In addition to today’s resource, please review
- Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies? Mohammad Reza Zamani 1,2, Pavel Šácha 2. Med Oncol. 2025 Jun 19;42(7):273. doi: 10.1007/s12032-025-02822-1
- Review of the Immune Checkpoint Inhibitors in the Context of Cancer Treatment. Norah A Alturki 1. J Clin Med. 2023 Jun 27;12(13):4301. doi: 10.3390/jcm12134301
- Immune Checkpoint Inhibitors in Cancer Therapy. Yavar Shiravand 1, Faezeh Khodadadi 2, Seyyed Mohammad Amin Kashani 3, Seyed Reza Hosseini-Fard 4, Shadi Hosseini 5, Habib Sadeghirad 6, Rahul Ladwa 7, Ken O’Byrne 7, Arutha Kulasinghe 6. Curr Oncol. 2022 Apr 24;29(5):3044–3060. doi: 10.3390/curroncol29050247
In addition to today’s resource, please review
CORE IM‘s Immune Checkpoint Inhibitors & IRAEs 101: 5 Pearls Segment.*
*Posted: May 22, 2024
By: Dr. Anuranita Gupta, Dr. Narjust Florez, Dr. Allison Betof Warner, Dr. Benjamin Schlechter and Dr. Shreya P. Trivedi
Graphic: Dr. Cathy Cichon
Audio: Daksh Bhatia
Peer Review: Dr. Hollis Viray, Dr. Tian Zhang
Today, I review, link to, and excerpt from CoreIM‘s Immune Checkpoint Inhibitor Adverse Events 2.0: 5 Pearls Segment.*
*Posted: January 8, 2025
By: Dr. Anuranita Gupta, Dr. Benjamin Schlechter, Dr. Allison Betof Warner, Dr. Narjust Florez and Dr. Shreya P. Trivedi
Graphic: Dr. Cathy Cichon
Audio: Jerome C. Reyes
Peer Review: Dr. Elad Sharon, Dr. Meng Wu
All that follows is from the above resource.
Podcast: Play in new window | Download
Time Stamps
- 02:01 Introduction
- 03:22 Pearl 1: Pneumonitis
- 13:39 Pearl 2: Colitis
- 24:35 Pearl 3: Skin IRAEs
- 30:28 Pearl 4: Endocrine IRAEs (Thyroid)
- 35:15 Pearl 5: Endocrine IRAEs (Pituitary)
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Show Notes
ICI: immune checkpoint inhibitor
IRAE: immune related adverse event
Pearl 1: Pneumonitis
- Time to onset:
- 1.5 to 127 weeks; (median 34 weeks)
- Clinical presentation: Ranges from asymptomatic to acute hypoxic respiratory failure.
- Cough, dyspnea, chest pain, fever
- Differential:
- Heart failure
- COPD
- Infection
- Pulmonary embolism
- Pneumonitis (radiotherapy, chemotherapy)
- Malignancy
- ILD flare
- Neuromuscular disorder
- Sarcoidosis.
- Work up:
- Immunocompetent
- CT Chest with contrast (CXR insufficient)
- Often showed ground glass opacities in lower lobes
- Five different types of imaging findings have been seen:
- Chronic obstructive pneumonia–like
- Ground-glass opacities
- Hypersensitivity type
- Interstitial type
- Pneumonitis not otherwise specified
- Infectious workup
- Sputum culture
- Respiratory viral panel
- COVID-19
- Blood culture
- Urine legionella
- Strep pneumo antigen
- +/- Bronchoscopy w/ BAL and biopsy
- Use is debated
- Can help to rule out infection or lymphangitic spread of tumor
- Immunocompromised
- Above work up +
- Fungal markers (B-glucan, galactomannan)
- Endemic fungal antigens
- TB
- PJP
- Treatment: Guidelines based on grade
- Grade 1 (asymptomatic/affecting one lobe or <25% of lung):
- Hold ICI and monitorRepeat imaging in 3-4 weeks
- If improved, can re-trial ICI
- If NOT improved, treat as grade 2
- Grade 2 (symptomatic/involving more than one lobe of the lung or 25-50% of lung parenchyma):
- Hold ICI
- Give Prednisone 1-2mg/kg/day and taper over 4-6 weeks
- If no improvement after 48-72 hours, treat as grade 3 and consider bronchoscopy with BAL +/- biopsy
- Grade 3 (hospitalization for severe symptoms or oxygen requirement/all lung lobes involved or >50% of lung parenchyma) or Grade 4 (life-threatening respiratory compromise/intubation required):
- Permanently discontinue ICI
- Give Methylprednisolone IV 1-2mg/kg/day and taper over 4-6 weeks
- If no improvement in 48 hours, add an additional agent such as infliximab, mycophenolate mofetil, IVIG or cyclophosphamide. Consider bronchoscopy with BAL +/- biopsy
- Decisions about empiric treatment with antibiotics and diuretics should be made on a case by case basis.
