Chapter 34 — Anti-Cancer Drugs Part II — Module 4 — Immune Checkpoint Inhibitors, Hormonal Oncology, and CAR-T Cell Therapy: Clinical Vignette
1. A 58-year-old man with metastatic melanoma is two weeks into combination ipilimumab-nivolumab therapy. He reports 8 stools per day above his baseline with cramping abdominal pain. Stool studies, including C. difficile testing, are negative, and infection has been excluded. This is consistent with grade 3 immune-mediated colitis. What is the most appropriate management?
A) Continue both agents at full dose and start loperamide as definitive therapy.
B) Begin oral vancomycin for presumed infectious colitis and continue both checkpoint inhibitors.
C) Permanently discontinue ipilimumab, start IV methylprednisolone 1-2 mg/kg/day, and add infliximab if there is no improvement within about 3 days.
D) Start low-dose prednisone at 0.25 mg/kg/day and continue ipilimumab at the next scheduled cycle.
E) Give a single dose of infliximab without corticosteroids and rechallenge ipilimumab in one week.
ANSWER: C
Rationale:
Grade 3 immune colitis requires permanent discontinuation of the CTLA-4 agent (ipilimumab), prompt high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day), and escalation to infliximab — the steroid-sparing agent of choice for colitis — if there is no improvement within roughly 72 hours.
Option A: Option A is incorrect because continuing the drugs and relying on an antimotility agent does not treat the immune inflammation and is unsafe, risking perforation.
Option B: Option B is incorrect because infection has been excluded, so antibiotics are not the treatment for immune colitis.
Option D: Option D is incorrect because grade 3 colitis requires high-dose, not subtherapeutic, corticosteroids, and ipilimumab should not be continued.
Option E: Option E is incorrect because infliximab is added to corticosteroids rather than used alone, and rechallenge with ipilimumab after grade 3 colitis is contraindicated.
2. A 64-year-old woman receiving pembrolizumab for non-small-cell lung cancer is found on routine monitoring to have an AST of 320 U/L and ALT of 410 U/L (grade 3 immune-mediated hepatitis, more than 5 times the upper limit of normal). Viral and obstructive causes are excluded, and methylprednisolone 1-2 mg/kg/day is started, but transaminases continue to climb over 4 days. What is the most appropriate next step?
A) Add infliximab, the standard steroid-sparing agent for all immune-related adverse events.
B) Stop corticosteroids because they are hepatotoxic and observe off all therapy.
C) Administer tocilizumab as first-line treatment and continue pembrolizumab.
D) Begin a somatostatin analog to reduce hepatic inflammation.
E) Add mycophenolate mofetil and avoid infliximab, because anti-TNF therapy carries its own risk of hepatotoxicity in this setting.
ANSWER: E
Rationale:
For steroid-refractory immune hepatitis, mycophenolate mofetil is the steroid-sparing agent of choice, while infliximab is avoided because anti-TNF therapy can itself cause hepatotoxicity. This is the key distinction from immune colitis, where infliximab is appropriate.
Option A: Option A is incorrect because infliximab is precisely the agent to avoid in hepatitis.
Option B: Option B is incorrect because corticosteroids are first-line for immune hepatitis, not a contraindicated class, and stopping all therapy abandons a worsening process.
Option C: Option C is incorrect because tocilizumab is not the standard treatment for immune hepatitis, and pembrolizumab should be held.
Option D: Option D is incorrect because somatostatin analogs treat neuroendocrine tumors and have no role in immune hepatitis.
3. A 71-year-old man on durvalumab develops progressive dyspnea and a dry cough. Chest CT shows new diffuse bilateral ground-glass opacities, and his oxygen saturation is 86% on room air at rest (grade 3 immune-mediated pneumonitis). Which management plan is most appropriate?
A) Continue durvalumab, give empiric antibiotics alone, and withhold corticosteroids.
B) Evaluate to exclude infection (bronchoscopy with lavage when feasible), start corticosteroids 1-2 mg/kg/day, and permanently discontinue durvalumab given the grade 3 severity.
C) Start corticosteroids but resume durvalumab at the next cycle regardless of grade.
D) Treat with tocilizumab as first-line therapy and continue durvalumab at full dose.
E) Observe without treatment, since pneumonitis resolves spontaneously even at grade 3.
ANSWER: B
Rationale:
Immune pneumonitis requires exclusion of infection (bronchoscopy with lavage when feasible), corticosteroids at 1-2 mg/kg/day for grade 2 or higher, and permanent discontinuation of the checkpoint inhibitor for grade 3-4 disease, because high-grade pneumonitis can be fatal.
