Acute and Long-term Adverse Events Associated With Checkpoint Blockade

ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2019) 150926

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Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing

Acute and Long-term Adverse Events Associated With Checkpoint Blockade Marianne Davies, DNP, AOCNP* Yale University School of Nursing, West Haven, CT and Yale Comprehensive Cancer Center, New Haven, CT

A R T I C L E

I N F O

Article History: Available online xxx Key Words: Immune checkpoint inhibitors ICPI Immune mediated adverse events Immune related adverse events IrAE

A B S T R A C T

Objective: To provide an overview of the spectrum of immune-related adverse events associated with immune checkpoint therapy, including presentation, evaluation, management, and nursing considerations. Data Sources: Peer-reviewed articles, published literature, national guidelines, Internet. Conclusion: Immune checkpoint inhibitor therapies are have become a therapeutic treatment options for many cancers. These therapies promote activity of a patient’s adaptive immune system to eradicate cancer. The agents are associated with a unique side-effect profile called Immune-related adverse events. Most of these are low severity. However, if they become more severe, they can be life-threatening or result in permanent organ dysfunction. The key to optimizing therapies is collaborative monitoring, evaluation, documentation, management, communication. Implications for Nursing Practice: Oncology nurses are the front line of patient care. Nurses must have a thorough understanding of the mechanism of action, potential immune-related adverse events, clinical implications, and management strategies. They are responsible for educating patients about immune checkpoint therapies and the potential side effects that may develop, triage management strategies, and coordination of care. © 2019 Elsevier Inc. All rights reserved.

Overview of Immune-Related Adverse Events Tumorigenesis is a multiphase process that promotes unleashed growth and metastasis. One process that supports tumorigenesis is the tumor’s ability to evade surveillance of the body’s immune system by exploiting checkpoint pathways. Immune checkpoints prevent T-cell activation, proliferation, and mediated inflammation. Tumors can exploit these checkpoints, preventing recognition by T cells. Immune checkpoint inhibitors (ICPI), such as anti-CTLA-4 and anti-PD-1/L1 inhibitors, block these pathways, allowing for anti-tumor immune response.1,2 In the process, this may allow for uncontrolled inflammation of any body tissue and development of adverse events. Immune-related adverse events (irAEs) occur in up to 90% of patients treated with ICPI, with more severe toxicities occurring in up to 13%.3 IrAEs occur more frequently and with greater severity with anti-CTLA-4 inhibitors that act in the primary lymphatic tissue, compared with anti-PD1/L-1 inhibitors that are active in the peripheral tissue and tumor microenvironment, with the highest irAE with combination blockade.4 10 The reported incidence of all-grade irAEs is 60% to 90% for antiCTLA-4 inhibitors versus 39% to 70% with anti-PD-1/L-1.5,11 The rate of Grade 3 irAEs reported is 14% with anti-PD-1/L1 inhibitors, 34% * Address correspondence to: Marianne Davies, DNP, AOCNP, Associate Professor, Yale University School of Nursing, PO Box 27399, West Haven, CT 06516-0972. E-mail address: [email protected] https://doi.org/10.1016/j.soncn.2019.08.005 0749-2081/© 2019 Elsevier Inc. All rights reserved.

with anti-CTLA-4 inhibitors, 55% with combination ICPI, and 46% with combination ICPI and chemotherapy.4,12 Higher-grade irAEs can lead to severe morbidity and fatality.13,14 The leading causes of fatality are gastrointestinal, pulmonary, cardiac, and hepatic toxicity, with higher fatal toxicity associated with the anti-CTLA-4 inhibitor ipilimumab versus anti-PD-1 inhibitors.15,16 Incidence is increased with higher doses of ipilimumab.15,17 IrAEs usually present within weeks to months after initiation of treatment; however, some can develop even after cessation of therapy (Fig. 1).7,10,18 General management strategies for irAEs will be reviewed, including strategies to manage refractory irAEs. A more in-depth overview of each organ system will be provided. This will include organ-specific strategies for prevention, anticipation, detection, grading, evaluation, and management of each irAE. In addition, specific nursing considerations will be highlighted.

General Management for Immune Checkpoint Therapy and IrAEs Effective management of irAE depends on early recognition and intervention. Champiat et al11 proposed five pillars for the management of patients on ICPI therapy: prevention, anticipation, detection, treatment, and monitoring (Fig. 2). This framework serves as a guide for nurses and other health care providers (HCPs) caring for patients on ICPI therapy. Strategies for prevention include the cautious selection of ICPI in high-risk patients and the education of all HCPs and

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Fig. 1. Timing of toxicities. (Reprinted with permission from Davies and Duffield. Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. Immunotargets and Therapy 2017;6:51-71.7)

patients about ICPI therapy. Patients must be educated about the spectrum of irAEs and the importance of communicating with HCPs about the development of any new or progressive symptoms. In anticipation of treatment, HCPs should evaluate the patient’s baseline physical function, including activities of daily living and independent activities of daily living. Organ function must be assessed through

laboratory and diagnostic evaluation. Early detection of an irAE is essential for proper management. HCPs should provide ongoing evaluation of patients for new or worsening symptoms or diagnostic changes. HCPs must consider all causes of symptoms, such as disease progression, disease regression, other medical conditions, or irAE. If an irAE is detected, treatment strategies should be initiated based on

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potential risk factors, interventions to minimize irAE, variability of onset and presentation, detection, and management strategies. Risk factors include pre-existing history of autoimmune conditions and use of medications that modulate the immune system (ie, immunosuppressants or immunostimulants) and organ transplant patients. Patients with pre-existing autoimmune disease may be at increases risk of developing an irAE or for flare of underlying condition.18,31 34 Key irAEs (dermatologic, gastrointestinal, pulmonary, endocrine, hepatic, renal musculoskeletal, neurologic, ocular, cardiac, and hematologic) will be described in more detail, synthesizing clinical practice guideline recommendations from AIM with Immunotherapy, American Society of Clinical Oncology, National Comprehensive Cancer Network, and European Society of Medical Oncology.10,11,19 25 Dermatologic

Fig. 2. Five Pillars of Immunotherapy Toxicity Management.

