Antibody-Drug Conjugate Toxicity

Antibody-Drug Conjugate Toxicity: Emergency Medicine Lecture Notes

Source

• Markides DM, Hita AG, Merlin J, Reyes-Gibby C, Yeung SJ. Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know. Annals of Emergency Medicine. 2025;85(3):214-229. doi:10.1016/j.annemergmed.2024.10.015

Why Emergency Clinicians Need to Recognize ADC Toxicity

• Antibody-drug conjugates (ADCs) combine a monoclonal antibody, linker, and cytotoxic payload to deliver treatment preferentially to tumor cells.
• Toxicity still occurs through target-related effects, payload leakage or off-target exposure, and incompletely understood mechanisms.
• Common adverse effects include myelosuppression, nausea and vomiting, diarrhea, peripheral neuropathy, and rash.
• Emergency care adds the greatest value by recognizing serious toxicities that mimic common presentations or become life-threatening when diagnosis is delayed.
• Real-world emergency department presentation rates for ADC-related adverse effects remain uncertain.

First Emergency Department Step

• Obtain 2 medication-history details immediately:
  • Exact ADC name.
  • Date and time of the most recent dose.
• Contact the treating oncology team for every suspected ADC-related toxicity because dose delay, reduction, or discontinuation may be required.

Life-Threatening Toxicities

Interstitial Lung Disease and Pneumonitis

• Consider in patients receiving trastuzumab deruxtecan (T-DXd), mirvetuximab soravtansine, brentuximab vedotin, enfortumab vedotin, trastuzumab emtansine (T-DM1), or tisotumab vedotin.
• Presentations are nonspecific: dry cough, exertional dyspnea, fatigue, chest pain, fever, wheezing, or crackles.
• Chest radiography has limited sensitivity. If ADC-related interstitial lung disease is in the differential diagnosis, obtain high-resolution chest computed tomography (CT).
• CT may show diffuse patchy consolidation, interlobular reticular opacities, and septal thickening.
• Treat infection and inflammation in parallel:
  • Empiric antibiotics may be appropriate because infectious and drug-related pneumonitis are difficult to distinguish initially.
  • Do not delay corticosteroids solely while awaiting microbiologic results when drug pneumonitis is suspected.
  • Grade 2: oral prednisone equivalent 1 to 2 mg/kg/day may be used, with disposition guided by clinical status.
  • Grade 3: oxygen, hospital admission, and prednisolone 1 mg/kg/day.
  • Grade 4: manage as respiratory failure; methylprednisolone 2 mg/kg/day or pulse methylprednisolone 500 to 1,000 mg/day for 3 days is described.
  • If no improvement after 48 to 72 hours, reported escalation options include infliximab, tocilizumab, mycophenolate mofetil, or intravenous immunoglobulin.
• Obtain early pulmonary consultation. Bronchoscopy with bronchoalveolar lavage is often needed.

Sinusoidal Obstruction Syndrome

• Most associated with gemtuzumab ozogamicin and inotuzumab ozogamicin.
• Early clue: rapid weight gain.
• Later findings: edema, ascites, jaundice, tender hepatomegaly, pleural effusions, hypoxemia, encephalopathy, and renal failure.
• Evaluate bilirubin, aminotransferases, platelet count, renal function, and abdominal ultrasonography with hepatic venous flow assessment.
• Begin supportive management without waiting for definitive confirmation:
  • Correct fluid and electrolyte abnormalities.
  • Use cautious diuresis for volume overload, such as furosemide or spironolactone when appropriate.
  • For respiratory compromise from ascites, therapeutic drainage may be considered; the source recommends limiting a single drainage to 1 L to protect renal function.
  • Consider renal replacement therapy or ultrafiltration when fluid cannot be controlled.
• Defibrotide is the evidence-supported specific therapy described in the source: 6.25 mg/kg every 6 hours for 21 days. Initiate urgently for severe disease and consider it for persistent mild to moderate disease despite 2 days of supportive care.

Hyperglycemia and Diabetic Ketoacidosis

• Enfortumab vedotin is associated with severe hyperglycemia and reported diabetic ketoacidosis, including in patients without known diabetes.
• Polatuzumab vedotin and brentuximab vedotin have also been associated with hyperglycemia and ketoacidosis.
• For thirst, polyuria, weakness, nausea, or altered mental status, use a low threshold to measure serum glucose and ketones.
• Treat diabetic ketoacidosis using standard emergency protocols.

