Table 2. Summary of checkpoint inhibitor toxicity management (13-15).
| Toxicity | REMS/clinical algorithm summary | Our recommendations |
|---|---|---|
| Dermatologic | ||
| Grade 2: (I) non-localized rash (diffuse, ≤50% of skin surface); (II) CTCAE grade 2 maculopapular rash [10-30% of body surface area with or without symptoms (pruritus, burning, tightness) and limiting instrumental ADL] | • Workup: physical exam for signs/symptoms and surface area of erythematous and/or maculopapular rash | • Workup: physical exam for signs/symptoms and surface area of erythematous and/or maculopapular rash |
| • Immunotherapy: withhold therapy and resume when mild severity or resolution. If systemic steroids initiated, resume when steroid daily dose is ≤7.5 mg prednisone or equivalent | • Immunotherapy: (I) if asymptomatic and rash <30% of body surface area: consider continuing immunotherapy with initiation and response to supportive care; (II) if symptomatic and rash 10-30% of body surface area: withhold therapy and resume when mild severity or resolution | |
| • Initial treatment: administer topical and/or systemic corticosteroids at 0.5-1 mg/kg/day if there is no improvement within 1 week. Taper over 1 month | • Initial treatment: (I) if <10% of body: administer an oral/topical histamine-1 blocker (diphenhydramine or hydroxyzine) and topical steroid (betamethasone 0.1% cream); (II) if 10-30% of body and affecting ADL: administer the same treatment for <10% of body with consideration for the addition of low-dose steroids (e.g., 0.5-1 mg/kg/day prednisone or equivalent) | |
| • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | |
| Grade 3 or 4: (I) generalized exfoliative, full thickness dermal ulceration, ulcerative or bullous dermatitis, skin necrosis, SJS, or TEN; (II) inability to reduce corticosteroid dose to 7.5 mg daily prednisone or equivalent; (III) CTCAE grade ≥3 maculopapular rash (>30% body surface area with or without symptoms; limiting self-care ADL) | • Workup: consider dermatology consultation and biopsy | • Workup: consider hospital admission and dermatology consultation and biopsy |
| • Immunotherapy: permanently discontinue | • Immunotherapy: permanently discontinue | |
| • Initial treatment: administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity. Taper over at least 1 month | • Initial treatment: administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity. Taper over at least 1 month | |
| Diarrhea | ||
| Grade 1: <4 stools/day over baseline | • Immunotherapy: continue therapy • Initial treatment: initiate supportive care management such as bowel rest and hydration |
• Workup: stool studies (Clostridium difficile infection, lactoferrin, ova and parasites), CBC with differential, CMP, magnesium and phosphorus |
| • Immunotherapy: continue therapy | ||
| • Initial treatment: (I) avoid antidiarrheal treatment (loperamide, diphenoxylate/atropine) if possible (may mask higher grade toxicity); (II) initiate supportive care management (oral hydration, bland diet); (III) treat based on stool study results and avoid reflex steroids for stable patients until results available: (i) negative stool studies and patient not on opioids: follow closely at each visit, and advise patients to call if symptoms worsen; (ii) negative stool studies and patient on opioids: follow patient closely with contact by clinic nurse to patient 3 times/week; (iii) positive stool studies: treat with standard of care in REMS/clinical algorithms and consider continuing ipilimumab until ongoing symptoms >7 days | ||
| Grade 2: (I) 4 to 6 stools/day over baseline; (II) abdominal pain; (III) blood or mucus in stool | • Workup: rule out bowel perforation and other causes (infection) | • Workup: same as grade 1 recommendations plus stool culture • Immunotherapy: withhold therapy and resume when mild severity or resolution. If systemic steroids initiated, resume when steroid daily dose is ≤7.5 mg prednisone or equivalent • Initial treatment: (I) avoid antidiarrheal treatment if possible; (II) initiate supportive care management (oral hydration and bland diet); (III) treat based on stool study results and avoid reflex steroids for stable patients until results available: (i) negative stool studies and patient not on opioids: continue immunotherapy; patient should be contacted by a clinical nurse 3 times/week; (ii) negative stool studies and patient on opioids: consider gastroenterology or immunotherapy specialist consultation; (iii) positive stool studies: treat with standard of care in REMS/clinical algorithms and consider continuing ipilimumab until ongoing symptoms >7 days. If symptoms persist, obtain flexible sigmoidoscopy to evaluate for colitis and steroid initiation. Patient may require additional imaging (e.g., CT scan of abdomen/pelvis) |
