Immune Checkpoint Inhibitor Toxicity — DCE Clinical Case

The patient

Mr K is a 64-year-old retired engineer who was diagnosed with metastatic melanoma (BRAF wild-type, PD-L1 positive) eight months ago. He commenced combination ipilimumab and nivolumab four months ago and has tolerated the first three cycles well, with a partial response on the most recent CT. Three weeks ago he developed loose stools, which have progressed to eight bloody bowel motions per day with mucus, abdominal cramps and urgency. Over the same period he has noticed a diffuse itchy rash over his trunk, profound fatigue, and dizziness on standing. He has lost 4 kg. He is otherwise well, takes no regular medications, and has no prior autoimmune disease. [1]

Examination findings

• General: alert but fatigued, mildly jaundiced. Diffuse maculopapular rash over the trunk, confluent, involving approximately 25 per cent of body surface area. No mucosal involvement.
• Vital signs: heart rate 108, blood pressure 104/62 lying and 88/54 standing, respiratory rate 20, oxygen saturation 96 per cent on room air, temperature 37.4.
• Abdomen: diffuse tenderness, no peritonism, bowel sounds hyperactive, no organomegaly.
• Respiratory: fine bibasal crackles.
• Cardiovascular: no murmur, no rub, no raised JVP.
• Neurological: no ptosis, no fatigability, no focal deficit, GCS 15.
• Endocrine: no thyroid bruit, no hyperpigmentation; confrontation visual fields show a mild bitemporal restriction. [1]

Investigations

• Sodium 126, potassium 5.1, urea 9.2, creatinine 140 (baseline 88).
• ALT 260, AST 210, ALP 180, bilirubin 58, INR 1.3, albumin 28.
• Haemoglobin 112, white cells 14.6, eosinophils 0.4, platelets 230.
• TSH 16.4 mU/L (high), free T4 6 pmol/L (low), random cortisol 70 nmol/L (low), ACTH 5 ng/L (low), FSH low, LH low, testosterone low, prolactin mildly raised.
• Troponin normal. ECG normal sinus rhythm.
• Stool culture, C. difficile toxin, ova cysts and parasites sent, results pending.
• Hepatitis A, B, C and E serology, CMV and EBV PCR, autoimmune markers — pending.
• Abdominal ultrasound with Doppler — pending. [1]

Candidate's opening statement (SASPOP)

"Thank you. I have reviewed Mr K, a 64-year-old retired engineer who presents with a three-week history of progressive bloody diarrhoea, an itchy rash, fatigue and postural dizziness, three weeks into cycle 4 of combination ipilimumab and nivolumab for metastatic melanoma. His cardinal findings are postural hypotension, diffuse abdominal tenderness, a grade 2 maculopapular rash over 25 per cent of his body surface area without mucosal involvement, a mild bitemporal visual field restriction, and laboratory evidence of panhypopituitarism with secondary adrenal insufficiency, transaminitis and acute kidney injury. My integrated diagnosis is multisystem grade 3 immune-related adverse event from his checkpoint inhibitors, with adrenal crisis as the immediate life threat." [1]

Prioritised problem list

1. Secondary adrenal insufficiency from checkpoint-inhibitor hypophysitis with evolving adrenal crisis — the immediate life threat.
2. Grade 3 immunotherapy colitis — the index emergency; perforation risk.
3. Grade 2 immunotherapy hepatitis — exclude viral, drug and obstructive causes.
4. Central hypothyroidism — replace after cortisol.
5. Grade 2 maculopapular rash — manageable alongside.
6. Metastatic melanoma — the underlying disease.
7. Acute kidney injury — pre-renal and possibly interstitial; will improve with resuscitation. [1]

Integrated management plan

Immediate (first hour):