established guidelines. This may include withholding of ICPI, permanent discontinuation of ICPI, and/or initiation of immunosuppressant agent. HCPs must provide ongoing monitoring of the trajectory of an irAE for resolution or flare of the affected organ or other irAEs. The mainstay of irAE management is corticosteroid immunosuppressant therapy.11,19 The recommendations for management of irAEs are based on reports from clinical trials, case reports, and expert consensus clinical practice guidelines developed by professional organizations.10,19 24 Interventions are based on the severity or grade of irAE, as measured by the Common Terminology Criteria for Adverse Events (CTCAE).25 In general, for Grade 1 (mild) irAEs, ICPI therapy can continue with close monitoring and supportive interventions. ICPI is held for Grade 2 (moderate) irAEs, until improved to Grade 1 or less. If symptoms do not resolve in a week, prednisone/methylprednisolone (0.5 mg 1.0 mg/kg/d) is recommended until irAE improves to Grade 1. Re-initiation of ICPI therapy can be considered cautiously. For Grade 3/4 (severe/life threatening) irAE, ICPI therapy is permanently discontinued. Corticosteroid is initiated at 1.0 to 2.0 mg/kg/d until Grade 1, with consideration for hospitalization.7,26 Early retrospective studies suggest that use of corticosteroids to manage an irAE does not negatively impact overall survival benefit.27,28 However, baseline use of steroids (prednisone 10 mg/d) has led to decreased overall response rate, progression-free survival, and survival benefit.29 Specific management algorithms for each organ-specific irAE as well as nursing management of patients on corticosteroids will be outlined in more detail below. If an irAE is refractory to corticosteroid therapy, additional or alternative immunosuppressant therapy may be required. In addition to high numbers of regulatory T cells in inflamed tissues/organs, additional cytokines may be present that mediate the irAE. Tumor necrosis factor-alpha has been found in high concentrations in patients that have developed CTLA-4 induced colitis and may place patients at increased risk for steroid resistance.30 Infliximab, an anti-tumor necrosis factor, is recommended unless contraindicated (ie, hepatitis, tuberculosis, perforation, congestive heart failure).7,10,19,21 24,26 Infliximab is dosed at 5 mg/kg/IV. It may be repeated in 2 weeks if symptoms persist. Corticosteroid administration continues until irAE is Grade 1 or less. If time allows, testing for tuberculosis, HIV, and hepatitis A and B is recommended in patients at high risk for those infections. Additional immunomodulating agents include mycophenolate mofetil, intravenous immune globulin, anti-thymocyte globulin, and others. Organ-specific IrAEs Organ-specific irAEs can occur at any time from the start of ICPI therapy until years after completion. Nurses must be aware of

Dermatologic symptoms are the most common irAE reported, occurring in up to 24% receiving ipilimumab, 10% with PD-1/L-1 inhibitors,26 and 40% with combination checkpoint blockade.35 This may be underreportedbecause often patients are not undergoing a full-body exam at each visit. Patterns of dermatologic irAES include maculopapular rash, erythema, pruritis, oral mucositis, dry mouth, and vitiligo. The onset is usually within the first 2 months of therapy. HCPs must rule out other potential causes of dermatologic toxicity, such as contact dermatitis, other drug sensitivities, vasculitis, infectious etiologies, and exacerbation of underlying skin disorders. Topical steroids are recommended for mild symptoms, with systemic steroids for more severe. In cases of severe pruritis, National Comprehensive Cancer Network guidelines recommend consideration of GABA agonists, aprepitant or omalizumab.24 Grade-based strategies for the management of rash and pruritis are outlined in Table 1. Severe dermatologic reactions are rare, reported in up to 4% of patients. These include Steven-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug rash with eosinophilia and systemic symptoms), and acute febrile neutrophilic dermatosis (Sweet syndrome). These potentially life-threatening skin conditions require more aggressive medical interventions and permanent discontinuation of ICPI. Gastrointestinal Gastrointestinal irAE is often one of the first to occur. Diarrhea, colitis, and pancreatitis are the most common gastrointestinal irAEs. However, nausea, mucositis, esophagitis, and gastritis have been reported. Diarrhea is described as an increase in the number of stools per day. Colitis is the presence of diarrhea with abdominal pain, mucous or blood in the stool, and inflammation. Diarrhea is more frequent with anti-CTLA-4 (54%) compared with anti-PD-1/L-1 (19%). The rate is increased with combination therapy. The risk of colitis and death because of colon perforation is 4% and 1.1%, respectively.36,37 Utilization of nonsteroidal anti-inflammatory drugs (NSAIDS), proton pump inhibitors (PPIs), and selective serotonin reuptake inhibitors for greater than 4 months has been associated with increased risk of microscopic colitis in the general population, with risk increasing with combination use.38,39 Therefore, patients on NSAIDs, PPIs, and selective serotonin reuptake inhibitors may be at increased risk of ICPI colitis. Median time to onset is 5 to 10 weeks but can develop after several months (Fig. 1).7,40 Patients should be instructed to notify their HCP if they experience abdominal pain, nausea, cramps, blood or mucous in the stool, changes in bowel pattern, abdominal distension, increased gas, constipation, or fever. HCPs must rule out other causes of diarrhea, such as dietary intake, infectious etiology, and other inflammatory etiology. Lactoferrin and calprotectin (stool inflammatory markers) help to differentiate functional versus inflammatory diarrhea and may help predict responsiveness to corticosteroid therapy.41 Corticosteroids are recommended for 4 to 6 weeks after resolution. If refractory, additional immunosuppressant therapy with

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M. Davies / Seminars in Oncology Nursing 00 (2019) 150926

Table 1 Dermatologic toxicity: rash and pruritis. Prevention and anticipation Detect Grade

Onset average 3 6 weeks Assess for altered skin integrity prior to start of therapy Avoid skin irritants; avoid sun exposure; topical emollients recommended Assess for history of prior dermatologic conditions (eczema, psoriasis) Comprehensive skin exam, including the mucosa Measure % body distribution and severity 1 2 3 4 Macules/papules covering < 10% of BSA with or without symptoms (eg, pruritus, burning, tightness) No impact on quality of life

Macules/papules covering 10% 30% of BSA with or without symptoms (eg, pruritus, burning, tightness) Limiting IADLs

Macules/papules covering > 30% BSA with or without symptoms Limiting self-care ADL

Medical evaluation

Rule out other causes: viral illness, infection, other drug rash, contact dermatitis; flare of eczema, psoriasis Assess for blistering and lymphedema Laboratory: CBC, CMP, LFTs; serologic testing for autoimmune skin disorders Consider documentation of dermatologic toxicities with photographs Consider skin biopsy for Grade 3 or greater If autoimmune disorder is suspected (lupus), obtain antinuclear antibody test

Medical management

Continue ICPI Consider holding ICPI Topical steroids (mild to Topical steroids (moderate moderate strength) cream strength) +/- oral or topical +/- oral or topical antihist- antihistamine for itch to amines for pruritis affected areas Consider initiation of prednisone (or equivalent) 0.5 1.0 mg/kg/d. Consider dermatology consult Monitor weekly If unresponsive, treat as Grade 3

Nursing management

Encourage topical emollient lotions and use of sensitive skin products Educate patients to avoid skin irritants, hot showers, and sun exposure Monitor skin exam closely for potential progression of rash and skin reaction

Papulopustular rash associated with life-threatening superinfection Stevens-Johnson syndrome, TEN, and bullous dermatitis covering > 30% BSA and requiring ICU admission

HOLD ICPI HOLD ICPI Initiate IV methylprednisolone Topical high-potent steroid cream Initiate IV methylprednisolone 0.5 1.0 mg/kg 1.0 2.0 mg/kg Urgent dermatologic evaluation Consult with dermatology Resume when Grade 1 Consider inpatient admission Consider resuming ICPI therapy when Grade 1 and when steroids are reduced to prednisone equivalent 10 mg