| • Immunotherapy: withhold therapy and resume when mild severity or resolution. If systemic steroids initiated, resume when steroid daily dose is ≤7.5 mg prednisone or equivalent | ||
| • Initial treatment: (I) initiate supportive care management; (II) administer antidiarrheal treatment (loperamide, diphenoxylate/atropine); (III) if ongoing symptoms >1 week, administer systemic corticosteroids at 0.5 mg/kg/day prednisone or equivalent | ||
| • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | ||
| Grade 3 or 4: (I) ≥7 stools/day over baseline; (II) peritoneal signs consistent with bowel perforation; (III) ileus; (IV) fever | • Workup: (I) consider gastroenterology consultation and endoscopic evaluation; (II) consider surgical consultation for persistent diarrhea or if ileus present despite maximal medical and supportive therapy | • Workup: (I) same as grade 2 recommendations; (II) admit to hospital and start intravenous hydration (e.g., normal saline at 125 mL/hour) |
| • Immunotherapy: permanently discontinue | • Immunotherapy: permanently discontinue | |
| • Initial treatment: (I) administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity or resolution. Taper over 1 month. Do not administer if bowel perforation; (II) consider infliximab 5 mg/kg ×1 dose or other immunosuppressive agent if symptoms are not relieved with 5 days of high-dose corticosteroids unless bowel perforation or sepsis | • Initial treatment: (I) treat based on stool study results and avoid reflex steroids for stable patients until results available; (II) clinically unstable: administer methylprednisolone 125 mg IV for 3 days, evaluate response, then slow taper starting at 1-2 mg/kg prednisone or equivalent over at least 1 month; (III) clinically stable: gastroenterology consultation for consideration of flexible sigmoidoscopy without initiation of steroids if able to evaluate within 24 hours, then follow the standard of care in REMS/clinical algorithms. If infliximab is required, consider repeat dose after 2 weeks if high-grade symptoms persist. Mycophenolate mofetil may be considered for selected patients; (IV) consider antibiotics if fever/leukocytosis | |
| Hepatic | ||
| Grade 2: (I) AST or ALT >2.5 to ≤5× ULN; (II) total bilirubin elevation >1.5× but ≤3× ULN | • Workup: (I) Rule out infectious or malignant causes; (II) increase frequency of liver function test monitoring until resolution to daily to every 3 days | • Workup: (I) rule out infectious or malignant causes; (II) increase frequency of liver function test monitoring until resolution to every 3 days; (III) consider additional labs: rule out ANA and SMA, CBC with differential, CMP, direct and indirect bilirubin, GGT |
| • Immunotherapy: withhold therapy and resume if liver function tests are mild severity or return to baseline | • Immunotherapy: withhold and resume if liver function tests are mild severity or resolution or return to baseline | |
| • Initial treatment: if no improvement after increased liver function test monitoring, administer systemic corticosteroids at 0.5-1 mg/kg/day prednisone or equivalent and continue until improvement to mild severity or resolution. Taper over 1 month |
• Initial treatment: if no improvement after increased liver function test monitoring, administer systemic corticosteroids at 0.5-1 mg/kg/day prednisone or equivalent and continue until improvement to mild severity or resolution. Taper over 1 month | |
| • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | |
