Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 1 Management of Immune Checkpoint Inhibitor Toxicities – Adult – Inpatient/Ambulatory/Emergency Department Clinical Practice Guideline Note: Active Table of Contents – Click each header below to jump to the section of interest Table of Contents INTRODUCTION ............................................................................................................. 3 SCOPE ............................................................................................................................ 3 DEFINITIONS ................................................................................................................. 3 RECOMMENDATIONS ................................................................................................... 5 METHODOLOGY .......................................................................................................... 21 COLLATERAL TOOLS & RESOURCES (AS APPROPRIATE) .................................. 22 REFERENCES .............................................................................................................. 24 Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 2 Content Expert(s): Name: Elizabeth Dow, PharmD, BCOP - Pharmacy Phone Number: (608) 265-1650 Email Address: edow@uwhealth.org Contact for Changes: Name: Philip Trapskin, PharmD, BCPS - Pharmacy Phone Number: (608) 263-1328 Email Address: ptrapskin@uwhealth.org Guideline Author(s): Jason Bergsbaken, PharmD, BCOP – Pharmacy Elizabeth Dow, PharmD, BCOP, BCPS – Pharmacy Daniel Kapp, PharmD – Pharmacy Ticiana Leal, MD – Hematology/Oncology Catherine Renna, PharmD – Pharmacy Reviewer(s): Mark Albertini, MD – Medicine – Hematology/Oncology Diane Elson, MD – Endocrinology Mary Mably, RPh, BCOP – Pharmacy Committee Approval(s): Chemotherapy Council Subcommittee (05/09/2018) Pharmacy & Therapeutics Committee (05/17/2018) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 3 Introduction Immune checkpoint inhibitors (ICPIs) are a class of agents approved for the treatment of cancer and act by indirectly mediating T-cell immune responses against tumors. The first ICPI, ipilimumab, was approved in 2011 for the treatment of metastatic melanoma. As of January 2018, there are 6 ICPIs approved by the FDA to treat more than 10 different malignancies. Immune checkpoint inhibitors have a unique side effect profile and cause many different toxicities referred to as immune-related adverse events (irAEs). The most common irAEs include rash and pruritus, diarrhea and colitis, endocrine abnormalities, and liver dysfunction.1 Less common toxicities include pneumonitis and cardiac dysfunction.2 Toxicities are similar amongst the agents, however, incidence varies. For example, ipilimumab, a cytotoxic T- lymphocyte antigen-4 (CTLA-4) inhibitor, has higher rates of irAEs than pembrolizumab and nivolumab, programmed cell death-1 (PD-1) inhibitors. The rate of grade 3 or 4 toxicities for CTLA-4 inhibitors has been 20-30% compared to 10-15% for PD-1 inhibitors.3-5 The combination of CTLA-4 and PD-1 inhibitors has the highest rates of irAEs.1 However, these can occur at any time during treatment and can be seen as a late toxicity, even after discontinuation of therapy. Most toxicities occur within weeks to 3 months after initiation of ICPIs. Most irAEs are mild in severity; however, some can progress and become severe enough to require hospital admission, discontinuation of the agent, and death. For the most part, severe and life- threatening toxicities can be avoided if identified early and managed appropriately and, fortunately, the rate of treatment-related death is ≤2%.4,6 Scope Intended User(s): Physicians, advanced practice providers, pharmacists, and registered nurses Objective(s): To provide clinicians with the most effective therapeutic recommendations for monitoring, identification, grading, and treatment to optimize management of irAEs Target Population: Adult patients in the following settings: inpatient, emergency department, ambulatory clinics Clinical Questions Considered:  When should immune checkpoint inhibitor therapy be continued, held, and resumed?  What is the starting dose of steroids for irAEs?  How long should corticosteroids be tapered over?  When is the patient considered to have steroid-refractory toxicity?  What are treatment options for steroid-refractory toxicities? Definitions Table 1. Abbreviations ACTH: adrenocorticotropic hormone ICPI(s): immune checkpoint inhibitor(s) CBC: complete blood count irAE(s): immune-related adverse event(s) CMP: complete metabolic panel IV: intravenous CMV: cytomegalovirus LFTs: liver function tests CRP: C-reactive protein LH: luteinizing hormone CTCAE: Common Terminology Criteria for Adverse Events By mouth: PO CTLA-4: cytotoxic T-lymphocyte antigen-4 PD-1: programmed cell death-1 ESR: erythrocyte sedimentation rate PD-L1: programmed cell death ligand 1 FSH: follicle stimulating hormone TSH: thyroid stimulating hormone HRT: hormone replacement therapy Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 4 1. Hypothyroidism: Low free T4 with elevated TSH or TSH > 10 with normal free T47 2. Prednisone equivalents a. Corticosteroid recommendations in the guideline are referred to in Prednisone equivalents b. For ease of conversion from intravenous to oral route, a 1:1 conversion is appropriate Table 2. Corticosteroid Equivalents Corticosteroid Equivalent Dose (mg) Prednisone 5 Methylprednisolone 4 Dexamethasone 0.75-1 Hydrocortisone 20 3. Pancreatitis defined as the presence of 2 of the following 3 features:1 a. Clinical symptoms b. Radiographic findings of inflamed pancreas c. Elevated amylase and lipase 4. Pituitary axis blood tests7 a. 9 am cortisol (or random if unstable patient) b. ACTH, TSH/free T4, LH, FSH c. Oestradiol if premenopausal women d. Testosterone in men e. Prolactin 5. Topical steroid potency Table 3. Potency of Common Topical Corticosteroids8 Potency (level) Intensity Medication Name Dosage vehicle Strength Least potent (VII) Mild Hydrocortisone C, L, O 0.5-2.5% Low (VI) Desonide G, L, O 0.05% Fluocinolone acetonide C 0.01% Medium (IV and V) Moderate Betamethasone valerate C, L 0.1% Fluocinolone acetonide C, O 0.025% Fluticasone propionate C 0.005% Mometasone furoate C, L, O 0.1% Triamcinolone C, L, O 0.025-0.1% Medium to high (III) Betamethasone dipropionate C 0.05% Fluticasone propionate O 0.005% Triamcinolone C, O 0.5% High (II) High Augmented betamethasone dipropionate C, L 0.05% Betamethasone dipropionate O 0.05% Fluocinonide C, G, O 0.05% Ultra-high (I) Augmented betamethasone dipropionate G, O 0.05% Clobetasol C, G, L, O 0.05% Fluocinonide C 0.1% Halobetasol C, O 0.05% C=cream, G=gel, L=lotion, O=ointment Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 5 Recommendations General – Immune-related adverse events 1. Patients should be evaluated for risk of developing irAE prior