untitled h1
16 appendices 16.1 appendix astudy

| All Cycles (28 days each)          |                             |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
|------------------------------------|-----------------------------|----|-----|--------|-----|----|-----|----|-----|------|--------|---------------|----|----|----|
| Screening2                         | C1                          | C6 |     |        |     |    |     |    |     |      |        |               |    |    |    |
| C1                                 | C2                          | C2 | C3  | C3     | C4  | C4 | C5  | C5 | C6  | D15& |        |               |    |    |    |
| D1                                 | D15                         | D1 | D15 | D1     | D15 | D1 | D15 | D1 | D15 | D1   | Beyond | Follow up9,11 |    |    |    |
| EOT visit                          |                             |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| History/PE incl  weight and skin   | X                           | X  | X   | X      | X   | X  | X   | X  | X   | X    | X      | X             | X  | X  |    |
| assessment 12 Confirmation of  1   | X                           | X  | X   |        |     |    |     |    |     |      |        |               |    |    |    |
| pathology/Biopsy ECOG, Vital Signs | X                           | X  | X   | X      | X   | X  | X   | X  | X   | X    | X      | X             | X  | X  |    |
| Tumor evaluation/                  | X                           | X  | X   | X      |     |    |     |    |     |      |        |               |    |    |    |
| measurements                       | 8, 9                        |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| M78243, 4                          | X                           | X  | X   | X      | X   | X  | X   | X  | X   | X    | X      | X             |    |    |    |
| Lab assessments 5                  | X                           | X  | X   | X      | X   | X  | X   | X  | X   | X    | X      | X             | X  | X  | X  |
| Pregnancy test 6                   | X                           | X  | X   | X      | X   | X  | X   |    |     |      |        |               |    |    |    |
| Lymphocyte  phenotyping7           | X                           |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| ECG                                | X                           |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| CT C/A/P or  CT C+MRI A/P8,9,10    | X                           | X  | X   | X 8, 9 | X   |    |     |    |     |      |        |               |    |    |    |
| Follow-up Phone                    | 9                           |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| calls/emails                       | X                           |    |     |        |     |    |     |    |     |      |        |               |    |    |    |
| Correlative Studies                | Please refer to Section 5.2 |    |     |        |     |    |     |    |     |      |        |               |    |    |    |  
1. Pre-treatment tissue biopsy and/or tissue availability is mandatory. On-treatment biopsy is required unless obtaining biopsy is not technically or clinically feasible. Post-treatment biopsy is optional.  
2. Tests done at screening do not need to be repeated on baseline (C1D1) if performed within 21 days prior to initiation of study therapy. 3. M7824 will be delivered intravenously every 2 weeks (+/- 3 days). 4. Vital signs must be measured within 30 minutes before and 30 minutes following M7824 infusions. In addition, at least one time during the infusion of M7824.  
5. Laboratory assessments: CBC with differential, acute care panel (sodium, potassium, chloride, total CO2 (Bicarbonate), creatinine, glucose, urea nitrogen), mineral panel (albumin, calcium total, magnesium total, phosphorus), hepatic panel (alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin), ionized calcium, amylase, lipase, TSH with reflex T3 and T4, LDH, total protein, GGT, PT/INR, PTT, and urine analysis. Hepatitis B and C will be done at screening only.  
6. For females of childbearing-potential (within 3 days prior to initiation of study therapy). 7. Lymphocyte phenotyping tests will be done to check the eligibility of HIV positive patients. HIV-positive patients are eligible only if CD4 counts are greater than 350 cells/mm3 and viral load is undetectable.  
8. CT of chest, abdomen and pelvis with IV contrast (oral contrast as indicated) or CT of the chest without contrast and MRI abdomen/pelvis with tumor measurements. For this study patients should be re-evaluated for response every 8 weeks (+/- 10 days). If a scan identifies objective response or progressive disease, a confirmatory scan should be obtained 4-8 weeks following initial documentation of objective response or progression. In patients with clinical progression or unequivocal scan, confirmatory progression scan can be deferred. Scans will continue every 8 weeks until disease progression or start of a new anti-cancer treatment.  
9. After disease progression or in those subjects who were removed from study therapy for reasons other than disease progression, subjects will be followed every 12 weeks in clinic or by telephone/email for assessment of survival status, related adverse events and documentation of initiation of new anti-cancer therapy.  
10. If appropriate screening imaging is done within 21 days of C1D1 repeat screening imaging is not required. 11. All SAEs ongoing at the 30-day (+/- 10 days) safety follow-up visit must be monitored and followed up by the investigator until stabilization or until the outcome is known, unless the subject is documented as "lost to follow-up." In addition, all trial drug-related SAEs occurring after 30 day safety follow up visit and ongoing at the Safety Follow-up visit have to be followed up in the same manner.  
12. Skin assessment must be performed at baseline and at least every 6 weeks during treatment and at the end of treatment or 28 (±5 days) days post-treatment safety follow-up (if not performed in the previous 6 weeks).  
| 16.2                                             | APPENDIX B: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale                                                                                          | Karnofsky Performance Scale                                                |                                                 |
|--------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------------------------------------------|
| Grade                                            | Descriptions                                                                                                                                                   | Percent                                                                    | Description                                     |
| 100                                              | Normal, no complaints, no  evidence of disease.                                                                                                                |                                                                            |                                                 |
| 0                                                | Normal activity. Fully active, able to carry on all  pre-disease performance without restriction.                                                              | Able to carry on normal                                                    |                                                 |
| 90                                               | activity; minor signs or  symptoms of disease. Normal activity with effort;                                                                                    |                                                                            |                                                 |
| 80                                               | some signs or symptoms of  disease.                                                                                                                            |                                                                            |                                                 |
| 1                                                | Symptoms, but ambulatory. Restricted in physically  strenuous activity, but ambulatory and able to carry  out work of a light or sedentary nature (e.g., light | Cares for self, unable to                                                  |                                                 |
| housework, office work).                         | 70                                                                                                                                                             | carry on normal activity or to  do active work. Requires occasional        |                                                 |
| 60                                               | assistance, but is able to care  for most of his/her needs.                                                                                                    |                                                                            |                                                 |
| 2                                                | In bed <50% of the time. Ambulatory and capable  of all self-care, but unable to carry out any work  activities. Up and about more than 50% of waking          | Requires considerable                                                      |                                                 |
| hours.                                           | 50                                                                                                                                                             | assistance and frequent  medical care.                                     |                                                 |
| 40                                               | Disabled, requires special  care and assistance.                                                                                                               |                                                                            |                                                 |
| In bed >50% of the time. Capable of only limited |                                                                                                                                                                |                                                                            |                                                 |
| 3                                                | self-care, confined to bed or chair more than 50% of                                                                                                           | Severely disabled,                                                         |                                                 |
| waking hours.                                    | 30                                                                                                                                                             | hospitalization indicated.  Death not imminent. Very sick, hospitalization |                                                 |
| 20                                               | indicated. Death not                                                                                                                                           |                                                                            |                                                 |
| 100% bedridden. Completely disabled. Cannot      | imminent.                                                                                                                                                      |                                                                            |                                                 |
| 4                                                | carry on any self-care. Totally confined to bed or  chair.                                                                                                     | 10                                                                         | Moribund, fatal processes  progressing rapidly. |
| 5                                                | Dead.                                                                                                                                                          | 0                                                                          | Dead.                                           |  
Version Date: 06/23/2021 Appendix C: Management of ir AEs  
| 16.2.1 Table A1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Management of Skin irAEs in Patients Treated With ICPis 1.0 Skin Toxicities   |