Option A: Option A is incorrect because withholding corticosteroids while continuing the drug ignores the immune etiology and the need to stop therapy.
Option C: Option C is incorrect because rechallenge is precluded by grade 3 severity.
Option D: Option D is incorrect because corticosteroids, not tocilizumab, are first-line, and the drug must be stopped.
Option E: Option E is incorrect because grade 3 pneumonitis is potentially life-threatening and mandates prompt corticosteroids and drug discontinuation.
4. A 55-year-old woman on nivolumab presents to the emergency department with hypotension (BP 82/50 mmHg), vomiting, a sodium of 128 mEq/L, and a potassium of 5.6 mEq/L. Immune-mediated hypophysitis with secondary adrenal insufficiency precipitating an adrenal crisis is suspected. What is the most appropriate immediate action?
A) Withhold all steroids until a morning cortisol and ACTH level return the next day.
B) Administer levothyroxine first and defer glucocorticoids until thyroid studies return.
C) Increase the nivolumab dose to restore adrenal output.
D) Give IV hydrocortisone (stress-dose, for example 100 mg) immediately, without waiting for confirmatory test results.
E) Start fludrocortisone alone, as mineralocorticoid replacement is sufficient.
ANSWER: D
Rationale:
Adrenal crisis is life-threatening; the immediate, life-saving action is stress-dose IV hydrocortisone given empirically without waiting for confirmatory testing. In a non-urgent presentation one would draw ACTH (adrenocorticotropic hormone) and cortisol first, but hemodynamic instability mandates treating immediately.
Option A: Option A is incorrect because delaying glucocorticoid to await testing in a crisis is dangerous and can be fatal.
Option B: Option B is incorrect and hazardous because giving levothyroxine before glucocorticoid replacement can worsen or precipitate adrenal crisis.
Option C: Option C is incorrect because raising the checkpoint inhibitor dose does not restore adrenal function and may worsen gland injury.
Option E: Option E is incorrect because glucocorticoid (hydrocortisone) replacement is the essential treatment; mineralocorticoid alone is inadequate in this crisis.
5. A 49-year-old woman receiving pembrolizumab reports palpitations and heat intolerance. Her TSH is 0.04 mIU/L (suppressed) with an elevated free T4, and her heart rate is 112 beats per minute. The picture is checkpoint inhibitor-induced thyroiditis with a hyperthyroid phase. What is the most appropriate management?
A) Treat symptoms with a beta-blocker, continue pembrolizumab, and monitor thyroid function, anticipating that the hyperthyroid phase is transient and commonly progresses to hypothyroidism within several weeks.
B) Start methimazole and refer for radioactive iodine ablation, as this represents Graves disease.
C) Begin levothyroxine immediately to correct the elevated free T4.
D) Start high-dose corticosteroids as first-line therapy and permanently discontinue pembrolizumab.
E) Discontinue pembrolizumab permanently and take no further action.
ANSWER: A
Rationale:
Checkpoint inhibitor thyroiditis typically begins with a transient hyperthyroid phase from release of preformed hormone as the gland is inflamed; management is symptomatic with a beta-blocker, the drug is continued, and the patient is monitored because the gland commonly becomes hypothyroid within weeks.
Option B: Option B is incorrect because this is destructive thyroiditis, not Graves disease; antithyroid drugs and radioactive iodine are not the treatment.
Option C: Option C is incorrect because levothyroxine treats hypothyroidism and would worsen the current hyperthyroid phase; it is started later if hypothyroidism develops.
Option D: Option D is incorrect because corticosteroids are not first-line for routine thyroiditis, which is self-limited, and discontinuation is generally unnecessary.
Option E: Option E is incorrect because symptomatic treatment and monitoring are required rather than no action.
6. A 68-year-old man with newly diagnosed metastatic prostate cancer has extensive vertebral metastases and a high tumor burden. His oncologist plans to begin leuprolide (a GnRH agonist). What intervention is required at initiation, and why?
A) No additional medication is needed because leuprolide lowers testosterone within hours of the first dose.
B) Start finasteride to block dihydrotestosterone formation during the initial surge.
C) Co-prescribe a short course of an antiandrogen (for example, bicalutamide 50 mg daily for about 4 weeks), starting before and during leuprolide initiation, to prevent the testosterone flare from worsening disease and precipitating spinal cord compression.
D) Begin an aromatase inhibitor to suppress the expected estrogen surge.
E) Initiate lifelong corticosteroids before the first leuprolide dose.