to starting ICPI therapy7 (UW Health GRADE low quality evidence, strong recommendation) 2. Patients, family, and caregivers should receive education about ICPI mechanism of action and toxicity profile prior to starting therapy and throughout treatment7,9 (UW Health GRADE low quality evidence, strong recommendation) 3. Suspected irAEs should be evaluated to rule out other etiologies7 (UW Health GRADE low quality evidence, strong recommendation) 4. Confirmed irAEs should be managed based on severity and grading7 (UW Health GRADE low quality evidence, strong recommendation) 4.1. All irAEs should be graded using the most updated version of CTCAE7,10 (UW Health GRADE low quality evidence, strong recommendation) 5. Corticosteroid use in the management of irAEs 5.1. Corticosteroids may be administered for most grade ≥2 toxicities9 (UW Health GRADE low quality evidence, weak recommendation) 5.2. Corticosteroid doses are provided in prednisone equivalents. Corticosteroid dose equivalents should be used when appropriate9 (UW Health GRADE low quality evidence, strong recommendation) 5.2.1. NOTE: for ease of conversion from IV to oral route, a 1:1 conversion is appropriate 5.3. Consider corticosteroid taper when symptoms improve to grade ≤19 (UW Health GRADE low quality evidence, weak recommendation) 5.4. If symptoms worsen, re-escalate corticosteroid dose to last dose resulting in stable or improvement in toxicity7 (UW Health GRADE low quality evidence, weak recommendation) 6. ICPI treatment may be resumed at the discretion of the treating provider if all of the following are true11 (UW Health GRADE low quality evidence, weak recommendation) 6.1. irAE reverts to grade 1 or improves to baseline 6.2. Systemic steroid dose is reduced to ≤ 10 mg per day prednisone or equivalent 6.3. Absence of other concurrent immunosuppressive agents for treatment of irAEs 7. ICPI treatment may be permanently discontinued at the discretion of the treating provider for the following irAEs11 (UW Health GRADE low quality evidence, strong recommendation) 7.1. Life-threatening (grade 4) toxicities 7.1.1. In general, grade 4 toxicities warrant permanent discontinuation, with the exception of endocrinopathies that have been controlled by hormone replacement9 (UW Health GRADE low quality evidence, weak recommendation) 7.2. Moderate to severe (grade 2-3) toxicities that require prolonged steroid taper (>3 months) or flare during steroid taper 8. Refer to toxicity-specific treatment for better guidance on appropriateness of ICPI rechallenge9 (UW Health GRADE low quality evidence, weak recommendation) 9. Supportive care 9.1. Pneumocystis jiroveci prophylaxis should be considered in patients anticipated to receive ≥20 mg daily of prednisone or equivalent for ≥4 weeks12 (UW Health GRADE low quality evidence, strong recommendation) 9.2. Gastrointestinal prophylaxis in high risk patients or in patients receiving high dose corticosteroids (≥1 mg/kg prednisone or equivalent)13 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 6 9.3. Blood glucose monitoring should be considered in patients on corticosteroids7 (UW Health GRADE low quality evidence, weak recommendation) 9.4. Vitamin D and calcium monitoring may be considered in patients on corticosteroids7 (UW Health GRADE low quality evidence, weak recommendation) 9.4.1. Vitamin D and calcium supplementation may be considered in patients with prolonged corticosteroid use9 (UW Health GRADE low quality evidence, weak recommendation) Skin Toxicities Diagnostic work-up of skin toxicities 1. Alternative etiologies such as infection, adverse effects from another drug, or contact dermatitis should be ruled out7 (UW Health GRADE low quality evidence, strong recommendation) 2. Consider directed serologic studies if an autoimmune condition is suspected such as lupus or dermatomyositis9 (UW Health GRADE low quality evidence, weak recommendation) 3. Consider skin biopsy for grade ≥2 toxicity7,9 (UW Health GRADE low quality evidence, weak recommendation) 4. A full review of patient medications should be completed to rule out other drug-induced causes9 (UW Health GRADE low quality evidence, weak recommendation) 5. Dermatology consultation may be considered for grade 2-3 and should be considered for grade 4 skin toxicities7 (UW Health GRADE low quality evidence, strong recommendation) 6. Dermatologic emergencies such as Stevens-Johnson syndrome/toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and Sweet syndrome should be ruled out7 (UW Health GRADE low quality evidence, strong recommendation) Management of rash and dermatitis 1. General management for all grades 1.1 Nonpharmacological interventions should be employed in all patients7 (UW Health GRADE low quality evidence, strong recommendation) 1.1.1 Educate patients to avoid skin irritants and sun exposure; topical emollients are recommended 1.2 Topical or oral antihistamines such as diphenhydramine and hydroxyzine hydrochloride should be used for itching1,7 (UW Health GRADE low quality evidence, strong recommendation) 1.2.1 Diphenhydramine 1-2% cream, apply topically to affected area 3-4 times per day as needed for itching 1.2.2 Diphenhydramine 25-50 mg PO every 4-6 hours needed for itching 1.2.3 Hydroxyzine 25 mg PO 3-4 times per day as needed for itching 2. Grade 1 2.1 ICPI treatment may be continued7 (UW Health GRADE low quality evidence, strong recommendation) 2.2 Mild to moderate potency topical corticosteroid creams may be used for localized itching or rash7,8 (UW Health GRADE low quality evidence, strong recommendation) 3.1.1 See Table. 3 Potency of Common Topical Corticosteroids 3. Grade 2 3.1 ICPI treatment may be continued; however, skin toxicity should be monitored weekly7,9 (UW Health GRADE low quality evidence, weak recommendation) 3.1.1 If symptoms worsen or persist for 1-2 weeks, ICPI treatment should be withheld7,9 (UW Health GRADE low quality evidence, strong recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 7 3.1.1.1 If symptoms worsen or persist for 1-2 weeks despite withholding ICPI treatment, systemic corticosteroids may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 3.1.1.2 Prednisone 1 mg/kg once daily PO for 3 days then taper over at least 4 weeks may be considered7,9 (UW Health GRADE low quality evidence, weak recommendation) 3.2 Moderate to high potency topical corticosteroid creams may be used for localized itching or rash7,8 (UW Health GRADE low quality evidence, strong recommendation) 3.2.1.1 See Table. 3 Potency of Common Topical Corticosteroids 4. Grade 3 4.1 ICPI treatment should be withheld and may be permanently discontinued1,2,7 (UW Health GRADE low quality evidence, weak recommendation) 4.2 High intensity topical corticosteroid creams may be used for localized itching or rash (See Table. 