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| 1.1 Rash/inflammatory dermatitis Definition: Erythema multiforme minor (a targetoid reaction in the skin and mucous membranes usually triggered  by infections, such as herpes simplex viruses, but can be associated with an immune-related drug eruption and if  progresses to erythema multiforme major, it and can be a harbinger of SCAR, such as SJS), lichenoid (resembling  the flat-topped, polygonal, and sometimes scaly or hypertrophic lesions of lichen-planus), eczematous  (inflammatory dermatitis characterized by pruritic, erythematous, scaly, or crusted papules or plaques on the skin,  which is vulnerable to superinfection, psoriasiform [resembling the well-demarcated, erythematous, and scaly  papules and plaques of psoriasis], morbilliform [a nonpustular, nonbullous measles-like exanthematous rash of the  skin often referred to as "maculopapular" and without systemic symptoms or laboratory abnormalities, excluding  occasional isolated peripheral eosinophilia, palmoplantar erythrodysesthesia [hand-foot syndrome; redness,  numbness, burning, itching, and superficial desquamation of the palms and soles], neutrophilic dermatoses [eg,  Sweet syndrome], and others) Diagnostic workshop Pertinent history and physical examination Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition  linked to another systemic disease or unrelated primary skin disorder If needed, a biologic checkup, including a blood cell count and liver and kidney tests Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a screening  antinuclear antibody test, SS-A/Anti-Ro, SS-B/Anti-La if predominantly photodistributed/photosensitivity,  antihistone, double-stranded DNA, and other relevant serologies. Consider expanding serologic studies or  diagnostic work-up if other autoimmune conditions are considered based on signs, symptoms Skin biopsy Consider clinical monitoring with use of serial clinical photography Review full list of patient medications to rule out other drug-induced cause for photosensitivity Grading Management Grading according to CTCAE is a challenge for skin.  Instead, severity may be based on BSA, tolerability,  morbidity, and duration. G1: Symptoms do not affect the quality of life or  Continue ICPi controlled with topical regimen and/or oral antipruritic Treat with topical emollients and/or mild-moderate  potency topical corticosteroids Counsel patients to avoid skin irritants and sun  exposure G2: Inflammatory reaction that affects quality of life and  Consider holding ICPi and monitor weekly for  equires intervention based on diagnosis improvement. If not resolved, interrupt treatment until  skin AE has reverted to Grade 1 Consider initiating prednisone (or equivalent) at dosing  1 mg/kg, tapering over at least 4 weeks In addition, treat with topical emollients, oral  antihistamines, and medium- to high-potency topical  corticosteroids G3: As G2 but with failure to respond to indicated  Hold ICPi therapy and consult with dermatology to  interventions for a G 2 dermatitis determine appropriateness of resuming Treat with topical emollients, oral antihistamines, and  high-potency topical corticosteroids Initiate (methyl)prednisolone (or equivalent) 1-2 mg/kg,  tapering over at least 4 weeks G4: All severe rashes unmanageable with prior  Immediately hold ICPi and consult dermatology to  interventions and intolerable determine appropriateness of resuming ICPi therapy |                                                                               |  
| Version Date: 06/23/2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 1.0 Skin Toxicities upon resolution of skin toxicity and once corticosteroids  are reduced to prednisone (or equivalent) ≤ 10 mg Systemic corticosteroids: IV (methyl)prednisolone (or  equivalent) dosed at 1-2 mg/kg with slow tapering when  the toxicity resolves Monitor closely for progression to severe cutaneous  adverse reaction Should admit patient immediately with direct oncology  involvement and with an urgent consult by dermatology Consider alternative antineoplastic therapy over  resuming ICPis if the skin irAE does not resolve to G1  or less; if ICPIs are the patient's only option, consider  restarting once these adverse effects have resolved to  a G1 level   |
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| 1.2 Bullous dermatoses Definition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction Diagnostic work-up Physical examination Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition  linked to another systemic disease If needed, a biologic checkup, including a blood cell count, liver, and kidney tests; consider serum antibody tests to  rule out bullous pemphigoid or, under the guidance of dermatology, sending patient serum for indirect  immunofluorescent testing to rule out other autoimmune blistering diseases Referral to dermatology for blisters that are not explained by infectious or transient other causes (eg, herpes  simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure blister) Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct immunofluorescence evaluation of perilesional skin) Grading Management G1: Asymptomatic, blisters covering < 10% BSA and no  If blisters are < 10% BSA, asymptomatic, and  associated erythema noninflammatory (such as the case with friction blisters  or pressure blisters), cessation of ICPi is not necessary,  and only observation and/or local wound care is  warranted. When symptomatic bullae or erosions, which are  deroofed vesicles or bullae, are observed on the skin or  mucosal surfaces, the cutaneous irAE is by definition considered at least G2 See G2 management recommendations G2: Blistering that affects quality of life and requires  intervention based on diagnosis not meeting criteria for  Grade > 2 Blisters covering 10%-30% BSA Hold ICPi therapy and consult with dermatology for  work-up and to determine appropriateness of resuming Attention given to general local wound care, which  includes plain petrolatum ointment and bandages or  plain petrolatum ointment gauze and bandage over any  open erosions, which are left over on the skin after the  blister has popped or if the roof of the blister easily  sloughs off Counsel patients to avoid skin irritants and  overexposure to sun, wear protective clothing, use  sunscreens Work-up for autoimmune bullous disease as above Initiate Class 1 high-potency topical corticosteroid (eg,  clobetasol, betamethasone or equivalent) and reassess  every 3 days for progression or improvement |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |  
| 1.0 Skin Toxicities Low threshold to initiate treatment with prednisone (or  equivalent) at 0.5-1 mg/kg dosing and taper over at  least 4 weeks Monitor patients with G2 irAEs closely for progression  to involvement of greater BSA and/or mucous  membrane involvement. Consider following patients  closely using serial photography Primer on monitoring for complicated cutaneous  adverse drug reactions: Review of systems: Skin pain (like a sunburn), fevers,  malaise, myalgias, arthralgias, abdominal pain,  ocular discomfort or photophobia, sores or  discomfort in the nares, sores or discomfort in the  oropharynx, odynophagia, hoarseness, dysuria,  sores or discomfort in the vaginal area for women or  involving the meatus of the penis for men, sores in  the perianal area, or pain with bowel movements Physical examination: Include vital signs and a full skin  examination specifically evaluating all skin surfaces  and mucous membranes (eyes, nares, oropharynx,  genitals, and perianal area). Assess for  lymphadenopathy, facial or distal extremity swelling  (may be signs of DIHS/DRESS). Assess for  pustules or blisters or erosions in addition to areas  of "dusky erythema," which may feel painful to  palpation. To assess for a positive Nikolsky sign,  place a gloved finger tangentially over erythematous  skin and apply friction parallel to the skin surface.  Nikolsky sign is positive if this results in detached or  sloughing epidermis demonstrating poor attachment  of the epidermis to the dermis, which is the case in  some autoimmune disorders (eg, pemphigus) and  SJS/TEN   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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| G3: Skin sloughing covering > 30% BSA with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Hold ICPi therapy and consult with dermatology to                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| associated pain and limiting self-care ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | determine appropriateness of resuming Administer IV (methyl)prednisolone (or equivalent) 1-2  mg/kg, tapering over at least 4 weeks If bullous pemphigoid is diagnosed, it may be possible  to avoid long-term use of systemic corticosteroids and  treat with rituximab, as an alternative approach to  treating the irAE Seek infectious disease consultation if patient might  have secondary cellulitis or if patient has other infection  risk factors, such as neutropenia, etc. |
| G4: Blisters covering > 30% BSA with associated fluid                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Permanently discontinue ICPi                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| or electrolyte abnormalities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Admit patient immediately and place under supervision  of a dermatologist Administer IV (methyl)prednisolone (or equivalent) 1-2  mg/kg with tapering over at least 4 weeks when the  toxicity resolves If bullous pemphigoid is diagnosed, it may be possible  to avoid long-term use of systemic corticosteroids and  treat with rituximab as an alternative approach to  treating the irAE                                                                                          |  
| 1.0 Skin Toxicities Seek infectious disease consultation if patient might  have secondary cellulitis or if patient has other infection  risk factors, such as neutropenia, etc                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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| 1.3 SCARs, including SJS, TEN, acute generalized exanthematous pustulosis, and DRESS/DIHS Definition: Severe changes in either structure or functions of skin, the appendages or the mucous membranes due  to a drug Diagnostic work-up Total body skin examination with attention to examining all mucous membranes as well as complete review of  systems Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition  linked to another systemic disease A biologic checkup, including a CBC with differential test, and liver and kidney function tests, including urinalysis,  in addition to the blood work; if the patient is febrile, blood cultures should be considered as well Skin biopsies to assess for full-thickness epidermal necrosis, as is seen in SJS/TEN, as well as other possible  etiologies like paraneoplastic pemphigus or other autoimmune blistering dermatoses or other drug reactions, such  as acute generalized exanthematous pusulosis Consider following patients closely using serial clinical photography If mucous membrane involvement or blistering is observed on the skin, consider early admission to a burn center  for further monitoring and management Primer on monitoring for complicated cutaneous adverse drug reactions: Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal pain, ocular  discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the oropharynx, odynophagia,  hoarseness, dysuria, sores or discomfort in the vaginal area for women or involving the meatus of the penis for  men, sores in the perianal area, or pain with bowel movements Physical examination: Include vital signs and a full skin examination specifically evaluating all skin surfaces and  mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess for lymphadenopathy, facial or  distal extremity swelling (may be signs of DIHS/DRESS). Assess for pustules or blisters or erosions in addition to  areas of "dusky erythema," which may feel painful to palpation. To assess for a positive Nikolsky sign, place a  gloved finger tangentially over erythematous skin and apply friction parallel to the skin surface. Nikolsky sign is  positive if this results in detached or sloughing epidermis demonstrating poor attachment of the epidermis to the  dermis, which is the case in some autoimmune disorders (eg, pemphigus) and SJS/TEN Grading Management All Grades In cases of suspected SJS or any mucous membrane  involvement, discontinue ICPi treatment and monitor  closely for improvement, regardless of grade G1: NA For SCARs, there is no G1 category; if lower BSA is  involved with bullae or erosions, there should remain a  high concern that this reaction will progress to G3 or G4 G2: Morbilliform ("maculopapular") exanthem covering  10%-30% BSA with systemic symptoms,  lymphadenopathy, or facial swelling Hold ICPi and monitor patients closely every 3 days  with G2 irAEs for progression to involvement of greater  BSA and/or mucous membrane involvement Consider following patients closely using serial  photography Initiate therapy with topical emollients, oral  antihistamines, and medium- to high-strength topical  corticosteroids Consider initiation of prednisone (or equivalent) 0.5-1  mg/kg tapered over at least 4 weeks G3: Skin sloughing covering < 10% BSA with mucosal  involvement associated signs (eg, erythema, purpura,  epidermal detachment, mucous membrane  detachment) Hold ICPi therapy and consult with dermatology Treat skin with topical emollients and other petrolatum  emollients, oral antihistamines, and high-strength  topical corticosteroids; dimethicone may also be offered  as an alternative to petrolatum |  
| 1.0 Skin Toxicities Administer IV (methyl)prednisolone (or equivalent) 0.5-1  mg/kg and convert to oral corticosteroids on response,  wean over at least 4 weeks Admit to burn and/or consult wound services with  attention to supportive care, including fluid and  electrolyte balance, minimizing insensible water losses,  and preventing infection Given the immune mechanism of action of these  medicines, use of immune suppression is warranted  and should be offered For mucous membrane involvement of SJS or TEN,  appropriate consulting services should be offered to  guide management in preventing sequelae from  scarring (eg, ophthalmology; ear, nose, and throat;  urology; gynecology; etc, as appropriate)                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
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| G4: Skin erythema and blistering/sloughing covering ≥ 10% to > 30% BSA with associated signs (eg,  erythema, purpura, epidermal detachment, mucous  membrane detachment) and/or systemic symptoms and  concerning associated blood work abnormalities (eg,  liver function test elevations in the setting of  DRESS/DIHS)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue ICPi Admit patient immediately to a burn unit or ICU with  consulted dermatology and wound care services Consider further consultations based on management  of mucosal surfaces (eg, ophthalmology; urology; gynecology; ear, nose,  and throat surgery; etc) Initiate IV (methyl)prednisolone  (or equivalent) 1-2 mg/kg, tapering when toxicity  resolves to normal IVIG or cyclosporine may also be considered in severe  or corticosteroid-unresponsive cases Consider pain/palliative consultation and/or admission  in patients presenting with DRESS manifestations |
| Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as the underlying  mechanism is a T-cell immunodirected toxicity Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of  DRESS/DIHS All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate Abbreviations: ADL, activities of daily living; AE, adverse event; BSA, body surface area; CBC, complete blood  count; CTCAE, Common Terminology Criteria for Adverse Events; DIHS, drug-induced hypersensitivity syndrome;  DRESS, drug reaction with eosinophilia and systemic symptoms; G, Grade; ICPi, immune checkpoint inhibitor;  ICU, intensive care unit; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin;  NA, not applicable; SCAR, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TENS, toxic  epidermal necrolysis. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
