module 2: assessment of immune-related adverse events to ...baseline, resume routine monitoring •...

Module 2: Assessment of Immune-Related Adverse Events to Proactively Counsel and

Mitigate Impact on Optimized Care

Joanne Riemer, RN, BSN

Karen Matijevich, RN

Immune Related Adverse Events

It’s the …”ITIS”s... of immune therapy

Our immune system has protective mechanisms in place to prevent destruction

of normal cells. Immune checkpoint therapy can withdraw some of those

protective mechanisms.

Pulmonary

Pneumonitis

Interstitial lung

disease

Acute interstitial

pneumonitis

Neurologic

Autoimmune neuropathy

Demyelinating

Polyneuropathy

Guillain-Barre

Myasthenia gravis–like

syndrome

Hepatic

Hepatitis,

autoimmune

Gastrointestinal

Colitis

Enterocolitis

Necrotizing

colitis

GI perforation

Endocrine

Hypothyroidism

Hyperthyroidism

Adrenal

insufficiency

Hypophysitis

Eye

Uveitis

Iritis

Renal

Nephritis,

autoimmune

Renal failure

Skin

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson

syndrome

Toxic epidermal

necrolysis

Vitiligo

Alopecia

Immune-Related Adverse Events (irAEs)

Immune checkpoint therapy may withdraw protective mechanisms and lead to an imbalance in immunologic

tolerance

Generally, anti-PD1 drugs are well-tolerated with a favorable

safety profile, but immune-related adverse events can effect

any organ.

Case Study

• 61 y.o. male with stage IV NSCLC

• 18 doses of anti-PD1, presented with a resting O2 93%

and walking 86% with mild dyspnea.

• Consider pneumonitis

• CT chest with contrast; result: new ground glass opacity

• What grade would you consider pneumonitis?

• Started on prednisone at 1 mg/kg/day, prophylactic

antibiotics, PPI

• Tapered steroids over 5 weeks

• Was able to resume I-O therapy

Grading irAEs

• CTCAE 4.0 (Common Terminology Criteria for

Adverse Events)

http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-

06-14_QuickReference_8.5x11.pdf

http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

Published Algorithms and Guidelines for irAEsfor Anti-PD-1 Agents

– Nivolumab (Opdivo)

http://www.opdivohcp.bmscustomerconnect.com/metastatic-

nsclc

– There is also a smartphone app

BMS

http://www.opdivohcp.bmscustomerconnect.com/metastatic-nsclc

Published Guidelines for Treatment

• Pembrolizumab (Keytruda) https://www.keytruda.com/static/pdf/Guide-to-Monitoring-Patients-During-Treatment-With-KEYTRUDA.pdf

• Immune-mediated pneumonitis

• Immune-mediated colitis

• Immune-mediated hepatitis

• Hypophysitis

• Hyperthyroidism

• Type 1 diabetes mellitus

• Immune-mediated nephritis

Merck

https://www.keytruda.com/static/pdf/Guide-to-Monitoring-Patients-During-Treatment-With-KEYTRUDA.pdf

Common irAEs in NSCLC with Anti PD-1

Spain et al, Cancer Treat Rev. 2016;44:51-60.

Less Common irAEs in NSCLC with Anti PD-1

Spain et al, Cancer Treat Rev. 2016;44:51-60.

PD-1 Checkpoint Inhibition Phase III Trials—Toxicities

Trial Agent

Rx-Related AEs–All & Grade 3/4

Most Common Rx-Related AEs

Pneumonitis Rate

Checkmate 017

Nivolumab 58%7%

Fatigue—16%↓Appetite—11%Asthenia—10%

All—5%Gr 3/4—0%

Docetaxel 86%55%

Neutropenia—33%Fatigue—33%Nausea 23%

0%

Checkmate 057

Nivolumab 69%10%

Fatigue—16%Nausea—12%↓Appetite—10%

All—3%Gr 3/4—1%

Docetaxel 88%54%

Neutropenia—31%Fatigue—29%Nausea—26%

0%

Keynote 010 Pembrolizumab2 mg/kg dose

63%13%

Fatigue—20%Pruritus—11%↓Appetite—11%

All—5%Grade 3-5—2%2 deaths

Docetaxel 81%35%

Fatigue—25%Diarrhea 18%↓Appetite—16%

0%

Brahmer et al, N Engl J Med. 2015;373:123-35.

