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Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View

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i3 Health
i3 Health

i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource. This slide deck, presented by Blanca Ledezma, MSN, NP, AOCNP® Nurse Practitioner Hematology/Oncology University of California, Los Angeles (UCLA) Health, will provide insight into the nurse’s view on managing immune-related adverse events to ensure optimal cancer immunotherapy outcomes. Immune checkpoint inhibitors, which alter immune regulatory pathways and promote cell-mediated destruction of tumor cells, have revolutionized the treatment of cancer in recent years, with numerous therapeutic agents approved and several targets under investigation (Chennamadhavuni et al, 2022). However, up to 90% of patients receiving immune checkpoint inhibitors experience immune-related adverse events, which can affect a wide variety of organ systems and can occur at any time during treatment or even after treatment completion (NCCN, 2023). Immune-related adverse events are associated with significant morbidity as well as the risk of therapy discontinuation, which can have an unpredictable impact on patients’ disease course. Therefore, it is critical for nurses to understand the mechanism, identification, and timely management of immune-related adverse events (Shankar et al, 2022). In this activity presented by Blanca Ledezma, MSN, NP, AOCNP®, Nurse Practitioner at the University of California, Los Angeles (UCLA) Health, will provide insight into the nurse’s view on managing immune-related adverse events to ensure optimal cancer immunotherapy outcomes. TARGET AUDIENCE Oncology nurses, nurse practitioners, clinical nurse specialists, and other health care professionals involved in the management of patients with immune-related adverse events (IRAEs). LEARNING OBJECTIVES Upon completion of this activity, participants should be able to: Discuss how the mechanisms of action of immunotherapies influence their safety profile Identify risk factors predisposing patients to IRAEs Distinguish IRAEs from chemotherapy- and targeted therapy-related adverse events Coordinate with the interdisciplinary health care team to apply evidence-based guidelines and best practices in personalized nursing management plans for patients with IRAEs Develop patient counseling strategies promoting awareness, self-monitoring, and escalated reporting of IRAEs

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Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View Blanca Ledezma, MSN, NP, AOCNP® Nurse Practitioner Hematology/Oncology University of California, Los Angeles (UCLA) Health
Disclosures Speaker’s bureau: Amgen, AstraZeneca, Eisai, Lilly i3 Health has mitigated all relevant financial relationships
Learning Objectives IRAEs = immune-related adverse events. Discuss how the mechanisms of action of immunotherapies influence their safety profile Identify risk factors predisposing patients to IRAEs Distinguish IRAEs from chemotherapy- and targeted therapy–related adverse events Coordinate with the interdisciplinary health care team to apply evidence- based guidelines and best practices in personalized nursing management plans for patients with IRAEs Develop patient counseling strategies promoting awareness, self- monitoring, and escalated reporting of IRAEs
Immunotherapy Overview
Epidemiology PD-L1 = programmed cell death protein ligand 1; CTLA-4 = cytotoxic T lymphocyte–associated protein 4. Pallin et al, 2018; Brahmer et al, 2021. In the US, 15.5 million people live with cancer or have a history of cancer In 2040, the number is expected to rise to 26.1 million Treatment with immunotherapy/immune checkpoint inhibitors (ICIs) is the standard of care for several cancers In 2018, a study found that 44% of patients with both metastatic solid tumors and hematologic tumors could use ICI A systemic review found that patients developed IRAEs at a rate of 74% with anti–PD-L1 inhibitors, 89% with anti–CTLA-4 inhibitors, and 90% with combination ICIs
Delayed Onset and Prolonged Duration of IRAEs AE = adverse events. Puzanov et al, 2017. IRAEs from immunotherapy treatments have led to delayed onset and prolonged duration when compared to AEs from chemotherapy As a result of the diverse clinical presentation of IRAEs, patients may present with IRAEs late in their treatment course, with some cases presenting months or years after discontinuation of treatment
Median Time to Onset of IRAEs Pallin et al, 2018; Puzanov et al, 2017. Can occur early on, days to months from initiation of therapy IRAEs are less predictable and can occur long after cessation of treatment Onset can be earlier when given in combination Important to monitor patients for IRAEs during and after treatment discontinuation
Epidemiology of Fatal IRAEs VEGF = vascular endothelial growth factor. Martins et al, 2019. Fatal IRAE incidence is estimated to be 0.3%-1.3% Lower risk than with conventional treatment Platinum doublet chemotherapy: 0.9% Allogenic hematopoietic stem cell transplant: 15% VEGF-targeted agents/tyrosine kinase inhibitors: 0%-4% Median time to onset for fatal toxic event is 14.5 days for ICI combinations and inclined to be delayed by 40 days for monotherapy
Majority of IRAEs Are Mild to Moderate GI = gastrointestinal; PD-1 = programmed cell death protein 1; neuro = neurological; ocul = ocular. Puzanov et al, 2017. Most Frequently Affect Skin and GI
What Is Immunotherapy?
Immunotherapy Mechanism of Action (MOA) Brahmer et al, 2021. ICIs block key regulatory signals that dampen immune responses, counteracting immune suppression in the tumor microenvironment and therefore enabling tumor-reactive T cells to mount an effective anticancer response
PD-L1/PD-1 Inhibitor and CTLA-4 Inhibitor MOA MHC = major histocompatibility complex; TCR = T-cell receptor; CD = cluster of differentiation; ipi = ipilimumab. Armezzani, 2019; Cooper et al, 2015. . Tumor Microenvironment Lymph Node
CAR T MOA CAR = chimeric antigen receptor; TAA = tumor-associated antigen. Li et al, 2018.
FDA-Approved Immune Checkpoint Inhibitors FDA = US Food and Drug Administration. Yang et al, 2023; Russo et al, 2020; USFDA, 2023a; USFDA 2023b. PD-1 inhibitors: Cemiplimab Nivolumab Pembrolizumab Dostarlimab Retifanlimab-dlwr (granted FDA accelerated approval, pending confirmatory trials) PD-L1 inhibitors: Atezolizumab Avelumab Durvalumab CTLA-4 inhibitor: Ipilimumab Combination therapy: Ipilimumab/nivolumab Chemo/ICI ICI/targeted therapy
FDA-Approved Immune Checkpoint Inhibitors L = line; TPS = tumor proportion score; NSCLC = non–small cell lung cancer; CPS = combined positive score; GEJ = gastroesophageal junction; CRC = colorectal cancer; MSI-H = microsatellite instability–high; dMMR = deficient mismatch repair; auto = autologous; allo = allogeneic; PMBCL = primary mediastinal B-cell lymphoma; R/R = relapsed/refractory; adv = advanced; met = metastatic. Vaddepally et al, 2020.
FDA-Approved CAR T-Cell Therapies BCMA = B-cell maturation antigen. NCI, 2022; Chen et al, 2023. Generic Name Target Antigen Targeted Disease Patient Population Tisagenlecleucel CD19 B-cell acute lymphoblastic leukemia (ALL) Children and young adults with refractory or relapsed B-cell ALL B-cell non-Hodgkin lymphoma (NHL) Adults with relapsed or refractory B-cell NHL Axicabtagene ciloleucel CD19 B-cell NHL Adults with relapsed or refractory B-cell NHL Follicular lymphoma Adults with relapsed or refractory follicular lymphoma Brexucabtagene autoleucel CD19 Mantle cell lymphoma (MCL) Adults with relapsed or refractory MCL B-cell ALL Adults with refractory or relapsed B-cell ALL Lisocabtagene maraleucel CD19 B-cell NHL Adults with relapsed or refractory B-cell NHL Idecabtagene vicleucel BCMA Multiple myeloma Adults with relapsed refractory multiple myeloma myeloma Ciltacabtagene autoleucel BCMA Multiple myeloma Adults with relapsed refractory multiple myeloma myeloma
Other Types of Immunotherapy IFN = interferon; TCR = T-cell receptor; IL = interleukin. Gupta et al, 2022; Kaplon et al, 2023; Koury et al, 2018; Sarnaik et al, 2021. Cytokine therapy High dose IL-2 IFN-𝛼 2b Monoclonal antibodies Rituximab Bispecific antibodies Blinatumomab Teclistimab, others Cancer vaccines Sipuleucel-T Oncolytic virus Talimogene laherparepvec Tumor-infiltrating lymphocytes Lifileucel (under FDA review) TCR-transduced T cells Clinical trials
Diagnosing IRAEs
Risk Factors for IRAEs HER2i = human epidermal growth factor receptor 2 inhibitors; TKIs = tyrosine kinase inhibitors; AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; BMI = body mass index; ECOG = Eastern Cooperative Oncology Group Performance Status Scale; ILD = interstitial lung disease; RT = radiation therapy; COPD = chronic obstructive pulmonary disease; CKD = chronic kidney disease; eGRF = estimated glomerular filtration rate; PPI = proton pump inhibitors; NSAID = nonsteroidal anti-inflammatory drugs; ACEI =angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers Chennamadhavuni, et al, 2022.