| 16.2.2 Table A2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Management of GI irAEs in Patients Treated With ICPis 2.0 GI Toxicities   |
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| 2.1 Colitis Definition: A disorder characterized by inflammation of the colon Diagnostic work-up G2 Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium difficile,  parasite, CMV or other viral etiology, ova and parasite) should be performed Consider testing for lactoferrin (for patient stratification to determine who needs more urgent endoscopy) and  calprotectin (to follow-up on disease activity) Screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start infliximab should be routinely done in patients at high risk for those infections and appropriately selected patients based on  infectious disease expert's evaluation Imaging (eg, CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be considered as there is  evidence showing that the presence of ulceration in the colon can predict a corticosteroid-refractory course, which  may require early infliximab Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating  endoscopy for disease monitoring can be considered when clinically indicated and when planning to resume  therapy G3-4 All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed immediately Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating  endoscopy for disease monitoring should only be considered when clinically indicated and when planning to  resume ICPi Grading (based on CTCAE for diarrhea, as most often  Management used clinically) All patients Counsel all patients to be aware of and inform their  health care provider immediately if they experience: Abdominal pain, nausea, cramping, blood or mucus in  stool or changes in bowel habits, fever, abdominal  distention, obstipation, constipation For G2 or higher, consider permanently discontinuing  CTLA-4 agents and may restart PD-1, PD-L1 agents if  patient can recover to G1 or less; concurrent  immunosuppressant maintenance therapy should be  considered only if clinically indicated in individual cases G1: Increase of fewer than four stools per day over  baseline; mild increase in ostomy output compared with  baseline Continue ICPi; alternatively, ICPi may be held  temporarily and resumed if toxicity does not exceed G1 Monitor for dehydration and recommend dietary  changes Facilitate expedited phone contact with  patient/caregiver May obtain gastroenterology consult  for prolonged G1 cases G2: Increase of four to six stools per day over baseline;  moderate increase in ostomy output compared with  baseline Should hold ICPi temporarily until patient's symptoms  recover to G1; can consider permanently discontinuing CTLA-4 agents and may restart PD-1,  PD-L1 agents if patient can recover to G1 or less Concurrent immunosuppressant maintenance therapy (,  10 mg prednisone equivalent dose) may be offered only  if clinically indicated in individual cases |                                                                           |  
| Version Date: 06/23/2021                                                                                                                                                                                                                                                                                    | 2.0 GI Toxicities May also include supportive care with medications such  as Imodium if infection has been ruled out Should consult with gastroenterology for G2 or higher Administer corticosteroids, unless diarrhea is transient,  starting with initial dose of 1 mg/kg/day prednisone or  equivalent When symptoms improve to G1 or less, taper  corticosteroids over at least 4-6 weeks before resuming  treatment, although resuming treatment while on lowdose corticosteroid may also be an option after an  evaluation of the risks and benefits EGD/colonoscopy, endoscopy evaluation should be  highly recommended for cases Grade $ 2 to stratify  patients for early treatment with infliximab based on the  endoscopic findings and to determine the safety of  resuming PD-1, PD-L1 therapy Stool inflammatory markers can be considered  (lactoferrin and calprotectin) in cases of G2 or higher to  differentiate functional versus inflammatory diarrhea,  and use calprotectin to monitor treatment response if  provider prefers Repeat colonoscopy is optional for cases of G2 or  higher for disease activity monitoring to achieve  complete remission, especially if there is a plan to  resume ICPi                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
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| G3: Increase of seven or more stools per day over  baseline, incontinence, hospitalization indicated, severe  increase in ostomy output compared with baseline,  limiting self-care ADL                                                                                                                     | Should consider permanently discontinuing CTLA-4  agents and may restart PD-1, PD-L1 agents if patient  can recover to G1 or less. Administer corticosteroids (initial dose of 1-2 mg/kg/d  prednisone or equivalent) Consider hospitalization or outpatient facility for patients  with dehydration or electrolyte imbalance If symptoms persist $ 3-5 days or recur after  improvement, consider administering IV corticosteroid  or noncorticosteroid (eg, infliximab) Consider colonoscopy in cases where patients have  been on immunosuppression and may be at risk for  opportunistic infections as an independent cause for  diarrhea (ie, CMV colitis) and for those who are antiTNF or corticosteroid refractory                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| G4: Life-threatening consequences; urgent intervention                                                                                                                                                                                                                                                      | Permanently discontinue treatment                                                                                                                                                                                                                                                                                                                                                                                                                              |
| indicated                                                                                                                                                                                                                                                                                                   | Should admit patient when clinically indicated; patients  managed as outpatients should be very closely  monitored Administer 1-2 mg/kg/d methylprednisolone or  equivalent until symptoms improve to G1, and then start  taper over 4-6 weeks Consider early infliximab 5-10 mg/kg if symptoms  refractory to corticosteroid within 2-3 days Consider  lower GI endoscopy if symptoms are refractory despite  treatment or there is concern of new infections |
| Additional considerations The use of vedolizumab may be considered in patients refractory to infliximab and/or contraindicated to TNF-a  blocker. The decision should be made on an individual basis from gastroenterology and oncology evaluation. This  is based on case series showing promising results |                                                                                                                                                                                                                                                                                                                                                                                                                                                                |  
| Version Date: 06/23/2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 2.0 GI Toxicities   |
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| Patients with hepatitis and irAE colitis are rare, and management should include permanently discontinuing ICPi  and offering other immunosuppressant agents that work systemically for both conditions Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the evaluation  tool. It may be managed similar as colitis,including corticosteroid and/or infliximab, etc 2.2 Hepatitis Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma Diagnostic work-up Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or weekly if G1  liver function test elevations. No treatment is recommended for G1 liver function test abnormality For G2 or higher: Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron study,  thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from primary  malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, antismooth muscle  antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline phosphatase alone, g-glutamyl  transferase should be tested. For isolated elevation of transaminases, consider checking CK for other etiologies Grading Management All patients Counsel all patients to be aware of and inform their  health care provider immediately if they experience: Yellowing of skin or whites of the eyes Severe nausea  or vomiting Pain on the right side of the abdomen Drowsiness Dark urine (tea colored) Bleeding or bruising more easily than normal Feeling  less hungry than usual G1: Asymptomatic (AST or ALT > ULN to 3.0 x ULN  Continue ICPi with close monitoring; consider alternate  and/or total bilirubin > ULN to 1.5 x ULN) etiologies Monitor laboratories one to two times weekly Manage with supportive care for symptom control G2: Asymptomatic (AST or ALT > 3.0 to ≤ 5 x ULN  Hold ICPi temporarily and resume if recover to G1 or  and/or total bilirubin > 1.5 to ≤ 3 x ULN) less on prednisone ≤ 10 mg/d For Grade 2 hepatic toxicity with symptoms, may  administer corticosteroid 0.5-1 mg/kg/d prednisone or  equivalent if the abnormal elevation persists with  significant clinical symptoms in 3-5 days Increase  frequency of monitoring to every 3 days Infliximab might not be the most appropriate treatment  option in the situation of immune-mediated hepatitis  given the potential risk of idiosyncratic liver failure  (Note: No clear evidence shows the liver toxicity from  infliximab from other studies) In follow-up, may resume ICPi treatment followed by  taper only when symptoms improve to G1 or less and  corticosteroid ≤ 10 mg/d; taper over at least 1 month Patients should be advised to stop unnecessary  medications and any known hepatotoxic drugs G3: Symptomatic liver dysfunction, fibrosis by biopsy,  compensated cirrhosis, reactivation of chronic hepatitis  (AST or ALT 5-20 x ULN and/or total bilirubin 3-10x3  ULN) Permanently discontinue ICPi Immediately start corticosteroid 1-2 mg/kg  methylprednisolone or equivalent If corticosteroid refractory or no improvement after 3  days, consider mycophenolate mofetil or azathioprine (if  using azathioprine should test for thiopurine  methyltransferase deficiency) |                     |  
| 2.0 GI Toxicities Laboratories at daily or every other day; consider  inpatient monitoring for patients with AST/ALT > 8 x  ULN and/or elevated TB 3 x ULN Increase frequency of monitoring to every 1-2 days Infliximab might not be the most appropriate treatment  option in the situation of immune-mediated hepatitis  given the potential risk of liver failure (Note: No clear  evidence shows that the liver toxicity from infliximab from other studies); alternatives include non–TNF-a  agents as systemic immunosuppressants If no  improvement is achieved with corticosteroids or for  patients on combination therapy with a novel agent,  with standard chemotherapy, or with targeted therapy,  refer to hepatologist for further pathologic evaluation of  hepatitis Corticosteroid taper can be attempted around 4-6  weeks; re-escalate if needed; optimal duration unclear   |    |
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| G4: Decompensated liver function (eg, ascites,  coagulopathy, encephalopathy, coma; AST or ALT > 20  x ULN and/or total bilirubin > 10 x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Permanently discontinue ICPi Administer 2 mg/kg/d methylprednisolone equivalents If corticosteroid refractory or no improvement after 3  days, consider mycophenolate mofetil Monitor laboratories daily; consider inpatient monitoring Avoid the use of infliximab in the situation of immunemediated hepatitis Hepatology consult if no improvement was achieved  with corticosteroid Corticosteroid taper can be attempted around 4-6  weeks when symptoms improve to G1 or less; reescalate if needed; optimal duration unclear Consider transfer to tertiary care facility if necessary    |
| All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations is moderate. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST,  aspartate aminotransferase; CBC, complete blood count, CK, creatine kinase; CMV, cytomegalovirus; CRP,  C-reactive protein; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; CTLA4, cytotoxic T-cell lymphocyte-4; EGD, esophagogastroduodenoscopy; ESR, erythrocyte sedimentation rate; G,  Grade; GI, gastrointestinal; HIV, human immunodeficiency virus; ICPi, immune checkpoint inhibitor; irAE, immunerelated adverse event; IV, intravenous; PD-1; programmed death 1; PD-L1, programmed death ligand 1; TB,  tuberculosis; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; ULN, upper limit of normal.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |    |  
Version Date: 06/23/2021  
| 16.2.3 Table A3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Management of Lung irAEs in Patients Treated With ICPis 3.0 Lung Toxicities   |