Borghaei et al, N Engl J Med. 2015;373:1627-39.

Herbst et al, Lancet. 2015; preprint

Pneumonitis: Focal or Diffuse Inflammation of Lung Parenchyma

• Diagnosis in NSCLC is complicated

• Symptoms can represent a host of causes

• Diagnosed by exclusion

– Rule out other etiologies (eg, infection, other drugs,

neoplasm, metabolic causes)

• Early recognition, evaluation, and treatment

are critical

Presented by Julie Brahmer, MD, and

Evan Lipson, MD

Pneumonitis

• Radiographs

– New or changes

in ground-glass

changes, nodular

or interstitial

• Symptoms

– New or worsening

cough, shortness

of breath

• Signs

– Decrease in

oxygen saturation

Pneumonitis

• Focal or diffuse inflammation

of the lung parenchyma

CTCAE Grading v3.0 or 4.0

1 Asymptomatic

2 Symptomatic,

requires intervention

3 Severe, limits ADLs,

requires oxygen

4 Life-threatening, requires

urgent intervention

5 Death

Uncommon but

potentially fatal toxicity

of anti-PD-1/PD-L1

agents

Limited data regarding:

Clinical, radiologic,

pathologic features

Treatment

Outcomes of

treatment

Naidoo et al, ECCO/ESMO 2015

Pneumonitis and NSCLC

• Severe drug-related pneumonitis

– Anti-PD-1 antibody: 2%

– Erlotinib: 1.6-4.5%

– Gefitinib: 3.5%

– Docetaxel: 4.6%

– Gemcitabine: 1-2%

– Pemetrexed: 2 reports in the literature

• Radiation pneumonitis: 13%

• Treatment: steroids

Liu et al, Chest. 2007;132:1042-4, Konishi et al, Anticancer

Res. 2005;25:435-441, Grand, Clin Transl Oncol.

2007;9:578-581, Roychowdhury, Invest New Drugs.

2002;20:311-315, Hochstrasser et al, Chemotherapy.

2012;58:84-88, Inoue et al, Int J Radiat Oncol Biol Phys.

2001;49:649-655.

Endocrine: Thyroid, Adrenal, Pituitary

Grade Management Follow up

Asymptomatic TSH abnormalities

Hypothyroidism: (more common with

anti-PD-1)

Monitor TSH, FT4, continue I-O,

supportive care . Thyroid hormone

replacement for hypothyroidism.

Monitor TSH and FT4 and thyroid

replacement dosing.

Symptomatic endocrinopathy,

hyperthyroidism,

hypophysitis, and

adrenal insufficiency (more

common with anti-CTLA-4)

• Hold I-O therapy

• Evaluate endocrine function

• Hyperthyroidism may require

beta-blocker

• Consider pituitary scan

• If symptomatic with abnormal

labs and scan; initiate steroids

and appropriate hormonal

therapy

Hyperthyroidism frequently is

followed by hypothyroidism and

may then need hormone

replacement

If placed on steroids, taper over

> 1 month

Suspicious of adrenal crisis

(severe dehydration,

hypotension, shock)

• Discontinue I-O

• Rule out sepsis

• Consider steroids

• IV fluids

• Endocrine consult

• If adrenal crisis is ruled out,

treat as symptomatic

endocrinopathy

Teply B and Lipson E. Cancer Network: Oncology Journal:

Identification and Management of Toxicities from Immune

Checkpoint Blocking Drugs.