Risk Factors for IRAEs (cont.) Shimozaki et al, 2021; Liu et al, 2021; Chennamadhuvuni et al, 2022. Demographics: <60 years of age Men (PD-1/PD-L1) Woman (CTLA-4) ECOG 2 >50 pack-year smoking history or currently smoking Higher body mass index Sarcopenia Low muscle mass Medical history: History of an allergy Autoimmune disease Hypertension Cardiac history Pulmonary history or previous thoracic radiation Chronic kidney disease
Risk Factors for IRAEs (cont.) Shimozaki et al, 2021; Liu et al, 2021; Chennamadhuvuni et al, 2022. Medications/vaccinations: PPIs & NSAIDs Diuretics & ACEI/ARD Anthracyclines, HER2 inhibitors, VEGF TKIs Antibiotics Influenza vaccinations Vitamin D deficiency Labs: Serum albumin >3.6 Neutrophil to lymphocyte ratio <3 Pre-existing autoantibodies Augmented expression of cytokines Gut microbiome Distinct human leukocyte antigen (HLA) HLA-DR4
Tumor- and Agent-Specific Risk Factors for IRAEs aOdds ratio is from 2 different studies. OR = odds ratio. Chennamadhavuni, et al, 2022. Factor High risk of IRAE (odds ratio) Tumor-specific Non-specific • Higher disease burden (≥2 metastatic sites, OR=8.62), higher tumor mutational burden Melanoma • High risk for diarrhea (1.9/1.3) a , rash (1.8/1.6) a , pruritis (2.4/1.5) a , colitis colitis (4.2/not reported) a • Low risk for pneumonitis (0.4/0.3) a Breast cancer • Higher fatal adverse events in patients with PD-1 (3.1%) AML/MDS • High risk for dermatitis and hepatitis Agent-specific CTLA-4 inhibitors • In combination with PD-1 (vs PD-1/PD-L1) (1.53/1.88) a • Monotherapy (vs PD-1/PD-L1): organ-nonspecific (2.02); colitis (8.7); hypophysitis (6.5); and rash (2) PD-1 inhibitors • Pneumonitis (6.4), arthralgia, vitiligo (3.5), and hypothyroidism (4.3) vs. vs. CTLA-4 Organ-nonspecific • High risk when combined with chemotherapy (OR for grade 1-5, 2.67; OR 2.67; OR for grade 3-4, 1.83)
Biomarkers for Predicting IRAEs a2 values represent results of 2 different studies; 2Cutoff values are not well established; GISpecific for gastrointestinal adverse events. ALC = absolute lymphocyte count; AMC = absolute monocyte count; AEC = absolute eosinophilic count; NLR = neutrophil-lymphocyte ratio; dNLR = derived NLR; PLR = platelet lymphocyte ratio; ANC = absolute neutrophil count; MLR = monocyte to lymphocyte ratio; TNFα = tumor necrosis factor alpha; CXCL = chemokine ligand; GNAL = guanine nucleotide-binding protein G subunit alpha; ITM2B = integral membrane protein 2B; BP = bullous pemphigoid; IgG = immunoglobulin G. Chennamadhavuni, et al, 2022. Circulating blood counts counts • ALC (>2.6 k/μL) • AEC a (>240/μL; >125/μL) • AMC (>0.29k/uL) • Platelet count (>145 k/μL) • NLR a (<3; <2.3) • dNLR (>3) • PLR a (< 534; < 180) • ANC (<6.5) • MLR (< 0.73) • Lower T-regulatory GI cells at the baseline (2.5% in IRAE group versus 8.4% in non-IRAE group) • CD8+ cells (clonal expansion >55) • Early T-cell receptor repertoire diversity • Drop-in white blood cell (WBC) count (by 59%) and relative lymphocytic count (by 32%) from baseline Cytokines • Lower baseline levels of TNF-α, IL-6, IL8, interferon γ-induced protein (IP)-10, CXCL9, CXCL10, CXCL11, and CXCL19. Post- Post-treatment significant rise in the levels of IL-6, CXCL5, CXCL9, and CXCL10 levels • Higher IL-7 at the baseline and exponential rise • Significant rise in granulocyte colony-stimulating factor (G-CSF) at 4 weeks compared to baseline • Serial interferon-gamma (IFN-γ), decrease to <10 IU/ml 3-6 weeks after starting ICI • A significant rise (mean rise from 8.4 mg/L to 52.7mg/L) C-reactive protein (CRP) Autoantibodies • Higher soluble CTLA-4 (>200 pg/ml) • Autoantibody detection: anti-GNAL, anti-ITM2B, and anti-CD74, rheumatoid factor, anti-nuclear and antithyroid antibody, antibody, antithyroid peroxidase antibody, antithyroglobulin antibody • Lower baseline (≤45μg/L) soluble major histocompatibility complex class I chain-related protein A (MICA), lower soluble CD25 CD25 (median level was 630 pg/ml in IRAE group), and a significant rise in soluble CD163 (± 21.3%) • Anti-BP180 IgG (median was 6.1 U/mL)
Biomarkers for Predicting IRAEs (cont.) skin = specific for dermal adverse events. HLA = human leukocyte antigen; SNP = single nucleotide polvmorphisms; ECG = electrocardiogram. Chennamadhavuni, et al, 2022 Serum proteins • Higher baseline albumin (≥3.6 g/dl) • Significant drop in post-treatment leptin levels from baseline • Higher baseline thyroid-stimulating hormone levels (1.67 mIU/L) • Elevated troponin for cardiac IRAE • Lactate dehydrogenase (LDH) ≥245 U/L HLA genotypes • HLA types: HLA-DRB1*11:01 skin and HLA-DQB1*03:01 GI alleles • Predominance of HLA-DR4 • HLA-DR15, B52 and Cw12 IRAE-pituitary • HLA-DRB1*04: 05 for IRAE-arthritis • HLA-DPA1*02:02 and DPB1*05:01 in IRAE-diabetes MicroRNA and gene expression profiling • Increased IRAE risk: mapped to 1 variant A allele in GABRP SNP rs11743438; 1 variant A allele in GABRP SNP rs11743435; 1 variant allele A in the DSC2 SNP JHU_20.57183980; 1 variant allele G in the BAZ2B SNP rs56328422; 1 1 variant allele T in the SEMA5A SNP rs3026321 • Post-treatment (3-week) increased expression of CD177 GI (12.2-fold higher in IRAE group than non-IRAE group) and and CEACAM1 GI genes • Suppressed miR-146a gene (by SNP s2910164) • Reduced IRAE risk: mapped to RGMA, ANKRD42, PACRG, GLIS3, ROBO1 genes Intestinal microbiota GI • Abundant Bacteroidetes phylum, specifically Bacteroidaceae, Rikenellaceae, and Barnesiellaceae (deficient polyamine polyamine transport and vitamin B biosynthesis) • Abundant Faecalibacterium genus and other Firmicutes at baseline • At the phylum level, low Bacteroidetes/Firmicutes ratio; at the genus level, a relative abundance of Alistipes, low Bacteroides, and high Blautia, Lachnospiraceae, and Faecalibacterium Stool testing GI • Stool calprotectin (>150mcg/g) and positive lactoferrin in colitis-IRAE Cardiac workup • ECG abnormalities, and low echocardiographic global longitudinal strain (GLS) may predict cardiac-IRAE
Risk Factors by Cancer Type and Treatment RCC = renal cell carcinoma; HIV = human immunodeficiency virus; BRAF = B-raf proto-oncogene; MEK = mitogen-activated protein kinase kinase; EGFR = epidermal growth factor receptor. Liu et al, 2021. Risk factor Cancer type Treatment IRAE Body composition parameters Low muscle attenuation Melanoma CTLA-4 inhibitor Grade 3-4 IRAE include rash, diarrhea, colitis, hypopituitarism, arthritis etc. Sex Female Melanoma CTLA-4 inhibitor Grade 3-4 IRAE include pruritus, diarrhea, diarrhea, hypophysitis etc. Tumor histology Melanoma compared to NSCLC CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of GI & skin IRAE ↓Risk of pneumonitis Melanoma compared to RCC CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of dermatitis, arthritis, myalgia ↓Risk of pneumonitis & dyspnea RCC compared to melanoma CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of pneumonitis & dyspnea Past medical history Pre-existing autoimmune disease (AD) Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Likely increased risk of IRAE, particularly patients on immunosuppressive therapy HIV infection Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Not increased Concurrent or sequential treatment High dose radiotherapy Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Likely increased risk of IRAE, particularly patients receiving higher radiation dose Vemurafenib Melanoma CTLA-4 inhibitors Hepatic toxicity Trametinib + vemurafenib Melanoma CTLA-4 inhibitors Severe colitis BRAF & MEK inhibitor Melanoma PD-L1 inhibitors Hepatic toxicity, pyrexia Crizotinib NSCLC PD-L1 inhibitors Hepatic toxicity EGFR-TKI except osimertinib NSCLC PD-L1 inhibitors Not increased Osimertinib prior to ICIs NSCLC PD-L1 inhibitors Grade 3-4 IRAEs include pneumonitis, hepatitis, colitis Osimertinib after ICIs NSCLC PD-L1 inhibitors Increased rate of ILD
Risk Factors by Cancer Type and Treatment (cont.) s = soluble; REC = relative eosinophil count. Liu et al, 2021. Risk factor Cancer type Treatment IRAE Antibodies Pretreatment anti-thyroid antibody NSCLC PD-L1 inhibitors Thyroid dysfunction Pre-treatment rheumatoid factor Skin reaction, myasthenia Cytokine assays ↑Baseline IL-17 Melanoma CTLA-4 inhibitors Grade 3 colitis ↓IL-10 after treatment Urothelial carcinoma CTLA-4 inhibitors Ischemic papillopathy & optic neuritis ↓IL-10 and ↑IL-2 after treatment Melanoma CTLA-4 inhibitors IRAE ↑Baseline IL-6 (P<0.05) Melanoma CTLA-4 inhibitors Grade 3-4 IRAEs include rash, diarrhea, colitis, hypopituitarism, arthritis etc. ↓Baseline IL-6, IL-8, & sCD25 Melanoma CTLA-4 inhibitors Colitis ↑IL-6 after treatment Melanoma PD-L1 inhibitor Cutaneous IRAE ↓Baseline CXCL9, CXCL10, CXCL11 and CXCL19 ↑Post-treatment CXCL9 and CXCL10 Solid tumors PD-L1 inhibitor & CTLA-4 inhibitor Pneumonitis, thyroid, arthritis, dermatitis, etc. ↑Circulating sCD163 Melanoma PD-L1 inhibitor IRAE ↑Baseline sCTLA-4 level Melanoma CTLA-4 inhibitor Gastrointestinal IRAE Blood cells ↑WBC ↓RLC ↑RNC Melanoma PD-L1 inhibitor GI IRAE pulmonary IRAE ↑CD177 & CEACAM1 (neutrophil-activation markers) Melanoma CTLA-4 inhibitor GI IRAE ALC > 2,000; ↑Baseline AEC Solid tumors PD-L1 inhibitor IRAEs include rash, colitis, hepatitis, pneumonitis, pneumonitis, etc. ↑Baseline AEC at and REC after treatment Melanoma PD-L1 inhibitor Endocrine IRAEs Circulating T cells repertoire Prostate cancer CTLA-4 inhibitor IRAEs Clonal expansion of CD8 T cells clones in peripheral blood Prostate cancer CTLA-4 inhibitor IRAEs? Gut microbiome Faecalibaterium and other firmicutes Melanoma CTLA-4 inhibitor Colitis B. fragilis and Burkholderia cepacia Murine sarcoma CTLA-4 inhibitor ↓ Intestinal IRAE Bacteroidetes phylum Melanoma CTLA4 inhibitor ↓ Colitis Genetic variability Predominance of HLA-DR4 Solid-organ cancer PD-L1 inhibitor Diabetes Homozygous variant of PDCD1 804 C>T(rs2227981) NSCLC PD-L1 inhibitor ↓ IRAEs
IRAEs-Toxicities in Every System DRESS = drug reaction with eosinophilia and systemic symptoms. Schneider et al, 2021; Martins et al, 2019; Puzanov et al, 2017.