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| 3.1 Pneumonitis Definition: Focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging) No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis Diagnostic work-up Should include the following: CXR, CT, pulse oximetry For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and sensitivity, blood  culture and sensitivity, urine culture and sensitivity Grading Management G1: Asymptomatic, confined to one lobe of the lung or  < 25% of lung parenchyma, clinical or diagnostic  observations only Hold ICPi with radiographic evidence of pneumonitis  progression May offer one repeat CT in 3-4 weeks; in patients who  have had baseline testing, may offer a repeat  spirometry/DLCO in 3-4 weeks May resume ICPi with radiographic evidence of  improvement or resolution. If no improvement, should  treat as G2 Monitor patients weekly with history and physical  examination and pulse oximetry; may also offer CXR G2: Symptomatic, involves more than one lobe of the  lung or 25%-50% of lung parenchyma, medical  intervention indicated, limiting instrumental ADL Hold ICPi until resolution to G1 or less Prednisone 1-2 mg/kg/d and taper by 5-10 mg/wk over  4-6 weeks Consider bronchoscopy with BAL Consider empirical antibiotics Monitor every 3 days with history and physical  examination and pulse oximetry, consider CXR; no  clinical improvement after 48-72 hours of prednisone,  treat as G3 G3: Severe symptoms, hospitalization required,  involves all lung lobes or 50% of lung parenchyma,  limiting self-care ADL, oxygen indicated G4: Life-threatening respiratory compromise, urgent  intervention indicated (intubation) Permanently discontinue ICPi Empirical antibiotics; (methyl)prednisolone IV 1-2  mg/kg/d; no improvement after 48 hours, may add  infliximab 5 mg/kg or mycophenolate mofetil IV 1 g  twice a day or IVIG for 5 days or cyclophosphamide;  taper corticosteroids over 4-6 weeks Pulmonary and infectious disease consults if necessary Bronchoscopy with BAL 6 transbronchial biopsy Patients should be hospitalized for further management Additional considerations GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged corticosteroid use  (> 12 weeks), according to institutional guidelines Consider calcium and vitamin D supplementation with prolonged corticosteroid use The role of prophylactic fluconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, and  physicians should proceed according to institutional guidelines Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: ADL, activities of daily living; BAL, bronchoalveolar lavage; CT, computed tomography; CXR, chest  x-ray; DLCO, diffusing capacity of lung for carbon monoxide; G, Grade; GI, gastrointestinal; ICPi, immune  checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; PPI,  proton pump inhibitor. |                                                                               |  
| 16.2.4 Table A4   | Management of Endocrine irAEs in Patients Treated With ICPis 4.0 Endocrine Toxicity   |
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| Counsel patients to inform their health care provider immediately if they experience any changes in their health  since their last visit, especially any of the following: Headaches that will not go away or unusual headache  patterns Vision changes Rapid heartbeat Increased sweating Extreme tiredness or weakness Muscle aches Weight gain or weight loss Dizziness or fainting Feeling more hungry or thirsty than usual Hair loss Changes in mood or behavior, such as decreased sex  drive, irritability, or forgetfulness Feeling cold Constipation Voice gets deeper Urinating more often than usual Nausea or vomiting Abdominal pain 4.1 Thyroid 4.1.1 Primary hypothyroidism Definition: Elevated TSH, normal or low FT4 Diagnostic work-up TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case detection in  symptomatic patients Grading Management G1: TSH < 10 mIU/L and asymptomatic G2: Moderate symptoms; able to perform ADL; TSH  persistently > 10 mIU/L Should continue ICPi with close follow-up and  monitoring of TSH, FT4 May hold ICPi until symptoms  resolve to baseline Consider endocrine consultation Prescribe thyroid hormone supplementation in  symptomatic patients with any degree of TSH elevation  or in asymptomatic patients with TSH levels that persist  > 10 mIU/L (measured 4 weeks apart) Monitor TSH every 6-8 weeks while titrating hormone  replacement to normal TSH FT4 can be used in the  short term (2 weeks) to ensure adequacy of therapy in  those with frank hypothyroidism where the FT4 was  initially low Once adequately treated, should monitor thyroid  function (at least TSH) every 6 weeks while on active  ICPi therapy or as needed for symptoms to ensure  appropriate replacement; repeat testing annually or as  indicated by symptoms once stable G3-4: Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Hold ICPi until symptoms resolve to baseline with  appropriate supplementation Endocrine consultation                   |                                                                                       |  
| 4.0 Endocrine Toxicity May admit for IV therapy if signs of myxedema  (bradycardia, hypothermia) Thyroid supplementation  and reassessment as in G2   |
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| Additional considerations For patients without risk factors, full replacement can be estimated with an ideal body weight–based dose of  approximately 1.6 µg/kg/d For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting at 25-50 mg Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in asymptomatic  patients to determine whether there is recovery to normal within 3-4 weeks Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with a history  of thyroiditis (initial thyrotoxic phase) Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated  4.1.2 Hyperthyroidism Definition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine Diagnostic work-up Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in symptomatic  patients Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (eg,  ophthalmopathy) Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to hypothyroidism in  patients with thyroiditis and hyperthyroidism Grading Management G1: Asymptomatic or mild symptoms Can continue ICPi with close follow-up and monitoring  of TSH, FT4 every 2-3 weeks until it is clear whether  there will be persistent hyperthyroidism (see below) or  hypothyroidism (see 4.1.1) Consider holding ICPi until symptoms return to baseline Consider endocrine consultation b-Blocker (eg, atenolol, propranolol) for symptomatic  relief Hydration and supportive care Corticosteroids are not usually required to shorten  duration For persistent hyperthyroidism (> 6 weeks) or clinical  suspicion, work-up for Graves disease (TSI or TRAb)  and consider thionamide (methimazole or PTU) Refer  to endocrinology for Graves disease G3-4: Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Hold ICPi until symptoms resolve to baseline with  appropriate therapy Endocrine consultation b-Blocker (eg, atenolol, propranolol) for symptomatic  relief For severe symptoms or concern for thyroid storm,  hospitalize patient and initiate prednisone 1-2 mg/kg/d  or equivalent tapered over 1-2 weeks; consider also  use of SSKI or thionamide (methimazole or PTU). Additional considerations Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. Hypothyroidism can  be treated as above. Graves disease is generally persistent and is due to increased thyroid hormone production                                                                                                                                                       |  
| 4.0 Endocrine Toxicity   |
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| Definition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatremia and  hyperkalemia with orthostasis and volume depletion due to loss of aldosterone Diagnostic work-up for patients in whom adrenal  insufficiency is suspected: Evaluate ACTH (AM), cortisol level (AM) Basic metabolic panel (Na, K, CO2, glucose) Consider ACTH stimulation test for indeterminate  results If primary adrenal insufficiency (high ACTH, low  cortisol) is found biochemically: Evaluate for precipitating cause of crisis such as  infection Perform an adrenal CT for  metastasis/hemorrhage Grading Management G1: Asymptomatic or mild symptoms Consider holding ICPi until patient is stabilized on  replacement hormone Endocrine consultation Replacement therapy with prednisone (5-10 mg daily)  or hydrocortisone (10-20 mg orally every morning, 5-10  mg orally in early afternoon) May require fludrocortisone (0.1 mg/d) for  mineralocorticoid replacement in primary adrenal  insufficiency Titrate dose up or down as symptoms dictate G2: Moderate symptoms, able to perform ADL Consider holding ICPi until patient is stabilized on  replacement hormone Endocrine consultation Initiate outpatient treatment at two to three times  maintenance (if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg  in the morning, and 10-20 mg in the afternoon) to  manage acute symptoms. Taper stress-dose corticosteroids down to maintenance  doses over 5-10 days Maintenance therapy as in G1. G3-4: Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Hold ICPi until patient is stabilized on replacement  hormone Endocrine consultation See in clinic or, for after hours, make an emergency  department referral for normal saline (at least 2 L) and  IV stress-dose corticosteroids on presentation  (hydrocortisone 100 mg or dexamethasone 4 mg (if the  diagnosis is not clear and stimulation testing will be  needed) Taper stress-dose corticosteroids down to maintenance  doses over 7-14 days after discharge Maintenance therapy as in G1 Additional considerations Primary and secondary adrenal insufficiency can be distinguished by the relationship between ACTH and cortisol.  If the ACTH is low with low cortisol, then management is as per 4.3. Patients on corticosteroids for management of other conditions will have low morning cortisol as a result of  iatrogenic, secondary adrenal insufficiency. ACTH will also be low in these patients. A diagnosis of adrenal  insufficiency is challenging to make in these situations (see next section on hypophysitis).                          |  
| 4.3 Pituitary - hypophysitis Definition: Inflammation of the pituitary with varying effects on hormone function. Most commonly presenting with  central adrenal insufficiency. May also have central hypothyroidism, diabetes insipidus, and hypogonadism.  Diagnostic work-up Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and volume depletion  with diabetes insipidus. Low testosterone or estradiol with low LH and FSH. Testing: Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females with  fatigue, loss of libido, and mood changes Consider MRI of the brain with or without contrast with pituitary/sellar  cuts in patients with multiple endocrine abnormalities 6 new severe headaches or complaints of vision changes Grading Management G1: Asymptomatic or mild symptoms Consider holding ICPi until patient is stabilized on  replacement hormones Endocrine consultation Hormonal supplementation as in G1 G3-4: Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL Hold ICPi until patient is stabilized on replacement  hormones Endocrine consultation Hormonal supplementation as in G1 Consider initial pulse dose therapy with prednisone 1-2  mg/kg oral daily (or equivalent) tapered over at least 1- 2 weeks Additional considerations Be aware of the need to start corticosteroids first when planning hormone replacement therapy for multiple  deficiencies All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for adrenal  insufficiency to trigger stress-dose corticosteroids by EMS Corticosteroid use can cause isolated central adrenal insufficiency Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions Laboratory confirmation of adrenal insufficiency should not be attempted until treatment with corticosteroids for  other disease is ready to be discontinued. For long-term exposure, consult endocrinology for recovery and  weaning protocol using hydrocortisone. 4.4 Diabetes Definition: T2DM is a combination of insulin resistance and insufficiency that may require oral or insulin therapy. It  may be new onset or exacerbated during therapy for nonimmunologic reasons, such as corticosteroid exposure. Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an insulin  requirement Diagnostic work-up Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including measuring  glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3-6 weeks thereafter.  To guide the work-up in new-onset hyperglycemia, clinicians should consider a patient's medical background,   |
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Version Date: 06/23/2021  
| 4.0 Endocrine Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
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| Grading                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Management                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| G1: Asymptomatic or mild symptoms; fasting glucose  value > ULN (160 mg/dL); fasting glucose value > ULN  (8.9 mmol/L); no evidence of ketosis or laboratory  evidence of T1DM                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Can continue ICPi with close clinical follow-up and  laboratory evaluation May initiate oral therapy for those with new-onset T2DM Screen for T1DM if appropriate, for example, acute  onset with prior normal values or clinical concern for  ketosis                                                                                                                                                                                                       |
| G2: Moderate symptoms, able to perform ADL, fasting  glucose value > 160-250 mg/dL; fasting glucose value>  8.9-13.9 mmol/L, ketosis or evidence of T1DM at any  glucose level                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | May hold ICPi until glucose control is obtained Titrate oral therapy or add insulin for worsening control  in T2DM Should administer insulin for T1DM (or as  default therapy if there is confusion about type) Urgent endocrine consultation for any patient with  T1DM; in the absence of endocrinology, internal  medicine may suffice Consider admission for T1DM if early outpatient  evaluation is not available or signs of ketoacidosis are  present |
| G3-4: Severe symptoms, medically significant or lifethreatening consequences, unable to perform ADL G3: > 250-500 mg/dL (> 13.9-27.8 mmol/L) G4: > 500 mg/dL (> 27.8 mmol/L)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Hold ICPi until glucose control is obtained on therapy  with reduction of toxicity to G1 or less Urgent endocrine consultation for all patients Initiate insulin therapy for all patients Admit for inpatient management: Concerns for  developing DKA, Symptomatic patients regardless of  diabetes type, New-onset T1DM unable to see  endocrinology                                                                                                       |