HCP Safety APP for Opdivo

Hepatitis: Graded by Liver Function Test


Grade 1: AST or ALT > ULN to

3.0 x

ULN and/or T. bili > ULN

- 1.5 x ULN

Close monitoring. Consider

delay in I-O therapy

• If irAE resolves quickly, may

continue I-O

• If it persist or worsens, treat

as > Grade 2

Grade 2: AST or ALT > 3.0 to ≤

5 x

ULN and/or T. bili > 1.5

to ≤ 3 x ULN

Delay I-O therapy. Initiate

steroids promptly. Taper over >

4 weeks. Evaluate alternate

etiology. Close monitoring

• If resolves, may consider

resuming

• I-O therapy: prophylactic

antibx and PPI

Grade 3 / 4: AST or ALT > 5 x

ULN

and /or T. bili >3 x ULN

Discontinue I-O therapy.

Hospitalize. Initiate high dose

steroids. If no improvement in

48-72 hours consider alternate

immunosuppressants;

Mycophenolate mofetil

(Infliximab is NOT used in irAE

hepatitis)

Evaluate alternate etiololgy

If returns to grade 2, taper

steroids over > 4 weeks

Teply B, and Lipson,E. Cancer Network: Oncology

Journal: Identification and Management of Toxicities

from Immune Checkpoint Blocking Drugs


Nephritis Graded by Creatinine Level


Grade 1: Creatinine 1-1.5 X

ULN

• Continue I-O therapy per

protocol

• Monitor creatinine weekly

• If creatinine returns to

baseline, resume routine

monitoring

• If worsens, treat as > Grade 2

Grade 2: Creatinine 1.5-3 X

ULN

• Delay I-O therapy per protocol

• Monitor creatinine every 2-3

days

• Steroids

• Consider renal biopsy

• Taper steroids > 1 month,

prophylactic antibiotics should

be renal sparing

Grade 3 ( > 3 -6 X ULN) /

Grade 4 (> 6X ULN)

Discontinue I-O therapy per

protocol

• Monitor creatinine daily

• Steroids

• Consult nephrologist

• Consider renal biopsy

• Taper steroids > 1 month,

prophylactic antibiotics should

be renal sparing

• Extended follow-up


irAEs Common with Ipilimumab

• GI/colitis

• Hypophysitis

• Uveitis

• Dermatitis

• Rare immune-related adverse events

Gastrointestinal Inflammation

Onset: 5-10 weeks

Patterns Minor irritation

Colitis: may be fatal if left untreated

Perforation—tears or holes in the colon

Symptoms Bloating

Cramps

Diarrhea

Blood in stool

Abdominal pain or tenderness

Nausea

Focal Active Colitis

Alterations in Crypt Epithelium

Ulceration in Descending Colon

Maker et al, Ann Surg Oncol. 2005;12:1005-1016.

Gastrointestinal Inflammation

Evaluation

Calculate frequency and volume of diarrhea

Stool sample to rule out infection (C. difficile, O/P, etc)

Abdominal ultrasound or CT scan

Colonoscopy (+/- biopsy)

Rule out other causes: perforation, peritonitis with pain, fever

Grade Management

Mild/grade 1: ≤ 4 stools/day above

baseline

Manage symptomatically (bland diet,

PPI, antidiarrheal)

Consider delaying tx until symptoms

improve

Moderate/grade 2: increase of 4-6

stools/day above baseline (persistent)

Colonoscopy and steroids

Low-dose steroids may be sufficient

Hold treatment

Severe/grade ≥ 3: ≥ 7 stools/day above

baseline

Initiate high-dose steroids

Discontinue treatment

Prevention No known methods

Ipilimumab Adverse Reaction Management Guide

Available at: https://www.hcp.yervoy.com/pdf/rems-

management-guide.pdf

Hypophysitis (Pituitary Gland Inflammation)