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: BSA, body surface area; IADL, instrumental activities of daily living; TEN, toxic epidermal necrolysis; CBC, complete blood count; CMP, complete metabolic panel; ICPI, immune checkpoint inhibitors; LFTs, liver function tests.

infliximab may be indicated. Initiation of infliximab within 10 days of colitis may shorten the duration of symptoms and reduce hospitalization and steroid taper failure.42 Though continued dosing of infliximab has not been clearly researched in irAE colitis, clinical practice guidelines suggest that a second dose of infliximab may be administered 2 weeks following the first, if needed.21,24 Vedolizumab, a MoAb immunosuppressant that is specific to the gastrointestinal tract, is recommended if patients are refractory to infliximab or if a tumor necrosis factor-alpha blocker is contraindicated.43 Emerging data suggests that earlier initiation of alternative immunosuppressant agents (eg, infliximab, vedolizumab) without waiting for response to corticosteroids may lead to a more favorable recovery.42,44 Diarrhea/colitis management is outlined in Table 2. Pancreatic dysfunction is usually asymptomatic with normal pancreatic imaging. Reported rates of > Grade 3 serum lipase elevations are 0.9% to 3% with anti-CTLA-4 agent, 0.5% to 4% with anti-PD-L/L-1, and 1.2% to 8% with combination.45,46 Median time to onset is 46 days for anti-PD-L/L-1 and 69 days for anti-CTLA-4 monotherapy. Patients with prior history of pancreatitis, type II diabetes, and excessive alcohol use may be at higher risk.45 In general, recovery occurs with temporary hold of ICPI therapy. If the toxicity progresses to acute pancreatitis, immunosuppressant therapy is indicated. Pulmonary Pulmonary toxicities, though rare, are one of the most common causes of irAE death. The incidence is higher with anti-PD-L/L1 agents than with anti-CTLA-4 agents (2.92% v 1%).47 49 Higher rates are

reported with combination therapy48 and in patients with a history of smoking, pre-existing lung disease, or non small cell lung cancer.50,51 Patients with non small cell lung cancer are at increased risk of death because of pneumonitis.48 The median time to onset is 2 to 24 months. Presenting symptoms may be subtle, including unresolving cough, dyspnea, fever, and hypoxia. Increasing oxygen support and declining oxygen saturation should be evaluated in a timely fashion. Symptoms may mimic other pulmonary conditions such as infection, pulmonary embolism, pleural effusion, and pulmonary metastasis. In some cases, pneumonitis may appear on computed tomography scan before the onset of noticeable symptoms. Pneumonitis can progress rapidly to respiratory failure and death; therefore, ICPI should be held for any signs or evidence of pneumonitis while complete evaluation is undertaken. Management of pneumonitis is outlined in Table 3. Endocrine Endocrine irAEs are a unique toxicity of ICPI therapy affecting the thyroid, pituitary, and adrenal glands. Thyroid dysfunction occurs in 2% to 10% of patients on anti-PD-l/L-1 inhibitors and 1.5% to 6% treated with anti-CTLA-4 agents.6,52 It typically begins with thyrotoxicosis (decreased TSH, elevated free T4) and progresses to hypothyroidism within a few weeks.53 The incidence of hypophysitis (inflammation of the pituitary gland) is reported in 1% to 17% of those treated with ipilimumab, 0.2% to 1.5% with anti-PD-1/L-1 agents, and 4% to 12.8% with combination therapy.5,6,52,53 Hypophysitis may lead to secondary hypothyroidism, secondary adrenal insufficiency, and hypogonadism. Primary adrenal insufficiency occurs in < 1% with single-agent ICPI and 4%

ARTICLE IN PRESS M. Davies / Seminars in Oncology Nursing 00 (2019) 150926 Table 2 Gastrointestinal

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diarrhea +/- colitis.

Prevention and anticipation Detect

Grade

Onset typically 6 weeks Assure adequate hydration; instruct patients to avoid foods that cause loose stools; assess patient use of stool softeners and laxatives Calculate frequency and volume of stools in 24 hours, including ostomy and incontinence; assess for watery diarrhea, urgency, cramping, blood or mucous in stool, abdominal pain; stool pattern may be different in patients with opioid-induced constipation or sluggish bowel pattern 1 2 3 4  4 stools/day or increase in ostomy output over baseline Asymptomatic

4 6 liquid/soft stools/day or moderate increase in ostomy output over baseline Abdominal pain, blood or mucous in stool

7 stools/day; incontinence; significant increase in ostomy output over baseline Interference with ADLs

Peritoneal signs; lifethreatening

Medical evaluation

Obtain blood (CBC, CMP, LFTs, CRP, ESR, TSH), stool cultures to rule out other causes (leucocytes/ova/parasites, viral PCR, Clostridium difficile toxin, CMV and cryptosporidia) Consider calprotectin and lactoferrin (stool inflammatory markers) Monitor for electrolyte imbalances Consider abdominal/pelvic CT scan; consider colonoscopy and/or endoscopy

Medical management

Observation; anti-motility agents (loperamide or oral diphenoxylate atropine sulfate) once infection is ruled out Budesonide Anti-spasmodic

Nursing management

HOLD ICPI Prednisone 1 mg/kg/d If no response in 2 3 days, increased dose of steroid and consider infliximab Consider gastroenterology consult

Discontinue anti-CTLA-4; PD1/PD-L1 may be resumed after recovery to Grade 1

Permanently discontinue ICPI

Gastroenterology consult: Consider inpatient care; IV methylprednisolone 1 2 mg/kg/d; if no response in 2 3 days, continue steroids and consider adding infliximab; if refractory, or infliximab is contraindicated, consider vedolizumab Counsel patients to report any change in bowel pattern or associated symptoms Measure stool output; obtain stool cultures Advise patient on dietary modifications (bland diet; avoid high fiber/lactose, fats, caffeine, alcohol); may progress to NPO with Grade 4 Discontinue stool softeners and laxatives Advise patients to use opioids and other pain medications cautiously to avoid masking symptoms Promote hydration; assure IV access for hydration Contact patient every 48 hours to assess for change

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: CBC, complete blood count; CMP, complete metabolic panel; CT, computed tomography; LFTs, liver function tests; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TSH, thyroid stimulating hormone; CMV, cytomegalovirus; ICPI, immune checkpoint inhibitors.