| Additional considerations Insulin therapy can be used as the default in any case with hyperglycemia Long-acting therapy alone is not usually sufficient for T1DM, where half of daily requirements are usually given in  divided doses as prandial coverage and half as long acting. Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be estimated at  0.3-0.4 units/kg/d). In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient's daily  requirements and can be used to more rapidly titrate basal needs. All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: ACTH, adrenocorticotropic hormone; ADL, activities of daily living; CT, computed tomography;  DKA, diabetic ketoacidosis; DM, diabetes mellitus; EMS, emergency medical services; FSH, follicle-stimulating  hormone; FT4, free thyroxine; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event;  LH, luteinizing hormone; MRI, magnetic resonance imaging; PTU, propylthiouracil; 2L, second-line; SSKI,  potassium iodide; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TRAb, thyroid-stimulating  hormone receptor antibody; TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin; ULN,  upper limit ofnormal. |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |  
Version Date: 06/23/2021  
| 16.2.5 Table A5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Management of Musculoskeletal irAEs in Patients Treated With ICPis 5.0 Musculoskeletal Toxicities   |
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| 5.1 Inflammatory arthritis Definition: A disorder characterized by inflammation of the joints Clinical symptoms: Joint pain accompanied by joint swelling; inflammatory symptoms, such as stiffness after  inactivity or in the morning, lasting > 30 minutes to 1 hour; improvement of symptoms with NSAIDs or  corticosteroids but not with opioids or other pain medications may also be suggestive of inflammatory arthritis. Diagnostic work-up G1 Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of  motion; examination of the spine Consider plain x-ray/imaging to exclude metastases and evaluate joint damage  (erosions), if appropriate Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inflammatory markers (ESR and  CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27  testing G2 Complete history and examination as above; laboratory tests as above Consider US 6 MRI of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment,  suspicion for differential diagnoses such as metastatic lesions or septic arthritis) Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of arthralgia persist  > 4 weeks G3-4 As for G2 Seek rheumatologist advice and review Monitoring: Patients with inflammatory arthritis should be monitored with serial rheumatologic examinations,  including inflammatory markers, every 4-6 weeks after treatment is instituted. Grading Management All Grades Clinicians should follow reports of new joint pain to  determine whether inflammatory arthritis is present;  question whether symptom new since receiving ICPi G1: Mild pain with inflammation, erythema, or joint  Continue ICPi swelling Initiate analgesia with acetaminophen and/or NSAIDs G2: Moderate pain associated with signs of  inflammation, erythema, or joint swelling, limiting  instrumental ADL Hold ICPi and resume upon symptom control and on  prednisone ≤ 10 mg/d  Escalate analgesia and consider higher doses of  NSAIDS as needed If inadequately controlled, initiate prednisone or  prednisolone 10-20 mg/d or equivalent for 4-6 weeks If improvement, slow taper according to response  during the next 4-6 weeks; if no improvement after initial  4-6 weeks, treat as G3 If unable to lower corticosteroid dose to < 10 mg/d after  3 months, consider DMARD Consider intra-articular corticosteroid injections for large  joints Referral to rheumatology G3-4: Severe pain associated with signs of  inflammation, erythema, or joint swelling; irreversible  joint damage; disabling; limiting self-care ADL Hold ICPi temporarily and may resume in consultation  with rheumatology, if recover to G1 or less Initiate oral prednisone 0.5-1 mg/kg If failure of improvement after 4 weeks or worsening in  meantime, consider synthetic or biologic DMARD Synthetic: methotrexate, leflunomide |                                                                                                     |  
| guidelines. 5.2 Myositis Definition: A disorder characterized by muscle inflammation with weakness and elevated muscle enzymes (CK).  Muscle pain can be present in severe cases. Can be life threatening if respiratory muscles or myocardium are  involved Diagnostic work-up Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and neurologic  examination, including muscle strength; and examination of the skin for findings suggestive of dermatomyositis.  Muscle weakness is more typical of myositis than pain. Consider preexisting conditions that can cause similar  symptoms. Blood testing to evaluate muscle inflammation CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as needed Inflammatory markers (ESR and CRP) Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and overlap with  neurologic syndromes, such as myasthenia gravis, is suspected Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia gravis  Monitoring: CK, ESR, CRP G1: Complete examination and laboratory work-up as above G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of affected joints Early referral to a rheumatologist or neurologist G3-4: As for G2 Urgent referral to a rheumatologist or neurologist Grading Management G1: Mild weakness with or without pain Continue ICPi If CK is elevated and patient has muscle weakness,  may offer oral corticosteroids, and treat as G2 Offer analgesia with acetaminophen or NSAIDs if there  are no contraindications G2: Moderate weakness with or without pain, limiting  Hold ICPi temporarily and may resume upon symptom  age-appropriate instrumental ADL control, if CK is normal and prednisone dose 10 mg; if  worsens, treat as per G3 NSAIDs as needed Referral to rheumatologist or neurologist If CK is elevated three times or more), initiate  prednisone or equivalent at 0.5-1 mg/kg May require permanent discontinuation of ICPi in most  patients with G2 symptoms and objective findings   |
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Version Date: 06/23/2021  
| Version Date: 06/23/2021                             | 5.0 Musculoskeletal Toxicities (elevated enzymes, abnormal EMG, abnormal muscle  MRI or biopsy)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
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| G3-4: Severe weakness with or without pain, limiting | Hold ICPi until G1 or less while off immune suppression                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| self-care ADL                                        | and permanently discontinue if any evidence of  myocardial involvement Consider hospitalization for severe weakness Referral to rheumatologist or neurologist Initiate prednisone 1 mg/kg or equivalent. Consider 1-2  mg/kg of methylprednisolone IV or higher-dose bolus if  severe compromise (weakness severely limiting mobility, cardiac,  respiratory, dysphagia) Consider plasmapheresis Consider IVIG therapy Consider other immunosuppressant therapy, such as  methotrexate, azathioprine, or mycophenolate mofetil, if  symptoms and CK levels do not improve or worsen  after 4-6 weeks; rituximab is used in primary myositis  but caution is advised given its long biologic duration |
| Additional considerations: Caution is advised with rechallenging 5.3 Polymyalgia-like syndrome Definition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and no signs of  true muscle inflammation such as CK elevation or EMG findings of myositis. No true muscle weakness, difficulty in  active motion related to pain Diagnostic work-up G1 Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to ophthalmologist if  present, and consider temporal artery biopsy ANA, RF, anti-CCP CK to evaluate differential diagnosis of myositis Inflammatory markers (ESR, CRP) Monitoring: ESR, CRP G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; early  referral to a rheumatologist G3-4: As for G2; see rheumatologist advice and review Grading Management G1: Mild stiffness and pain Continue ICPi Initiate analgesia with acetaminophen and/or NSAIDs if  there are no contraindications G2: Moderate stiffness and pain, limiting ageappropriate instrumental ADL Consider holding ICPi and resuming upon symptom  control, prednisolone < 10 mg; if worsens, treat as per  G3 Initiate prednisone 20 mg/d or equivalent; if symptoms  improve, start to taper dose after 3-4 weeks If no improvement or need for higher dosages after 4  weeks, escalate to G3 Consider referral to  rheumatology G3-4: Severe stiffness and pain, limiting self-care ADL Hold ICPi and may resume, in consultation with  rheumatology, if recover toG1 or less; however, note  that cases of toxicity returning upon rechallenge have  been reported. Referral to rheumatology                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
5.0 Musculoskeletal Toxicities  
Should initiate prednisone 20 mg/d or equivalent. If no improvement or need for higher dosages for prolonged time, may offer a corticosteroid-sparing agent such as methotrexate or IL-6 inhibition with tocilizumab (Note: As caution, IL-6 inhibition can cause intestinal perforation; while this is extremely rare, it should not be used in patients with colitis or GI metastases). Consider admission for pain control  
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, aspartate aminotransferase; CCP, citrullinated protein antibody; CK, creatine kinase; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, Grade; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; IL, interleukin; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging, NSAID, nonsteroidal anti-inflammatory drug; PCP, Pneumocystis pneumonia; RF, rheumatoid factor; TB, tuberculosis; TNF, tumor necrosis factor.  
Version Date: 06/23/2021  
| 16.2.6 Table A6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Management of Renal irAEs in Patients Treated With ICPis 6.0 Renal Toxicities   |
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| Nephritis and renal dysfunction: diagnosis and monitoring For any suspected immune-mediated adverse reactions, exclude other causes Monitor patients for elevated serum creatinine prior to every dose Routine urinalysis is not necessary, other than to rule out UTIs, etc; nephrology may consider further If no potential alternative cause of AKI identified, then one should forego biopsy and proceed directly with  immunosuppressive therapy Swift treatment of autoimmune component important 6.1 Nephritis Definition: Inflammation of the kidney affecting the structure Grading Management G1: Creatinine level increase of > 0.3 mg/dL; creatinine  Consider temporarily holding ICPi, pending  1.5-2.0 3 over baseline consideration of potential alternative etiologies (recent  IV contrast, medications, fluid status) and baseline renal  function. A change that is still < 1.5 ULN could be  meaningful G2: Creatinine 2-3 x above baseline Hold ICPi temporarily Consult nephrology Evaluate for other causes (recent IV contrast,  medications, fluid status, etc); if other etiologies ruled  out, administer 0.5-1 mg/kg/d prednisone equivalents If worsening or no improvement: 1 to 2 mg/kg/d  prednisone equivalents and permanently discontinue  treatment If improved to G1 or less, taper corticosteroids over 4-6  weeks If no recurrence of chronic renal insufficiency, discuss resumption of ICPI with patient after taking into  account the risks and benefits. G3: Creatinine > 3 x baseline or > 4.0 mg/dL;  Permanently discontinue ICPi hospitalization indicated G4: Life-threatening consequences; dialysis indicated Consult nephrology Evaluate for other causes (recent IV contrast,  medications, fluid status, etc) Administer corticosteroids (initial dose of 1-2 mg/kg/d  prednisone or equivalent) Additional considerations Monitor creatinine weekly Reflex kidney biopsy should be discouraged until corticosteroid treatment has been attempted 6.2 Symptomatic nephritis: follow-up Grading Management G1 Improved to baseline, resume routine creatinine  monitoring G2 If improved to G1, taper corticosteroids over at least 3  weeks before resuming treatment with routine  creatinine monitoring If elevations persist > 7 days or  worsen and no other cause found, treat as G3 G3 If improved to G1, taper corticosteroids over at least 4  weeks  If elevations persist 3-5 days or worsen, consider  additional immunosuppression (eg, mycophenolate) |                                                                                 |  
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| 6.0 Renal Toxicities                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                      |
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| G4                                                                                                                                                                                                                                                                                                                                    | If improved to G1, taper corticosteroids over at least 4  weeks If elevations persist 2-3 days or worsen, consider  additional immunosuppression (eg, mycophenolate) |
| All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: AKI, acute kidney injury; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related  adverse event; IV, intravenous; ULN, upper limit of normal; UTI, urinary tract infection. |                                                                                                                                                                      |  
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| 16.2.7 able A7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Management of Nervous System irAEs in Patients Treated With ICPis 7.0 Nervous System Toxicities   |