3 Potency of Common Topical Corticosteroids)7,8 (UW Health GRADE low quality evidence, strong recommendation) 4.3 Systemic corticosteroids should be initiated7,9 (UW Health GRADE low quality evidence, weak recommendation) 4.3.1 Prednisone 1-2 mg/kg IV or PO once daily may be considered7 (UW Health GRADE low quality evidence, weak recommendation) 4.3.1.1 Corticosteroids should be tapered over at least 4 weeks when skin toxicity improves to baseline2,7 (UW Health GRADE low quality evidence, weak recommendation) 5. Grade 4 5.1 Hospital admission is recommended9 (UW Health GRADE low quality evidence, strong recommendation) 5.2 Dermatology consultation is recommended9 (UW Health GRADE low quality evidence, strong recommendation) 5.3 ICPI treatment should be withheld and may be permanently discontinued1,2,7 (UW Health GRADE low quality evidence, weak recommendation) 5.4 High intensity topical corticosteroid creams may be used for localized itching or rash (See Table. 3 Potency of Common Topical Corticosteroids)7,8 (UW Health GRADE low quality evidence, strong recommendation) 5.5 Systemic corticosteroids should be initiated7,9 (UW Health GRADE low quality evidence, weak recommendation) 5.5.1 Prednisone 1-2 mg/kg IV or PO once daily may be considered7 (UW Health GRADE low quality evidence, weak recommendation) 5.5.1.1 Corticosteroids should be tapered over at least 4 weeks when skin toxicity improves to baseline2,7 (UW Health GRADE low quality evidence, weak recommendation) 6. Rechallenge ICPI after skin toxicity 6.1 Consider alternative antineoplastic therapy over resuming ICPI if skin toxicity does not resolve to grade ≤1. If ICPI is only treatment option, consider restarting once resolved to grade 19 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 8 Table 4. Summary of Recommendations for Management of Skin Toxicities Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper R a s h D e rm a ti ti s 1 Continue NR - - 2 Continue/Hold Consider 1 mg/kg ≥4 weeks Consider steroids for persistent symptoms 3 Hold Initiate 1-2 mg/kg ≥4 weeks 4 Hold or Permanently discontinue Initiate 1-2 mg/kg ≥4 weeks Hospital admission Dermatology consultation *Doses reported in prednisone equivalents Abbreviations: ICPI, immune checkpoint inhibitor; NR, not recommended Diarrhea/colitis Diagnostic work-up of diarrhea/colitis 1. Consider CBC, CMP, magnesium, phosphate, TSH, ESR, and CRP9 (UW Health GRADE low quality evidence, weak recommendation) 2. Alternative etiologies such as infection or disease progression should be ruled out7 (UW Health GRADE low quality evidence, strong recommendation) 2.2 Consider culture and/or stool analysis for enteropathogens (Clostridium difficile, enteric bacterial pathogens, CMV or other viral pathogens, ova and parasitic infections) for all patients7,9 (UW Health GRADE low quality evidence, strong recommendation) 3. Consider testing for lactoferrin and calprotectin9 (UW Health GRADE low quality evidence, weak recommendation) 4. Consider imaging of the abdomen and pelvis9 (UW Health GRADE low quality evidence, weak recommendation) 5. Consider endoscopy/sigmoidoscopy/colonoscopy with biopsy in patients without clear etiology for diarrhea or with severe diarrhea or persistent grade 2 diarrhea7,9 (UW Health GRADE low quality evidence, strong recommendation) 6. Gastroenterology consultation is recommended for grade ≥29 (UW Health GRADE low quality evidence, strong recommendation) Management of diarrhea/colitis immune-related toxicity 1. Grade 1 1.1 ICPI treatment may be continued7 (UW Health GRADE low quality evidence, strong recommendation) 1.2 Monitor for dehydration and consider increase in oral fluid intake and other dietary changes7,9,14 (UW Health GRADE low quality evidence, strong recommendation) 1.3 Antidiarrheal agents may be considered if infection has been ruled out7 (UW Health GRADE low quality evidence, strong recommendation) 1.3.1 Antidiarrheal agents should be used with caution and with careful monitoring due to the risk of GI perforation 1.3.2 Use of antidiarrheal agents should be avoided in patients with suspected GI perforation 1.3.3 Examples of antidiarrheal agents include 1.3.3.1 Loperamide 2 mg tablets, 1-2 tablets PO every 6 hours as needed up to 8 tablets per day 1.3.3.2 Diphenoxylate-atropine 2.5-0.025 mg tablets or diphenoxylate-atropine 2.5- 0.025 mg/5 mL, every 6 hours as needed up to 20 mg of diphenoxylate per day Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 9 1.4 Treatment may be escalated to grade 2, if grade 1 toxicity persists for >14 days9 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 2 2.1 ICPI treatment should be withheld7 (UW Health GRADE low quality evidence, weak recommendation) 2.1.1 May consider permanently discontinuing CTLA-4 agents9 (UW Health GRADE low quality evidence, weak recommendation) 2.2 Monitor for dehydration and consider increase in oral fluid intake and other dietary changes7,9,14 (UW Health GRADE low quality evidence, strong recommendation) 2.3 Antidiarrheal agents may be considered if infection is ruled out7 (UW Health GRADE low quality evidence, weak recommendation) 2.3.1 Antidiarrheal agents should be used with caution and with careful monitoring due to the risk of GI perforation 2.3.2 Use of antidiarrheal agents should be avoided in patients with suspected GI perforation 2.4 Systemic corticosteroids should be initiated unless diarrhea is transient7 (UW Health GRADE low quality evidence, strong recommendation) 2.4.1 Prednisone 1 mg/kg once daily PO7,9,15 (UW Health GRADE low quality evidence, weak recommendation) 2.4.1.1 If no improvement in 3 days after initiation of corticosteroids, treatment should be escalated to grade 32 (UW Health GRADE low quality evidence, weak recommendation) 2.4.2 Corticosteroids may be tapered over 4-6 weeks once symptoms resolve to grade 12 (UW Health GRADE low quality evidence, weak recommendation) 3. Grade 3 3.1 Consider hospital admission for patients with dehydration or electrolyte imbalance9 (UW Health GRADE low quality evidence, weak recommendation) 3.2 ICPI treatment should be withheld7 (UW Health GRADE low quality evidence, weak recommendation) 3.3 Monitor for dehydration and consider increase in oral fluid intake and other dietary changes7,9,14 (UW Health GRADE low quality evidence, strong recommendation) 3.4 Systemic corticosteroids should be initiated7,15 (UW Health GRADE low quality evidence, strong recommendation) 3.4.1 Prednisone 1-2 mg/kg IV or PO once daily may be considered7,15 (UW Health GRADE low quality evidence, weak recommendation) 3.4.1.1 If symptoms persist ≥3-5 days despite oral prednisone, consider administering prednisone IV9 (UW Health GRADE low quality evidence, weak recommendation) 3.4.1.2 If symptoms persist ≥3-5 days despite IV prednisone, consider administering noncorticosteroid (see Steroid-refractory Colitis)9 (UW Health GRADE low quality evidence, weak recommendation) 3.5 Corticosteroid may be switched to oral after improvement in symptoms7 (UW Health GRADE low quality