to 8% with combination therapy.52 Type I diabetes mellitus is a rare irAE that can present with life-threatening diabetic ketoacidosis.6 It has been reported in 1.4% of patients treated with ipilimumab, 0.2% to 0.9%% with anti PD-1/L-1, and 5.2% to 7.6% with combination blockade.52 54 Endocrine irAEs may present with vague symptoms of fatigue, weakness, muscle aches, arthralgias, headache, vision changes, heart rate changes, increased sweating, weight gain or loss, feeling more hungry or thirsty, hair loss, feeling cold, heat intolerance, constipation, diarrhea, nausea, emesis, abdominal discomfort, loss of libido, dizziness, and fainting. Symptoms may reflect specific hormone deficiencies. Median time to onset is 8 to 12 weeks. Before the start of ICPI therapy, baseline serum electrolytes and thyroid function tests (TSH, free T4) should be obtained. If there is suspicion of endocrine irAE, additional hormone levels should be obtained (ie, ACTH, cortisol, FSH, LH, GH, prolactin, estrogen, and testosterone). Magnetic resonance imaging of the brain with pituitary/ sellar cuts is used to diagnose hypophysitis. However, pituitary enlargement is usually seen in the acute phase, but then decreases as loss of function occurs.6,53 Unlike other irAEs, endocrine irAEs (especially hypothyroidism and adrenal insufficiency) are chronic, requiring lifetime hormone replacement.55 In most cases, patients may continue ICPI therapy if deriving clinical benefit and do not require systemic steroids. Patients with diabetes should be counseled in dietary and lifestyle modifications. Those with adrenal insufficiency may require mineralocorticoid (fludrocortisone) in addition to glucocorticoid replacement. HCPs must be cautioned that in the case of adrenal insufficiency and other endocrine irAEs, steroids must be replaced prior to other hormonal replacement to avoid adrenal crisis.6,24,56 Management of endocrine irAEs is outlined in Table 4.

Hepatic Hepatic dysfunction is usually asymptomatic, detected by abnormalities in liver function tests. In rare cases of higher-grade dysfunction, symptoms may include nausea, emesis, pain in right side of abdomen, drowsiness, dark urine color, yellowing of skin or eyes, bleeding, or bruising. It is reported in 1% to 5% with anti-PD-1/L-1, 3% to 9% with anti-CTLA-4 agents, and up to 30% when administered in combination.57,58 Onset ranges from 6 to 14 weeks.7,17 HCPs should consider other potential causes that include hepatotoxic medications (including chemotherapy, acetaminophen, statins, over-the-counter medications, herbal supplements, contrast dye administration, alcohol, thromboembolic events, and viral infectious causes [CMV, hepatitis A, B, C]). Liver metastases and cholangitis should be ruled out. Liver function tests should be evaluated before the start of therapy and prior to each dose. Hepatic irAEs are treated with steroid immunosuppression. In the case of refractory or recurrent toxicity, mycophenolate mofetil is recommended. Infliximab is contraindicated because of the risk of liver failure. Management of hepatic irAE is outlined in Table 5. Renal Asymptomatic acute kidney injury is commonly identified with routine serum testing of creatinine and BUN. It is most prevalent with anti-CTLA-4 agents (4.9%), versus anti-PD-1/L-1 (1.4% 1.9%) and combination (2.2%).59 Although some report as high as 13.5%.60 It is likely underreported if changes in creatinine are subtle and baseline serum creatinine is low (0.4 0.6 mg/dL) and with low muscle mass because a rise in creatinine may still be within normal limits.61

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M. Davies / Seminars in Oncology Nursing 00 (2019) 150926 Table 3 Pulmonary toxicity: pneumonitis. Prevention and anticipation Assess for prior pulmonary conditions (asthma, COPD, pulmonary hypertension), prior chest irradiation, smoking, and travel history Monitor for new or worsening cough, chest pain, hypoxia, shortness of breath Detect Monitor pulse oximetry at rest and with ambulation prior to treatment initiation and each dose of ICPI Grade 1 2 3 4 Radiographic changes only confined to one lobe of lung or < 25% of parenchyma; Ground-glass change, non-specific interstitial pneumonia Asymptomatic

Life-threatening; ARDS Severe new symptoms; new or Mild/moderate symptoms: dysUrgent intervention indicated worsening hypoxia; pnea, cough, chest pain Involves all lung lobes or > 50% Involves 25% 50% of lung of lung parenchyma parenchyma Limiting self-care ADLs Medical intervention indicated; Oxygen indicated limiting instrumental ADLs

Medical evaluation

Rule out other causes: disease progression, lymphangitic spread, infection, pulmonary embolism, pleural effusion, radiation recall, sarcoidosis Laboratory: CBC, sputum culture, screening for viral, opportunistic or bacterial infection; nasal swab for viral pathogens CXR, CT scan with and without contrast, for full evaluation

Medical management

HOLD ICPI Reassess in 1 2 weeks Consider repeat CT in 3 4 weeks Resume ICPI with radiographic evidence of improvement. Monitor pulse oximetry

Nursing management

Provide oxygen support Assess pulse oximetry at rest and with ambulation Auscultate breath sounds Assure adequate hydration Reduce respiratory irritants Encourage smoking cessation

HOLD ICPI Prednisone 1 2 mg/kg/d and taper by 5 10 mg/week over 4 6 weeks Consider bronchoscopy with bronchoalveolar lavage Consider empiric antibiotics Monitor every 3 days; if no improvement after 48 hours of prednisone, treat as Grade 3 Repeat CT in 3 4 weeks; may consider resuming ICPI with radiographic evidence of improvement

Permanently discontinue ICPI Inpatient care Methylprednisolone 1 2 mg/kg/d; if no improvement in 48 hours, add infliximab 5 mg/kg or mycophenolate mofetil IV 1 gram twice daily Pulmonary and infectious disease consults Bronchoscopy

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: COPD, chronic obstructive pulmonary disease; ICPI, immune checkpoint inhibitors; CT, computed tomography; ARDS, acute respiratory distress syndrome; CBC, complete blood count; CXR, chest x-ray.

Acute kidney injury may be influenced by dehydration, sepsis, nephrotic drug exposure, contrast dye, antibiotics, ACE inhibitors, diuretics, PPIs, and chemotherapy. Median time to onset is 3 to 6 months.59 However, there have been cases reported after one dose of ICPI.62 Nephritis management is outlined in Table 6. Musculoskeletal Myalgias and arthralgias are common symptoms of patients in up to 40% treated on ICPI therapy. However, more severe irAEs that interfere with activities of daily living and independent activities of daily living occur in approximately 1% to 7% of patients.63 Arthralgias (inflammation of joints) may affect one joint or many, with mild discomfort to disabling limitations.63,64 Patients with pre-existing autoimmune rheumatic disease may be at risk for flare of their disease and symptoms when treated with ICPI therapy.65 The onset varies considerably from 1 to 24 months from start of therapy.66 Mild symptoms can be managed with NSAIDS. If arthritic symptoms persist, low-dose corticosteroids (prednisone 10 mg) may be initiated. For more severe cases, disease-modifying antirheumatic drugs such as hydroxychloroquine or methotrexate have been used to provide opportunity to taper steroids.64,67,68 Myositis is muscle inflammation with weakness and elevated muscle enzymes (CK), requires more aggressive management because cardiac myositis can be life-threatening.21,24 Management of arthralgias is outlined in Table 7. Neurologic Neurologic irAEs and paraneoplastic neurologic syndromes, though rare (<1%), include polyneuropathy, facial nerve palsy, Guillain-Barre syndrome, myasthenia gravis, encephalitis, aseptic