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| 7.1 Myasthenia gravis Definition: Fatigable or fluctuating muscle weakness, generally more proximal than distal. Frequently has ocular  and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double vision, dysphagia,  dysarthria, facial muscle weakness). May have neck and/or respiratory muscle weakness. (Note: May occur with  myositis and/or myocarditis. Respiratory symptoms may require evaluation to rule out pneumonitis, myocarditis.  Miller Fisher variant of Guillain-Barré syndrome (ophthalmoparesis) and the oculobulbar myositis (ptosis,  ophthalmoparesis, dysphagia, neck and respiratory weakness) with ICPi may have overlapping symptoms. Diagnostic work-up AChR and antistriated muscle antibodies in blood; if AChR antibodies are negative, consider muscle specific kinase and lipoprotein-related 4 antibodies in blood Pulmonary function assessment with NIF and VC CPK, aldolase, ESR, CRP for possible concurrent myositis Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or alternate  diagnosis If respiratory insufficiency or elevated CPK, troponin T, perform cardiac examination with ECG and TTE for  possible concomitant myocarditis Neurologic consultation Electrodiagnositic studies, including neuromuscular junction testing with repetitive stimulation and/or jitter studies,  NCS to exclude neuropathy, and needle EMG to evaluate for myositis Grading Management All grades All grades warrant work-up and intervention given  potential for progressive myasthenia gravis to lead to  respiratory compromise No G1 G2: Some symptoms interfering with ADL MGFA  severity class 1 (ocular symptoms and findings only)  and MGFA severity class 2 (mild generalized  weakness) Hold ICPi and may resume in G2 patients (MGFA 1 and  2) only if symptoms resolve  Should consult neurology Pyridostigmine starting at 30 mg orally three times a  day and gradually increase to maximum of 120 mg  orally four times a day as tolerated and based on  symptoms Administer corticosteroids (prednisone, 1-1.5  mg/kg orally daily) if symptoms G2; wean based on  symptom improvement G3-4: Limiting self-care and aids warranted, weakness  limiting walking, ANY dysphagia, facial weakness,  respiratory muscle weakness, or rapidly progressive  symptoms, or MGFA severity class 3-4 moderate to  severe generalized weakness to myasthenic crisis Permanently discontinue ICPi Admit patient, may need ICU-level monitoring Neurology consult Continue corticosteroids and initiate IVIG 2 g/kg IV over  5 days (0.4 g/kg/d) or plasmapheresis for 5 days Frequent pulmonary function assessment Daily neurologic review Additional considerations Avoid medications that can worsen myasthenia: b-blockers, IV magnesium, fluoroquinolones, aminoglycosides,  and macrolides Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG over 5 days 1-2 mg/kg methylprednisolone daily, wean based on symptom improvement Pyridostigmine, wean based on improvement ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may not be  required 7.2 Guillain-Barré syndrome Definition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon reflexes. Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May involve extremities |                                                                                                   |  
| 7.0 Nervous System Toxicities   |
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| (typically ascending weakness but not always), facial, respiratory, and bulbar and oculomotor nerves. May have  dysregulation of autonomic nerves. Diagnostic work-up Neurologic consultation MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root  enhancement/thickening) Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not typically  seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a patient with cancer. Serum antibody tests for Guillain-Barré syndrome variants (GQ1b for Miller Fisher variant a/w ataxia and  ophthalmoplegia) Electrodiagnostic studies to evaluate polyneuropathy Pulmonary function testing (NIF/VC) Frequent neurochecks Grading Management All grades Warrant work-up and intervention given potential for  progressive Guillain-Barré syndrome to lead to  respiratory compromise Note: There is no G1 toxicity G1: Mild, none NA G2: Moderate, some interference with ADL, symptoms  Discontinue ICPi concerning to patient G3-4: Severe, limiting self-care and aids warranted,  weakness, limiting walking, ANY dysphagia, facial  weakness, respiratory muscle weakness, or rapidly  progressive symptoms Admission to inpatient unit with capability of rapid  transfer to ICU-level monitoring Start IVIG (0.4 g/kg/d  for 5 days for a total dose of 2 g/kg) or plasmapheresis.  Corticosteroids are usually not recommended for  idiopathic Guillain-Barré syndrome; however, in ICPirelated forms, a trial is reasonable (methylprednisolone  2-4 mg/kg/d), followed by slow corticosteroid taper Pulse corticosteroid dosing (methylprednisolone 1 g/d  for 5 days) may also be considered for G3-4 along with  IVIG or plasmapheresis Frequent neurochecks and pulmonary function  monitoring Monitor for concurrent autonomic dysfunction Nonopioid management of neuropathic pain Treatment of constipation/ileus Additional considerations Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat IVIG courses Caution with rechallenging for severe cases 7.3 Peripheral neuropathy Definition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deficit. Focal  mononeuropathies, including cranial neuropathies (eg, facial neuropathies/Bell palsy) may be present. Numbness  and paresthesias may be painful or painless. Hypo- or areflexia or sensory ataxia may be present. Diagnostic work-up G1 Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein  electrophoresis, and other vasculitic and autoimmune screen Neurologic consultation Consider MRI of spine with or without contrast G2: in addition to above MRI spine advised/MRI of brain if cranial nerve Consider EMG/NCS Consider neurology consultation G3-4: go to Guillain-Barré syndrome algorithm                                 |  
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| 7.0 Nervous System Toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                         |
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| Grading                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Management                                                                                                                                                              |
| G1: Mild, no interference with function and symptoms  not concerning to patient. Note: Any cranial nerve  problem should be managed as moderate                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Low threshold to hold ICPi and monitor symptoms for a  week If to continue, monitor very closely for any  symptom progression                                           |
| G2: Moderate, some interference with ADL, symptoms  concerning to patient (ie, pain but no weakness or gait  limitation)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Hold ICPi and resume once return to G1 Initial observation OR initiate prednisone 0.5-1 mg/kg (if  progressing from mild) Neurontin, pregabalin, or duloxetine for pain |
| G3-4: Severe, limiting self-care and aids warranted,  weakness limiting walking or respiratory problems (ie,  leg weakness, foot drop, rapidly ascending sensory  changes) Severe may be Guillain-Barré syndrome and  should be managed as such                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Permanently discontinue ICPi Admit patient Neurologic consultation Initiate IV methylprednisolone 2-4 mg/kg and proceed  as per Guillain-Barré syndrome management      |
| 7.4 Autonomic neuropathy Definition: Nerves that control involuntary bodily functions are damaged. This may affect blood pressure,  temperature control, digestion, bladder function, and sexual function. A case of severe enteric neuropathy with  ICPi has been reported. Can present with GI difficulties such as new severe constipation, nausea, urinary  problems, sexual difficulties, sweating abnormalities, sluggish pupil reaction, and orthostatic hypertension. Diagnostic work-up An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may include Screening for other causes of autonomic dysfunction: diabetic screen, adrenal insufficiency, HIV, paraproteinemia,  amyloidosis, botulism; consider chronic diseases such as Parkinson and other autoimmune screening AM orthostatic vitals Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy Consider paraneoplastic Lambert-Eaton myasthenic syndrome, antineutrophil cytoplasmic antibodies, and  ganglionic AChR antibody testing Grading Management G1: Mild, no interference with function and symptoms  Low threshold to hold ICPi and monitor symptoms for a  not concerning to patient week; if to continue, monitor very closely for any  symptom progression G2: Moderate, some interference with ADL, symptoms  Hold ICPi and resume once return to G1 concerning to patient Initial observation OR initiate prednisone 0.5-1 mg/kg (if  progressing from mild) Neurologic consultation G3-4: Severe, limiting self-care and aids warranted Permanently discontinue ICPi Admit patient Initiate methylprednisolone 1 g daily for 3 days followed  by oral corticosteroid taper Neurologic consultation 7.5 Aseptic meningitis Definition: may present with headache, photophobia, and neck stiffness; often afebrile but may be febrile. There  may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis). |                                                                                                                                                                         |  
| 7.0 Nervous System Toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                 |
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| Grading                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Management                                                                                                                                                                                                                                                                                                                                                                                      |
| G1: Mild, no interference with function and symptoms  not concerning to patient. Note: Any cranial nerve  problem should be managed as moderate. G2: Moderate, some interference with ADL, symptoms  concerning to patient (ie, pain but no weakness or gait  limitation) G3-4: Severe, limiting self-care and aids warranted                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Hold ICPi and discuss resumption with patient only after  taking into account the risks and benefits Consider empirical antiviral (IV acyclovir) and  antibacterial therapy until CSF results Once bacterial  and viral infection are negative, may closely monitor off  corticosteroids or consider oral prednisone 0.5-1 mg/kg  or IV methylprednisolone 1 mg/kg if moderate/severe  symptoms |
| 7.6 Encephalitis Definition: As for aseptic meningitis, need to exclude infectious causes, especially viral (ie, HSV). Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness,  focal weakness, speech abnormality Diagnostic work-up Diagnostic work-up Neurologic consultation MRI of brain with or without contrast may reveal T2/fluid-attenuated inversion recovery changes typical of what is  seen in autoimmune encephalopathies or limbic encephalitis or may be normal Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV and other  viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic  panels. May see elevated WBC count with lymphocytic predominance and/or elevated protein EEG to evaluate for subclinical seizures Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and  thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and  confusion Grading Management G1: Mild, no interference with function and symptoms  not concerning to patient. Note: Any cranial nerve  problem should be managed as moderate. G2: Moderate, some interference with ADL, symptoms  concerning to patient (ie, pain but no weakness or gait  limitation) G3-4: Severe, limiting self-care and aids warranted Hold ICPi and discuss resumption with patient only after  taking into account the risks and benefits As above for aseptic meningitis, suggest concurrent IV  acyclovir until PCR results obtained and negative Trial of methylprednisolone 1-2 mg/kg If severe or progressing symptoms or oligoclonal bands  present, consider pulse corticosteroids  methylprednisolone 1 g IV daily for 3-5 days plus IVIG 2  g/kg over 5 days If positive for autoimmune  encephalopathy antibody and limited or no  improvement, consider rituximab or plasmapheresis in  consultation with neurology 7.7 Transverse myelitis Definition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon reflexes Diagnostic work-up Neurologic consultation MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural antibodies  Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG Evaluation for urinary retention, constipation Grading Management G1: Mild, no interference with function and symptoms  not concerning to patient. Note: Any cranial nerve  problem should be managed as moderate. Permanently discontinue ICPi Methylprednisolone 2 mg/kg Strongly consider higher doses of 1 g/d for 3-5 days  Strongly consider IVIG |                                                                                                                                                                                                                                                                                                                                                                                                 |  
7.0 Nervous System Toxicities G2: Moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation) G3-4: Severe, limiting self-care and aids warranted All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate. Abbreviations: AChR, acetylcholine receptor; ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; CBC, complete blood count; CNS, central nervous system; CPK, creatine phosphokinase; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, Grade; GI, gastrointestinal; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ICPi, immune checkpoint inhibitor; ICU, intensive care unit; IgG, immunoglobulin G; IV, intravenous; IVIG, intravenous immunoglobulin; irAE, immune-related adverse event; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; NA, not applicable; NCS, nerve conduction study; NIF, negative inspiratory force; PCR, polymerase chain reaction; RPR, rapid plasma reagin, TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiogram; VC, vital capacity; WBC, white blood cell count.  
