delirium, disturbance in attention, drowsiness)
Neuromuscular & skeletal: Arthralgia (12%), increased creatinine phosphokinase in blood specimen (22%), musculoskeletal pain (27%)
Ophthalmic: Blurred vision (13%)
Renal: Kidney impairment (12%; including acute kidney injury)
Miscellaneous: Fever (16%)
1% to 10%:
Infection: Sepsis (7%)
Nervous system: Insomnia (10%), peripheral neuropathy (<10%)
Frequency not defined:
Cardiovascular: Tachycardia
Ophthalmic: Visual disturbance (including decreased visual acuity, vision color changes)
Respiratory: Respiratory failure
Postmarketing: Endocrine & metabolic: Hyperthyroidism, hypothyroidism, thyroiditis, thyrotoxicosis
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Capillary leak syndrome: Denileukin diftitox may cause capillary leak syndrome (CLS), including life-threatening or fatal reactions. In the clinical trials, CLS was defined as the occurrence of 2 or more of the following symptoms at any time during denileukin diftitox therapy: hypotension, edema, and serum albumin <3 g/dL; these symptoms were not required to occur simultaneously to be characterized as CLS. Across 3 studies, CLS occurred in just over one-fourth of patients in the pooled population; grade 3 CLS occurred in some patients and one case of fatal CLS was reported. Of patients who experienced CLS, nearly one-fourth had CLS recurrence. Most CLS events occurred within the first 2 cycles of treatment. The median time to onset from cycle 1, day 1 was 6.5 days (range: 1 to 77 days) and the median duration was 14 days (range: 2 to 40 days). A majority of patients had resolution of CLS. The most common CLS symptoms included edema, hypoalbuminemia, and hypotension. Pleural effusion, pericardial effusion, and dehydration also occurred. Higher exposures to denileukin diftitox were associated with a higher incidence of CLS.
• Hepatotoxicity: Denileukin diftitox can cause hepatotoxicity. In the pooled safety population, elevated ALT and/or AST occurred in over two-thirds of patients, with grade 3 ALT occurring in nearly one-fourth of patients and grade 3 AST elevation occurring in a small percentage of patients. For grade 3 events, the median time to onset was 8 days (range: 1 to 15 days) and the median time to resolution was 15 days (range: 7 to 50 days); all cases of grade 3 ALT or AST elevations resolved. Elevated total bilirubin has occurred, with rare cases of grade 3 elevated total bilirubin. Higher exposures to denileukin diftitox were associated with a higher incidence of hepatotoxicity.
• Infusion-related reactions: Denileukin diftitox may cause serious infusion-related reactions. Across 3 studies, infusion-related reactions were reported in over two-thirds of patients in the pooled population, with grade 3 infusion-related reactions in a small percentage of patients. The majority of infusion-related reactions occurred in cycles 1 and 2. The most common symptoms included nausea, fatigue, chills, musculoskeletal pain, vomiting, fever, and arthralgia. Premedication is recommended for the first 3 cycles.
• Visual impairment: Denileukin diftitox can cause serious visual impairment, including changes in visual acuity and color vision. In the pooled population from 3 clinical trials, visual impairment occurred in 9% of patients. Most events were grade 1, with a small number of grade 2 events. The most commonly reported symptom was blurred vision. Of the patients with visual impairment, two-thirds experienced resolution.
Lymphir: FDA approved August 2024; anticipated availability in the 4th quarter of 2024.
IV: Infuse over 60 minutes through an IV line using a syringe pump or IV infusion bag. Do not administer through an inline filter. Do not administer other medications in the same IV line.
Cutaneous T-cell lymphoma, stage I to III, relapsed or refractory: Treatment of relapsed or refractory stage I to III cutaneous T-cell lymphoma in adults after at least one prior systemic therapy.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
BCG (Intravesical): Myelosuppressive Agents may decrease therapeutic effects of BCG (Intravesical). Myelosuppressive Agents may increase adverse/toxic effects of BCG (Intravesical). Risk X: Avoid
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Cladribine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk X: Avoid
CloZAPine: Myelosuppressive Agents may increase adverse/toxic effects of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor
Deferiprone: Myelosuppressive Agents may increase neutropenic effects of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider Therapy Modification
Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider Therapy Modification
Verify pregnancy status prior to initiating treatment in patients who could become pregnant.
Patients who could become pregnant should use effective contraception during therapy and for 7 days after the last denileukin diftitox dose.
Based on the mechanism of action, in utero exposure to denileukin diftitox may cause fetal harm; animal reproduction studies have not been conducted.
It is not known if denileukin diftitox is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 7 days after the denileukin diftitox last dose.
Assess hepatic (liver enzymes and total bilirubin; at baseline and during treatment as clinically indicated) and kidney function prior to each cycle. Monitor serum albumin (prior to each cycle, and more often if clinically indicated). Verify pregnancy status prior to initiating treatment in patients who could become pregnant. Perform baseline ophthalmic examination and monitor as clinically indicated; refer for ophthalmologic evaluation if symptoms of visual impairment occur (eg, changes in visual acuity, changes in color vision, blurred vision) during treatment. Assess regularly during treatment for signs/symptoms of CLS (eg, weight gain, new onset or worsening of edema, dyspnea, and hypotension, including orthostatic changes). Monitor for sign/symptoms of hepatotoxicity. Monitor frequently during infusion for signs/symptoms of an infusion-related reaction.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (Ref) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Denileukin diftitox is a fusion protein consisting of a human interleukin-2 (IL-2) protein sequence and diphtheria toxin (DT) fragments (A and B), which directs the cytocidal action of DT to cells expressing the IL-2 receptor. Following uptake into the cell, the DT fragment is cleaved and the free DT fragments inhibit protein synthesis, resulting in cell death. Denileukin diftitox demonstrated depletion of immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity via direct cytocidal action on IL-2 receptor-expressing tumors.
Onset: Median time to response 1.4 months (range: 0.7 to 5.6 months).
Distribution: Vd: 5 L (on day 1 of cycle 1).
Metabolism: Expected to be metabolized via catabolic pathways into small peptides.
Half-life elimination: 1.87 hours (on day 1 of cycle 1).
Excretion: Clearance: 36.5 mL/minute (on day 1 of cycle 1).
Exposure considerations: Higher exposures to denileukin diftitox were associated with a higher incidence of capillary leak syndrome, hepatotoxicity, adverse reactions, and treatment discontinuations due to adverse reactions.