meningitis, motor neuropathy, and cerebellar ataxia.69 72 The rate may be higher with combination ICPI therapy.73 Neuropathies are the more common neurologic irAE and can present as symmetric or asymmetric, painful or painless, motor or sensory deficits. The time to onset is 6 to 12 weeks. There are some reports to suggest that patients who experienced neurotoxicity experienced durable responses to ICPI therapy.73,74 Swift treatment is essential for more severe paraneoplastic neurologic syndromes because they may lead to irreversible neurologic deficits.75 A full neurologic evaluation is warranted, which may include electromyography, magnetic resonance imaging of brain/spine, lumbar puncture, and EEG. Corticosteroid immunosuppression should be started for any Grade 2 or higher irAE. If there is no improvement in 2 to 3 days, additional immunosuppressant therapy is warranted. Intravenous immune globulin has been used to help mitigate the progress of severe paraneoplastic neurologic syndromes.75,76 In most cases, ICPI therapy is permanently discontinued. Table 8 provides an overview of the management of peripheral neuropathy. Ocular Ocular side effects, reported in < 1% of patients, can occur within weeks to months of ICPI therapy, with more frequency noted with anti-CTLA-4 agents.77 These include inflammation of any part of the eye, with uveitis being the most common.78 Dry eyes occurred in up to 24% of patients in clinical trials.79 Uveitis is most often anterior, but it can progress to posterior or pan uveitis. Symptoms include blurred vision, tenderness, eye pain, and swelling. Most ocular irAEs can be managed with topical or periorbital steroids, with more severe cases requiring systemic steroids.80 Artificial tears and topical

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Table 4 Endocrine toxicities. Hypothyroidism Prevention and anticipation Detect Grade

Medical evaluation

Obtain baseline thyroid function tests (TSH, free T4, free T3) Symptoms: unexplained fatigue, weakness, asthenia, dry skin, weight gain, hair loss, cold intolerance, constipation, or depression Thyroid function test evaluation every 4 6 weeks: high TSH, normal to low free T4 in primary hypothyroidism; low TSH and low free T4 indicates secondary because of hypophysitis; thyroid antibodies 1 2 3 4 Moderate symptoms; able to perform Severe symptoms; medically significant or TSH < 10 mIU/L and free T4 normal ADLs; TSH persistent > 10 mIU/L life-threatening; unable to perform ADLs range Asymptomatic Monitor TSH, free T4 every 4-6 weeks. Once stable, every 6 months; dose adjustment of levothyroxine every 4 6 weeks For patients with no risk factors, full replacement can be estimate with ideal body weight-based dosing of 1.6 mcg/kg/d For elderly or frail with multiple comorbidities, titrate dose starting at 25 50 mcg/d May hold ICPI until symptoms resolve to baseline Thyroid hormone replacement Consider endocrine consultation

Hold ICPI until symptoms resolve to baseline with hormone repletion Endocrine consultation May admit for medical management if signs of myxedema (changes in behavior, extreme fatigue, shortness of breath, swelling of hands or feet)

Medical management

Observation Continue ICPI Close monitoring of TSH and free T4

Nursing management

In the case of adrenal insufficiency and hypothyroidism, steroids must be given prior to thyroid replacement to avoid adrenal crisis Instruct patient to take thyroid replacement alone and on an empty stomach

Thyrotoxicosis Hyperthyroidism Prevention and anticipation Detect

Grade

Baseline thyroid function test (TSH, free T4, free T3) Symptoms: weight loss, palpitations, heat intolerance, excessive diaphoresis, tremors, anxiety, diarrhea Monitor TSH and free T4 every 4 6 weeks Low to normal TSH, elevated free thyroxine (T4), elevated free triiodothyronine (T3), thyroid antibodies, thyroid stimulating immunoglobulin (TSI); consider thyroid peroxidase (TPO) antibody Thyroid scan 1 2 3 4 Asymptomatic or mild symptoms

Medical evaluation

Moderate symptoms Severe symptoms; medically significant or Able to perform ADLs life-threatening; unable to perform ADLs Monitor TSH, free T4 every 2 3 weeks after diagnosis B-blockers for symptomatic relief; corticosteroids for severe symptoms; if Graves’ disease is detected, antithyroid agent (thionamide such as methimazole or PTU).

Medical management

Continue ICPI

Nursing management

Monitor symptoms closely as thyrotoxicosis usually transitions to hypothyroidism Monitor vital signs and ECG Assure adequate hydration and supportive care

Hypophysitis Prevention and anticipation Detect

Grade

Medical management

Nursing management

HOLD ICPI until symptoms resolve to baseline with appropriate therapy Endocrine consult For severe symptoms or concern for thyroid storm, hospitalize patient and initiate prednisone 1 2 mg/kg/d or equivalent

Assess for nausea, emesis, fatigue, anorexia, weakness, confusion, headaches, visual changes Evaluate for electrolyte imbalances, specifically hyponatremia; evaluate for secondary adrenal insufficiency and central hypothyroidism, monitor ACTH, cortisol, TSH, free T4 (low or normal TSH and low free T4; early morning low ACTH, low cortisol) Evaluate for secondary hypogonadism LH, FSH, prolactin, estradiol in females and testosterone in males; 1 2 3 4 Asymptomatic or mild symptoms

Medical evaluation

Consider holding ICPI until symptoms resolve to baseline Consider endocrine consult Beta-blockers for symptomatic relief

Moderate symptoms; able to perform ADL

MRI of brain with pituitary/sellar cuts Glucocorticoid and thyroid hormone replacement Testosterone and estradiol replacement considered Full work-up and laboratory confirmation cannot be done with morning cortisol if patient is on corticosteroids Consider holding ICPI until patient Consider holding ICPI until patient is stabilized on replacement is stabilized on replacement hormone hormone Endocrine vonsult Hormonal supplementation as Hormone supplementation as in Grade 1 needed, using dosing from hypothyroidism and adrenal insufficiency Testosterone and estrogen as needed Endocrine consult In the case of adrenal insufficiency and hypothyroidism, steroids must be given for several days prior to thyroid replacement to avoid adrenal crisis Instruct patient on stress dosing of steroids for illness Medical alert bracelet to be worn

Severe symptoms; medically significant or life-threatening consequences; unable to perform ADL

HOLD ICPI until patient is stabilized on hormone replacement therapy Endocrine consult Hormone supplementation as in Grade 1 Consider initial pulse dose therapy with prednisone 1 2 mg/kg tapered over 2 weeks

(continued)

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Table 4 (Continued) Adrenal insufficiency Prevention and anticipation Detect

Grade

Fatigue, nausea, hypotension, electrolyte imbalances (hyponatremia, hyperkalemia) Assess ACTH and cortisol (low or suppressed morning serum cortisol, high ACTH) Monitor for electrolyte disturbances; nausea, vomiting, fatigue, lethargy, confusion or coma Monitor for adrenal crisis: hypovolemic shock 1 2 3 Asymptomatic or mild symptoms