| Grade 3 or 4: (I) AST or ALT >5× ULN; (II) total bilirubin >3× ULN | • Workup: (I) consider hepatology/gastroenterology consultation and liver biopsy; (II) increase frequency of liver function test monitoring until resolution to every 1-2 days | • Workup: (I) admit to hospital if AST/ALT > 8× ULN and administer methylprednisolone 125 mg IV daily for at least 5 days; (II) consider hepatology/gastroenterology consultation and liver biopsy; (III) increase frequency of liver function test monitoring until resolution to daily; (IV) same additional labs as grade 2 recommendations with consideration of additional imaging (e.g., CT scan of abdomen/pelvis) • Immunotherapy: permanently discontinue • Initial treatment: if no response to initial methylprednisolone dose, symptoms are ongoing after 3-5 days, or refractory to steroid taper, follow the standard of care in REMS/clinical algorithms and consider alternative immunosuppressive therapy (e.g., mycophenolate mofetil 500 mg orally every 12 hours) |
| • Immunotherapy: permanently discontinue | ||
| • Initial treatment: administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity or resolution. Taper over 1 month | ||
| • Follow-up: consider alternative immunosuppressive therapy if symptoms are ongoing after 3-5 days or refractory to steroid taper | ||
| Endocrine | ||
| Grade 2: (I) Signs and/or symptoms of dysfunction; (II) endocrinopathies requiring hormone replacement or medical intervention | • Workup: (I) evaluate endocrine function (TSH, free T4, T3, cortisol, ACTH, LH, FSH, prolactin, testosterone) as indicated; (II) consider radiographic pituitary gland imaging; (III) rule out infectious, malignant and medication causes | • Workup: (I) evaluate endocrine function (TSH, free T4, T3, cortisol, ACTH, LH, FSH, prolactin, testosterone) as indicated; (II) consider radiographic pituitary gland imaging; (III) rule out infectious (sepsis), malignant (progression), and medication causes |
| • Immunotherapy: withhold therapy and resume if symptoms have improved to mild severity, resolve, or are stable on hormone replacement therapy | • Immunotherapy: withhold therapy and resume if symptoms have improved to mild severity, resolve, or are stable on hormone replacement therapy; can consider continuing immunotherapy with initiation and response to hormone replacement | |
| • Initial treatment: (I) administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity, resolve, or return to baseline. Taper over 1 month. If systemic steroids initiated, resume when steroid daily dose is ≤7.5 mg prednisone or equivalent; (II) administer systemic corticosteroids at 1-2 mg/kg/day prednisone or equivalent and continue until improvement to mild severity, resolve, or return to baseline. Taper over 1 month; (III) Initiate appropriate hormone replacement therapy | • Initial treatment: treat based on symptoms and suspected endocrinopathy: (I) hyperthyroidism (TSH decreased; tremors, insomnia, hypertension): (i) continue immunotherapy, and consider endocrinology consultation if symptoms persist; (ii) consider a short period of 1 mg/kg prednisone or equivalent for acute thyroiditis presenting as hyperthyroidism; (II) hypothyroidism (TSH increased with low T4; skeletal discomfort and fatigue): continue immunotherapy and consider endocrinology consultation if symptoms persist; (III) hypophysitis (fatigue, fever, headaches, visual field defects): (i) obtain additional labs (TSH, cortisol, ACTH, LH, FSH, prolactin, testosterone), MRI brain with and without contrast with pituitary cuts, and endocrinology consultation; (ii) administer methylprednisolone 125 mg IV daily or dexamethasone 6 mg IV every 6 hours for 3 days. If improved, change to oral prednisone 1-2 mg/kg daily. Taper over 1 month with follow-up every 2 weeks or more frequently if unstable. If no improvement, continue 2 more days of intravenous steroid and obtain endocrinology consultation; (IV) primary/secondary hypoadrenalism (hypotension, fatigue, weakness, decreased sodium and increased potassium): (i) obtain additional labs (ACTH, cortisol) and endocrinology consultation; (ii) initiate prednisone 60-80 mg daily. Taper over 1 month; (V) pancreatic insufficiency/diabetes (polydipsia, polyuria, blurry vision): (i) obtain glucose to evaluate for hyperglycemia and endocrinology consultation; (ii) if diarrhea is present due to suspected pancreatic insufficiency, obtain stool studies and gastroenterology consultation | |