ANSWER: C
Rationale:
Continuous GnRH receptor stimulation initially raises luteinizing hormone and testosterone (the flare) before downregulation lowers testosterone over one to two weeks; in a patient with vertebral metastases, this flare risks spinal cord compression. A short antiandrogen course (bicalutamide) given before and during initiation blocks the androgen receptor and covers the flare.
Option A: Option A is incorrect because testosterone initially rises rather than falling within hours.
Option B: Option B is incorrect because finasteride does not adequately block the androgen-receptor-mediated flare and is not the standard protection.
Option D: Option D is incorrect because the relevant surge is testosterone, not estrogen, and aromatase inhibitors are used in breast cancer.
Option E: Option E is incorrect because corticosteroids do not block the androgen receptor and are not used for flare protection.
7. A 73-year-old man on abiraterone for metastatic castration-resistant prostate cancer is found at a routine visit to have a blood pressure of 160/98 mmHg and a serum potassium of 3.0 mEq/L. He feels well otherwise. Which interpretation and management plan is correct?
A) These findings are unrelated to abiraterone and need no change in therapy.
B) This indicates abiraterone underdosing; increase the dose and stop the prednisone.
C) This reflects cortisol excess; discontinue prednisone immediately.
D) Abiraterone has been converted to a mineralocorticoid antagonist; restrict dietary potassium.
E) This is mineralocorticoid excess from CYP17A1 inhibition (reduced cortisol drives compensatory ACTH and accumulation of mineralocorticoid precursors); confirm the patient is taking prednisone 5 mg twice daily, replete potassium, and add an antihypertensive as needed.
ANSWER: E
Rationale:
Inhibiting CYP17A1 lowers cortisol, which raises ACTH (adrenocorticotropic hormone) and drives accumulation of mineralocorticoid precursors, producing hypertension and hypokalemia. Management confirms adherence to prednisone 5 mg twice daily (which suppresses ACTH and replaces cortisol), repletes potassium, and adds an antihypertensive as needed.
Option A: Option A is incorrect because the derangement is directly caused by abiraterone's mechanism.
Option B: Option B is incorrect because the syndrome reflects expected pharmacology, not underdosing, and stopping prednisone would worsen it.
Option C: Option C is incorrect because the problem is reduced cortisol with mineralocorticoid excess, not cortisol excess; stopping prednisone would aggravate it.
Option D: Option D is incorrect because abiraterone causes mineralocorticoid excess, not antagonism, and potassium needs repletion rather than restriction.
8. A 70-year-old man with non-metastatic castration-resistant prostate cancer and a rapidly rising PSA needs an androgen-receptor inhibitor. His history includes a seizure disorder, and he takes several medications metabolized by CYP3A4. Which agent is the best choice, and why?
A) Enzalutamide, because its central nervous system penetration is protective against seizures.
B) Darolutamide, because its structurally distinct binding domain limits central nervous system penetration (so it does not lower the seizure threshold as enzalutamide can) and it is not a strong CYP inducer, giving a more favorable interaction profile in a patient with seizure history and polypharmacy.
C) Enzalutamide, because a seizure history increases its anti-tumor efficacy.
D) Abiraterone without prednisone, since it has no central nervous system effects.
E) Apalutamide, because it has the lowest reported rate of skin rash and hypothyroidism of the class.
ANSWER: B
Rationale:
Darolutamide's distinct structure limits central nervous system penetration, so it does not lower the seizure threshold the way enzalutamide can, and it lacks strong CYP induction, producing a cleaner interaction profile; this makes it preferred in a patient with a seizure history and significant polypharmacy.
Option A: Option A is incorrect because greater central nervous system penetration raises, not lowers, seizure risk, and enzalutamide is the agent to avoid here.
Option C: Option C is incorrect because seizure history is a safety concern, not a driver of efficacy.
Option D: Option D is incorrect because abiraterone requires mandatory concurrent prednisone, so giving it without prednisone is unsafe, and it is a different mechanistic class.
Option E: Option E is incorrect because apalutamide shares enzalutamide's seizure-threshold and CYP-induction concerns and actually carries notable rash and hypothyroidism risk, so it is not the best choice for this patient.
9. A 45-year-old premenopausal woman taking adjuvant tamoxifen for ER-positive breast cancer reports disruptive hot flashes and asks for medication to relieve them. Which choice is most appropriate, and why?
A) Paroxetine, because it enhances conversion of tamoxifen to its active metabolite.
B) Fluoxetine, because CYP2D6 inhibition does not affect tamoxifen activity.
C) Discontinue tamoxifen and switch to an aromatase inhibitor, since hot flashes contraindicate endocrine therapy.