evidence, weak recommendation) 3.6 Corticosteroids may be tapered over at least 4-6 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 4. Grade 4 4.1 Hospital admission is recommended9 (UW Health GRADE low quality evidence, strong recommendation) 4.2 ICPI treatment should be permanently discontinued9 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 10 4.3 Monitor for dehydration and consider increase in oral fluid intake and other dietary changes7,9,14 (UW Health GRADE low quality evidence, strong recommendation) 4.4 Systemic corticosteroids should be initiated7,15 (UW Health GRADE low quality evidence, strong recommendation) 4.4.1 Prednisone 1-2 mg/kg IV once daily may be considered7,15 (UW Health GRADE low quality evidence, weak recommendation) 4.4.1.1 If symptoms persist ≥2-3 days, consider administering noncorticosteroid (see Steroid-refractory Colitis)9 (UW Health GRADE low quality evidence, weak recommendation) 4.5 Corticosteroid may be switched to oral after improvement in symptoms7 (UW Health GRADE low quality evidence, weak recommendation) 4.6 Corticosteroids may be tapered over at least 4-6 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 5. Steroid-refractory colitis 5.1 If no improvement in ≥3-5 days (≥2-3 days for life-threatening symptoms) after initiation of corticosteroids then infliximab may be considered7,9 (UW Health GRADE low quality evidence, weak recommendation) 5.1.1 Infliximab 5 mg/kg IV for 1 dose may be considered7,15 (UW Health GRADE low quality evidence, weak recommendation) 5.1.2 Infliximab may be redosed in 14 days if needed7,15 (UW Health GRADE low quality evidence, weak recommendation) 5.1.3 Vedolizumab may be an alternative to infliximab7,16 (UW Health GRADE very low quality evidence, weak recommendation) 5.1.4 Tacrolimus and mycophenolate may be considered in steroid- and infliximab- refractory colitis2 (UW Health GRADE very low quality evidence, strong recommendation) Table 5. Summary of Recommendations for Management of Diarrhea/Colitis Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper C o li ti s D ia rr h e a 1 Continue NR - - Escalate to grade 2 if symptoms persist >14 days 2 Hold Initiate 1 mg/kg 4-6 weeks Escalate to grade 3 if no improvement in >3 days 3 Hold Initiate 1-2 mg/kg ≥4-6 weeks Consider hospital admission Consider infliximab if symptoms worsen or persist ≥3-5 days 4 Permanently discontinue Initiate 1-2 mg/kg ≥4-6 weeks Hospital admission recommended Consider infliximab if symptoms persist ≥2-3 days *Doses reported in prednisone equivalents Abbreviations: ICPI, immune checkpoint inhibitor; MMF, mycophenolate mofetil; NR, not recommended; Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 11 Hepatotoxicity Diagnostic work-up of hepatitis 1. Consider LFTs and total bilirubin9 (UW Health GRADE low quality evidence, weak recommendation) 2. Alternative etiologies such as infection (viral hepatitis), disease-related causes, thromboembolic events, concomitant drug administration, and alcohol abuse should be ruled out7 (UW Health GRADE low quality evidence, strong recommendation) 3. Consider liver biopsy for grade ≥37,9 (UW Health GRADE low quality evidence, weak recommendation) 4. Consider hepatology consultation7 (UW Health GRADE low quality evidence, strong recommendation) 4.1 Hepatology consultation is recommended in grade 3-49 (UW Health GRADE low quality evidence, strong recommendation) Management of hepatotoxicity secondary to immunotherapy 1. Grade 1 1.1 ICPI treatment may be continued7 (UW Health GRADE low quality evidence, weak recommendation) 1.2 Consider monitoring LFTs and total bilirubin 1-2 times weekly9 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 2 2.1 ICPI treatment should be withheld7 (UW Health GRADE low quality evidence, strong recommendation) 2.2 If the patient is clinically stable, it is reasonable to hold off on initiation of corticosteroids and monitor transaminases and total bilirubin twice weekly2,7 (UW Health GRADE low quality evidence, weak recommendation) 2.3 Systemic corticosteroids should be initiated if there is evidence of worsening toxicity or in persistent grade 2 toxicity lasting longer than 1-2 weeks7 (UW Health GRADE low quality evidence, strong recommendation) 2.3.1 Prednisone 0.5-1 mg/kg once daily PO should be considered7,9 (UW Health GRADE low quality evidence, strong recommendation) 2.4 Consider monitoring LFTs and total bilirubin every 3 days9 (UW Health GRADE low quality evidence, weak recommendation) 2.5 Corticosteroids may be tapered over ≥4 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 2.6 In persistent or worsening hepatotoxicity, ICPI treatment may be permanently discontinued2,7 (UW Health GRADE low quality evidence, weak recommendation) 3. Grade 3-4 3.1 Hospital admission is recommended9 (UW Health GRADE low quality evidence, weak recommendation) 3.2 Consider transfer to tertiary care facility9 (UW Health GRADE low quality evidence, weak recommendation) 3.3 ICPI treatment should be permanently discontinued9 (UW Health GRADE low quality evidence, weak recommendation) 3.4 Systemic corticosteroids should be initiated7 (UW Health GRADE low quality evidence, strong recommendation) 3.4.1 Prednisone 1-2 mg/kg IV or PO once daily9 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 12 3.4.2 If no improvement in 2-3 days, consider mycophenolate mofetil or azathioprine (see Steroid-refractory hepatotoxicity)9 (UW Health GRADE low quality evidence, weak recommendation) 3.4.2.1 NOTE: If using azathioprine, test for thiopurine methyltransferase deficiency 3.5 Corticosteroids may be tapered over 4-6 weeks7,9 (UW Health GRADE low quality evidence, weak recommendation) 4. Steroid-refractory hepatotoxicity 4.1 If symptoms worsen or persist for 2-3 days despite initiation of corticosteroids, consider mycophenolate mofetil or azathioprine1,7,9 (UW Health GRADE low quality evidence, weak recommendation) 4.1.1 Mycophenolate mofetil 1000 mg twice daily PO 4.1.2 Azathioprine 1 mg/kg/day PO 4.1.2.1 NOTE: If using azathioprine, test for thiopurine methyltransferase deficiency 4.2 Higher doses of prednisone and antithymocyte globulin have been used in clinically unstable patients17 (UW Health GRADE very low quality evidence, weak recommendation) 4.3 Infliximab is contraindicated in cases of hepatitis1,9 (UW Health GRADE low quality evidence, strong recommendation) Table 6. Summary of Recommendations for Management of Hepatotoxicity Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper H e p a ti ti s 1 Continue NR - - 2 Hold Consider 0.5-1 mg/kg ≥4 weeks Consider steroids for worsening or persistent symptoms 3-4 Permanently discontinue Initiate 1-2 mg/kg 4-6 weeks Hospital admission recommended Consider AZA/MMF if no improvement in 2-3 days *Doses reported in prednisone equivalents Abbreviations: AZA, azathioprine; ICPI, immune checkpoint inhibitor; MMF, mycophenolate mofetil; NR, not