| • Follow-up: if symptoms worsen, continue to grade 3 or 4 management | • Follow-up: following treatment and resolution, consider repeat labs in 1-3 weeks and/or imaging in 1 month | |
| Grade 3 or 4: (I) adverse reactions requiring hospitalization, urgent medical intervention, or interfering with ADL (including adrenal crisis); (II) inability to reduce corticosteroid daily dose to 7.5 mg prednisone or equivalent | • Workup: (I) consider endocrine consultation; (II) rule out sepsis | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: permanently discontinue | ||
| • Initial treatment: (I) administer high-dose systemic corticosteroids (e.g., methylprednisolone 2 mg/kg/day IV every 12 hours or equivalent) and continue until improvement (may need permanent steroid and hormone replacement therapy); (II) if suspicion of adrenal crisis, administer stress dose of steroids with mineralcorticoid activity | ||
| Respiratory | ||
| Grade 2: mild to moderate new symptoms; medical intervention indicated or limiting instrumental ADL (pneumonitis) | • Workup: (I) consider hospitalization and pulmonary consultation; (II) consider bronchoscopy and lung biopsy; (III) radiographic imaging every 1-3 days | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: withhold therapy and resume if symptoms are mild severity, resolve, or return to baseline | ||
| • Initial treatment: administer methylprednisolone 1 mg/kg/day IV or oral equivalent and continue until improvement to mild severity. Taper over 1 month | ||
| Grade 3 or 4: severe or life-threatening new symptoms; new/worsening hypoxia; limiting self-care ADL; oxygen indicated; respiratory compromise with urgent intervention | • Workup:(I) admit to hospital; (II) consider pulmonary and infectious disease consultations; (III) consider bronchoscopy and lung biopsy; (IV) radiographic imaging every 1-3 days | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: permanently discontinue | ||
| • Initial treatment: (I) administer methylprednisolone 2-4 mg/kg/day IV or equivalent and continue until improvement to mild severity. Taper over at least 6 weeks; (II) consider alternative immunosuppressive therapy if symptoms are ongoing after 48 hours, worsening, or refractory to steroid taper | ||
| Renal | ||
| Grade 1: Serum creatinine > ULN and ≤1.5× above baseline (CTCAE grade 1 creatinine elevation) | • Workup: Monitor creatinine at least weekly | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: Continue therapy | ||
| • Initial treatment: If creatinine worsens, treat as grade 2 or 3/4 | ||
| Grade 2 to 3: Serum creatinine >1.5× above baseline to ≤6× ULN (CTCAE grade 2 to 3 creatinine elevation) | • Workup: Monitor creatinine at least every 2-3 days | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: Withhold therapy and resume if symptoms are mild severity, resolve, or return to baseline | ||
| • Initial treatment: (I) Administer methylprednisolone 0.5 to 1 mg/kg/day IV or equivalent and continue until improvement to mild severity. Taper over 1 month; (II) if creatinine increased >7 days or symptoms worsen, treat as grade 4 | ||
| Grade 4: Serum creatinine >6× ULN (CTCAE grade 4 creatinine elevation) | • Workup: (I) Monitor creatinine daily; (II) consider nephrologist consultation with consideration of renal biopsy | Same as standard of care in REMS/clinical algorithms |
| • Immunotherapy: Permanently discontinue | ||
| • Initial treatment: Administer methylprednisolone 1 to 2 mg/kg/day IV or equivalent and continue until improvement to mild severity. Taper over at least 1 month | ||
REMS, Risk Evaluation and Mitigation Strategy; CTCAE, Common Terminology Criteria for Adverse Events; ADL, activities of daily living; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; CBC, complete blood count; CMP, complete metabolic panel; CT, computed tomography; IV, intravenously; AST, aspartate aminotransferase; ALT, alanine transaminase; ULN, upper limit of normal; ANA, antinuclear antibodies; SMA, smooth muscle antibody; GGT, glutamyl transferase; TSH, thyroid stimulating hormone; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; MRI, magnetic resonance imaging.