Onset 11 weeks

Often leads to hypopituitarism and adrenal insufficiency

Adrenal insufficiency: lack of gluco-and mineralocorticoids

SymptomsGeneral: fatigue, weakness, loss of appetite

CNS: headaches, confusion, hallucinations, memory loss, insomnia

Ocular: visual disturbances, eye pressure

EvaluationHormone Levels

(eg, TSH, T3/T4, cortisol, ACTH, FSH, growth hormone, luteinizing hormone, prolactin)

Consider endocrinology consult

Corsello et al, J Clin Endocrinol Metab.

2013;98:1361-1375.

Pituitary gland

Hypothalamus

Thyroid gland

T4 T3

SULTs

UGTs

liver

01

T4→T3

T3/TR

rT3,T2

inactive

T4/T3-sulfate

T4/T3-glucuronide

inactive

Excretion

T4 >> T3

02.03

Ocular Inflammation/Uveitis

Pattern Uveitis/ Iritis—inflammation of the colored portion of eye

Conjunctivitis—inflammation of conjunctiva

Symptoms: painful, itchy watery eyes, decreased visual acuity, dry eyes

Diagnosis Referral to ophthalmologist

Slit lamp evaluation

Treatment: corticosteroid eye drops

Andrews and Holden, Cancer Manag Res. 2012;4:299-307.

Dermatitis

Symptoms: Onset 3–4 weeks

Distribution on trunk, hands, and feet

May be intense and widespread

Stevens-Johnson syndrome, toxic epidermal necrolysis, or mucosal/oral lesions very rare

Hodi et al. N Engl J Med. 2010;363:711-723.

Image courtesy Matthew M. Burke, MBA, RN, MSN, APRN-BC.

Severity Management

Mild/moderate (rash/pruritus) Topical nonsteroidal cream,

antihistamine, oatmeal baths

Skin care, moisturize,

sunscreen, avoid sun

Persistent (> 1 wk) or interferes

with ADLs

Moderate-potency steroid

creams or

Moderate-dose parenteral

steroids

Dermatology referral

Severe Discontinue treatment

High-dose steroids

Avoid rapid steroid taper

Other Rare irAEs

Neurologic Sensory or motor neuropathies

Sarcoidosis Pulmonary nodules most common

Vasculitis Cardiovascular effects

Carditis Myocarditis, Pericarditis leading to dyspnea, NSTEMI, etc

Hematologic Bone marrow aplasia, hemolytic anemia, thrombocytopenia

Infusion reaction Rare < 10%

Nursing Approach to Immune-Related Symptoms

Drug-induced autoimmunity always included in

differential, often diagnosed by exclusion

Rule out other etiologies (eg, infection, other drugs, neoplasm,

metabolic causes)

Evaluation of auto antibodies often helpful (eg, anti-platelet

antibodies in thrombocytopenia)

Can affect any organ system

Early recognition, evaluation, and treatment are critical for

patient safety

General Management Principles for irAEs

Generally based on severity of symptoms

Grade 1: supportive care; +/- withhold drug

Grade 2: withhold drug, consider re-dose if toxicity

resolves to ≤ grade 1. Low-dose corticosteroids

(prednisone 0.5mg/kg/day or equivalent) if symptoms

do not resolve within a week

Grade 3-4: discontinue drug; high-dose corticosteroids

(prednisone 1–2mg/kg/day or equivalent) tapered over

≥ 1 month once toxicity resolves to ≤ grade 1


Ipilimumab: Managing irAEs


Available at: https://www.hcp.yervoy.com/pdf/rems-

management-guide.pdf

Weber et al, J Clin Oncol. 2012;30:2691-2697.

System Symptoms Management

GI tract DiarrheaAbdominal pain

Dark, bloody stools

Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day:

start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory pts.

Skin Rash (± itching) Blistering/peeling

Oral sores

Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids.