Medical evaluation

Medical management

Nursing management

Moderate symptoms; able to perform ADL

4

Severe symptoms; medically significant or lifethreatening consequences; unable to perform ADLs

If symptomatic, and/or low cortisol, high ACTH, administer cortisol replacement If diagnosis already made, stress dosing of corticosteroids can be with hydrocortisone However, if diagnosis is not yet made, treat with Decadron, as stimulation test can still be done Consider CT to rule out adrenal metastasis HOLD ICPI until patient is stabilized on replacement Consider holding ICPI until patient is stable Consider holding ICPI until patient hormone on replacement hormone is stable on replacement horEndocrine consultation Endocrine consult mones IV hydration with normal saline and IV stress dose Initiate treatment at 2 3 times mainteReplacement therapy with predcorticosteroids (hydrocortisone 100 mg or nance nisone 7.5 10 mg daily (taper to dexamethasone 4 mg) dosing to manage acute symptoms 5 mg Taper stress-dose corticosteroids over 7 10 days Taper stress-dosing down over 5 10 daily as able) or hydrocortisone Maintenance therapy as in Grade 1 days (10 20 mg orally every morning, Maintain maintenance 5 10 mg early afternoon May require fludrocortisone (0.1 mg/d) for mineralocorticoid replacement in primary adrenal insufficiency Titrate up or down based on blood pressure and symptoms Endocrine consultation In the case of adrenal insufficiency and hypothyroidism, steroids must be given prior to thyroid replacement to avoid adrenal crisis Educate patients about stress-dose steroids prior to procedures or in case of infection All patients should wear a medical alert bracelet

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: ICPI, immune checkpoint inhibitors; T3, triiodothyroinine; T4, thyroxine; TSH, thyroid stimulating hormone; CT, computed tomography; PTU, propylthiouracil; ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

cyclosporin have been used for dry eyes.81 Ophthalmologist should be consulted immediately because there is a risk for corneal perforation and permanent vision loss.81

panel, and bone marrow examination. Table 11 provides an algorithm for the assessment and management of hemolytic anemia. Nursing Considerations

Cardiac 82

Cardiac irAEs are extremely rare, occurring in < 0.1% of patients. However, it is imperative that HCPs be aware of these irAEs because there is a potential for life-threatening consequences. irAEs includes myocarditis, pericarditis, heart failure, and arrhythmias.83 The onset is as early as days after ICPI initiation. Patients must be educated to report any signs of chest pain, palpitations, shortness of breath, or edema. Hematologic Hematologic irAEs are rare at approximately 0.5%. 84 Hemolytic anemia is the most commonly reported hematologic toxicity, with higher reported cases associate with anti-PD-1/L-1.85 Onset is usually 1 to 2 months after start of therapy. It may be challenging to HCPs to attribute cause of the anemia in patients receiving combination chemotherapy and ICPI therapy. Immune-mediated hemolytic irAEs should be considered after ruling out other potential causes. Additional hematologic irAEs reported include hemophagocytic lymphohistiocytosis, acquired TTP, hemolytic uremic syndrome, aplastic anemia, neutropenia, and immune thrombocytopenia. 85 Evaluation includes a review of prior history of auto-immune hematologic disease, nutritional evaluation to rule out vitamin deficiency, complete blood count, peripheral blood smear, reticulocyte count, direct antiglobulin test, infection

Nurses are essential members of the health care team that support the patient’s ability to be treated safely on ICPI therapy. It is imperative that nurses understand the full spectrum of irAEs (ie, presentation, trajectory, organs involved), at-risk patient populations, methods of prevention, detection, and management.86 Nurses must educate patients about potential irAES, the symptoms to monitor for, and the need to report the onset of irAEs. Education enhances the patient’s and family’s ability to participate in the assessment, reporting, and management of potential irAEs.87 “Patient Action Plans” and the “Patient Resource Guide for Immunotherapy” are supporting patient education materials developed by AIM with Immunotherapy and the Society for Immunotherapy in Cancer, respectively. They are available online to support patient teaching.20,88 Nurses should document in the electronic medical record, in detail, the administration of ICPI therapy to assure timely communication with other HCPs.87 Patients should be encouraged to carry a wallet card that identifies their diagnosis, type of ICPI therapy, date of administration, and contact information for the treating health care team.89 Wallet cards are available online through professional organizations.90,91 The wallet card serves as an essential communicate tool with other HCPs about the unique side-effect profile of ICPIs and the need for coordinated specialized management. Telephone triage is often the first step in the assessment and detection of irAEs. Patients must be instructed to contact their health care team at the onset of symptoms. Nurses are usually the point

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Table 5 Hepatic toxicity. Prevention and anticipation Onset 8 12 weeks Limit hepatotoxic drugs; evaluate for prior history of viral hepatitis Detect Monitor LFTs (AST, ALT, total bilirubin), INR, albumin prior to each infusion Assess for symptoms: pruritic, change in stool, dark colored urine, abdominal pain, bruising or bleeding, change in mental status, ascites Grade 1 2 3 4

Medical evaluation Medical management

Nursing management

AST or ALT 5 to 20 x ULN, AST or ALT > 20 x ULN AST or ALT > ULN to 3 x ULN and AST or ALT > 3 x ULN but 5 x ULN, or total or total bilirubin and/or total bilirubin or total bilirubin > ULN bilirubin >1.5 X ULN 3 10 x ULN > 10 times ULN to 1.5 x ULN Asymptomatic but 3 x ULN Symptomatic Asymptomatic Rule out other causes: viral hepatitis, CMV reactivation, alcohol history, thromboembolic event, iron studies, liver metastasis If suspected autoimmune hepatitis, obtain CK, ANA, GGT Consider liver ultrasound May require liver biopsy Permanently discontinue ICPI HOLD ICPI and resume Permanent discontinuation Continue ICPI Administer corticosteroids if decreased to Grade 1 or less Administer corticosteroids Monitor labs 1 2 times 2.0 mg/kg/d on prednisone 10 mg/d 1.0 2.0 mg/kg/d If refractory weekly If refractory after 3 days consider Increase frequency of monitoring after 3 days consider mycofenelate mofetil labs (every 3 5 days) mycofenelate mofetil Monitor LFTs daily Administer corticosteroids Monitor LFTs Urgent referral to hepatologist 0.5 1.0 mg/kg/d every 1 2 days or gastroenterology Refer to hepatologist or gastroenterology Assure hydration Counsel patients to discontinue unnecessary medications that are known hepatotoxic agents, including over-the-counter, herbal, and nutritional supplements NOTE: Infliximab is contraindicated for use with hepatic irAE

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: ICPI, immune checkpoint inhibitors; irAE, immune-related adverse events; LFTS, liver function tests; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; CMV, cytomegalovirus; CK, creatine kinase; ANA, antinuclear antibody; GGT, gamma-glutamyl transferase.

of contact for patients on telephone triage. Telephone triage protocols can provide a framework for nurses to guide the assessment of symptoms and direct the appropriate intervention for management.92 This may include supportive interventions for low-grade irAES or evaluation at the treating facility for more serious irAEs.