recommended; Hypophysitis Diagnostic work-up of hypophysitis 1. A pituitary axis blood test assessment should be sent7 (UW Health GRADE low quality evidence, strong recommendation) 2. Evaluate morning ACTH and cortisol levels, TSH, free T4, and electrolytes9 (UW Health GRADE low quality evidence, weak recommendation) 3. May consider LH, FSH, testosterone/estrogen9 (UW Health GRADE low quality evidence, weak recommendation) 4. Consider brain MRI if significant symptoms or severe headache/vision changes9 (UW Health GRADE low quality evidence, weak recommendation) 5. Endocrinology consultation is recommended9 (UW Health GRADE low quality evidence, strong recommendation) Management of hypophysitis 1. Grade 1-2 1.1 ICPI may be withheld until patient is stabilized on replacement hormones9 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 13 1.2 Hormonal supplementation as needed using dosing recommendations from adrenal insufficiency and hypothyroidism9 (UW Health GRADE low quality evidence, weak recommendation) 1.2.1 Cortisol replacement should be administered 24-48 hours prior to initiation of levothyroxine2,9,18 (UW Health GRADE low quality evidence, strong recommendation) 1.1 May consider estrogen and testosterone replacement therapy as needed in those without contraindications9 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 3-4 2.1 ICPI treatment should be withheld until patient is stabilized on replacement hormones9,19 (UW Health GRADE low quality evidence, weak recommendation) 2.2 Hormonal supplementation as needed using dosing recommendations from adrenal insufficiency and hypothyroidism9 (UW Health GRADE low quality evidence, weak recommendation) 2.2.1 Cortisol replacement should be administered 24-48 hours prior to initiation of levothyroxine2,9,18 (UW Health GRADE low quality evidence, strong recommendation) 2.3 Consider estrogen and testosterone replacement therapy as needed in those without contraindications9 (UW Health GRADE low quality evidence, weak recommendation) 2.4 Consider initial pulse dose therapy with prednisone 1-2 mg/kg IV once daily2,9,19,20 (UW Health GRADE low quality evidence, weak recommendation) 2.4.1 NOTE: this is for treatment of hypophysitis, not replacement corticosteroid therapy 2.5 Corticosteroids may be tapered over 1-2 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 2.5.1 Corticosteroids should not be discontinued7 (UW Health GRADE low quality evidence, strong recommendation) 9 (UW Health GRADE low quality evidence, weak recommendation) 2.5.1.1 Maintenance HRT with hydrocortisone or prednisone may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 2.5.1.1.1 Example dosing of HRT 2.5.1.1.1.1 Hydrocortisone 10 mg PO in the morning and 5 mg PO in the afternoon 2.5.1.1.1.2 Prednisone 5 mg PO once daily *Doses reported in prednisone equivalents Abbreviations: HRT, hormone replacement therapy; ICPI, immune checkpoint inhibitor; NR, not recommended Table 6. Summary of Recommendations for Management of Hypophysitis Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper H y p o p h y s it is 1-2 Hold Consider HRT - Hold ICPI until stable on replacement hormones Consider thyroid, estrogen, and testosterone replacement Taper steroids to maintenance dose of HRT 3-4 Hold Initiate HRT - Consider 1-2 mg/kg 1-2 weeks Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 14 Adrenal insufficiency Diagnostic work-up of adrenal insufficiency 1. Evaluate morning ACTH and cortisol levels9 (UW Health GRADE low quality evidence, weak recommendation) 1.1 Consider ACTH stimulation test for indeterminate results9 (UW Health GRADE low quality evidence, weak recommendation) 2. Consider BMP9 (UW Health GRADE low quality evidence, weak recommendation) 3. Endocrinology consultation is recommended9 (UW Health GRADE low quality evidence, strong recommendation) Management of adrenal insufficiency 1. Grade 1 1.1 ICPI may be withheld until patient is stabilized on HRT9 (UW Health GRADE low quality evidence, weak recommendation) 1.2 Maintenance HRT with hydrocortisone or prednisone may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 1.2.1 Example dosing of HRT 1.2.1.1 Hydrocortisone 10 mg PO in the morning and 5 mg PO in the afternoon 1.2.1.2 Prednisone 5 mg PO once daily 1.3 Fludrocortisone 0.1 mg PO once daily may be considered for mineralocorticoid replacement9 (UW Health GRADE low quality evidence, weak recommendation) 1.4 Titrate doses up or down as symptoms dictate or as recommended by endocrinology9 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 2 2.1 ICPI may be withheld until patient is stabilized on replacement hormone therapy9 (UW Health GRADE low quality evidence, weak recommendation) 2.2 Consider corticosteroids at 2-3 times maintenance dose9 (UW Health GRADE low quality evidence, weak recommendation) 2.3 Taper corticosteroids down to maintenance dose over 5-10 days9 (UW Health GRADE low quality evidence, weak recommendation) 2.4 Maintenance HRT with hydrocortisone or prednisone may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 2.4.1 Example dosing of HRT 2.4.1.1 Hydrocortisone 10 mg PO in the morning and 5 mg PO in the afternoon 2.4.1.2 Prednisone 5 mg PO once daily 2.5 Fludrocortisone 0.1 mg PO once daily may be considered for mineralocorticoid replacement9 (UW Health GRADE low quality evidence, weak recommendation) 2.6 Titrate doses up or down as symptoms dictate or as recommended by endocrinology9 (UW Health GRADE low quality evidence, weak recommendation) 3. Grade 3-4 1. ICPI may be withheld until patient is stabilized on replacement hormone therapy9 (UW Health GRADE low quality evidence, weak recommendation) 2. Consider hospital admission especially if patient is hemodynamically unstable, vomiting, or unable to take medications PO9 (UW Health GRADE low quality evidence, weak recommendation) 3.2.1 Patients should be seen in clinic or the emergency department for initial management9 (UW Health GRADE low quality evidence, strong recommendation) 3. Aggressive fluid hydration with D5W, NS should be considered9 (UW Health GRADE low quality evidence, strong recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 15 3.1 Stress-dose corticosteroids should be initiated20 (UW Health GRADE low quality evidence, strong recommendation) 3.1.1 Examples include hydrocortisone 50 mg every 8 hours IV9 (UW Health GRADE low quality evidence, weak recommendation) 3.2 Taper corticosteroids down to maintenance dose over 7-14 days after discharge9 (UW Health GRADE low quality evidence, weak recommendation) 3.2.1 Maintenance HRT with hydrocortisone 20-30 mg PO in the morning and 10-20 mg PO in early afternoon may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 3.3 Fludrocortisone 0.1 mg PO once daily may be considered for mineralocorticoid replacement9 (UW Health GRADE low quality evidence, weak recommendation) 3.4 Titrate doses up or down as symptoms dictate or as recommended