Most Common IRAEs Schneider et al, 2021; Puzanov et al, 2017; Trinh et al, 2019. Lung • Pneumonitis Cutaneous • Rash • Dermatitis • Pruritis Endocrine • Thyroid dysfunction • Hypophysitis Gastrointestinal • Colitis • Diarrhea • Hepatitis Musculoskeletal • Arthralgia • Myalgias
Uncommon IRAEs Schneider et al, 2021; Puzanov et al, 2017; Trinh et al, 2019. Renal • Interstitial nephritis • Granulomatous nephritis Hematologic • Hemolytic anemia • Red cell aplasia • Thrombocytopenia • Myelodysplasia • Hemophilia Endocrine • Pancreatitis • Type 1 diabetes mellitus • Adrenal insufficiency Cardiac • Myocarditis • Pericarditis • Arrhythmias Neurologic • Encephalitis • Meningitis • Myasthenia gravis • Guillain-Barré syndrome • Peripheral neuropathies Ophthalmologic • Uveitis • Episcleritis • Blepharitis • Optic nerve swelling • Ulcerative keratitis • Vogt-Koyanagi-Harada
Identifying Signs and Symptoms of IRAEs Yeung et al, 2020. Presenting symptom Warning signs Potential immune-related adverse effect Part A: neurological symptoms Headache Neck stiffness Meningitis Hypotension Hypophysitis Mental status change Neck stiffness Meningitis Weakness Respiratory failure Guillain-Barre syndrome, myasthenia gravis Paraplegia Transverse myelitis Mental status change Encephalitis Part B: cardiopulmonary symptoms Chest pain Peripheral edema Myocarditis Dyspnea on exertion, pulsus paradoxus, electric alternans alternans Pericarditis Cough Hypoxia Pneumonitis Shortness of breath Hypoxia Pneumonitis Peripheral edema Myocarditis Pulsus paradoxus, electric alternans Pericarditis Pale Hemolytic anemia, hemophagocytic lymphohistiocytosis Dehydration and tachypnea Diabetic ketoacidosis Palpitation/irregular tachycardia Thyrotoxicosis (Graves disease vs thyroiditis)
Identifying Signs and Symptoms of IRAEs (cont.) Yeung et al, 2020. Presenting symptom Warning signs Potential immune-related adverse effect involved Part C: gastrointestinal symptoms Abdominal pain Mental status change, jaundice Hepatitis Nausea and vomiting Pancreatitis Diarrhea, dehydration Colitis Dehydration and tachypnea Diabetic ketoacidosis Diarrhea Dehydration, abdominal pain/tenderness Colitis Vomiting Stiff neck, mental status change Meningitis Abdominal pain Pancreatitis Jaundice Hepatitis Part D: miscellaneous symptoms Vision change Eye pain Uveitis Rash Bullae with Niklosky sign Pemphigus vulgaris Niklosky sign with mucosal involvement Steven-Johnson syndrome/toxic epidermal necrolysis necrolysis Fatigue Hypotension Adrenal insufficiency Hypophysitis Bradycardia Hypothyroidism Myocarditis Dehydration and tachypnea Diabetic ketoacidosis Splenomegaly Hemolytic anemia Hemophagocytic lymphohistiocytosis Joint pain Swelling, restricted movement Arthritis
Toxicity Grading Scale for IRAEs ADL = activities of daily living; iADL = instrumental ADLs. NCI, 2017; Trinh et al, 2019. Treated and evaluated based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Asymptomatic Symptomatic Limits iADLs Severe symptoms Limits self-care ADLs Life-threatening Death No treatment indicated; clinical or lab observation Treatment indicated Hospitalization indicated Urgent interventions interventions needed needed Therapy should be continued Should hold treatment until IRAE has resolved and reinitiated, low dose dose corticosteroids can can be used (0.5-1.0 mg/kg/day) Treatment should be held or permanently discontinued & use of use of corticosteroids (1-2 mg/kg/day). Other immunosuppressants may be required if steroid refractory such as such as infliximab or mycophenolate
Differences in Adverse Events Khan et al, 2018; Trinh et al, 2019; Magee et al, 2020. Meta-analysis found PD-1 inhibitors (nivolumab and pembrolizumab) had significantly fewer adverse events overall when compared to chemotherapy Chemotherapy was associated with increased neutropenia, anemia, alopecia, stomatitis, and myalgias Fatigue, nausea, decreased appetite, diarrhea, and asthenia were caused by both treatments but were more frequent with chemotherapy With PD-1 inhibitors, there were more hypothyroidism, hyperthyroidism, rash, and pneumonitis It has been noted that use of immunotherapy is associated with fewer AEs (65.82% for immunotherapy vs chemotherapy 85.26%) Treatment discontinuation was less with immunotherapy-treated patients (6.41%) vs chemotherapy (10.75%) Deaths are less with immunotherapy-treated patients (0.87%) vs chemotherapy (1.28%) Chemotherapy Versus Immunotherapy
Guidelines Recommended for Nursing Management of Common IRAEs
Endocrine IRAEs: Thyroid TSH = thyroid-stimulating hormone; FT4 = free thyroxine; FSH = follicle stimulating hormone. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Hyperthyroid: Symptoms: tachycardia, weight loss, heat intolerance, tremors, anxiety, diarrhea Rule out alternative etiology: Graves disease Labs TSH, FT4, TSH receptor antibody if Graves is suspected Hypothyroid: Symptoms: fatigue, weight gain, hair loss, cold intolerance, constipation, depression Rule out alternative etiology: if low FSH and low FT4, evaluate for hypophysitis Labs: TSH, FT4 Endocrinopathies are seen in approximately 10% Management: May need to hold, replacement of hormone, beta blocker Endocrine consultation based on presentation or grade
Thyroid IRAEs: Hypothyroidism G1 = grade 1; G2 = grade 2; G3 = grade 3; G4 = grade 4. Schneider et al, 2021. Primary hypothyroidism Workup and evaluation • TSH, with the option of close including FT4, can be checked every 4-6 weeks as part of routine clinical monitoring for asymptomatic patients on ICI therapy • TSH and FT4 should be used for case detection in symptomatic patients • Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis • Commonly develops after thyroiditis Grading Management G1: TSH >4.5 and <10 and asymptomatic Should continue ICI with monitoring of TSH (option for FT4) every 4-6 weeks as part of routine care G2: Moderate symptoms, able to perform ADL. TSH persistently >10 mIU/L May continue or hold ICI until symptoms resolve to baseline Consider endocrine consultation for unusual clinical presentations, concern for central hypothyroidism, or difficulty titrating hormone therapy Prescribe thyroid hormone supplementation in symptomatic patients with any degree of TSH elevation or in asymptomatic patients with TSH levels that persist over 10 mIU/L G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform ADL Hold ICI until symptoms resolve to baseline with appropriate supplementation Endocrine consultation to assist with rapid hormone replacement Hospital admission for developing myxedema (bradycardia, hypothermia, and altered mental status) Inpatient endocrinology consultation can assist with IV levothyroxine dosing, steroids, and supportive care If there is uncertainty about whether primary or central hypothyroidism is present, hydrocortisone should be given before thyroid hormone is initiated Myxedema coma is a life-threatening emergency requiring admission and a high level of care Thyroid supplementation and reassessment as in G2 Additional considerations • For patients with risk factor (ie, <70 years old, not frail, and without cardiac disease or multiple comorbidities), full replacement can be estimated using ideal body weight for dose of approximately 1.6 approximately 1.6 mcg/kg/day • For those >70 years old and/or frail patients with multiple comorbidities (including cardiac disease), considering titrating up from a lower starting dose of 25-50 μg • Elevated TSH can be seen in the recovery phase of thyroiditis. In asymptomatic patients with FT4 that remains in the reference range, it is an option to monitor before treating to determine whether there is whether there is recovery to normal within 3-4 weeks. Progression or development of symptoms should be treated as per G2 • Development of a low TSH on therapy suggests overtreatment or recovery of thyroid function and dose should be reduced or discontinued with close follow-up
Thyroid IRAEs: Thyrotoxicosis Schneider et al, 2021. Thyrotoxicosis Workup and evaluation • TSH can be checked every 4-6 weeks as part of routine clinical monitoring for asymptomatic patients on ICI therapy • TSH and FT4 should be used for case detection in symptomatic patients. T3 can be helpful in highly symptomatic patients with minimal FT4 elevations • Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis • Consider TSH receptor antibody testing if there are clinical features and suspicion of Graves disease (eg, ophthalmopathy and T3 toxicosis) Grading Management G1: Asymptomatic or mild symptoms Can continue ICI Beta-blocker (eg, atenolol or propranolol) for symptomatic relief Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch the transition to hypothyroidism, the most common outcome for transient transient subacute thyroiditis Treat transition to elevated TSH and low FT4 as for primary hypothyroidism For persistent thyrotoxicosis (>6 weeks) consider endocrine consultation for additional workup G2: Moderate symptoms, able to ADL Consider holding ICI until symptoms return to baseline Consider endocrine consultation Beta-blocker (eg, atenolol or propranolol) for symptomatic relief Hydration and supportive care For persistent thyrotoxicosis (>6 weeks) refer to endocrinology for additional workup and possible medical thyroid suppression G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL ADL Hold ICI until symptoms resolve to baseline with appropriate therapy Endocrine consultation for all patients Beta blocker (eg, atenolol or propranolol) Hydration and supportive care Consider hospitalizing patients in severe cases as inpatient endocrine consultation can guide the use of additional medical therapies including steroids, potassium potassium iodide (SSKI), or thionamide (methimazole or propylthiouracil) and possible surgery Additional considerations • Thyroiditis is self-limited and the initial hyperthyroidism generally resolves in weeks with supportive care, most often to primary hypothyroidism or occasionally to normal. Persistent or symptomatic symptomatic hypothyroidism developing after hyperthyroidism should be treated as above • Graves disease has not been reported with ICI specifically, but sporadic cases could occur. Graves disease is generally persistent and is treated with antithyroid medical therapy, radioactive iodine, or iodine, or surgery. Endocrine consultation is recommended if suspected • Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves disease and should prompt early endocrine referral
Endocrine IRAEs: Pituitary Hypophysitis Diagnosis/evaluation Frequency: endocrinopathies are seen in approximately 10% Symptoms: headaches, fatigue, visual changes, loss of libido, mood changes, oligomenorrhea Rule out alternative etiology: pituitary mass, Addison’s or adrenal hemorrhage Labs to include 8 am cortisol, ACTH, TSH, FT4, electrolytes, consider LH/testosterone in males and FSH and estrogen in females, MRI of the brain with pituitary or sellar cuts Management: Replacement of deficient hormones High-dose steroids may be needed if MRI findings of pituitary enlargement May need to consider holding until stabilized Endocrine consultation based on grade ACTH = adrenocorticotropic hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021; Chang & Yialamas, 2018.
Pituitary IRAEs: Hypophysitis EMS = emergency medical services; HPA = hypothalamic pituitary adrenal; Q = every. Schneider et al, 2021. Pituitary—Hypophysitis Workup and evaluation • Evaluate ACTH (am), cortisol (am), TSH, FT4, and electrolytes • Consider standard-dose ACTH stimulation testing for indeterminate results (am cortisol >3 µg/dL and <15 µg/dL) • Consider evaluation LH and testosterone in males, FSH, and estrogen in premenopausal females with fatigue, loss of libido and mood changes, or oligomenorrhea • Consider MRI brain with or without contrast with pituitary or sellar cuts in all patients with new hormonal deficiencies and particularly those with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes • Perform MRI brain with or without contrast with pituitary or sellar cuts for all patients presenting with diabetes insipidus (Diabetes insipidus is most commonly from metastatic disease) Grading Management All grades Referral to endocrinology Education on steroid stress dosing, emergency injections, and a medical alert bracelet or necklace, accessory, or system G1: or mild symptoms symptoms Consider holding ICI until patient is stabilized or replacement hormones Endocrine consultation Corticosteroid replacement for adrenal insufficiency with preference for hydrocortisone (15-20 mg in divided doses) Initiate other hormone replacement only after any needed adrenal replacement to avoid precipitating adrenal crisis • Thyroid hormone replacement if needed using dosing as above for primary hypothyroidism, with a goal FT4 in the upper half of the reference range (TSH is not accurate in central hypothyroidism) • Testosterone or estrogen therapy if needed in those without contraindications (eg, prostate cancer, breast cancer, or history of deep vein thrombosis (DVT) G2: Moderate symptoms, able to to perform ADL Consider holding ICI until patient is stabilized or replacement hormones Endocrine consultation Clinic evaluation to assess need for steroids and volume repletion Consider oral pulse dose therapy in patients with MRI findings of swelling or threatened optic chiasm compression [prednisone 1 mg/kg/day (or equivalent)]. Taper over 1-2 weeks and transition to physiologic maintenance therapy once down to 5 mg once down to 5 mg prednisone equivalent Hormonal supplementation as in G1 G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform perform ADL Hold