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| 16.2.8 Table A8                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Management of Hematologic irAEs in Patients Treated With ICPis 8.0 Hematologic Toxicities   |
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| 8.1 Autoimmune hemolytic anemia Definition: A condition in which RBCs are destroyed and removed from the blood stream before their normal  lifespan is over. Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, inability to do physical  activity, and heart murmur. Diagnostic work-up History and physical examination (with special consideration of history of new drugs and insect, spider, or snake  bites) Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear; LDH,  haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PTNIR infectious causes Autoimmune serology Paroxysmal nocturnal hemoglobinuria screening Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis,  cytogenetic analysis to evaluate for myelodysplastic syndromes Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies Protein electrophoresis, cryoglobulin analysis Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, thyroid,  infection Glucose-6-phosphate dehydrogenase Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs,  quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, diclofenac, etc) Assessment of methemoglobinemia Grading Management G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 mmol/L; <  Continue ICPi with close clinical follow-up and  LLN to 100 g/L laboratory evaluation G2: Hgb < 10.0 to 8.0 g/dL; < 6.2to4.9mmol/L; < 100 to  Hold ICPi and strongly consider permanent  80 g/L discontinuation Administer 0.5-1 mg/kg/d prednisone equivalents G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; transfusion  Permanently discontinue ICPi indicated Should use clinical judgment and consider admitting the  patient Hematology consult Prednisone 1-2 mg/kg/d (oral or IV depending on  symptoms/speed of development) If worsening or no improvement, 1-2 mg/kg/d  prednisone equivalents and permanently discontinue  ICPi treatment Consider RBC transfusion per existing guidelines; do  not transfuse more than the minimum number of RBC  units necessary to relieve symptoms of anemia or to  return a patient to a safe Hgb range (7-8 g/dL in stable,  noncardiac inpatients) Should offer patients supplementation with folic acid 1  mg once daily G4: Life-threatening consequences, urgent intervention  Permanently discontinue ICPi indicated Admit patient Hematology consult IV prednisone corticosteroids 1-2 mg/kg/d If no improvement or if worsening while on  corticosteroids or severe symptoms on presentation,  initiate other immunosuppressive drugs, such as |                                                                                             |  
| 8.0 Hematologic Toxicities rituximab, IVIG, cyclosporin A, and mycophenolate  mofetil RBC transfusion per existing guidelines; discuss with  blood bank team prior to transfusions that a patient with  possible ICPi serious AE is in house.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
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| Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering process is  complete; thereafter, less-frequent testing is needed 8.2 Acquired TTP Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic  purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, hemiplegia, and visual  disturbances. It is an acute or subacute condition.  Diagnostic work-up History with specific questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, opana ER  antibiotics, quinine) Physical examination, peripheral smear ADAMTS13 activity level and inhibitor titer LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes PT, activated PTT, fibrinogen Blood group and antibody screen, direct antiglobulin test, CMV serology Consider CT/MRI brain, echocardiogram, ECG Viral studies Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia precipitously Grading Management All grades The first step in the management of TTP is a high index  of suspicion for the diagnosis and timely recognition;  hematology consult should immediately be called, as  delay in identification is associated with increased  mortality/morbidity. Initially, the patient should be stabilized and any critical  organ dysfunction stabilized G1: Evidence of RBC destruction (schistocytosis)  without anemia, renal insufficiency, or  thrombocytopenia clinically G2: Evidence of RBC destruction (schistocytosis)  without clinical consequence with G2 anemia and  thrombocytopenia Hold ICPi and discuss resumption with patient only after  taking into account the risks and benefits, noting that  there are currently no data to recommend restarting  ICPi therapy Hematology consult Administer 0.5-1 mg/kg/d prednisone G3: Laboratory findings with clinical consequences (G3  thrombocytopenia, anemia, renal insufficiency > 2) G4: Life-threatening consequences (eg, CNS  hemorrhage or thrombosis/embolism or renal failure) Hold ICPi and discuss resumption with patient only after  taking into account the risks and benefits, noting that  there are currently no data to recommend restarting  ICPi therapy Hematology consult In conjunction with hematology, initiate PEX according  to existing guidelines with further PEX dependent on  clinical progress Administer methylprednisolone 1 g IV daily for 3 days,  with the first dose typically administered immediately  after the first PEX May offer rituximab 8.3 Hemolytic uremic syndrome Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia,  and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome can include: |  
8.0 Hematologic Toxicities Abdominal pain, vomiting, and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion or seizures High blood pressure Swelling of the face, hands, feet, or entire body Diagnostic work-up History and physical examination (special consideration for new history of high-risk drugs, hypertension, or cardiac causes) CBC with indices Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis. Serum creatinine ADAMTS13 (to rule out TTP) Homocysteine/methylmalonic acid Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial) Evaluate reticulocyte count and mean corpuscular volume Evaluation of infectious cause, including screening for EBV, CMV, HHV6 Evaluation for nutritional causes of macrocytosis (B12 and folate) Pancreatic enzymes Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc) Evaluation for concurrent confusion Grading Management G1-2: Evidence of RBC destruction (schistocytosis) without clinical consequences of anemia, thrombocytopenia Grade 2 G3: Laboratory findings with clinical consequences (eg, renal insufficiency, petechiae) G4: Life-threatening consequences (eg, CNS thrombosis/ embolism or renal failure)
Continue ICPi with close clinical follow-up and laboratory evaluation Supportive care Permanently discontinue ICPi Begin therapy with eculizumab therapy 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks Red blood transfusion according to existing guidelines 8.4 Aplastic anemia Definition: Condition in which the body stops producing enough new blood cells Diagnostic work-up History and physical examination (close attention to medications, exposure to radiation, toxins, recent viral infections) CBC, smear, reticulocyte count Viral studies, including CMV, HHV6, EBV, parvovirus Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D Serum LDH, renal function Work-up for infectious causes Identify marrow hypo/aplasia Bone marrow biopsy and aspirate analysis Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by flow for PNH Flow cytometry to evaluate loss of GPI-anchored proteins Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and filtered Grading Management G1: Nonsevere, < 0.5 polymorphonuclear cells x 109/L
hypocellular marrow, with marrow cellularity < 25%, peripheral platelet count . 20,000, reticulocyte count < 20,000  
| Hold ICPi and provide growth factor support and close  clinical follow-up, and laboratory evaluation  Supportive transfusions as per local guidelines   |
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| 8.0 Hematologic Toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                             |
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| G2: Severe, hypocellular marrow < 25% and two of the  following: ANC < 500, peripheral platelet < 20,000, and  reticulocyte < 20,000                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Hold ICPi and provide growth factor support and close  clinical laboratory evaluations daily Administer ATG + cyclosporine; HLA typing and  evaluation for bone marrow transplantation if patient is  candidate; all blood products should be irradiated and  filtered Supportive care with granulocyte colony-stimulating  factor may be added in addition |
| G3-4: Very severe, ANC > 200, platelet count > 20,000,  reticulocyte count > 20,000, plus hypocellular marrow >  25%                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Hold ICPi and monitor weekly for improvement; if not  resolved, discontinue treatment until AE has reverted to  G1 Hematology consult, growth factor support Horse ATG plus cyclosporine If no response, repeat immunosuppression with rabbit  ATG plus cyclosporine, cyclophosphamide For refractory patients, consider eltrombopag plus  supportive care  |
| 8.5 Lymphopenia Definition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3  Diagnostic work-up History and physical examination (special attention for lymphocyte-depleting therapy such as fludarabine, ATG,  corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of autoimmune disease, family  history of autoimmune disease) Evaluation of nutritional state as cause Spleen size CBC with differential, peripheral smear and reticulocyte counts CXR for evaluation of presence of thymoma Bacterial cultures and evaluation for infection (fungal, viral, bacterial specifically CMV/HIV) Grading Management G1-2: 500-1,000 PB lymphocyte count G3: 250-499 PB lymphocyte count G4: < 250 PB lymphocyte count Continue ICPi Continue ICPi, checking CBC weekly for monitoring,  initiation of CMV screening Consider holding ICPi Initiate Mycobacterium avium complex prophylaxis and  Pneumocystis jirovecii prophylaxis, CMV screening.  HIV/hepatitis screening if not already done May consider EBV testing if evidence of  lymphadenopathy/hepatitis, fevers, hemolysis  consistent with lymphoproliferative disease 8.6 Immune thrombocytopenia Definition: An autoimmune disorder characterized by immunologic destruction of otherwise normal platelets  Diagnostic work-up History and physical examination (special attention for lymphocyte-depleting therapy, such as fludarabine, ATG,  corticosteroids, cytotoxic therapy) Family history of autoimmunity or personal history of autoimmune disease History of viral illness CBC Peripheral blood smear, reticulocyte count Bone marrow evaluation only if abnormalities in the above test results and further investigation is necessary for a  diagnosis Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C virus,  hepatitis B virus, and Helicobacter pylori Direct antigen test should be checked to rule out concurrent Evan  syndrome Nutritional evaluation |                                                                                                                                                                                                                                                                                                                                                             |  
| 8.0 Hematologic Toxicities   |
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| Bone marrow evaluation if other cell lines affected and concern for aplastic anemia Grading Management G1: Platelet count < 100/µL Continue ICPi with close clinical follow-up and  laboratory evaluation G2: Platelet count < 75/µL Hold ICPi but monitor for improvement; if not resolved,  interrupt treatment until AE has reverted to G1 Administer prednisone 1 mg/kg/d (dosage range, 0.5-2  mg/kg/d) orally for 2-4 weeks after which time this  medication should be tapered over 4-6 weeks to the  lowest effective dose IVIG may be used in conjunction  with corticosteroids if a more-rapid increase in platelet  count is required. G3: Platelet count < 50/µL Hold ICPi but monitor for improvement; if not resolved,  interrupt treatment until AE has reverted to G1 G4: Platelet count < 25/µL Hematology consult Prednisone 1-2 mg/kg/d (oral or IV depending on  symptoms) If worsening or no improvement, 1-2 mg/kg/d  prednisone equivalents and permanently discontinue  treatment IVIG used with corticosteroids when a more-rapid  increase in platelet count is required If IVIG is used, the dose should initially be 1 g/kg as a  one-time dose. This dosage may be repeated if  necessary If previous treatment with corticosteroids and/or IVIG  unsuccessful, subsequent treatment may include  rituximab, thrombopoietin receptor agonists, or morepotent immunosuppression (From American Society of  Hematology guideline on immune thrombocytopenia97;  consult for further details) 8.7 Acquired hemophilia Definition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation  factors  Diagnostic work-up Full blood count to assess platelet number, fibrinogen, PT, PTT, INR; the typical finding in patients with acquired  hemophilia A is a prolonged activated PTT with a normal PT MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and  response of bleeding Medication review to assess for alternative causes Determination of Bethesda unit level of inhibitor Grading Management G1: Mild, 5%-40% of normal factor activity in blood,  Hold ICPi and discuss resumption with patient only after  0.05-0.4 IU/mL of whole blood taking into account the risks and benefits Administer 0.5-1 mg/kg/d prednisone Transfusion support as required Treatment of bleeding disorders with hematology  consult G2: Moderate, 1%-5% of normal factor activity in blood,  Hematology consult 0.01- 0.05 IU/mL of whole blood Administration of factor replacement (choice based on  Bethesda unit of titer) Administer 1 mg/kg/d prednisone 6 rituximab (dose, 375  mg/m2  weekly for 4 weeks) and/or cyclophosphamide                              |  