D) Venlafaxine (or gabapentin or clonidine), because it relieves hot flashes without strongly inhibiting CYP2D6, preserving conversion of tamoxifen to active endoxifen.
E) Paroxetine combined with a CYP2D6 inducer to keep endoxifen levels neutral.
ANSWER: D
Rationale:
Tamoxifen requires CYP2D6 to form active endoxifen, so strong CYP2D6 inhibitors such as paroxetine and fluoxetine can reduce endoxifen and blunt efficacy; venlafaxine, desvenlafaxine, gabapentin, or clonidine relieve hot flashes without significant CYP2D6 inhibition and are preferred.
Option A: Option A is incorrect because paroxetine inhibits, rather than enhances, the CYP2D6-mediated activation of tamoxifen.
Option B: Option B is incorrect because CYP2D6 inhibition clearly reduces endoxifen, which is the basis for avoiding fluoxetine.
Option C: Option C is incorrect because hot flashes are managed pharmacologically and do not contraindicate endocrine therapy; moreover, an aromatase inhibitor is ineffective in a premenopausal woman without ovarian suppression.
Option E: Option E is incorrect because combining an inhibitor with an inducer is unreliable and still risks reduced efficacy.
10. On day 6 after axicabtagene ciloleucel (a CD19-directed CAR-T product) infusion, a 38-year-old man with refractory large B-cell lymphoma develops confusion, expressive aphasia, and an ICE (immune effector cell-associated encephalopathy) score of 4, without fever or hypotension (grade 3 ICANS). What is the most appropriate management?
A) Start IV dexamethasone (for example, 20 mg every 6 hours), begin levetiracetam for seizure prophylaxis, arrange ICU-level monitoring, and do not give tocilizumab, which is ineffective for ICANS and may worsen it.
B) Give tocilizumab as first-line therapy, as for cytokine release syndrome.
C) Withhold all treatment because ICANS resolves spontaneously without intervention.
D) Increase the CAR-T cell dose to overcome the neurotoxicity.
E) Start phenytoin as the preferred antiseizure agent and avoid all corticosteroids.
ANSWER: A
Rationale:
ICANS responds to corticosteroids (dexamethasone), which cross into the central nervous system; tocilizumab is ineffective for ICANS and may worsen it because peripheral IL-6-receptor blockade can raise free IL-6 that crosses the blood-brain barrier. Grade 3 ICANS warrants IV dexamethasone, seizure prophylaxis with levetiracetam, and ICU-level monitoring.
Option B: Option B is incorrect because tocilizumab is first-line for cytokine release syndrome, not ICANS.
Option C: Option C is incorrect because grade 3 ICANS is dangerous and requires prompt treatment.
Option D: Option D is incorrect and dangerous because raising the CAR-T dose would intensify the immune-mediated injury.
Option E: Option E is incorrect because levetiracetam (not phenytoin) is preferred and corticosteroids are the mainstay rather than something to avoid.
11. Four days after tisagenlecleucel (a CD19-directed CAR-T product) infusion, a 22-year-old woman with relapsed B-cell acute lymphoblastic leukemia develops a fever of 39.2 degrees Celsius and hypotension that responds to intravenous fluids; she requires low-flow supplemental oxygen. Her neurological examination is normal. Infection is being evaluated concurrently. Which targeted treatment is most appropriate?
A) Dexamethasone alone, treating this as neurotoxicity.
B) No treatment, since fever after CAR-T never requires intervention.
C) Tocilizumab (an anti-IL-6-receptor antibody), because fever with fluid-responsive hypotension and a normal neurological examination fits cytokine release syndrome; corticosteroids are added for higher-grade or refractory disease.
D) A GnRH agonist to blunt the inflammatory surge.
E) Levothyroxine, to correct a presumed thyroid cause.
ANSWER: C
Rationale:
Fever with fluid-responsive hypotension and a normal neurological examination is the picture of cytokine release syndrome, the IL-6-driven syndrome, so the targeted treatment is tocilizumab, with corticosteroids added for higher-grade or refractory disease. The normal neurological exam argues against ICANS.
Option A: Option A is incorrect because there are no neurological findings to indicate ICANS, so steroid-first neurotoxicity treatment does not fit.
Option B: Option B is incorrect because cytokine release syndrome can be serious and this presentation requires treatment while infection is evaluated.
Option D: Option D is incorrect because GnRH agonists are prostate cancer therapies with no role in cytokine release syndrome.
Option E: Option E is incorrect because there is no evidence of thyroid dysfunction, and levothyroxine does not treat cytokine release syndrome.
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