ICI until patient is stabilized on replacement hormones Endocrine consultation Hospitalize or make an emergency department (ED) referral for: • Normal saline (at least 2L) or monitored free water replacement if diabetes insipidus • Intravenous (IV) Stress dose steroids. Hydrocortisone 50-100 mg Q 6-8 hours initial dosing • Oral pulse dose therapy with prednisone 1-2 mg/kg/day (or equivalent) tapered over at least 1-2 weeks to physiologic maintenance in patients with significant swelling on MRI, optic chiasm compression, severe headache, or visual changes changes Taper stress dose corticosteroids down to oral maintenance doses over 5-7 days Maintenance therapy as in G1 Additional considerations • Please be aware of the need to start corticosteroids first when planning hormone replacement therapy for multiple deficiencies as other hormones accelerate the clearance of cortisol and can precipitate adrenal crisis • ACTH stimulation can give a false-negative result early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost. In the presence of clinical uncertainty, opt for replacement and test for ongoing need at 3 months • If prednisone or equivalent is started for mild or moderate symptoms, consider lower doses (average daily dose over 2 months <7.5 mg) because of report of reduced survival on higher doses • All patients need education on stress dosing for sick days, use of emergency steroid injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet for adrenal insufficiency to trigger stress dose corticosteroids by EMS EMS • Steroid use for other IRAEs can cause isolated central adrenal insufficiency with a low ACTH. In a patient with adrenal insufficiency, a recent history of treatment with corticosteroids, and no other central hormone deficiencies, the HPA axis should be tested for recovery tested for recovery after 3 months of maintenance therapy with hydrocortisone • Laboratory confirmation of adrenal insufficiency (AI) should not be attempted in patients given high-dose corticosteroids for other IRAEs until treatment is ready to be discontinued • AM cortisol in a patient on corticosteroids is not diagnostic as the measurement of therapeutic steroids in the assay for cortisol varies. Hydrocortisone needs to be held for 24 hours and other steroids for longer before endogenous function is assessed. Consider consulting Consider consulting endocrinology for recovery and weaning protocols using hydrocortisone in patients with symptoms of AI after wearing off corticosteroids
Pulmonary IRAEs: Pneumonitis Schneider et al, 2021; Brahmer et al, 2021; Puzanov et al, 2017; Naidoo et al, 2016. Diagnosis/evaluation: Frequency: ranges from 0%-10% Symptoms: worsening shortness of breath, cough, wheezing, chest pain, new or increasing oxygen requirements Rule out alternative etiology: disease progression, infection, pulmonary embolism Labs to consider blood cultures, urine culture, sputum culture, nasal swab, sensitivity for COVID-19, and imaging with computed tomography, pulse oximetry Management: Prompt intervention is imperative Patient symptom reporting will be key Based on grade corticosteroids may need to be initiated If steroid refractory, additional immunosuppression may be needed Pulmonary and infectious disease referral if necessary
Pulmonary IRAEs: Pneumonitis (cont.) CT = computed tomography; CXR = chest X-ray; DLCO = diffusing capacity of lung for carbon monoxide; BAL = bronchoalveolar lavage; IVIG = intravenous immune globulin Schneider et al, 2021. Pneumonitis Workup and evaluation • Should include the following: pulse oximetry and CT chest preferably with contrast if concerned for other etiologies such as pulmonary embolus • For G2 or higher, may include the following infectious workup: nasal swab, sputum culture and sensitivity, blood culture and sensitivity, urine culture and sensitivity • COVID-19 evaluations—per institutional guidelines where relevant Grading Management G1: Asymptomatic; confined to one lobe of the or <25% of lung parenchyma, clinical or diagnostic diagnostic observations only Hold ICI or proceed with closing monitoring Monitor patients weekly with history and physical examination, pulse oximetry; may also offer chest imaging (CXR, CT) if uncertain diagnosis and/or to and/or to follow progress Repeat chest imaging in 3-4 weeks or sooner if patient becomes symptomatic In patients who have had baseline testing, may offer a repeat spirometry or DLCO in 3-4 weeks May resume ICI with radiographic evidence of improvement or resolution if held. If no improvement, should treat as G2 G2: Symptomatic; involves more than one lobe of the lung or 25%-50% of lung parenchyma; medical medical intervention indicated; limiting instrumental instrumental ADL Hold ICI until clinical improvements to ≤G1 Prednisone 1-2 mg/kg/d and taper over 4-6 weeks Consider bronchoscopy with BAL ± transbronchial biopsy Consider empiric antibiotics if infection remains in the differential diagnosis after workup Monitor at least once per week with history and physical examination, pulse oximetry, consider radiologic imaging; if no clinical improvement after 48-72 improvement after 48-72 hours of prednisone, treat as grade 3 Pulmonary and infectious disease consults if necessary G3: Severe symptoms; hospitalization required; involves all lung lobes or >50% of lung parenchyma; limiting self-care ADL; oxygen indicated Permanently discontinue ICI Empiric antibiotics may be considered Methylprednisone IV 1-2 mg/kg/d If no improvement after 48 hours, may add immunosuppressive agent. Options include infliximab or mycophenolate mofetil IV or IVIG or cyclophosphamide. Taper corticosteroids over 4-6 weeks Pulmonary and infectious disease consults if necessary May consider bronchoscopy with BAL ± transbronchial biopsy if patient can tolerate G4: Life-threatening respiratory compromise; intervention indicated (intubation)
Gastrointestinal IRAEs: Colitis Brahmer et al, 2021; Trinh et al, 2019; Schneider et al, 2021; Geukes Foppen et al, 2018. Diagnosis/evaluation: Frequency: 8%-27% but can be as high as 54% with CTLA-4 inhibitors Symptoms: diarrhea, abdominal pain, rectal bleeding, mucus in stool Rule out alternative etiology: infection Labs for stool studies for Clostridium difficile, cytomegalovirus, DNA polymerase chain reaction (PCR), stool ova and parasites, fecal calprotectin, fecal occult blood, endoscopy Management: Close monitoring and dietary changes Loperamide Hold treatment for grade ≥2 Grade ≥3: corticosteroids, consider hospitalization; additional immunosuppression may be needed Consider referral to gastroenterology for grade ≥2
Gastrointestinal IRAEs: Colitis (cont.) CBC = complete blood count; CMP = comprehensive metabolic panel; CMV = cytomegalovirus. Schneider et al, 2021. Colitis workup and evaluation G2 • Workup of blood (CBC, CMP, and TSH) and stool (culture, C. diff, parasite, CMV, or other viral etiology, ova and parasite if appropriate) should be performed for the initial for the initial presentation, and also considered for immunosuppressant refractory cases • Consider testing for fecal lactoferrin (for patient stratification to determine who needs more urgent endoscopy) and calprotectin (to follow up on disease activity) activity) • Screening labs (HIV, hepatitis A and B, and tuberculous testing), repeated annually in patients who require biologic treatment, eg, infliximab or vedolizumab for >1 year for >1 year until treatment is completed • Consider reviewing concomitant medications that could alter the gut microbiome and their indications for prolonged use (eg, proton pump inhibitors, antibiotics, and antibiotics, and probiotics) • Imaging, eg, CT scan of abdomen and pelvis for colitis-related symptoms (abdominal pain and bleeding) to rule out colitis-related complications, including typhlitis and typhlitis and bowel perforation or abscess • GI endoscopy or colonoscopy with biopsy for patients who have positive stool inflammatory markers or colitis-related symptoms should be considered as there is evidence there is evidence showing the presence of ulceration in the colon can predict steroid refractory course, which may require early infliximab • Repeat colonoscopy may be considered for cases G≥2 for disease activity monitoring to document complete remission, especially if there is a plan to resume ICI. Mucosal ICI. Mucosal healing on repeat endoscopy and/or fecal calprotectin level ≤116 µg/g can be considered the treatment target to guide decisions on when to stop biologic stop biologic treatment and when to resume ICI therapy G3-4 • Complete all recommendations as above and consider inpatient care Management All patients Counsel all patients to be aware of and inform their health care provider immediately if they experience abdominal pain, nausea, cramping, blood cramping, blood or mucus in stool, or changes in bowel habits, fever, abdominal distention, or constipation For G ≥2, consider permanently discontinuing CTLA-4 agents and may restart PD-1 or PD-L1 agents if patients recover to G≤1; concurrent concurrent immunosuppressant maintenance therapy should be considered only if clinically indicated in individual cases
Gastrointestinal IRAEs: Colitis (cont.) EGD = esophagogastroduodenoscopy; JAK = Janus kinase. Schneider et al, 2021. Grading Management G1: Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline Continue ICI. Alternatively, ICI may be held temporarily and resumed if toxicity does not exceed grade 1 or resolves May also include supportive care with medications such as loperamide if infection has been ruled out in patients with diarrhea only and not colitis-related symptoms as a temporary measure Monitor for dehydration and recommend dietary changes Patient should be closely monitored by phone or electronic medical system for symptoms changes by clinical providers every 3 days or more frequently if needed until stabilized May obtain gastroenterology consult for prolonged G1 cases and consider endoscopy with biopsies G2: Increase of 4-6 stools per day over baseline; moderate moderate increase in ostomy ostomy output compared with with baseline Hold ICI at least until recovery to G1—see last bullets May also include supportive care with medications such as loperamide if infection has been ruled out in patients with diarrhea only and not colitis-related symptoms as a temporary measure Consider consult with gastroenterology for ≥G2 Administer corticosteroids, unless diarrhea is transient, starting with initial dose of 1 mg/kg/day prednisone or equivalent until symptoms improve to G1, and then start taper over 4-6 weeks Consider narrower-spectrum or more potent agents, including anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) antibody to patients whose colitis is corticosteroid-refractory (ie, no decrease (ie, no decrease by one grade in 72 hours) or dependent or with high-risk endoscopic features on initial endoscopy examination When symptoms improve to ≤G1, taper corticosteroids over 4-6 weeks; may consider shorter tapers in patients also treated with biologics Endoscopic evaluation with EGD or colonoscopy is highly recommended for cases grade ≥2 to stratify patients for early treatment of biologics based on endoscopic findings Resuming ICI after symptoms improve to ≤G1 may be considered when steroid taper is completed, risk and benefits reviewed if maintained on biologics, and/or if endoscopic and histologic remissions are remissions are achieved. Fecal calprotectin ≤116 µg/g may be considered as a surrogate for endoscopic and histologic remission Resuming PD-1/PD-L1 agent is associated with lower risk of flare-up; however, CTLA-4 inhibitor can still be considered in selected cases, such as in patients who have not yet responded or whose response whose response is deemed inadequate G3: Increase of ≥7 stools per day over baseline; incontinence; hospitalization hospitalization indicated; severe increase in ostomy output compared with baseline; and limiting self- care ADL Follow G2 recommendations as listed, with the following additions for G3: Administer corticosteroids (initial dose of 1-2 mg/kg/day prednisone or equivalent) until symptoms improve to G1, and then start taper over 4-6 weeks. Consider IV methylprednisolone, especially if concern for especially if concern for concurrent upper GI inflammation Consider early introduction of infliximab or vedolizumab in addition to steroids in patients with high-risk endoscopic features on initial endoscopy examination or inadequate response to steroids (persistent steroids (persistent symptoms after 3 days) Consider hospitalization for patients with dehydration or electrolyte imbalance Consider repeat colonoscopy in patients who are immunosuppression-refractory Should consider permanently discontinuing CTLA-4 agents G4: Life-threatening consequences; urgent intervention indicated Follow G2-3 recommendations as listed, with the following additions for G4: Permanently discontinue treatment Should provide inpatient care Administer 1-2 mg/kg/day methylprednisolone or equivalent until symptoms improve to G1, and then start taper over 4-6 weeks Consider early biologics (infliximab or vedolizumab) if inadequate response to steroids after 3 days. Consider lower GI endoscopy if symptoms refractory, despite treatment or there is concern of new of new infections Additional considerations • May consider fecal microbiota transplant, JAK inhibitor tofacitinib, or IL-12–blocking antibody ustekinumab in patients who are refractory to the previous immunosuppressants • Patients with both IRAE-related hepatitis and IRAE-related colitis are less common, and management may include permanently discontinuing ICI and offering other immunosuppressant agents (eg, prednisone and mycophenolate) that mycophenolate) that works systemically for both conditions. Infliximab is contraindicated for hepatic IRAE • Currently, enteritis and/or gastritis alone as the cause of GI toxicity is uncommon and endoscopy with biopsy is recommended as the evaluation tool. It may be managed similarly to colitis including steroid and/or biologics etc biologics etc