• Intravenous hydrocortisone 100 mg stat then 50 mg every 6 hours for adrenal crisis — do not wait for the pituitary MRI.
• Intravenous fluids (1 L normal saline over the first hour, then resuscitate to haemodynamics); correct sodium slowly (no more than 8 to 10 mmol/L in 24 hours).
• Stool studies already sent — once the sample is in the lab, start intravenous methylprednisolone 1 to 2 mg/kg per day for the colitis (this also covers the hepatitis and the rash).
• Hold both checkpoint inhibitors; thromboprophylaxis; continuous monitoring.
• Do not give levothyroxine until hydrocortisone is running — thyroid replacement increases cortisol clearance and can precipitate collapse. [1]

First 24 to 72 hours:

• Pituitary MRI to confirm hypophysitis (enlarged, homogeneously enhancing gland).
• Gastroenterology and surgical review; abdominal CT if peritonism develops.
• Viral and autoimmune hepatitis screen and abdominal ultrasound with Doppler to exclude biliary obstruction and Budd-Chiari.
• Infliximab 5 mg/kg at 48 to 72 hours if the colitis is steroid-refractory (after QuantiFERON and hepatitis B surface antigen).
• Mycophenolate for steroid-refractory hepatitis (infliximab is avoided in liver toxicity).
• Topical corticosteroid and antihistamine for the rash. [1]

Medium term:

• Lifelong endocrine replacement: hydrocortisone, levothyroxine, testosterone; endocrinology follow-up.
• Slow corticosteroid taper over 4 to 6 weeks once the irAEs resolve to grade 1.
• Multidisciplinary decision on permanent discontinuation of combination therapy; the combination is permanently discontinued after a grade 3 event in two vital organs. If the melanoma is responding, discuss anti-PD-1 monotherapy after shared decision-making.
• Patient education, GP communication, patient-held irAE card, sick-day rules for hydrocortisone. [1]

Discussion questions

Examiner: Why does hypophysitis cause a LOW cortisol and a LOW ACTH, while primary adrenal insufficiency causes a low cortisol and a HIGH ACTH? [1]

Candidate: "Hypophysitis is a pituitary problem — the inflamed gland cannot produce ACTH, so the adrenal is under-stimulated and cortisol falls. The lesion is in the pituitary, so ACTH is low or inappropriately normal. In primary adrenal insufficiency the adrenal itself is destroyed (by autoimmunity, infection, or bleeding), so cortisol falls and the intact pituitary responds with a high ACTH (which also drives the hyperpigmentation seen in chronic primary adrenal failure). The ACTH level is the discriminator. Both cause hyponatraemia, but primary adrenal insufficiency also causes hyperkalaemia from mineralocorticoid deficiency, while secondary adrenal insufficiency does not typically — because the renin-angiotensin-aldosterone axis is intact. The bitemporal hemianopia in this patient points to a pituitary mass effect, confirming the secondary mechanism." [1]

Examiner: Walk me through the CTCAE grading and how it changes your management. [1]

Candidate: "The CTCAE version 5.0 grades irAEs from 1 to 4 by organ-specific severity. The grade drives both the corticosteroid dose and the hold-versus-stop decision. Grade 1 is mild and asymptomatic — I usually continue the drug with close monitoring. Grade 2 is moderate and limits self-care — I hold the drug and start oral prednisolone 0.5 to 1 mg/kg per day. Grade 3 is severe and requires hospitalisation — I give intravenous methylprednisolone 1 to 2 mg/kg per day and usually permanently discontinue the drug for vital-organ events. Grade 4 is life-threatening — permanent discontinuation and intensive-care-level support. For Mr K, the colitis is grade 3 (8 stools per day above baseline with abdominal pain), so he gets intravenous methylprednisolone and the combination is held pending a permanent-discontinuation decision. The hepatitis is grade 2 to 3 by the AST and ALT. The endocrine events are the exception — they are managed with hormone replacement and the drug can often be continued, but in this patient the multisystem nature of the toxicity tips the balance toward permanent discontinuation of the combination." [1]

Examiner: What is the evidence that infliximab works for immunotherapy colitis, and what are the contraindications? [1]