Tumor Lysis Syndrome

• Consider with gemtuzumab ozogamicin, polatuzumab vedotin, and brentuximab vedotin.
• Evaluate patients at risk with electrolytes, renal function, calcium, phosphate, uric acid, and electrocardiography as clinically indicated.
• Manage according to standard tumor lysis syndrome pathways and involve oncology early.

Hemorrhage

• Tisotumab vedotin and T-DM1 can cause clinically significant bleeding.
• Gemtuzumab ozogamicin and inotuzumab ozogamicin may cause bleeding through thrombocytopenia.
• Assess platelet count, coagulation studies when indicated, bleeding site, hemodynamic status, and intracranial symptoms.
• Maintain heightened concern for intracranial bleeding or hematoma expansion in patients with brain metastases, especially after radiation therapy.

Infusion-Related Reactions

• Reactions commonly occur 30 to 120 minutes after infusion but severe or delayed reactions may present more than 24 hours later.
• Features include fever, generalized maculopapular rash, chills, nausea, and pruritus.
• Clinical distinction from an allergic reaction may not be possible in the emergency setting.
• Treat as anaphylaxis or severe hypersensitivity when clinically indicated and coordinate with oncology.

Other High-Yield Presentations

Ocular Toxicity

• Mirvetuximab soravtansine may cause blurred vision, dry eye, and keratopathy.
• Tisotumab vedotin may cause conjunctivitis and keratitis.
• Keratitis warrants topical treatment and ophthalmology referral.
• Suspected uveitis requires urgent ophthalmology evaluation and may require local or systemic corticosteroids.
• Notify oncology because treatment interruption or dose modification may be required.

Liver Test Abnormalities

• Aminotransferase elevation greater than 20 times the upper limit of normal, or any elevation with jaundice, warrants expedited evaluation and oncology plus hepatology consultation.
• Asymptomatic elevation 5 to 15 times the upper limit of normal without jaundice may be suitable for close outpatient reassessment within days, depending on the full clinical context and oncology guidance.

Progressive Multifocal Leukoencephalopathy

• Associated with brentuximab vedotin and polatuzumab vedotin.
• Although rare, it may be fatal.
• Consider with progressive language, motor, cognitive, visual, or gait dysfunction over weeks to months.
• Magnetic resonance imaging is preferred over CT. Cerebrospinal fluid JC virus polymerase chain reaction can support the diagnosis.

Effusions and Peripheral Edema

• Loncastuximab tesirine may cause peripheral edema, pleural effusion, and pericardial effusion.
• In a dyspneic patient receiving this ADC, evaluate for effusions in addition to pneumonia or pulmonary embolism.

Gastrointestinal Toxicity and Pancreatitis

• Diarrhea and vomiting may require aggressive intravenous fluid and electrolyte replacement, not only antiemetics.
• Grade 1 diarrhea: oral hydration and loperamide.
• Grade 2 diarrhea: intravenous fluids and consideration of octreotide.
• Grade 3 or higher diarrhea: hospital admission and electrolyte correction.
• Brentuximab vedotin is associated with pancreatitis, including reported fatal cases. Evaluate and manage as standard acute pancreatitis; fasting triglycerides may be useful.

Severe Cutaneous Reactions

• Enfortumab vedotin, tisotumab vedotin, and brentuximab vedotin have reported Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Treat suspected severe cutaneous adverse reactions according to standard emergency and specialty pathways.

Cardiac Toxicity

• Cardiac toxicity is uncommon but includes reduced left ventricular ejection fraction and QTc prolongation with T-DXd, as well as cardiac events with T-DM1.
• Evaluate and treat using standard acute cardiovascular pathways because no ADC-specific emergency treatment is established.

Practical Emergency Department Checklist

• Identify the exact ADC and last administration date.
• For respiratory symptoms with T-DXd or mirvetuximab, consider pneumonitis and obtain CT rather than relying on chest radiography alone.
• For dyspnea with loncastuximab tesirine, actively assess for pleural or pericardial effusion.
• For rapid weight gain, ascites, jaundice, or hepatic pain with gemtuzumab ozogamicin or inotuzumab ozogamicin, consider sinusoidal obstruction syndrome.
• For thirst or polyuria with enfortumab vedotin, measure glucose and ketones promptly.
• Maintain a low threshold to admit, consult the relevant specialty service, and contact the treating oncology team.

Key Takeaway

In patients receiving ADCs, medication identification and timing of the last dose reshape the differential diagnosis. Early recognition of pneumonitis, sinusoidal obstruction syndrome, hyperglycemia or diabetic ketoacidosis, tumor lysis syndrome, hemorrhage, and delayed infusion reactions may prevent avoidable harm.

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Generated from the provided source note. Clinical decisions should be made in consultation with oncology and relevant specialty services.