Hematology, Oncology & Immunology · Topic 21 of 26

Immune Checkpoint Inhibitor Toxicities

Oncology · immune-related adverse events

Immune Checkpoint Inhibitor Toxicities

Checkpoint inhibitors unleash autoimmunity: grade it, hold the drug from grade 2, give high-dose steroids at grade 3, stop for good at grade 4.

Key numbers

Grade 3: steroids; grade 4: stop1–2 mg/kg/day

Myocarditis: admit, methylprednisolone 1 g IV daily1 g IV daily × 3–5 days

Steroid-refractory colitis: infliximab or vedolizumabno response in 3–5 days

Taper steroids over at least 4–6 weekstaper ≥ 4–6 weeks

Diarrhea grade 2: 4–6 stools over baseline≥ 7 stools/day = grade 3

01 · The ruleGrade 3: steroids; grade 4: stop

Grade 3: hold the checkpoint inhibitor and start high-dose corticosteroids (prednisone or IV methylprednisolone 1–2 mg/kg/day). Grade 4: discontinue permanently, except endocrinopathies controlled by hormone replacement.

02 · Watch forMyocarditis: admit, methylprednisolone 1 g IV daily

Suspect ICI myocarditis with troponin rise, ECG change or arrhythmia after checkpoint therapy in the past 12 weeks: admit, consult cardiology, get cardiac MRI, and give methylprednisolone 1 g IV daily for 3–5 days.

03 · GiveSteroid-refractory colitis: infliximab or vedolizumab

Immune colitis not improving after 3–5 days of steroids, or recurring on taper, needs infliximab 5 mg/kg or vedolizumab 300 mg; test for HBV, HIV and TB but never delay the dose for results.

Causes & risk factors

Why it happens

Combination therapy: highest risk, onset anytimeAnti-CTLA-4 plus anti-PD-1 combination causes the most and most severe irAEs; toxicity can start at any time, including months after the last dose, so ask about checkpoint inhibitor exposure in any oncology patient.

Presentation

What you'll see

Hypophysitis: headache with low TSH and ACTHHypophysitis (about 4% with anti-CTLA-4, 9–11% with combination therapy) causes headache, fatigue and nausea; low TSH with low or normal free T4 prompts morning cortisol, ACTH and a pituitary MRI to exclude metastases.

Thyroiditis: brief thyrotoxicosis, then hypothyroidismThyroiditis is the commonest endocrine irAE: transient thyrotoxicosis (median about 5 weeks; beta-blocker for symptoms) usually progresses to permanent hypothyroidism (median about 10 weeks) needing levothyroxine. Check TSH and free T4 throughout treatment.

Diagnosis & monitoring

Work-up

Diarrhea grade 2: 4–6 stools over baselineCTCAE diarrhea grades: grade 1 is < 4 stools/day over baseline, grade 2 is 4–6, and grade 3 is ≥ 7 over baseline or incontinence, hospitalization or limits on self-care.

Do right now

In this order

First moves

Grade 1: continue; grade 2: hold the ICI

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Grade 3: steroids; grade 4: stop1–2 mg/kg/day

→

Steroid-refractory colitis: infliximab or vedolizumabno response in 3–5 days

→

Taper steroids over at least 4–6 weekstaper ≥ 4–6 weeks

Why each step

Grade 1: continue; grade 2: hold the ICIGrade every immune-related adverse event (CTCAE): grade 1 — continue the checkpoint inhibitor with close monitoring (except some neurologic, hematologic and cardiac toxicities); grade 2 — hold it, consider corticosteroids, resume once ≤ grade 1.

Grade 3: steroids; grade 4: stopGrade 3: hold the checkpoint inhibitor and start high-dose corticosteroids (prednisone or IV methylprednisolone 1–2 mg/kg/day). Grade 4: discontinue permanently, except endocrinopathies controlled by hormone replacement.

Steroid-refractory colitis: infliximab or vedolizumabImmune colitis not improving after 3–5 days of steroids, or recurring on taper, needs infliximab 5 mg/kg or vedolizumab 300 mg; test for HBV, HIV and TB but never delay the dose for results.

Taper steroids over at least 4–6 weeksTaper corticosteroids over at least 4–6 weeks once the toxicity is ≤ grade 1 — fast tapers cause flares — and counsel about hyperglycemia, mood change, insomnia and opportunistic infection such as Pneumocystis pneumonia.