Gastrointestinal IRAEs: Hepatitis ANA = antinuclear antibody; ASMA = anti–smooth muscle antibodies; ANCA = antineutrophil cytoplasmic antibody; GTT = gamma-glutamyl transferase; ALKP = alkaline phosphatase; CK = creatine kinase. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: 2%-10%; in combination with ICI+ICI, can be up to 25%-30% for all grades Symptoms: diagnosed with increase in serum liver function test (LFT), alanine transaminase (ALT) and aspartate transaminase (AST) Rule out alternative etiology: rule out viral causes, hepatoxic medications and hepatic dysfunction that is drug related, progression of the liver Labs for viral hepatitis, alcohol history, imaging and blood work to rule liver metastasis, ANA/ASMA/ANCA, GTT (if ALKP alone elevated), CK (for isolated transaminases) Management: Hold treatment/discontinue for grade ≥2 Start corticosteroids If no improvement in 2 days, consider alternative immunosuppression, mycophenolate Consider referral to hepatology for grade ≥2
Gastrointestinal IRAEs: Hepatitis (cont.) ULN = upper limit of normal; NASH = nonalcoholic steatohepatitis. Schneider et al, 2021. Hepatitis Workup and evaluation • Monitor patient for abnormal blood tests: AST, ALT, and bilirubin before each infusion and/or consider weekly if grade 1 LFT elevations. No treatment is recommended for grade 1 LFT abnormality • Review medications and supplements that may cause hepatotoxicity and rule out abnormal liver enzymes from development or progression of liver metastases • Liver biopsy should be considered if the patient is steroid-refractory or if concern for other differential diagnoses that would alter medical management • For grade ≥2: workup for other causes of elevated liver enzymes (eg, viral hepatitis, alcohol history, iron studies, thromboembolic event, or potential liver metastasis from primary malignancy) by doing blood work and imaging and imaging (ultrasound and cross-sectional imaging). If suspicion for primary autoimmune hepatitis is high, can consider ANA/ASMA/ANCA. If patients with elevated ALKP alone, GGT should be tested. For isolated elevation of isolated elevation of transaminases, consider checking CK for other etiologies Grading Management G1: Asymptomatic (AST or ALT >ULN 3.0x ULN and/or total bilirubin >ULN >ULN to 1.5x ULN) Continue ICI with close monitoring; consider alternate etiologies Consider monitoring labs 1-2 times weekly Manage with supportive care for symptom control G2: Asymptomatic (AST or ALT >3.0 ≤5x ULN and/or total bilirubin >1.5 to to ≤3x ULN) Hold ICI temporarily Patients should be advised to stop unnecessary medications and any known hepatotoxic drugs. Temporarily hold other potentially hepatotoxic oncologic agents For G2 hepatic toxicity, may administer steroid (0.5-1 mg/kg/day prednisone) or equivalent if no improvement is seen after 3-5 days Increase frequency of monitoring to every 3 days If inadequate improvement after 3 days, consider adding mycophenolate mofetil May initiate steroid taper when symptoms improve to ≤G1 and may resume ICI treatment when steroid ≤10 mg/day. Taper over at least 1 month G3: AST or ALT 5-20x ULN and/or bilirubin 3-10x ULN, or symptomatic symptomatic liver dysfunction; fibrosis fibrosis by biopsy; compensated cirrhosis; and reactivation of chronic chronic hepatitis Follow G2 recommendations as listed, with the following additions for G3: Consider permanently discontinuing ICI if asymptomatic; permanently discontinue if symptomatic Immediately start steroid 1-2 mg/kg methylprednisolone or equivalents. If steroid refractory, consider liver biopsy to rule out NASH, tumor, cholestatic variants, other drug-related hepatic related hepatic inflammation, infection, or other autoimmune entity and consider adding azathioprine or mycophenolate if infectious cause is ruled out Labs daily or every other day; consider inpatient monitoring for patients with AST/ALT > 8x ULN and/or elevated total bilirubin 3x >ULN If no improvement is achieved with steroid for patients on ICI therapy combined with novel agents, with chemotherapy, or with targeted therapy, refer to hepatologist for further pathologic pathologic evaluation of hepatitis Steroid taper can be attempted around 4-6 weeks when ≤ G1, re-escalate if needed, optimal duration unclear Consider transfer to tertiary care facility if necessary G4: AST or ALT >20x ULN and/or bilirubin >10x ULN or decompensated decompensated liver function (eg, ascites, coagulopathy, encephalopathy, and coma) Follow G3 recommendations as listed, with the following additions for G4: Administer 2 mg/kg/d methylprednisone equivalents Additional considerations: Infliximab is contraindicated for immune-related hepatitis
Dermatologic IRAEs: Rash/Pruritus/Dermatitis Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: reported up to 71.5% Symptoms: pruritis, maculopapular rash, atopic dermatitis, eczema, acneiform, lichenoid rash Rule out alternative etiology: infection, adverse effect of another drug or unrelated primary skin disorder Labs to include blood count, complete metabolic panel, consider skin biopsy, consider follow-up with serial clinical photography Management: Starting topical steroids, rich emollients May considering holding and starting oral corticosteroids depending on grade Referral to dermatology for grade 4
Dermatologic IRAEs Schneider et al, 2021. Rash or Inflammatory Dermatitis Workup and evaluation • Pertinent history and physical examination including examination of the oral mucosa, assessment for blister formation, and assessment of BSA involved • Review full list of patient medications to rule out other drug-induced cause of photosensitivity • Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, including prior or other recent cancer therapies, or a skin condition linked to another systemic disease or systemic disease or unrelated primary skin disorder • Recent or new complete blood count and comprehensive metabolic panel (if needed for skin differential diagnosis) • Consider referral to dermatologist if autoimmune skin disease is suspected • Consider skin biopsy • Consider clinical monitoring with use of serial clinical photography Grading Management G1: Rash covering <10% BSA, which may or may not be associated with symptoms of pruritis or tenderness Continue ICI Treat with topical emollients and/or mild-moderate potency topical corticosteroids Counsel patients to avoid skin irritants G2: Rash covering 10%-30% BSA with or without (eg, pruritis, burning, and tightness); limiting instrumental instrumental ADL; rash covering >30% BSA with or without mild symptoms Consider holding ICI and monitor weekly for improvement. If skin toxicity is not improved after 4 weeks, then regrade toxicity as G3 In addition, treat with topical emollients, oral antihistamines, and medium-to-high potency topical corticosteroids Consider initiating prednisone (or equivalent) at dosing 0.5-1 mg/kg, tapering over 4 weeks. In patients with pruritus without rash, consider topical consider topical anti-itch remedies (eg, refrigerated menthol and pramoxine) G3: Rash covering >30% BSA with moderate or severe symptoms; limiting self-care ADL Hold ICI therapy and consult with dermatology to determine appropriateness of resuming Treat with topical emollients, oral antihistamines, and high-potency topical corticosteroids. May also consider phototherapy to treat severe pruritus severe pruritus Initiate oral prednisone or equivalent (1 mg/kg/d) tapering over at least 4 weeks Once downgraded to ≤G1 and prednisone (or equivalent) below 10 mg/d, clinicians may consider resuming ICI therapy with close monitoring and monitoring and follow-up with dermatology in certain cases such as psoriasis In patients with pruritus without rash, may treat with gabapentin, pregabalin, aprepitant, or dupilumab G4: Severe consequences requiring hospitalization or intervention indicated or life-threatening consequences consequences Immediately hold ICI May admit patient immediately with direct oncology involvement and with an urgent consult by dermatology Systemic steroids: IV methylprednisolone (or equivalent) dosed at 1-2 mg/kg with slow tapering when the toxicity resolves Monitor closely for progression to severe cutaneous adverse reaction (SCAR) Consider alternative antineoplastic therapy over resuming ICIs if the skin IRAE does not resolve to ≤G1. If ICIs are the patients only option, option, consider restarting once these side effects have resolved to a G1 level with close dermatology follow-up
Musculoskeletal IRAEs: Arthralgia / Myalgia RF = rheumatoid factor; CCP = citrullinated protein antibody; ESR = erythrocyte sedimentation rate. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: reported up to 40% Symptoms: arthralgia, myalgia, large joint reactive arthritis, polyarthritis Rule out alternative etiology: degenerative joint disease, osteoarthritis, gout, pseudogout, septic arthritis, rotator cuff tendinitis, Labs to consider ANA, RF, anti-CCP, ESR, CRP, X-ray or MRI imaging of affected joint Management: Initiate acetaminophen ± NSAIDS for analgesia May considering holding and starting oral corticosteroids depending on grade Referral to Rheumatology for grade >2
Musculoskeletal IRAEs Schneider et al, 2021. Inflammatory Arthritis Workup and evaluation 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 or imaging to exclude metastases and evaluate joint damage (erosions) if appropriate • Consider autoimmune panel including ANA, RF, anti-CCP, and inflammatory markers (ESR and CRP) if symptoms persist. If symptoms are suggestive of reactive reactive arthritis or affect the spine, consider HLA B27 testing G2 • Complete history and examination as above; laboratory tests as above • Consider ultrasound ± MRI imaging of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment, and suspicion for differential diagnoses diagnoses such as metastatic lesions or septic arthritis). Consider arthrocentesis if septic arthritis or crystal-induced arthritis is suspected • Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms persist >4 weeks G3 • As for grade 2 • Seek rheumatologist advice and review • Test for viral hepatitis B, C, and latent or active tuberculous test before disease-modifying antirheumatic drug (DMARD) treatment. Repeated screening labs annually in annually in patients who require biologic treatment for >1 year until treatment is completed Monitoring Patients with inflammatory arthritis should be monitored with serial rheumatologic examinations, including inflammatory markers, every 4-6 weeks after treatment is instituted treatment is instituted Additional considerations Early recognition is critical to avoid erosive joint damage Corticosteroids can be used as part of initial therapy therapy in inflammatory arthritis, but because of likely likely prolonged treatment requirements, physicians physicians should consider starting steroid-sparing sparing agents earlier than one would with other IRAEs Oligoarthritis can be treated early on with intra- articular steroids, consider early referral Grading Management All grades Clinicians should follow reports of new joint pain to determine if IA is present. Question whether symptoms are new since receiving ICI G1: Mild pain with inflammation, erythema, or joint swelling Continue ICI; initiate analgesia with acetaminophen and/or NSAIDs G2: Moderate pain associated with signs inflammation, erythema, or joint swelling; swelling; limiting instrumental ADL Consider holding ICI; escalate analgesia and consider higher doses of NSAIDs as needed If inadequately controlled, initiate prednisone 10-20 mg/d or equivalent If improvement, slow taper according to response during the next 4-6 weeks, if no improvement after initial 4 weeks treat as G3 If unable to lower corticosteroid dose to below 10 mg/d after 6-8 weeks, consider DMARD Consider inter-articular steroid injections for large joints Referral to rheumatology G3-4: Severe pain associated with signs of inflammation, erythema, or joint swelling; swelling; irreversible joint damage; disabling; and limiting self-care ADL Hold ICI temporarily and may resume in consultation with rheumatology, if recover to ≤G1 Initiate oral prednisone 0.5-1 mg/kg If failure of improvement after 2 weeks or worsening in meantime, consider synthetic or biologic DMARD • Synthetic: methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine alone or in combination • Biologic: consider anticytokine therapy such as TNF⍺ or IL-6 antagonists. Referral to rheumatology
Guidelines Recommended for Nursing Management of Uncommon IRAEs