Telephone triage guidelines for irAE have been developed by the Oncology Nursing Society93 and AIM with Immunotherapy.92 Moderate to severe irAEs will be treated with corticosteroid immunosuppressant therapy. Nurses must educate patients about the need to adhere to the steroid regime. Dosing is started at 0.5 to

Table 6 Renal toxicity: nephritis, acute kidney injury. Prevention and anticipation Assure adequate hydration; review for potential nephrotoxic agents (medications, chemotherapy, contrast dye) Detection Routine monitoring of serum creatinine and BUN before every infusion Evaluate for signs and symptoms: fatigue, nausea, weakness Assess for dehydration Grade 1 2 3 4 SCr Proteinuria

Medical evaluation Medical management

Nursing management

>1.5 x ULN

>1.5 3.0 x baseline, >1.5 3.0 x >3.0 x baseline, >3.0 6.0 x ULN >6.0 x ULN ULN Creatinine > 3 times baseline or Life-threatening consequences; dialysis Creatinine level increase of > 0.3 Creatinine 2 3 times above indicated >4.0 mg/dL; hospitalization baseline mg/dL; creatinine indicated Proteinuria 2+ and 3+, 1.5 2.0 times over baseline Proteinuria 4+, 3.5 g/24 hr 1.0 3.5 g/24 hr Proteinuria 1+, urine protein <1.0 g/24 hours Rule out urinary tract infection, dehydration, urinary tract obstruction Same as Grade 3 Permanently discontinue ICPI IV hydration Consider holding ICPI, pending If improved to Grade 1, taper steroids Admission for IV hydration HOLD ICPI evaluation of other causes over at least 4 weeks Steroids 1 2 mg/kg/d Consult nephrology Hydration If elevation persists > 2 3 days or If elevation persists > Consider hospitalization Discontinue nephrotoxic worsens, additional 3 5 days, add additional Discontinue nephrotoxic drugs immunosuppressant immunosuppressant drugs Refer to nephrology Corticosteroids 0.5 1 mg/kg/ Consider biopsy d; If worsening or no improvement, 1 2 mg/kg/d prednisone and permanently discontinue ICPI; if improved, taper steroid over 4 6 weeks If no recurrence, consider restart of ICPI Monitor urine output; encourage oral hydration; educate patient about renal dietary restrictions Medication reconciliation to screen for potential nephrotoxic drugs Counsel patients to discontinue unnecessary medications and supplements that are known nephrotoxins

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: ICPI, immune checkpoint inhibitors; BUN, blood urea nitrogen; ULN, upper limit of normal.

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Table 7 Musculoskeletal: arthralgias. Prevention and anticipation Detect Grade

Obtain rheumatology history (osteoarthritis, degenerative joint disease, rheumatoid arthritis) Examination of all joints for tenderness, swelling, range of motion Examination of all muscle groups for strength and function 1 2 3 4 Moderate pain associated with inflammation Severe pain; irreversible joint damage; disabling; limits self-care ADL erythema or joint swelling Severe muscle weakness with or without pain, Moderate muscle weakness with or withlimiting self-care out pain Limits age-appropriate instrumental ADLs Full skeletal examination: all peripheral joints and spine Consider plain x-rays, ultrasound, or MRI to exclude metastases Consider autoimmune laboratory assessment: ANA, rheumatoid factor, anti-CCP and inflammatory markers (CRP and ESR, CK).If inflammatory, monitor markers every 4 6 weeks Consider paraneoplastic autoantibody testing, EMG, MRI or biopsy if myositis suspected If oligoarthritis, may treat with intra-articular corticosteroids HOLD ICPI Consider holding ICPI Continue ICPI Initiate methylprednisolone or prednisone Prednisone 10 20 mg/d if no improveSymptom management with acetequivalent 0.5 1.0 mg/kg/d ment aminophen and/or NSAIDS (topical Rheumatology or neurology consult If CK elevated >3x ULN, consider predniand/or oral) If no improvement may consider: sone 0.5 1.0 mg/kg If ineffective, may consider low-dose Arthritis: biologic DMARD such as IL-6 receptor Consider rheumatology consult prednisone 10 mg/d inhibitor or TNF-a or synthetic DMARD (methoConsider neurology consult If no improvement in 4 weeks, treat as moderate trexate, hydroxychloroquine) Myositis: plasmapheresis or IVIG, mycophenolate mofetil Early and ongoing evaluation Provide assistance with ADLs and IADLS; physical therapy, occupational therapy Counsel patients in safety measures to prevent injury Mild pain with inflammation, erythema or joint swelling Mild weakness, with or without pain

Medical evaluation

Medical management

Nursing management

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: ANA, antinuclear antibody; anti-CCP, anti-cyclic citrullinated peptide; CRP, C-reactive protein; ICPI, immune checkpoint inhibitors; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; CK, creatine kinase; EMG, electromyography; NSAIDS, nonsteroidal anti-inflammatory drugs; MRI, magnetic resonance imaging; TNF-a, tumor necrosis factor-alpha.

1.0 mg/kg/d oral equivalent for patients treated in the outpatient setting. The dose continues until the grade of irAE is a Grade 1 or less. Steroids are tapered down slowly over a minimum of 4 weeks to prevent relapse of the irAE. In some cases, the taper may take weeks to months.24,61 Patients will require ongoing assessment of potential

side-effects from the corticosteroids, such as mood changes, weight gain, hyperglycemia, hypertension, gastritis, opportunistic infections, muscle atrophy, and skin fragility. Gastritis and indigestion can be reduced by taking the steroid with food and with either a PPI or H2 blocker. Anti-microbial

Table 8 Neurologic: neuropathy. Prevention and anticipation Screen for pre-existing autoimmune neurologic conditions Screen for diabetic peripheral neuropathy Limit other medications that may lead to peripheral neuropathy Detect Physical exam to evaluate for motor and/or sensory deficit Monitor blood glucose levels Grade 1 2 Mild; no interference with function; symptoms not concerning to patient

Moderate, some interference with ADLs Symptoms concerning to patient

3/4 Severe; limiting self-care and aides warranted; weakness limiting walking or respiratory problems (leg weakness, foot drop, rapidly progressing sensory changes); severe may be Guillain-Barre syndrome

Medical evaluation

Rule out CNS metastases or progression, CVA, seizure, infection, metabolic abnormalities, diabetes, medications Laboratory assessment: serum glucose, B12/folate, TSH, ALT, CK, CKMB, paraneoplastic panel, CRP, ESR Consider need for MRI/MRA of brain and spine Consider need for EMG and/or EEG Lumbar puncture for CSF evaluation

Medical management

Close observation Low threshold to hold ICPI and monitor symptoms for a week If to continue ICPI, close observation

Nursing management

HOLD ICPI and resume once Grade 1; initiate prednisone 0.5 1.0 mg/kg Neurology consult Neurontin, pregabalin or duloxetine for pain

Permanent discontinuation of ICPI Admit patient to hospital Neurology consult Initiate methylprednisolone 2 4 mg/kg

Severe or refractory irAE: IVIG Safety considerations; support multidisciplinary care with physical therapy, occupational therapy, speech therapy

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: CNS, central nervous system; CVA, cardiovascular accident; TSH, thyroid stimulating hormone; ALT, aminotransaminase; CK, creatine kinase; CKMB, creatine kinase muscle/brain; CRP, C-reactive protein; ICPI, immune checkpoint inhibitors; MRI, magnetic resonance imaging; irAE, immune-related adverse events; ESR, erythrocyte sedimentation rate; CSF, cerebral spinal fluid; EMG, electromyography; EEG, electroencephalogram; IVIG, intravenous immune globulin.