Management

Orders

Colitis: prednisone 1 mg/kg for grade 2Start steroids for grade ≥ 2 diarrhea or colitis: prednisone 1 mg/kg/day for grade 2, 1–2 mg/kg/day for grades 3–4, with IV corticosteroids initially for grade 4.

Exclude infection; scope grade ≥ 3 colitisExclude infection (C. difficile, CMV) and order flexible sigmoidoscopy or colonoscopy with biopsy for grade ≥ 3 diarrhea or colitis, or grade 2 symptoms persisting 5 days or more.

Pneumonitis: high-resolution CT, then steroidsEvaluate suspected pneumonitis with high-resolution chest CT. Grade 2: prednisone 1–2 mg/kg/day; grade ≥ 3: IV methylprednisolone 1–2 mg/kg/day; taper over 4–6 weeks. Refractory cases: infliximab, mycophenolate, IVIG or cyclophosphamide.

Give hydrocortisone before levothyroxineWith central adrenal insufficiency plus hypothyroidism, start hydrocortisone before levothyroxine — thyroid hormone first can precipitate adrenal crisis. Hold the ICI, teach stress dosing and give a medical alert bracelet.

Refractory myocarditis: abatacept or ATG, not infliximabSteroid-refractory ICI myocarditis is treated with antithymocyte globulin, mycophenolate, abatacept or alemtuzumab; infliximab is avoided because it was associated with higher cardiovascular death.

Red flags & don'ts

Avoid harm

Hepatitis: add mycophenolate, never infliximab avoidImmune hepatitis: prednisone 0.5–1 mg/kg/day for grade 2, methylprednisolone 1–2 mg/kg/day for grades 3–4. If ALT/AST do not improve within 10–14 days, add mycophenolate — infliximab is avoided because it is hepatotoxic.

ICI diabetes can present as DKA complicationCheckpoint-induced type 1 diabetes (mainly anti-PD-1/PD-L1, under 1–2%) often presents as fulminant DKA: check A1c, C-peptide and autoantibodies, hospitalize for DKA, hold the ICI until it resolves, and expect lifelong insulin.

Myocarditis, myositis, myasthenia overlap complicationMyocarditis, myositis and myasthenia gravis cluster in the same patients and are among the deadliest irAEs (fatality about 17% for myocarditis, 20% for myasthenia gravis): check CK, troponin, ECG and respiratory function whenever one appears.

The rules

Know these

Endocrinopathies: replace hormones, ICI can continue must knowEndocrine irAEs — hypothyroidism, hypophysitis, adrenal insufficiency, type 1 diabetes — are often permanent and are managed mainly with hormone replacement; the checkpoint inhibitor can usually continue once replacement controls them.

More detail

Reference

Show 6 reference facts

Pneumonitis occurs in about 4% on PD-(L)1 inhibitors, 1% on anti-CTLA-4 and 7% on combination therapy; hepatitis in about 5% on monotherapy and 19% on combination therapy.

Infliximab carries a boxed warning for latent TB reactivation; vedolizumab blocks α4β7 integrin, is gut-selective, and appears safe with TB, HIV and hepatitis B.

Giving infliximab or vedolizumab early (within 10 days of colitis onset) is associated with fewer steroid-taper failures, shorter steroid courses and shorter symptoms; infliximab is usually given at weeks 0, 2 and 6.

Immune nephritis is usually tubulointerstitial: rising creatinine, low-grade proteinuria and sterile pyuria; glomerular disease (minimal change, FSGS, membranous) is rare.

After grade ≥ 3 colitis the checkpoint inhibitor may be resumed once symptoms are ≤ grade 1 on less than 10 mg/day of prednisone; about one-third of rechallenged patients have recurrent colitis.

Hypophysitis replacement is hydrocortisone about 10–12 mg/m²/day; cortisol and ACTH results are unreliable if the patient is already taking steroids (for example dexamethasone premedication).

Pearl

Glands get hormones; most other organs get steroids — and grade 4 toxicity ends the checkpoint inhibitor for good.

Sources · Brahmer JR et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021;9:e002435 (PMC8237720) · Schneider BJ et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol 2021;39:4073–4126 (abstract read via Europe PMC) · Shivaji UN et al. Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management. Ther Adv Gastroenterol 2019 (PMC6831976; CTCAE grading table) · Merck Manual Professional — Immunotherapy of Cancer · Merck Manual Professional — Generalized Hypopituitarism (checkpoint-inhibitor hypophysitis) · Merck Manual Professional — Hypothyroidism (no levothyroxine in secondary hypothyroidism until cortisol is adequate or replaced) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).