by endocrinology9 (UW Health GRADE low quality evidence, weak recommendation) *Doses reported in prednisone equivalents Abbreviations: HRT, hormone replacement therapy; ICPI, immune checkpoint inhibitor; NR, not recommended Hypothyroidism Diagnostic work-up of hypothyroidism 1. Monitor TSH and free T4 every 4-6 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 2. Consider endocrinology consultation for all grades9 (UW Health GRADE low quality evidence, weak recommendation) 2.1 Endocrinology consultation is recommended in grade 3-49 (UW Health GRADE low quality evidence, strong recommendation) Management of hypothyroidism 1. Grade 1 1.1 ICPI treatment may be continued for asymptomatic elevated TSH7,20 (UW Health GRADE low quality evidence, weak recommendation) 1.2 Consider obtaining thyroid peroxidase antibodies if recommended by endocrinology9 (UW Health GRADE low quality evidence, strong recommendation) 2. Grade 2-4 2.1 ICPI treatment may be withheld9 (UW Health GRADE low quality evidence, weak recommendation) 2.1.1 ICPI treatment may be resumed after thyroid hormone replacement is stabilized9 (UW Health GRADE low quality evidence, weak recommendation) 2.2 Consider hospital admission for IV therapy is signs if myxedema (bradycardia, hypothermia)9 (UW Health GRADE low quality evidence, weak recommendation) Table 6. Summary of Recommendations for Management of Endocrinopathies Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper A d re n a l In s u ff ic ie n c y 1 Hold Consider HRT - Hold ICPI until stable on HRT Consider fludrocortisone for mineralocorticoid replacement Taper steroids to maintenance dose of HRT 2 Hold Consider 2-3x HRT 5-10 days 3-4 Hold Initiate Stress dose 7-14 days Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 16 2.3 Levothyroxine 0.5-1.5 mcg/kg PO once daily should be initiated in symptomatic patients or in asymptomatic patients with TSH levels that persist >10 mIU/L7,9 (UW Health GRADE low quality evidence, strong recommendation) 2.3.1 Starting dose of levothyroxine 25-50 mcg PO once daily may be considered in patients with cardiac history9 (UW Health GRADE low quality evidence, weak recommendation) 2.3.1.1 Starting dose of levothyroxine 12.5-25 mcg PO once daily may be considered in elderly patients21 (UW Health GRADE low quality evidence, weak recommendation) Hyperthyroidism Diagnostic work-up of hyperthyroidism 1. Monitor TSH and free T4 every 4-6 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 2. Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease9 (UW Health GRADE low quality evidence, weak recommendation) 3. Consider endocrinology consultation9 (UW Health GRADE low quality evidence, weak recommendation) 3.1 Endocrinology consultation is recommended in grade 3-49 (UW Health GRADE low quality evidence, strong recommendation) Management of hyperthyroidism 1. Grade 1 1.1 ICPI treatment may be continued7 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 2 2.1 ICPI treatment may be withheld if the patient is symptomatic7 (UW Health GRADE low quality evidence, weak recommendation) 2.1.1 ICPI treatment may be resumed when symptoms resolve or are controlled7 (UW Health GRADE low quality evidence, weak recommendation) 2.2 A beta-blocker may be considered for symptomatic relief7 (UW Health GRADE low quality evidence, weak recommendation) 2.2.1 Propranolol IR, 10-40 mg PO 3-4 times per day22 (UW Health GRADE low quality evidence, weak recommendation) 2.2.2 Atenolol, 25-100 mg PO 1-2 times per day22 (UW Health GRADE low quality evidence, weak recommendation) 3. Grade 3-4 3.1 ICPI treatment may be withheld until symptoms return to baseline9 (UW Health GRADE low quality evidence, weak recommendation) 3.2 Hospital admission may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 3.3 A beta-blocker may be considered for symptomatic relief7 (UW Health GRADE low quality evidence, weak recommendation) 3.4 Prednisone 1-2 mg/kg IV once daily may be considered7,9 (UW Health GRADE low quality evidence, weak recommendation) 3.5 Taper corticosteroids over 1-2 weeks9 (UW Health GRADE low quality evidence, weak recommendation) 3.6 Methimazole or propylthiouracil may be considered23 (UW Health GRADE very low quality evidence, weak recommendation) 3.6.1 Check baseline CBC, ALT, and AST prior to initiation of therapy Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 17 4. NOTE: hyperthyroidism is often followed by hypothyroidism (see previous section for management) Type 1 diabetes mellitus Diagnostic work-up of diabetes mellitus 1. Monitor for hyperglycemia9 (UW Health GRADE low quality evidence, weak recommendation) 2. Laboratory monitoring in suspected type 1 diabetes should include ketone urine test and anion gap assessment9 (UW Health GRADE low quality evidence, weak recommendation) 3. Endocrinology consultation is recommended9 (UW Health GRADE low quality evidence, strong recommendation) Management of diabetes mellitus 1. In grade 1-2, ICPI treatment may be continued7 (UW Health GRADE low quality evidence, weak recommendation) 2. In grade 3-4, ICPI treatment may be withheld until glucose control is achieve7,19 (UW Health GRADE low quality evidence, weak recommendation) 3. Hyperglycemia should be management according to standard of care7 (UW Health GRADE low quality evidence, strong recommendation) 4. Corticosteroids will most likely negatively impact glucose control and should be withheld7 (UW Health GRADE low quality evidence, weak recommendation) Pancreatitis Diagnostic work-up of pancreatitis 1. Consider monitoring amylase and lipase if pancreatitis is clinically suspected9 (UW Health GRADE low quality evidence, weak recommendation) Management of Pancreatitis 1. In grade 1-2, ICPI treatment may be continued in asymptomatic patients24 (UW Health GRADE low quality evidence, weak recommendation) 2. In grade 3-4, ICPI treatment may be withheld until symptoms resolve24 (UW Health GRADE low quality evidence, weak recommendation) 3. Corticosteroids are not recommended in asymptomatic patients with modest elevations in amylase and lipase9 (UW Health GRADE low quality evidence, weak recommendation) 4. Consider corticosteroids in symptomatic patients1 (UW Health GRADE low quality evidence, weak recommendation) 5. Prednisone 1 mg/kg IV or PO once daily1 (UW Health GRADE low quality evidence, weak recommendation) Pneumonitis Diagnostic work-up of pneumonitis 1. Alternative etiologies such as infection and disease/treatment-related causes should be ruled out7 (UW Health GRADE low quality evidence, strong recommendation) 2. Consider chest x-ray, CT, pulse oximetry7,9 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 18 3. Initiation of treatment should not be delayed if there is no other apparent cause or if the patient is clinically unstable2,7 (UW Health GRADE low quality evidence, strong recommendation) 4. Consider bronchoscopy with bronchoalveolar lavage for