Pearl 2: Colitis
- Time to onset:
- 1 to 107.5 weeks (median 8 weeks)
- Clinical presentation:
- Abdominal pain, nausea, diarrhea, blood or mucus in the stool, fever
- Upper GI toxicity
- Presents with dysphagia, nausea, vomiting or epigastric pain
- Less common than lower GI toxicity (most commonly affects descending colon)
- Associated with NSAID and prolonged PPI use
- Differential:
- Infectious colitis (bacterial, viral, parasitic)
- Ischemic colitis
- Inflammatory bowel disease
- Radiation colitis
- Diverticulitis
- Drug-induced colitis (chemotherapy, tyrosine kinase inhibitors)
- Graft vs host disease in transplant patients
- Work up:
- Bloodwork with CBC, CMP, TSH
- Stool studies Culture
- C. diff,
- Ova and parasites
- CMV
- Norovirus
- Fecal inflammatory markers lactoferrin,calprotectin)
- Review medication list (antibiotics, prolonged PPI use, NSAID).
- CT scan for abscess
- Findings often mimic inflammatory bowel disease
- Mesenteric vessel engorgement
- Bowel wall thickening
- Fluid filled colon distension
- +/- Endoscopy and colonoscopy with biopsy
- Perform if Grade 2 or positive fecal inflammatory markers
- Patients on biologics:
- HIV
- Hepatitis A
- Hepatitis B
- TB
- Treatment: Guidelines based on grade
- Grade 1 (increase of <4 stools per day over baseline):
- Can continue ICI or hold temporarily until resolution of symptoms.
- Supportive care with hydration and medications such as loperamide if infection has been ruled out.
- Grade 2 (increase of 4-6 stools per day over baseline):
- Hold ICI until symptoms resolve to grade 1.
- Give prednisone 1mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks.
- If no improvement in 72 hours or there are high risk endoscopic features, then add infliximab or vedolizumab.
- Grade 3 (increase of > or =7 stools per day over baseline/hospitalization):
- Grade 2 recommendations apply.
- Can consider IV methylprednisolone especially if concurrent upper GI inflammation.
- If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab.
- Consider permanent discontinuation of CTLA-4 agents.
- Grade 4 (life threatening symptoms/urgent intervention required):
- Grade 2 and 3 recommendations apply.
- Give IV methylprednisolone 1-2mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks.
- If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab.
- Permanently discontinue ICI.
- Resume ICI if fecal calprotectin is less than 116 or if repeat endoscopy shows mucosal healing.
Pearl 3: Skin IRAE
- Time to onset:
- 2 to 150 weeks (median 7 weeks)
- Clinical presentation:
- Maculopapular rash
- Bullae
- Vitiligo
- Stevens Johnson Syndrome
- Toxic Epidermal Necrolysis
- DRESS
- Symptoms: ranges from itch +/- rash to fever, skin sloughing, pustules, blisters or mucosal erosions
- Differential:
- Allergic or irritant contact dermatitis
- Atopic dermatitis
- Psoriasis
- Seborrheic
- Dermatitis
- Infectious dermatitis (fungal, bacterial, viral)
- Unrelated drug rash with eosinophilia and systemic symptoms (DRESS)
- Work up:
- History and physical exam is very important including
- Examination of oral mucosa
- assessment of blisters and body surface area affected
- Medication list should be reviewed
- CBC and CMP should be obtained
- Dermatology may obtain skin biopsy for further evaluation
- Treatment: Guidelines based on grade
- NOTE: Vitiligo is associated with treatment response
- Grade 1 (rash<10% body surface area):
- Continue ICI and give topical emollients and/or mild-moderately potent topical steroids.
- Grade 2 (rash covering 10-30% BSA with or without symptoms):
- Consider holding ICI. Give topical emollients, oral anti-histamines and medium-highly potent topical steroids.
- Consider prednisone 0.5-1mg/kg and taper over 4 weeks.
- Grade 3 (rash >30% BSA with moderate or severe symptoms):
- Hold ICI and discuss with dermatology about the timeline for restarting.
- Give topical emollients, oral antihistamines and highly potent topical steroids.
- Start oral prednisone 1mg/kg/day and taper over 4 weeks.
- If pruritus is present without rash, you can try gabapentin or pregabalin.
- Grade 4 (severe symptoms requiring hospitalization):
- Hold ICI,
- Hospitalize patients and give IV methylprednisolone 1-2mg/kg/day.