Endocrine IRAEs: Diabetes DM = diabetes mellitus; PCP = primary care physician. Schneider et al, 2021. Diabetes Workup and evaluation • Monitor patients for symptoms of new or worsening diabetes mellitus (polyuria, polydipsia, and fatigue) • Monitor glucose at baseline and with each treatment cycle while on therapy and at follow-up visits for at least 6 months • Laboratory evaluation in suspected checkpoint inhibitor–associated diabetes mellitus (CIADM) should include: o Urine and/or serum ketones o Anion gap on a metabolic panel o Anti-glutamic acid decarboxylase (GAD) or anti-islet cell antibodies o C-peptide levels Grade Management G1: Asymptomatic or mild symptoms; type 2 DM with fasting glucose value >ULN to mg/dL (>ULN to 8.9 mmol/L). No evidence of CIADM such as ketoacidosis or laboratory evidence of pancreatic autoimmunity Can continue ICI with close clinical follow-up and laboratory evaluation Refer to PCP for additional management or: • May initiate oral therapy for those with new-onset type 2 DM • Intensify medical therapy for those with worsening type 2 DM G2: Moderate symptoms, able to perform ADL; type 2 DM with fasting glucose value >150-250 mg/dL (>8.9 to 13.9 mmol/L). No ketoacidosis or metabolic derangements derangements but other evidence of CIADM at any glucose level May hold ICI until glucose control is obtained Urgent endocrine consultation for any patient with new-onset CIADM Initiate insulin for CIADM (or as default therapy if there is any questions about the diagnosis) Referral to ED or hospital admission if unable to initiate therapy, urgent outpatient specialist evaluation is not available, developing ketoacidosis, or other ketoacidosis, or other concern for CIADM G3-4: Severe symptoms, medically significant or life-threatening consequences, to perform ADL; G3: >250-500 mg/dL (>13.9 to 27.8 mmol/L); G4: >500 mg/dL (>27.8 mmol/L). Ketoacidosis or other metabolic abnormality Hold ICI until glucose control is obtained with reduction of toxicity to ≤G1 Admit for inpatient management of diabetic ketoacidosis, volume and electrolyte resuscitation, and insulin initiation Endocrine consultation for all patients Insulin therapy appropriate for all patients Additional considerations • Insulin therapy should be used in any case with significant hyperglycemia pending additional diagnostic workup if mechanism of DM is not known • Long-acting insulin therapy alone is not sufficient for CIADM because of the absence of pancreatic function after beta-cell destruction • Starting total daily requirement can be estimated at 0.3-0.4 units/kg/day • Half of daily requirements are typically given in divided doses as prandial coverage, while half should be administered as once-daily long-acting homolog. This requires self-monitoring 4 or more times daily or the use of continuous glucose continuous glucose monitor • Sliding scale insulin can be used in conjunction with multiple daily injection regimens to accommodate the variability in glucose levels • Decreased requirements after the initial acute admission for diabetic ketoacidosis are commonly seen in the so-called honeymoon period • Education is critical to learn skills like responding to hypoglycemia, anticipating exercise, monitoring for diabetic ketoacidosis, or carbohydrate counting, and to transition to technologies such as insulin pumps. Early endocrinology endocrinology consultation is a high priority for all patients • Type 2 DM patients will need to increase the frequency of self-monitoring as therapy intensifies and agents that can cause hypoglycemia are added to their regimen • Steroids can exacerbate postprandial hyperglycemia, and endocrinology consult should be considered for initiating or managing insulin in patients with Type 2 DM being started on high-dose steroids. If insulin is used, the doses generally doses generally needs to be adjusted again as steroids are tapered down
Endocrine IRAEs: Adrenal NA = sodium; K = potassium. Schneider et al, 2021. Adrenal–Primary Adrenal insufficiency (AI) Workup and evaluation • Evaluate am levels of ACTH (if >2x ULN) and cortisol level (if <3 µg/dL) • Basic metabolic panel (Na K, CO2, and glucose) • Renin and aldosterone • Consider standard dose ACTH stimulation test for indeterminate results (am cortisol >3 µg/dL and <15 µg/dL) • Evaluate for precipitating cause of crisis such as infection • Adrenal CT for metastasis or hemorrhage (most common causes of primary AI) Grading Management All grades Referral to endocrinology Education on steroid stress dosing, emergency injections, and medical alert bracelet or necklace, accessory, or system G1: Asymptomatic or mild symptoms Consider holding ICI until patient is stabilized or replacement hormone Endocrine consultation Initiate replacement therapy with hydrocortisone (15-20 mg in divided doses) Titrate hydrocortisone to maximum of 30 mg daily total dose for residual symptoms of AI Reduce maintenance dosing for symptoms of iatrogenic Cushings’ syndrome (eg, bruising, thin skin, edema, weight gain, hypertension, and hyperglycemia) Most primary AI will also require fludrocortisone (starting dose 0.5-1 mg/d). Adjust based on volume status, sodium level, and renin response (target upper half of the reference range) G2: Moderate symptoms, able to perform ADL Consider holding ICI until patient is stabilized on replacement hormone Endocrine consultation See in clinic to assess need for hydration, supportive care, and hospitalization Initiate outpatient corticosteroid treatment at 2-3 times maintenance (eg, hydrocortisone 30-50 mg total dose or prednisone 20 mg daily) to manage acute symptoms Initiate fludrocortisone (0.5-1 mg/day) Decrease stress dose corticosteroids down to maintenance doses after 2 days Maintenance therapy as in G1 G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform ADL Hold ICI until patient is stabilized on replacement hormone Endocrine consultation Inpatient management may be needed to provide: • Normal saline (at least 2L) • IV stress dose steroids: hydrocortisone 50-100 mg Q 6-8 hours initial dosing Taper stress dose corticosteroids down to oral maintenance doses over 5-7 days 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 hypophysitis for secondary (central) adrenal insufficiency • Using hydrocortisone allows for recreation of the diurnal rhythm of cortisol. Typically, 2/3 of the dose is given in the morning and 1/3 in the early afternoon. Long-acting steroids such as prednisone, rather than short-acting hydrocortisone, carry risk of over hydrocortisone, carry risk of over replacement but can be used in special circumstances, for example, if a patient is not able to adhere to a short-acting steroid regimen. Hydrocortisone 20 mg is equivalent to prednisone 5 mg • Dehydroepiandrosterone (DHEA) replacement is controversial but deficiency can be tested and replacement considered in women with low libido and/or energy who are judged to be otherwise well replaced • All patients need education on stress dosing for sick days, use of emergency injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet or necklace for adrenal insufficiency to trigger stress dose corticosteroids corticosteroids by emergency medical personnel. Therefore, early endocrinology consultation is appropriate • Endocrine consultation should be part of planning before surgery or high-stress treatments such as cytotoxic chemotherapy at any time during a patient’s care
Renal IRAEs hpf = high power field. Schneider et al, 2021. Renal Toxicities Nephritis and renal dysfunction—diagnosis and monitoring Clinical presentation and diagnosis • Definite ICI-related nephritis or acute kidney injury • Kidney biopsy-confirmed diagnosis compatible with ICI nephritis or acute kidney injury, and after clinical review of risk factors • Probably ICI-related nephritis or acute renal failure: o BOTH of the following:  Sustained increase in serum creatinine ≥50% on at least two consecutive values or need for renal replacement therapy, after clinical review of risk factors risk factors  Absence of an alternative plausible etiology o AND at least 1 of the following:  Sterile pyuria (≥5 WBCs/hpf)  Concomitant or recent extrarenal IRAE-eosinophilia (≥500 cells per µL) • Possible ICI-related nephritis or acute renal failure: o BOTH of the following:  Increase in serum creatinine ≥50%  Need for renal replacement therapy nephritis or acute kidney injury is not readily attributable to alternative causes Monitoring • Monitor patients for elevated serum creatinine before every dose • Routine urinalysis is not necessary, other than to rule out urinary tract infections, etc • For any suspected immune-mediated adverse reactions, exclude other causes (see below) • For suspected renal IRAE obtain urinalysis, consider referral to nephrology • For patients receiving combination therapy with ICIs and other agents, assess the potential contribution of the non-ICI treatment to the renal failure • Assess for concomitant medications, prescribed and over the counter, herbals, vitamins, nephrotoxic agents, or contrast media • If no potential alternative cause of acute kidney injury is identified, then one can assume it is ICI-related and should forego biopsy • Swift treatment of autoimmune-component is important
Renal IRAEs: Nephritis or Acute Kidney Injury Schneider et al, 2021. Grading Management G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5–2.0x above baseline Consider temporarily holding ICI and/or other potential contributing agents in combination regimens, pending consideration of consideration of potential alternative etiologies (recent IV contrast, medications, fluid status, and urinary tract infection) and infection) and baseline renal function. A change that is still <1.5 ULN could be meaningful G2: Creatinine 2–3x above baseline Hold ICI temporarily Consult nephrology Evaluate for other causes (recent IV contrast, medications, and fluid status) if other etiologies are ruled out, administer 0.5–1 administer 0.5–1 mg/kg/day prednisone equivalents If worsening or no improvement after 1 week, increase to 1–2 mg/kg/day prednisone equivalents and permanently discontinue ICI If improved to G ≥1, taper steroids over at least 4 weeks If no recurrence of chronic renal insufficiency discuss resumption of ICI with patient after taking into account the risks and risks and benefits. Resumption of ICI can be considered once steroids have been successfully tapered to ≤10 mg/day or mg/day or discontinued G3: Creatinine >3x baseline or >4.0 mg/dL; hospitalization indicated Permanently discontinue ICI if ICI is directly implicated in renal toxicity Consult nephrology Evaluate for other causes (recent IV contrast, medications, fluid status, and urinary tract infection) Administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent) G4: Life-threatening consequences; dialysis indicated; creatinine 6x above above baseline Additional considerations • Monitor creatinine weekly • Reflex kidney biopsy should be discouraged until steroid treatment has been attempted
Nephritis or Acute Kidney Injury: Follow-Up Schneider et al, 2021. Renal IRAEs Grading Management G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5–2.0x above baseline If improved to baseline: resume routine creatinine monitoring G2: Creatinine 2–3x above baseline If improved to G1: taper corticosteroids over at least 4 weeks before resuming treatment with routine routine creatinine monitoring If elevations persist >7 days or worsen and no other cause found, treat as G3 G3: Creatinine >3x baseline or >4.0 mg/dL; hospitalization indicated If improved to G1: taper corticosteroids over at least 4 weeks If elevations persist >3–5 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate) G4: Life-threatening consequences; dialysis indicated; creatinine 6x above above baseline If improved to G1: taper corticosteroids at least 4 weeks If elevations persist >2–3 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate)
Neurologic IRAEs: Myasthenia Gravis AChR = acetylcholine receptor; MuSK = muscle-specific kinase; LPR4 = lipoprotein-related 4; MGFA = Myasthenia Gravis Foundation of America; PO = by mouth. Schneider et al, 2021. Myasthenia Gravis Workup and evaluation • AChR and antistriated muscle antibodies in blood If AChR antibodies are negative, consider MuSK and LPR4 antibodies in blood—while presence of antibodies is confirmatory, the absence of antibodies of antibodies does not rule out the syndrome • Pulmonary function assessment with negative inspiratory force (NIF) and vital capacity (VC) • Creatine phosphokinase (CPK), aldolase, ESR, and CRP for possible concurrent myositis • Consider MRI brain and/or spine depending on symptoms to rule out central nervous system (CNS) involvement by disease or alternate diagnosis • Troponin, ECG, and consider transthoracic echocardiogram and/or cardiac MRI to evaluate concomitant myocarditis • Electrodiagnosis studies, under neurologic consultation, including neuromuscular junction testing with repetitive stimulation and/or jitter studies, nerve conduction study (NCS) to exclude neuropathy, and neuropathy, and needle electromyography (EMG) to evaluate for concomitant myositis • Inflammatory markers (ESR and CRP) • Consider paraneoplastic workup • Review and stop medications with known risk of worsening myasthenia: beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics Grading Management All grades All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Inpatient admission may be may be appropriate at all grades No G1 NA G2: Some symptoms interfering with ADLs. MGFA severity class I (ocular symptoms and findings only) and MGFA severity class II (mild generalized weakness) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve and steroid taper completed Neurology consultation Strongly consider inpatient care as patients can deteriorate quickly Pyridostigmine starting at 30 mg PO 3x a day and gradually increase to maximum of 120 mg PO 4x a day as tolerated and based on symptoms and wean based on wean based on improvement. These procedures should be done in close collaboration with the neurologist Administer corticosteroids (prednisone 0.5 mg/kg orally daily). Wean based on symptom improvement G3-4: Limiting self-care and aids warranted, weakness limiting walking, walking, ANY dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms or MGFA severity class III-V III-V (moderate to severe generalized generalized weakness to myasthenic crisis Follow G2 recommendations as listed, with the following additions for G3-4: Permanently discontinue ICI Admit patient, may need intensive care unit (ICU) level monitoring Continue steroids, taper should begin 3-4 weeks after initiation then wean based on symptom improvement Initiate IVIG 2 G/kg IV over 5 days (0.4 G/kg/day) or plasmapheresis x 5 days Consider adding rituximab if refractory to IVIG or plasmapheresis Frequent pulmonary function assessment Daily neurologic review