grade ≥29 (UW Health GRADE low quality evidence, weak recommendation) 5. Pulmonary consultation is recommended9 (UW Health GRADE low quality evidence, strong recommendation) Management of pneumonitis 1. Grade 1 1.1 ICPI treatment may be withheld7 (UW Health GRADE low quality evidence, weak recommendation) 1.1.1 Considering resuming ICPI with radiographic evidence of improvement7,9 (UW Health GRADE low quality evidence, weak recommendation) 1.2 Symptoms should be monitored every weekly9 (UW Health GRADE low quality evidence, strong recommendation) 1.3 If symptoms worsen or no improvement, treatment should be escalated to appropriate grade of severity7,9 (UW Health GRADE low quality evidence, weak recommendation) 2. Grade 2 2.1 ICPI treatment should be withheld2,7 (UW Health GRADE low quality evidence, strong recommendation) 2.2 Consider initiation of systemic corticosteroids9 (UW Health GRADE low quality evidence, weak recommendation) 2.1.1.1 Prednisone 1-2 mg/kg IV or PO once daily may be considered7,9 (UW Health GRADE low quality evidence, weak recommendation) 2.1.1.1.1 Taper corticosteroids over 4-6 weeks1,7 (UW Health GRADE low quality evidence, strong recommendation) 2.1.1.2 If no improvement in symptoms for ≥2-3 days, manage as per grade 37,9 (UW Health GRADE low quality evidence, weak recommendation) 3. Grade 3 and 4 3.1 ICPI treatment should be permanently discontinued7 (UW Health GRADE low quality evidence, strong recommendation) 3.2 Systemic corticosteroids should be initiated7 (UW Health GRADE low quality evidence, strong recommendation) 3.2.1 Prednisone 1-2 mg/kg IV once daily may be considered9 (UW Health GRADE low quality evidence, weak recommendation) 3.2.2 If no improvement or worsening 48 hours after initiation of corticosteroids, additional immunosuppressive medications may be considered (see Steroid- refractory pneumonitis)7,25 (UW Health GRADE low quality evidence, weak recommendation) 3.2.3 Corticosteroids may be tapered over 4-6 weeks7 (UW Health GRADE low quality evidence, weak recommendation) 4. Steroid-refractory pneumonitis 1. If no improvement or worsening 48 hours after initiation of corticosteroids, additional immunosuppressive medications may be considered7,25 (UW Health GRADE low quality evidence, weak recommendation) 4.1.1 Infliximab or mycophenolate may be considered if concurrent hepatotoxicity7 (UW Health GRADE low quality evidence, weak recommendation) 4.1.2 Infliximab 5 mg/kg IV for 1 dose may be considered9 (UW Health GRADE low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 19 4.1.3 Mycophenolate mofetil 1000 mg twice daily may be considered9 (UW Health GRADE low quality evidence, weak recommendation) Table 7. Summary of Recommendations for Management of Pulmonary Toxicities P n e u m o n it is Grade ICPI Therapy Corticosteroids Comments Dose/Day* Taper 1 Hold NR - - Escalate treatment is symptoms persist 2 Hold Consider 1-2 mg/kg 4-6 weeks Treat as grade 3 if symptoms persist ≥2-3 days 3-4 Permanently discontinue Initiate 1-2 mg/kg 4-6 weeks Consider additional immunosuppressive agents if symptoms persist ≥48 hours *Doses reported in prednisone equivalents Abbreviations: ICPI, immune checkpoint inhibitor; NR, not recommended Cardiotoxicities Diagnostic work-up of cardiotoxicities 1. Consider checking echocardiogram and troponin at baseline9 (UW Health GRADE low quality evidence, weak recommendation) 2. Consider checking troponin, CK, and BNP, echocardiogram, CXR 9 (UW Health GRADE low quality evidence, weak recommendation) 2.1 Additional testing to be considered include stress test, cardiac catheterization, and cardiac MRI9 (UW Health GRADE low quality evidence, weak recommendation) 3. Alternative etiologies should be ruled out7 (UW Health GRADE low quality evidence, weak recommendation) 4. Cardiology consultation is recommended7,9 (UW Health GRADE low quality evidence, strong recommendation) Management of cardiotoxicities 1. ICPI therapy should be permanently discontinued7,26 (UW Health GRADE low quality evidence, weak recommendation) 2. Hospital admission is recommended9 (UW Health GRADE low quality evidence, strong recommendation) 2.1 Immediate transfer to coronary care unit for patients with elevated troponin or conduction abnormalities is recommended9 (UW Health GRADE low quality evidence, strong recommendation) 3. Symptom management with best standard of care7,26 (UW Health GRADE low quality evidence, weak recommendation) 4. Systemic corticosteroid should be initiated7,26 (UW Health GRADE low quality evidence, strong recommendation) 4.1 Methylprednisolone 1-2 mg/kg IV once daily may be considered26 (UW Health GRADE low quality evidence, weak recommendation) 5. If no response is appreciable in 24 hours, should consider early institution of cardiac transplant rejection protocol9 (UW Health GRADE low quality evidence, strong recommendation) 5.1 Should consider increase in methylprednisolone to 1000 mg IV once daily27,28 (UW Health GRADE low quality evidence, weak recommendation) 5.2 Should consider addition of either mycophenolate infliximab or antithymocyte globulin (equine)9,28 (UW Health GRADE very low quality evidence, weak recommendation) Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 20 Less common irAEs 1. Providers should refer to the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline for recommendations on the management of the following toxicities9 (UW Health GRADE low quality, weak recommendation) Table 8. Reported Immune-Related Adverse Events Acquired TTP Inflammatory arthritis Aplastic anemia Lymphopenia Aseptic meningitis Myasthenia gravis Autoimmune hemolytic anemia Myositis Autonomic neuropathy Nephritis Blepharitis Ocular toxicities Bullous Dermatoses Peripheral neuropathy Diabetes Polymyalgia-like syndrome Encephalitis SCARs (SJS, TENs, DRESS) Episcleritis Transverse myelitis Guillain-Barre Syndrome Uveitis/iritis Hemolytic uremic syndrome Venous thromboembolism Disclaimer Clinical practice guidelines assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 21 Methodology Development Process Each guideline is reviewed and updated a minimum of every 3 years. All guidelines are developed using the guiding principles, standard processes, and styling outlined in the UW Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup composition and recruitment strategies, disclosure and management of conflict of interest for participating workgroup members, literature review techniques, evidence grading resources, required approval bodies, and suggestions for communication and implementation. Methods Used to Collect the Evidence: The following criteria were used by the guideline author(s) and workgroup members to conduct electronic database searches in the collection of evidence for review. Literature Sources:  Electronic database search (e.g., PubMed)  Databases of systematic reviews (e.g., Cochrane Library)  Hand-searching journals, external