- Discuss with dermatology/oncology about appropriateness of restarting ICI
Pearl 4: Endocrine IRAEs (thyroid)
- Time to onset:
- 1.5-130 weeks (median 14.5 weeks)
- Clinical presentation:
- Pituitary dysfunction,
- Hypothyroidism,
- Hyperthyroidism,
- Adrenal insufficiency
- Nausea, vomiting, abdominal pain, weight loss, lightheadedness or orthostasis or syncope, and profound fatigue
- T1DM
- Polyuria or polydipsia, nausea or vomiting, abdominal pain, and/or visual blurring
- Primary hypothyroidism
- Cold intolerance, dry skin, constipation, weight gain, and/or fatigue
- Differential:
- Hashimoto’s thyroiditis
- Central hypothyroidism
- Post-viral subacute thyroiditis
- Induced by other drugs (lithium, amiodarone, anti-epileptics)
- Induced by head and neck radiation
- Work up:
- TSH and free T4
- Low TSH and low free T4= central hypothyroidism (see hypophysitis below)
- High TSH and low free T4= primary hypothyroidism
- T3
- TSH receptor antibody testing if suspicion for Graves’ Disease (ophthalmopathy or thyroid bruit).
- Treatment: Guidelines based on grade:
- Grade 1 (4.5<TSH<10 and asymptomatic):
- Continue ICI and monitor TSH every 4-6 weeks.
- Grade 2 (TSH>10 and symptomatic):
- Can continue or hold ICI
- Start levothyroxine
- Check TSH levels every 6-8 weeks until TSH is in reference range.
- Grade 3-4 (severe symptoms):
- Hold ICI until symptoms resolve.
- Hospital admission if concern for developing myxedema (bradycardia, hypothermia, altered mental status).
- Discuss with endocrinology about IV levothyroxine and steroids.
- Thyroid supplementation per grade 2 recommendations.
- Consider referring to endocrine at grade 2; should be referred at grade 3 or higher.
- For thyrotoxicosis:
- Grade 1 (asymptomatic or mild symptoms): Continue ICI. Beta blocker for symptoms. Monitor thyroid function 2-3 weeks to detect subsequent hypothyroidism (commonly occurs in transient subacute thyroiditis) in which case the patient should be treated for primary hypothyroidism.
- Grade 2 (moderate symptoms): Consider holding ICI, give beta blocker for symptoms. If persistent >6 weeks, will need thyroid suppression.
- Grade 3-4 (severe symptoms, unable to perform ADLs): Hold ICI until symptoms resolve and give beta blockers for symptoms. Discuss with endocrine about medical therapies such as steroids, potassium iodide, methimazole, propylthiouracil or surgery.
- Refer to endocrine if thyrotoxicosis persists for more than 6 weeks.
Pearl 5: Endocrine IRAEs (pituitary)
- Time to onset:
- Variable
- Hypophysitis is most commonly seen with ipilimumab.
- Clinical presentation:
- Fatigue
- Loss of libido
- Mood changes
- Oligomenorrhea due to hormone imbalances
- Headaches
- Visual changes
- Work up:
- AM cortisol
- AM ACTH
- TSH and free T4
- Electrolytes
- Hormone levels: LH, FSH, estrogen and testosterone.
- +/- AM ACTH stimulation testing
- Complete IF AM cortisol results are indeterminate (between 3 and 15)
- +/- MRI brain with and without contrast with sellar cuts
- Complete if visual changes, headache or diabetes insipidus
- Treatment: Use Guidelines based on grade
- NOTE :Principles are somewhat different because hormone replacement is the mainstay of treatment instead of immunosuppression for endogenous hormone production recovery.
- Grade 1 (asymptomatic/mild symptoms):
- Consider holding ICI until the patient stabilizes on hormones.
- Steroid replacement for adrenal insufficiency if needed.
- Thyroid replacement if needed with free T4 goal in upper half of reference range.
- Testosterone or estrogen therapy if needed and no contraindications.
- Grade 2 (moderate symptoms):
- Consider holding ICI
- Hormone replacement as grade 1 recommendations
- If MRI shows pituitary swelling or optic chiasm compression, treat with prednisone 1mg/kg/day and taper over 1-2 weeks to maintenance therapy dose.
- Grade 3-4 (severe symptoms/unable to perform ADLs):
- Hold ICI until stabilized on hormones.
- IV hydrocortisone 50-100mg q6-8 hours tapered down over 5-7 days or prednisone 1-2mg/kg/day tapered over 1-2 weeks to maintenance dose.
- Hormone replacement as grade 1 and 2.
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