Neurologic IRAEs: Guillain-Barré Syndrome CSF = cerebrospinal; NCS = nerve conduction study; NIF = negative inspiratory force; VC = vital capacity; ICU = intensive care unit. ANNA-1 = antineuronal nuclear antibody type 1. Schneider et al, 2021. Guillain-Barré Syndrome Workup and evaluation • Neurologic consultation • MRI spine with or without contrast (rule out compressive lesion and evaluate for nerve root enhancement/thickening) • Lumbar puncture: CSF analysis for cell count and differential, cytology for malignant cells, protein, glucose, and viral/bacterial cultures. Note that CSF typically has elevated protein and protein and often elevated WBC as well, although this not typically seen in classical Guillain-Barré Syndrome (GBS) • Consider paraneoplastic workup eg ANNA-1 antibody testing • Serum antiganglioside antibody tests for GBS and its subtypes (eg, anti-GQ1b for Miller Fisher variant associated with ataxia and ophthalmoplegia) • Flow cytometry in patients with hematologic malignancies • Electrodiagnostic studies (NCS and EMG) to evaluate polyneuropathy • Pulmonary function (NIF or VC) • Frequent neuro checks Grading Management All grades warrant workup and intervention given potential for progressive GBS to lead to respiratory compromise. Note, there is no G1 toxicity G2: Moderate: some interference with ADLs, symptoms concerning concerning to patient Discontinue ICI Neurology consultation Admission to inpatient unit with capability of rapid transfer to ICU-level monitoring Start IVIG (0.4 G/kg/day for 5 days for a total dose of 2 G/kg) or plasmapheresis. Note: plasmapheresis immediately after IVIG will remove immunoglobulin Corticosteroids are usually not recommended for idiopathic GBS; however, in ICI-related forms, a trial is reasonable (methylprednisolone 16 mg/kg/d), mg/kg/d), followed by slow steroid taper. Pulse steroid dosing (methylprednisolone 1 g daily for 5 days) may also be considered for G3-4 along with along with IVIG or plasmapheresis. After pulse steroids, taper steroids over 4-6 weeks Frequent neuro checks and pulmonary function monitoring Monitor for concurrent autonomic dysfunction Nonopioid management of neuropathic pain, for example, pregabalin, gabapentin, or duloxetine Treatment of constipation/ileus G3-4: Severe: limiting self-care and aids warranted, weakness limiting walking, ANY dysphagia, dysphagia, facial weakness, respiratory muscle weakness, or or rapidly progressive symptoms Additional considerations • Extreme caution with rechallenging for severe cases after complete resolution of symptoms and tapered off immunosuppression
Neurologic IRAEs: Peripheral Neuropathy HbA1c = hemoglobin A1c; RNP = ribonucleoprotein; dsDNA = double stranded DNA; ab = antibody; MAG = myelin-associated glycoprotein. Schneider et al, 2021. Peripheral Neuropathy Workup and evaluation G1 • Consider neurology consultation to guide neuropathy phenotype determination and workup • Serum testing for reversible neuropathy causes: HbA1c, vitamin B12, TSH, vitamin B6, folate, serum protein electrophoresis, and immunofixation, CPK • Consider additional testing guided by neuropathy phenotype: ANA, ESR, CRP, ANCA, anti-smooth muscle, Sjögren’s syndrome A/Sjögren’s syndrome B, RNP, anti- anti-dsDNA, ganglioside ab, anti-MAG, anti-Hu (ANNA-1 ab), thiamine, Lyme, hepatitis B or C, and HIV • Consider MRI spine with or without contrast G2: In addition to the above • MRI spine advised, MRI brain if cranial nerve involvement, and MRI plexus if concern for plexus involvement • Consider lumbar puncture: CSF analysis for cell count and differential, cytology for malignant cells, protein, glucose, and viral or bacterial cultures • Consider EMG or NCS G3-4: go to GBS algorithm Grading Management G1: Mild: no interference with function and symptoms not concerning patient. Note: any cranial nerve problem should be managed as moderate Low threshold to hold ICI and monitor symptoms for a week. If to continue, monitor very closely for closely for any symptom progression G2: Moderate: some interference with ADLs, symptoms concerning to patient (ie, pain but not weakness or gait limitation) Hold ICI and resume once return to ≤G1 Initial observation OR initiate prednisone 0.5–1 mg/kg/day (if progressing from mild) Gabapentin, 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, and rapidly ascending sensory changes). Severe may be GBS and should should be managed as such Permanently discontinue ICI Admit patient Neurology consultation Initiate IV methylprednisolone 2–4 mg/kg/day and proceed as per GBS management
Neurologic IRAEs: Autonomic Neuropathy Schneider et al, 2021. Autonomic Neuropathy Workup and evaluation • An evaluation by neurologist or relevant specialist depending on organ system, with testing that may include: o Screen for other causes of autonomic dysfunction: diabetic screen, adrenal insufficiency, HIV, paraproteinemia, amyloidosis, and amyloidosis, and botulism; consider chronic diseases such as Parkinson’s and other autoimmune screen o Orthostatic vital signs o Consider electrodiagnostic studies (NCS and EMG) to evaluate for concurrent polyneuropathy o Consider paraneoplastic autoimmune dysautonomia antibody testing (eg, antiganglionic AChR, ANNA-1, and N-type voltage- voltage-gated calcium channel antibodies) Grading Management G1: Mild: no interference with function and symptoms not concerning to patient Low threshold to hold ICI and monitor symptoms for a week. If to continue, continue, monitor very closely for any symptom progression G2: Moderate: some interference with ADLs, concerning to patient Hold ICI and resume once return to ≤G1 and off prednisone if used Initial observation OR initiate prednisone 0.5–1 mg/kg/day (if progressing from from mild) Neurology consultation G3-4: Severe: limiting self-care and aids warranted Permanently discontinue ICI Admit patient Initiate methylprednisolone 1 g daily x 3 days followed by oral steroid taper taper Neurology consultation
Neurologic IRAEs: Aseptic Meningitis HSV = herpes simplex virus. Schneider et al, 2021. Aseptic Meningitis Workup and evaluation • MRI brain with or without contrast with pituitary or sellar cuts protocol • Am cortisol, ACTH to rule out adrenal insufficiency • Strongly consider lumbar puncture with CSF analysis for opening pressure, cell count and differential, cytology for malignant cells that could could indicate leptomeningeal metastases, protein, glucose, gram stain, viral or bacterial cultures, PCR for HSV, and other viral PCRs depending depending on suspicion • May see elevated WBC in CSF with normal glucose, normal culture, and gram stain. May see reactive lymphocytes, neutrophils, or histiocytes on histiocytes on cytology Grading Management G1: Mild: no interference with function and symptoms not concerning to patient. Note: any cranial nerve problem problem should be managed as moderate Hold ICI and discuss resumption with patient only after taking into account the risks and risks and benefits Consider neurology consult Consider empiric antiviral (IV acyclovir) and antibacterial therapy until CSF results results Once bacterial and viral infection negative, may closely monitor off corticosteroids or corticosteroids or consider oral prednisone 0.5–1 mg/kg/day or IV methylprednisolone 1 methylprednisolone 1 mg/kg/day if moderate or severe symptoms Steroids can be tapered after 2-4 weeks, monitoring for symptom recurrence Consider hospitalization for G3-4 G2: Moderate: some interference with ADLs, symptoms concerning to patient (ie, pain but no weakness or gait gait limitation) G3-4: Severe: limiting self-care and aids warranted
Neurologic IRAEs: Encephalitis FLAIR = fluid-attenuated inversion recovery; EEG = electroencephalogram; TPO = thyroid peroxidase. Schneider et al, 2021. Encephalitis Workup and evaluation • Neurologic consultation • MRI brain with or without contrast may reveal T2/FLAIR changes typical of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal normal • Lumbar puncture with CSF analysis for opening pressure, cell count and differential, cytology for malignant cells that could indicate leptomeningeal metastases, protein, metastases, protein, glucose, gram stain, viral or bacterial cultures, PCR for HSV and other viral PCRs depending on suspicion, oligoclonal bands, autoimmune autoimmune encephalopathy, and paraneoplastic panels • May see elevated WBC with lymphocytic predominance and/or elevated protein • EEG to evaluate for subclinical seizures • Serum studies: chem panel, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and thyroglobulin, am cortisol and ACTH, GQ1b antibodies (Bickerstaff encephalitis and rhombencephalitis), celiac antibody panel, and paraneoplastic and autoimmune encephalitis panels • 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 Hold ICI 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/day Neurology consultation If severe or progressing symptoms or oligoclonal bands present, consider pulse corticosteroids (methylprednisolone (methylprednisolone 1 g IV daily for 3-5 days) plus IVIG 2 g/kg over 5 days (0.4 g/kg/day) or plasmapheresis plasmapheresis Taper steroids following acute management at least 4-6 weeks If positive for autoimmune encephalopathy or paraneoplastic antibody or limited or no improvement, consider consider rituximab in consultation Admit patient for G3-4 G2: Moderate: some interference with ADLs, concerning to patient (ie, pain but no weakness or gait gait limitation) G3-4: Severe: limiting self-care and aids warranted
Neurologic IRAEs: Demyelinating Diseases Schneider et al, 2021. Demyelinating Diseases, Including Multiple Sclerosis, Transverse Myelitis, Acute-Disseminated Encephalomyelitis, Optic Neuritis, and Neuromyelitis Optica Workup and evaluation • Neurologic consultation • Ophthalmic or neuro-ophthalmic evaluation if ocular involvement • MRI with contrast of brain, orbit, cervical, and thoracic spinal cord (tailor to examination finding) • Lumbar puncture with CSF analysis including autoimmune encephalitis panel and oligoclonal bands, CNS demyelinating disease antibodies (aquaporin 4 and myelin oligodendrocyte oligodendrocyte glycoprotein), and viral PCRs especially John Cunningham virus PCR to exclude progressive multifocal leukoencephalopathy • Serum studies: B12, HIV, rapid plasma regain (RPR), ANA, Ro/La, TSH, aquaporin-4 IgG, paraneoplastic panel or anti-HU and anti–CRMP5-CV2, thyroid panel including TPO and and thyroglobulin, am cortisol and ACTH, and paraneoplastic autoimmune encephalitis panels • Evaluation for urinary retention and constipation • EEG to evaluate for subclinical seizures • Although less common, biopsy may provide definitive evidence of CNS demyelination Grading Management G1: Asymptomatic or mild symptoms; clinical or diagnostic observations only Intervention not indicated Continue immunotherapy unless symptoms worsen or do not improve G2: Moderate symptoms; minimal, limiting age-appropriate instrumental ADL Stop ICI Neurology consultation Start prednisone 1 mg/kg/day and taper over 1 month Rule out infection G3: Severe or medically significant symptoms but not immediately life-threatening; limiting self-care ADL Permanently discontinue ICI Neurology consultation Nonopioid management of neuropathic pain, for example, pregabalin, gabapentin, or duloxetine Admit patient for methylprednisolone pulse dose 1 g/day and consider IVIG or plasmapheresis if no improvement or or symptoms worsen after 3 days G4: Life-threatening consequences Permanently discontinue ICI Neurology consultation ICU level inpatient care Start methylprednisolone pulse dosing 1 g/day and consider IVIG or plasmapheresis if no improvement or symptoms worsen symptoms worsen after 3 days