| 8.0 Hematologic Toxicities (dose, 1-2 mg/kg/d); choice of rituximab v  cyclophosphamide is patient specific and should be  done with assistance of hematology consult;  prednisone, rituximab, and cyclophosphamide should  be given for at least 5 weeks Factors should be provided to increase level during  bleeding episodes, with choice of factor based on  presence or absence of inhibitor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
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| G3-4: Severe, < 1% of normal factor activity in blood, <                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Permanently discontinue ICPi                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| 0.01 IU/mL of whole blood                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Admit patient Hematology consult Administration of factor replacement, choice based on  Bethesda unit level of inhibitor Bypassing agents may  be used (factor VII, factor VIII inhibitor bypass activity);  caution should be taken in the elderly and those with  coronary artery disease Prednisone 1-2 mg/kg/d (oral or IV depending on  symptoms) 6 rituximab (dose, 375 mg/m2  weekly for 4  weeks) and/or cyclophosphamide (dose, 1-2 mg/kg/d). Transfusion support as required for bleeding If worsening or no improvement add cyclosporine or  immunosuppression/immunoadsorption |
| Additional considerations: The American Heart Association requires specialist clinical and laboratory expertise.  Consult and/or transfer to a specialist center is often appropriate. If consultation with or transfer to a hemophilia  center is not immediately possible, then investigation and treatment should be initiated while a liaison is being  established. All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: AE, adverse event; ANC, absolute neutrophil count; ATG, antithymocyte globulin; CBC, complete  blood count; CMV, cytomegalovirus; CNS, central nervous system; CT, computed tomography; CXR, chest x-ray;  DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; ECG, electrocardiogram; ER, extended  release; FE, ferritin; G, Grade; GPI, glycosylphosphatidylinositol; Hgb, hemoglobin; HHV6, human herpesvirus 6;  HIV, human immunodeficiency virus; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; INR,  international normalized ratio; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous  immunoglobulin; LDH, lactate dehydrogenase; LLN, lower limit of normal; MRI, magnetic resonance imaging;  NSAID, nonsteroidal anti-inflammatory drug; PB, peripheral blood; PEX, plasma ex-change; PNH, paroxusmal  nocturnal hemoglobinuria; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell count; TTP,  thrombotic thrombocytopenic purpura. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |  
Version Date: 06/23/2021 16.2.9 Table A9 Management of Cardiovascular irAEs in Patients Treated With ICPis  
| 9.0 Cardiovascular Toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
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| 9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis Definition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, progressive or  acute dyspnea, pleural effusion, fatigue Diagnostic work-up At baseline ECG Consider troponin, especially in patient treated with combination immune therapies Upon signs/symptoms  (consider cardiology consult) ECG Troponin BNP Echocardiogram CXR Additional testing to be guided by cardiology and may include Stress test Cardiac catherization Cardiac MRI Grading Management G1: Abnormal cardiac biomarker testing, including  abnormal ECG G2: Abnormal screening tests with mild symptoms G3: Moderately abnormal testing or symptoms with mild  activity G4: Moderate to severe decompensation, IV medication  or intervention required, life-threatening conditions All grades warrant work-up and intervention given  potential for cardiac compromise Consider the following: Hold ICPi and permanently discontinue after G1 High-dose corticosteroids (1-2 mg/kg of prednisone)  initiated rapidly (oral or IV depending on symptoms) Admit patient, cardiology consultation Management of cardiac symptoms according to  ACC/AHA guidelines and with guidance from cardiology Immediate transfer to a coronary care unit for patients  with elevated troponin or conduction abnormalities In patients without an immediate response to high-dose  corticosteroids, consider early institution of cardiac  transplant rejection doses of corticosteroids  (methylprednisolone 1 g every day) and the addition of  either mycophenolate, infliximab, or antithymocyte  globulin Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-threatening  nature of cardiovascular complications. Holding checkpoint inhibitor therapy is recommended for all grades of  complications. The appropriateness of rechallenging remains unknown. Note that infliximab has been associated  with heart failure and is contraindicated at high doses in patients with moderate-severe heart failure. 9.2 Venous thromboembolism Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via  the blood stream. Clinical signs and symptoms are variable and may include pain, swelling, increased skin vein  visibility, erythema, and cyanosis accompanied by unexplained fever for DVT and dyspnea, pleuritic pain, cough,  wheezing, or hemoptysis for PE Diagnostic work-up Evaluation of signs and symptoms of PE or DVT may include Clinical prediction rule to stratify patients with  suspected venous thromboembolism Venous ultrasound for suspected DVT CTPA for suspected PE Can also consider D-dimer for low-risk patients based on risk stratification by clinical prediction rule for DVT/PE  when CT or Doppler are not available or appropriate Ventilation/perfusion scan is also an option when CTPA is not  appropriate Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas |  
Version Date: 06/23/2021  
| 9.0 Cardiovascular Toxicities                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                 |
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| Grading                                                                                                                                                                                                       | Management                                                                                                                                                                                                                                                                                                                                                                      |
| G1: Venous thrombosis (eg, superficial thrombosis)                                                                                                                                                            | Continue ICPi Warm compress Clinical surveillance                                                                                                                                                                                                                                                                                                                               |
| G2: Venous thrombosis (eg, uncomplicated DVT),  medical intervention indicated G3: Thrombosis (eg, uncomplicated PE [venous],  nonembolic cardiac mural [arterial] thrombus), medical  intervention indicated | Continue ICPi Management according to CHEST, ACC, and/or AHA  guidelines and consider consult from cardiology or  other relevant specialties LMWH is suggested over VKA, dabigatran, rivaroxaban  apixaban, or edoxaban for initial and long-term  treatment IV heparin is an acceptable alternative for initial use,  and oral anticoagulants are acceptable for the long term |
| G4: Life-threatening (eg, PE, cerebrovascular event,  arterial insufficiency), hemodynamic or neurologic  instability, urgent intervention indicated                                                          | Permanently discontinue ICPi Admit patient and management according to CHEST,  ACC, and/or AHA guidelines and with guidance from  cardiology Respiratory and hemodynamic support LMWH is suggested over VKA, dabigatran,  rivaroxaban, apixaban, or edoxaban for initial and longterm treatment IV heparin is an acceptable alternative for initial use,  and oral anticoagulants are acceptable for the long term Further clinical management as indicated based on  symptoms                                                                                                                                                                                                                                                                                                                                                                                 |
| Additional considerations While it may be impossible to determine the etiology of thromboembolic disease in patients with advanced cancer  and the role, if any, that ICPi treatment plays, it is reasonable to remove the potential inciting agents given the  severity and life-threatening potential of G4 complications. Clinicians are to use clinical judgment and take into  account the risks and benefits when deciding whether to discontinue ICPi treatment. Anticoagulant therapy duration should continue for a minimum of 9-12 months to indefinitely in the setting of active  cancer unless patient is asymptomatic, doing well, or in remission. All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; BNP, brain natriuretic  peptide; CT, computed tomography; CTPA, computed tomography pulmonary angiography; CXR, chest x-ray;  DVT, deep vein thrombosis; ECG, electrocardiogram; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immunerelated adverse event; IV, intravenous; LMWH, low-molecular-weight heparin; MRI, magnetic resonance imaging;  PE, pulmonary embolism; VKA, vitamin K agonist.                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                 |  
Version Date: 06/23/2021  
| 16.2.10                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Table A10   | Management of Ocular irAEs in Patients Treated With ICPis 10.0 Ocular Toxicities   |
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| Counsel all patients to inform their health care provider immediately if they experience any of the following ocular  symptoms Blurred vision Change in color vision Photophobia Distortion Scotomas Visual field changes Double vision Tenderness Pain with eye movement Eyelid swelling Proptosis Evaluation, under the guidance of ophthalmology Check vision in each eye separately Color vision Red reflex Pupil size, shape, and reactivity Fundoscopic examination Inspection of anterior part of eye with penlight Prior conditions Exclude patients with history of active uveitis History of recurrent uveitis requiring systemic immunosuppression or continuous local therapy Additional considerations Ocular irAEs are many times seen in the context of other organ irAEs High level of clinical suspicion as symptoms may not always be associated with severity Best to treat after  ophthalmologist eye examination 10.1 Uveitis/iritis Definition: Inflammation of the middle layer of the eye Diagnostic work-up: as per above Grading Management G1: Asymptomatic Continue ICPi Refer to ophthalmology within 1 week Artificial tears G2: Medical intervention required, anterior uveitis Hold ICPi temporarily until after ophthalmology consult Urgent ophthalmology referral Topical corticosteroids, cycloplegic agents, systemic  corticosteroids May resume ICPi treatment once off systemic  corticosteroids, which are purely indicated for ocular  adverse effects or once corticosteroids for other  concurrent systemic irAEs are reduced to # 10 mg;  continued topical/ocular corticosteroids are permitted  when resuming therapy to manage and minimize local  toxicity Re-treat after return to G1 or less G3: Posterior or panuveitis Permanently discontinue ICPi Urgent ophthalmology referral. Systemic corticosteroids and  intravitreal/periocular/topical corticosteroids G4: 20/200 or worse Permanently discontinue ICPi Emergent ophthalmology referral Systemic corticosteroids (IV prednisone 1-2 mg/kg or  methylprednisolone 0.8-1.6 mg/kg) and |             |                                                                                    |  
Version Date: 06/23/2021  
| 10.0 Ocular Toxicities intravitreal/periocular/topical corticosteroids per  ophthalmologist opinion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
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| Additional considerations: Consider use of infliximab or other TNF-a blockers in cases that are severe and  refractory to standard treatment 10.2 Episcleritis Definition: Inflammatory condition affecting the episcleral tissue between the conjunctiva and the sclera that occurs  in the absence of an infection Diagnostic work-up: As per 10.0 Grading Management G1: Asymptomatic Continue ICPi Refer to ophthalmology within 1 week Artificial tears G2: Vision 20/40 or better Hold ICPi therapy temporarily until after ophthalmology  consult Urgent ophthalmology referral Topical corticosteroids, cycloplegic agents, systemic  corticosteroids G3: Symptomatic and vision worse than 2/40 Permanently discontinue ICPi Urgent ophthalmology referral. Systemic corticosteroids and topical corticosteroids with  cycloplegic agents G4: 20/200 or worse Permanently discontinue ICPi Emergent ophthalmology referral. Systemic corticosteroids and topical corticosteroids with  cycloplegic agents Additional considerations: Consider use of infliximab or other TNF-α blockers in cases that are severe and  refractory to standard treatment 10.3 Blepharitis Definition: Inflammation of the eyelid that affects the eyelashes or tear production Diagnostic work-up: As per 10.0 Grading Management No formal grading system Warm compresses and lubrication drops Continue therapy unless persistent and serious All recommendations are expert consensus based, with benefits outweighing harms, and strength of  recommendations are moderate. Abbreviations: ICPi, immune checkpoint inhibitor; G, Grade; irAE, immune-related adverse event; IV, intravenous,  TNF, tumor necrosis factor. |