Candidate: "Infliximab is an anti-TNF-alpha chimeric monoclonal antibody that was first shown to be effective for ipilimumab colitis in case series and is now the established second-line agent in the ASCO and ESMO guidelines, at 5 mg/kg at weeks 0, 2 and 6. It is added when there is no improvement after 48 to 72 hours of adequate-dose intravenous corticosteroid. The contraindications are active infection (especially tuberculosis, which must be screened for with an interferon-gamma release assay), active hepatitis B (screen with surface antigen and core antibody), moderate-to-severe heart failure, and a recent or current demyelinating disease. Vedolizumab, a gut-selective anti-integrin, is the alternative when infliximab is contraindicated or ineffective; it has a slower onset but a better safety profile in coexisting hepatitis." [1]

Examiner: How would you counsel Mr K about his prognosis and his cancer treatment? [1]

Candidate: "I would explain three things. First, the very fact that he has developed toxicity is a positive prognostic signal for his melanoma — the Schadendorf pooled analysis showed that patients who discontinue combination therapy for toxicity have antitumour responses and survival that are at least as good as those who continue, because the primed immune response persists. Second, the immediate priority is his safety — the adrenal crisis and the colitis are both treatable, and he is expected to recover. Third, the combination regimen will be permanently discontinued because of the multisystem grade 3 event, but if his melanoma is responding, anti-PD-1 monotherapy may be an option after multidisciplinary discussion. I would give him a written irAE action plan, a steroid taper calendar, a patient-held card naming the drugs and the toxicities, and clear instructions on sick-day hydrocortisone rules and infection precautions." [1]

Examiner: What is the most feared irAE you have not yet seen in this patient, and how would you recognise it? [1]

Candidate: "Checkpoint-inhibitor myocarditis. It is rare — around 1 per cent in the Mahmood registry — but it has a case fatality of 25 to 50 per cent and frequently coexists with myositis and myasthenia gravis. The trigger to investigate is any cardiac symptom (chest pain, dyspnoea, palpitations) or any unexplained tachycardia; I would check a troponin and an ECG immediately. The ECG may show a conduction block or arrhythmia, the echocardiogram may show a reduced ejection fraction or wall-motion abnormality, and cardiac MRI shows late gadolinium enhancement and T2 oedema. The management is permanent discontinuation of the checkpoint inhibitor at any grade, intravenous methylprednisolone at pulse doses (500 mg to 1 g daily for up to 3 days, higher than the standard irAE dose), early cardiology and intensive-care involvement, and mycophenolate, antithymocyte globulin or plasmapheresis in fulminant disease." [1]

Communication and shared decision-making

The key communication points for Mr K and his family:

• Acknowledge his fear that stopping therapy means his cancer will progress, and provide the evidence that it does not.
• Explain that the toxicity is a sign the immune system is active, which is what the treatment aims for.
• Be honest about the permanent discontinuation of the combination and the uncertainty about future cancer therapy.
• Provide a written irAE action plan, a steroid taper calendar, a patient-held card, and a direct contact for the oncology and general medicine teams.
• Involve his general practitioner with a discharge summary that explicitly names the drugs, the events, the grades, and the plan.
• Educate on sick-day hydrocortisone rules, the need to avoid live vaccines, and the principle that any new symptom is an irAE until proven otherwise for months after the last dose. [1]

Summary of discriminating points

• Adrenal crisis is treated before colitis — hydrocortisone is safe, rapid and reversible; the colitis management takes days.
• Stool before steroids — C. difficile and Campylobacter mimic immunotherapy colitis.
• Mycophenolate for hepatitis and nephritis, infliximab for colitis — never infliximab for hepatitis.
• Permanent discontinuation for grade 3 vital-organ events — pneumonitis, myocarditis, hepatitis, nephritis, severe colitis, neurological events.
• Endocrine events are managed with replacement and the drug is often continued — the exception to the grade-stop rule.
• Troponin for any cardiac symptom or unexplained tachycardia — myocarditis is the one you cannot afford to miss. [1]