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Table 9 Ophthalmic toxicity: uveitis, scleritis, iritis, conjunctivitis, episcleritis. Prevention and anticipation Detect Grade

Exclude patients with history of active uveitis, and those with recurrent uveitis requiring systemic immunosuppressant Assess for ocular symptoms: blurred vision, change in color vision, photophobia, distortion, visual field changes, double vision, tenderness, pain with eye movement, eyelid swelling 1 2 3 4 Asymptomatic

Medical evaluation Medical management

Nursing management

Medical intervention required; Posterior or pan uveitis Vision 20/200 or worse anterior uveitis Bilateral visual exam with ophthalmology including fundoscopic evaluation Permanently discontinue ICPI Permanently discontinue ICPI Continue ICPI HOLD ICPI Emergent ophthalmology consult Urgent ophthalmology evaluaRefer to ophthalmology Urgent ophthalmology consulSystemic corticosteroids tion Artificial tears tation (1 2 mg/kg) Systemic corticosteroid Topical corticosteroids, sysConsider periocular temic corticosteroids corticosteroids May resume once off systemic corticosteroids or if irAE improved when dosing is <10 mg/d Retreat after reduced to Grade 1 Assess for other eye irritants Educate patient to avoid eye irritants such as make up, contact lenses Encourage use of eye sunglasses, as well as nighttime eye protection to decrease risk of inadvertent eye contact

Abbreviations: ICPI, immune checkpoint inhibitors; irAE, immune-related adverse events. Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25

prophylaxis with trimethoprim/sulfamethoxazole DS 3 times a week can reduce the risk of opportunistic infections such as pneumocystis jiroveci pneumonia (PJP).94 If patients have a sulfa allergy, atovaquone (Mepron, GlaxoSmithKline, Research Triangle Park, NC.) may be prescribed. The use of PPIs and trimethoprim/sulfamethoxozole carry a risk for acute interstitial nephritis, so kidney function must be monitored closely.61 Antiviral and antifungal coverage may be recommended in patients requiring long-term steroid therapy. Calcium and vitamin D are recommended to reduce the risk of osteoporosis.

Nurses and all members of the health care team must monitor patients closely for the trajectory of the irAE. In more severe, refractory or recurrent irAEs, nurses can expect that additional immunosuppressant therapy may be necessary. Nurses are at the forefront of assisting in the coordination of patient care and the multidisciplinary management of irAEs. In general, ICPIs are well tolerated, with a mild side-effect profile. However, in the case of irAEs, nurses are critical to the successful monitoring and management of patients on ICPIs.

Table 10 Cardiac: pericarditis, myocarditis, cardiomyopathy, ischemia, arrhythmias. Prevention and anticipation Assess for pre-existing cardiovascular diagnosis and risk factors (hypertension, hyperlipidemia); asses prior ECG Assess symptoms of fatigue, weakness, chest pain, syncope, lightheadedness, palpitations, symptoms of heart failure (peripheral edema, dyspnea, pleural effusion) Detect Baseline electrocardiogram Asses blood pressure and heart rate regularly Grade 1 2 3 4

Medical evaluation

Abnormal screening tests; Abnormal cardiac biomarker Mild symptoms testing, including abnormal ECG Rule out myocardial infarction, arrhythmias Obtain ECG, echocardiogram; laboratory: troponin, BNP Consider cardiac MRI May consider stress test, cardiac MRI with cardiology oversight

Moderately abnormal testing or symptoms with mild activity

Moderate to severe decompensation; IV medication or intervention required; life-threatening consequences

Medical management

All grades: hold ICPI for more in-depth evaluation; permanently discontinue for any Grade 2 or higher High-dose methylprednisolone 1 2 mg/kg/d initiated rapidly. If no response in 1 2 days, additional immunosuppressant therapy with infliximab or ATG Admit patient to hospital Cardiology consult Management of cardiac symptoms per ACC/AHA

Nursing management

Monitor vital signs closely Encourage smoking cessation Monitor ECG Supportive care

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: ECG, electrocardiogram; ATG, anti-thymocyte globulin; MRI, magnetic resonance imaging; ICPI, immune checkpoint inhibitors; BNP, brain natriuretic peptide; ACC/ AHA, American College of Cardiology/American Heart Association.

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Table 11 Hematologic: hemolytic anemia. Prevention and anticipation Lightheadedness, fatigue, weakness, paleness, fever, inability to do daily activities Detect Baseline CBC and prior to each dose Evaluate for start of other new drugs that cause hemolytic anemia Screen for history of insect or spider bites Bone marrow biopsy Grade 1 2 3 Hgb
Medical management

Nursing management

Hgb <10.0 8.0

4

Hgb < 8.0; transfusion indicated Life-threatening consequences; urgent intervention indicated

History of exposures CBC with peripheral smear; LDH, haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel Autoimmune screening Paroxysmal nocturnal hemoglobinuria screening Direct and indirect bilirubin, LDH, direct agglutinin test Rule out viral and bacterial causes of hemolysis Protein electrophoresis, cryoglobulin analysis Rule out bone marrow failure syndrome: B12, folate, copper, paravirus, FE, thyroid, infection RBC transfusion support per institutional guidelines Permanently discontinue ICPI Continue ICPI HOLD ICPI Hematology consult Close follow-up of labs Consider permanent discontinuaPrednisone 1.0 2.0 mg/kg tion Administer prednisone equivalent 0.5 1.0 mg/kg Monitor vital signs RBC transfusion per institutional guidelines Assure adequate rest and energy sparing activities

Permanently discontinue ICPI Admit for management Hematology consult IV corticosteroid 1.0 2.0 mg/kg

Data from AIM with Immunotherapy Essentials,20 American Society of Clinical Oncology,21 National Comprehensive Cancer Network,24 European Society of Medical Oncology,22,23 and Common Toxicity Criteria.25 Abbreviations: CBC, complete blood count; Hgl, hemoglobin; LLN, lower limit of normal; DIC, disseminated intravascular coagulation; ICPI, immune checkpoint inhibitors; FE, ferritin/ iron; RBC, red blood cell.

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