Liver JaundiceNausea/vomiting

Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN;

permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for

hepatotoxicity in corticosteroid-refractory pts.

CNS Weakness in extremitiesNumbness/tingling Sensory changes

Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids.

Endocrine HeadachesFatigue

Behavior/mood changesMenstruation changes

Dizziness/light-headedness

Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific

symptoms. Consider having an endocrinologist follow the pt.

Eyes Vision problemsIrritation

Monitor for redness suggesting uveitis; treat with topical steroidal eye drops.

Principles of Managing irAEs

Hold ipilimumab

Initiate steroids therapy (1–2 mg/kg of

prednisone or equivalent daily)

Consider infliximab (if gastrointestinal toxicity) or

mycophenolate (if hepatotoxicity) if steroids do

not resolve symptoms

https://www.hcp.yervoy.com/pdf/rems-management-guide.pdf

PD-1/PD-L1 Inhibition: Managing irAEs

Any grade 1 AEIsolated hypothyroidism

Continue PD-1 txand monitor

Hold PD-1 tx and administer steroids;

After improvement to ≤ grade 1, taper

steroids over at least 1 mo.

Resume if:

AE remains at grade

0/1 after steroid taper

Discontinue if:

No improvement to ≤

grade 1 within 12 wks

Pembrolizumab adverse reaction management

guide. Nivolumab adverse reaction management

guide.

Initiate steroids or replacement therapy for hypothyroidism

Grade 2 pneumonitis,

nephritis, colitis, hepatitis,

symptomatic hypophysitis

Any grade 3 AE

Grade 3/4 pneumonitis

Grade 3/4 nephritis

Grade 3/4 infusion-related reaction

Any life-threatening or grade 4 AE

Any severe or grade 3 recurrent AE

Hepatitis associated with AST/ALT > 5 x ULN

AST/ALT ≥ 50% ↑ from baseline

lasting ≥ 1 wk*

Total bilirubin > 3 x ULN

*In pts with liver metastasis who begin treatment with grade 2 elevation of AST/ALT.

Initiate steroid therapy

Permanently discontinue PD-1 tx

Pembrolizumab adverse reaction management guide.

Nivolumab adverse reaction management guide.

PD-1/PD-L1 Inhibition: Managing irAEs

Best Practices Are Ones that Lead to Early Awareness, Evaluation, and Treatment of irAEs!

• Baseline evaluation

• Assessment before every dose

• Patient education

• Effective management of irAEs

• Frequent monitoring

• Extended follow-up

Cancer network.com: Identification and

Management of Toxicities from Immune

Checkpoint-Blocking Drugs. Teply, Benjamin,

and Lipson, Evan

APP: HSC Safety : Opdivo

Patient Education

• Discuss all medications

• Report new or worsening symptoms

– Know when to call

• If admitted to an emergency

department for any symptoms, patient

should report taking immunotherapy

and have ED contact oncology

provider

Cancer network.com: Identification and

Management of Toxicities from Immune

Checkpoint-Blocking Drugs. Teply,Benjamin,

and Lipson,Evan


Instructing Patients When to Call

• New or worsening cough, chest pain, or shortness of breath

• Loose stools or increased frequency; blood in your stool or

abdominal pain

• Nausea, vomiting, drowsiness or significant fatigue, dark

urine, or jaundice

• Decreased urine output, blood in urine, swollen ankles, loss of

appetite

• Headaches, extreme tiredness, lightheadedness, confusion

• Change in vision

• Fever or chills

• Rash

• Joint or muscle pain or weakness


Immune Related Adverse EventsConsult Contact List

• irAE specialist consult list

– Endocrinologist

– Gastroenterologist

– Pulmonologist

– Nephrologist

– Rheumatologist

– Infectious disease

– Dermatologist

– Neurologist

– Ophthalmologist

module 2: assessment of immune-related adverse events to ...baseline, resume routine monitoring •...

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