guidelines, and conference publications Time Period: 2011 to 2018 Search Terms:  (Immunotherapy OR immune check point inhibitors OR PD-1 inhibitors OR CTLA-4 inhibitors OR pembrolizumab OR nivolumab OR ipilimumab OR atezolizumab OR avelumab OR durvalumab) AND (side effect OR adverse event OR adverse reaction OR toxicity) Methods to Select the Evidence:  Inclusion criteria o Population: Human subjects ≥18 years old o Study design: randomized controlled trials, metaanalysis, systematic review, case series, case reports, expert opinion o Language: English Methods Used to Formulate the Recommendations: The workgroup members agreed to adopt recommendations developed by external organizations and/or created recommendations internally via a consensus process using discussion of the literature and expert experience/opinion. If issues or controversies arose where consensus could not be reached, the topic was escalated appropriately per the guiding principles outlined in the UW Health Clinical Practice Guideline Resource Guide. Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations: Recommendations developed by external organizations maintained the evidence grade assigned within the original source document and were adopted for use at UW Health. Internally developed recommendations, or those adopted from external sources without an assigned evidence grade, were evaluated by the guideline workgroup using an algorithm adapted from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (see Figure 1). Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 22 Figure 1. GRADE Methodology adapted by UW Health Rating Scheme for the Strength of the Evidence/Recommendations: GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Very Low The true effect is likely to be substantially different from the estimated effect. GRADE Ratings for Recommendations For or Against Practice Strong The net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision. Weak/conditional Recommendation may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented. Recognition of Potential Health Care Disparities: Health care disparities exist in cancer care. Patients that are uninsured are less likely to receive proper cancer screening and express lower rates of delayed follow-up after any abnormal test results, which lead to diagnosis at more advanced stages. Furthermore, institutions most likely to serve minorities may not have as much access to state of the art diagnostic and therapeutic measures and the ability to participate in cancer clinical trials, affecting the overall quality of care. Additional factors that may influence outcomes of minorities include distrust of the health care system, stigmas related to cancer and death, literacy and language barriers, and poor expectations regarding the outcome from cancer care. Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 23 Collateral Tools & Resources The following collateral tools and resources support staff execution and performance of the evidence-based guideline recommendations in everyday clinical practice. Metrics  Adherence to guideline recommendations  Discontinuation (temporary or permanent) due to adverse drug events from immunotherapies (ie, PD/PD-L1 inhibitors, CTL-4 inhibitors)  Inpatient use of infliximab for severe colitis associated with immunotherapies Beacon Protocols: in development Smart Phrases: in development Reporting Workbench Reports Pharmacist Immune Checkpoint Inhibitor Medication Outreach Patients [4096556] Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 24 References 1. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA Oncol. 2016;2(10):1346-1353. 2. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51-60. 3. National Cancer Institute. Checking in on cancer checkpoint inhibitors. www.cancer.gov/news-events/cancercurrents- blog/2015/gulley-checkpoint. Accessed October 26, 2016. 4. Ventola CL. Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations. P t. 2017;42(7):452-463. 5. Helissey C, Vicier C, Champiat S. The development of immunotherapy in older adults: New treatments, new toxicities? J Geriatr Oncol. 2016;7(5):325-333. 6. Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(18):2004-2012. 7. Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. 8. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135-140. 9. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018:Jco2017776385. 10. Services UDoHaH. Common terminology criteria for adverse events (CTCAE) version 4.0: National Cancer Institute; 2009. 11. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559-574. 12. Baden LR, Swaminathan S. Prevention and Treatment of Cancer-Related Infections. NCCN Clinical Practice Guidelines in Oncology: National Comprehensive Cancer Network; 2017. 13. Guslandi M. Steroid ulcers: Any news? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2013;4(3):39-40. 14. Lalana-Josa P, Laclaustra-Mendizabal B, Aza-Pascual-Salcedo MM, Carcas-de- Benavides C, Lallana-Alvarez MJ, Pina-Gadea MB. [Does the prescribing of antibiotics in paediatrics improve after a multidisciplinary intervention?]. Enferm Infecc Microbiol Clin. 2015;33(2):78-83. 15. Gupta A, De Felice KM, Loftus EV, Jr., Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42(4):406-417. 16. Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother. 2017;66(5):581- 592. 17. Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29(9):e237-240. 18. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017;13(4):195-207. Effective 05/17/2018. Contact CCKM@uwhealth.org for previous versions. 25 19. Nivolumab: Immune-Mediated Adverse Reactions Management Guide: Bristol-Myers Squibb Company; 2017. 20. Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70-76. 21. Gharib H, Papini E, Garber JR, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ASSOCIAZIONE MEDICI ENDOCRINOLOGI MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND MANAGEMENT OF THYROID NODULES-- 2016 UPDATE. Endocr Pract. 2016;22(5):622-639. 22. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. 23. Rossi E, Sgambato A, De Chiara G. Thyroid-induced toxicity of check-point inhibitors immunotherapy in the treatment of advanced non-small cell lung cancer. Vol 3. Journal of Endocrinology and Diabetes2016. 24. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Translational Lung Cancer Research. 2015;4(5):560-575. 25. Naidoo J, Wang X, Woo K. Pneumonitis in Patients Treated With Anti–Programmed Death-1/Programmed Death Ligand 1 Therapy. Vol 35(7). Journal of Clinical Oncology2017. 26. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016;375(18):1749-1755. 27. Brustle K, Heidecker B. Checkpoint inhibitor induced cardiotoxicity: managing the drawbacks of our newest agents against cancer. Vol 8. Oncotarget2017. 28. Tay RY, Blackley E, McLean C, et al. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br J Cancer. 2017;117(7):921-924.