Hematologic IRAEs: Hemolytic Anemia DIC = disseminated intravascular coagulation; PT = prothrombin time; INR = international normalized ratio; PTT = partial thromboplastin time; PNH = paroxysmal nocturnal hemoglobinuria; Hgb = hemoglobin; LLN = lower limit of normal; RBC = red blood cell; SAE = serious adverse events. Schneider et al, 2021. Hemolytic Anemia Workup and evaluation • History and physical examination (with special consideration of history of new drugs, insect, spider, or snake bites) • Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear, LDH, haptoglobin, bilirubin, reticulocyte count, and free hemoglobin • DIC panel, which could include PT or INR or PTT, and infectious causes • Autoimmune serology • PNH screening • Direct and indirect bilirubin, direct agglutinin test, and if no obvious cause, bone marrow analysis, and cytogenetic analysis to evaluate MDS • Evaluation for viral or bacterial (mycoplasma etc.) causes of hemolysis studies • Workup for bone marrow failure syndrome if refractory including B12, folate, copper, parvovirus, iron, and thyroid, infection • Glucose-6-phosphate dehydrogenase level • Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine or quinidine, fludarabine, ciprofloxacin, lorazepam, and diclofenac) • Assessment of methemaglobinemia Grading Management G1: Hgb <LLN to 10.0 g/dL; <LLN to 6.2 mmol/L; LLN to 100 g/L Continue ICI with close clinical follow-up and laboratory evaluation G2: Hgb <10.0 to 8.0 g/dL; <6.2 to 4.9 mmol/L; <100 to 80 g/L Hold ICI and strongly consider permanent discontinuation Administer 0.5-1 mg/kg/d prednisone equivalents G3: Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated Permanently discontinue ICI; should use clinical judgement and consider admitting the patient; Hematology consult Prednisone 1-2 mg/kg/d (oral or IV equivalent depending on symptoms or speed of development 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 or to return to a patient to a safe hemoglobin range (7-8 g/dL instable, noncardiac inpatients) Should offer patients supplementation with folic acid 1 mg daily G4: Life-threatening consequences; urgent intervention indicated Permanently discontinue ICI; admit patient; hematology consult IV prednisone corticosteroids 1-2 mg/kg/day If no improvement on or if worsening on corticosteroids or severe symptoms on presentation, initiate other immunosuppressive drugs, such as rituximab, IVIG, IVIG, cyclosporine, infliximab, mycophenolate mofetil, or antithymocyte globulin (ATG) RBC transfusion per existing guidelines. Discuss with blood bank team before transfusions that a patient with possible ICI SAE is in the hospital Additional considerations Monitor hemoglobin levels weekly until the steroid tapering process is complete. Thereafter, less frequent testing is needed
Hematologic IRAEs: Acquired TTP TTP = thrombotic thrombocytopenic purpura; ADAMS13 = a disintegrin and metalloprotease with thrombospondin type motifs 13; PEX = plasma exchange. Schneider et al, 2021. Acquired TTP Workup and evaluation • History with specific questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, oxymorphone, antibiotics, and quinine) • Hematology consult • Physical examination, peripheral smear to check for schistocytes • ADAMTS13 activity level and inhibitor titer • LDH, haptoglobin, reticulocyte count, bilirubin, and urinalysis to rule out other causes • Prothrombin time, activated partial thromboplastin time, and fibrinogen • Blood group and antibody screen, and direct antiglobulin test • Consider CT or MRI brain, echocardiogram, electrocardiogram • Cytomegalovirus serology • Note: this disorder is usually associated with severe drop in platelets and hemolysis or anemia precipitously (microangiopathy) 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 consult should immediately be called, as delay in identification is associated with increased mortality or morbidity Initially, the patient should be stabilized, and any critical organ dysfunction stabilized G1: Evidence of RBC destruction (schistocytosis) without renal insufficiency, or thrombocytopenia clinically G2: Evidence of RBC destruction (schistocytosis) without clinical consequence with G2 anemia and thrombocytopenia Hold ICI and discuss resumption with patient only after taking into account the risks and benefits, nothing that there are currently no data to currently no data to recommend restarting ICI therapy Administer 0.5–1 mg/kg/day prednisone G3: Laboratory findings with clinical consequences (G3 thrombocytopenia, anemia, and renal insufficiency >2) G4: Life-threatening consequences (eg, CNS hemorrhage or thrombosis or embolism or renal failure) Hold ICI and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to currently no data to recommend restarting ICI therapy In conjunction with hematology, initiate therapeutic PEX according to existing guidelines with further PEX dependent on clinical progress progress Administer methylprednisolone 1 g IV daily for 3 days, with the first dose typically administered immediately after the first PEX. For patients For patients who has an initial platelet count response, discontinue PEX May offer rituximab Consider caplacizumab if ADAMTS13 activity level is <10 IU/dL or <10% of normal, with an inhibitor or elevated anti-ADAMTS13 IgG ADAMTS13 IgG If no exacerbation within 3-5 days after stopping PEX, taper steroids over 2-3 weeks, complete course of rituximab (if receiving), and and discontinue caplacizumab (if receiving)
C = complement protein; MCV = mean corpuscular volume; EBV = Epstein Barr virus; CMV = cytomegalovirus; HHV6 = human herpesvirus 6. Schneider et al, 2021. Hematologic IRAEs: Hemolytic Uremic Syndrome Hemolytic Uremic Syndrome (HUS) Workup and evaluation • 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 or methylmalonic acid • Complement testing C3, C4, and CH50 (complement inhibitory antibodies for suspected familial) • Evaluate reticulocyte-count and MCV • Evaluation of infectious cause including screening for viral EBV, CMV, and HHV6 • Evaluation for nutritional causes of macrocytosis (B12 and folate) • Pancreatic enzymes • Evaluation for diarrheal causes, shiga toxin, and Escherichia coli 0157 • Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia • Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, and sirolimus) • Evaluation for neurologic changes (alteration in consciousness, concurrent confusion, seizures, pyramidal syndrome, and extrapyramidal syndrome with hypertonia) Grading Management G1-2: Evidence of RBC destruction (schistocytosis) without clinical consequences of anemia, and thrombocytopenia grade 2 Continue ICI with close clinical follow-up and laboratory evaluation Supportive care G3: Laboratory findings with clinical consequences (eg, renal insufficiency and petechiae) Permanently discontinue ICI Hematology consult Begin therapy with eculizumab (anti-C5 antibody) 900 mg weekly x4 doses, 1,200 mg Week 5, then 1,200 mg every 2 weeks Red blood transfusion according to existing guidelines G4: Life-threatening consequences, (eg, CNS thrombosis or or renal failure)
BM = bone marrow. Schneider et al, 2021. Hematologic IRAEs: Aplastic Anemia Aplastic Anemia Workup and evaluation • History and physical examination (close attention to medications, exposure to radiation, toxins, and recent viral infections) • CBC, smear, and reticulocyte count • Viral studies including CMV, HHV6, EBV, and parvovirus • Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, and vitamin D • Serum LDH and renal function • Evaluation for infectious causes • Identify marrow hypo/aplasia • BM biopsy and BM aspirate analysis • Peripheral blood analysis including neutrophil count, proportion of Glycosyl-phosphatidylinositol (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: Mild: >0.5 PMNs x 109/L hypocellular marrow, marrow cellularity <25%, peripheral platelet count count >20,000, reticulocyte count >20,000 Hold ICI, provide growth factor support, and close clinical follow-up and laboratory evaluation Supportive transfusions as per local guidelines G2: Moderate: hypocellular marrow <25% and two of the following ANC <500, peripheral platelet <20,000 <20,000 and reticulocyte <20,000 Hold ICI and provide growth factor support and close clinical laboratory evaluations daily Hematology consult Administer horse ATG plus cyclosporine Supportive transfusions as per local guidelines. All blood products should be irradiated and filtered HLA typing and evaluation for bone marrow transplantation if patient is a candidate G3-4: Severe: ANC <200, platelet count <20,000, reticulocyte count of <20,000, plus hypocellular marrow <25% As per G2 Hold ICI and monitor weekly for improvement. If not resolved, discontinue treatment until AE has reverted to G1 If no response, repeat immunosuppression with rabbit ATG plus cyclosporine, and cyclophosphamide For refractory patients, consider eltrombopag plus supportive care
Hematologic IRAEs: Lymphopenia Lymphopenia Workup and evaluation • History (special attention to nutritional status and for lymphocyte depleting therapy such as fludarabine, ATG, steroids, cytotoxic chemotherapy, chemotherapy, and radiation exposure, as well as history of autoimmune disease [AD] and family history of AD) • Physical examination with special attention to spleen size • CBC with differential, peripheral smear, and reticulocyte count • CXR for evaluation of presence of thymoma • Bacterial cultures and evaluation for infection (fungal, bacterial, and viral—specifically CMV or HIV) Grading Management All grades No specific action is required for lymphopenia G1-G3 and ICI therapy should be continued For G4 (<250 PB lymphocyte count), continue ICI therapy and initiate Mycobacterium avium complex prophylaxis and and Pneumocystis jirovecii prophylaxis, CMV screening. HIV or hepatitis screening if not already done May consider EBV testing if evidence of lymphadenopathy or hepatitis, fevers, and hemolysis occur consistent with lymphoproliferative disease occurs PB = peripheral blood. Schneider et al, 2021.
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View

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Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View

  • 1. Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy Outcomes: The Nurse’s View Blanca Ledezma, MSN, NP, AOCNP® Nurse Practitioner Hematology/Oncology University of California, Los Angeles (UCLA) Health
  • 2. Disclosures Speaker’s bureau: Amgen, AstraZeneca, Eisai, Lilly i3 Health has mitigated all relevant financial relationships
  • 3. Learning Objectives IRAEs = immune-related adverse events. Discuss how the mechanisms of action of immunotherapies influence their safety profile Identify risk factors predisposing patients to IRAEs Distinguish IRAEs from chemotherapy- and targeted therapy–related adverse events Coordinate with the interdisciplinary health care team to apply evidence- based guidelines and best practices in personalized nursing management plans for patients with IRAEs Develop patient counseling strategies promoting awareness, self- monitoring, and escalated reporting of IRAEs
  • 5. Epidemiology PD-L1 = programmed cell death protein ligand 1; CTLA-4 = cytotoxic T lymphocyte–associated protein 4. Pallin et al, 2018; Brahmer et al, 2021. In the US, 15.5 million people live with cancer or have a history of cancer In 2040, the number is expected to rise to 26.1 million Treatment with immunotherapy/immune checkpoint inhibitors (ICIs) is the standard of care for several cancers In 2018, a study found that 44% of patients with both metastatic solid tumors and hematologic tumors could use ICI A systemic review found that patients developed IRAEs at a rate of 74% with anti–PD-L1 inhibitors, 89% with anti–CTLA-4 inhibitors, and 90% with combination ICIs
  • 6. Delayed Onset and Prolonged Duration of IRAEs AE = adverse events. Puzanov et al, 2017. IRAEs from immunotherapy treatments have led to delayed onset and prolonged duration when compared to AEs from chemotherapy As a result of the diverse clinical presentation of IRAEs, patients may present with IRAEs late in their treatment course, with some cases presenting months or years after discontinuation of treatment
  • 7. Median Time to Onset of IRAEs Pallin et al, 2018; Puzanov et al, 2017. Can occur early on, days to months from initiation of therapy IRAEs are less predictable and can occur long after cessation of treatment Onset can be earlier when given in combination Important to monitor patients for IRAEs during and after treatment discontinuation
  • 8. Epidemiology of Fatal IRAEs VEGF = vascular endothelial growth factor. Martins et al, 2019. Fatal IRAE incidence is estimated to be 0.3%-1.3% Lower risk than with conventional treatment Platinum doublet chemotherapy: 0.9% Allogenic hematopoietic stem cell transplant: 15% VEGF-targeted agents/tyrosine kinase inhibitors: 0%-4% Median time to onset for fatal toxic event is 14.5 days for ICI combinations and inclined to be delayed by 40 days for monotherapy
  • 9. Majority of IRAEs Are Mild to Moderate GI = gastrointestinal; PD-1 = programmed cell death protein 1; neuro = neurological; ocul = ocular. Puzanov et al, 2017. Most Frequently Affect Skin and GI
  • 11. Immunotherapy Mechanism of Action (MOA) Brahmer et al, 2021. ICIs block key regulatory signals that dampen immune responses, counteracting immune suppression in the tumor microenvironment and therefore enabling tumor-reactive T cells to mount an effective anticancer response
  • 12. PD-L1/PD-1 Inhibitor and CTLA-4 Inhibitor MOA MHC = major histocompatibility complex; TCR = T-cell receptor; CD = cluster of differentiation; ipi = ipilimumab. Armezzani, 2019; Cooper et al, 2015. . Tumor Microenvironment Lymph Node
  • 13. CAR T MOA CAR = chimeric antigen receptor; TAA = tumor-associated antigen. Li et al, 2018.
  • 14. FDA-Approved Immune Checkpoint Inhibitors FDA = US Food and Drug Administration. Yang et al, 2023; Russo et al, 2020; USFDA, 2023a; USFDA 2023b. PD-1 inhibitors: Cemiplimab Nivolumab Pembrolizumab Dostarlimab Retifanlimab-dlwr (granted FDA accelerated approval, pending confirmatory trials) PD-L1 inhibitors: Atezolizumab Avelumab Durvalumab CTLA-4 inhibitor: Ipilimumab Combination therapy: Ipilimumab/nivolumab Chemo/ICI ICI/targeted therapy
  • 15. FDA-Approved Immune Checkpoint Inhibitors L = line; TPS = tumor proportion score; NSCLC = non–small cell lung cancer; CPS = combined positive score; GEJ = gastroesophageal junction; CRC = colorectal cancer; MSI-H = microsatellite instability–high; dMMR = deficient mismatch repair; auto = autologous; allo = allogeneic; PMBCL = primary mediastinal B-cell lymphoma; R/R = relapsed/refractory; adv = advanced; met = metastatic. Vaddepally et al, 2020.
  • 16. FDA-Approved CAR T-Cell Therapies BCMA = B-cell maturation antigen. NCI, 2022; Chen et al, 2023. Generic Name Target Antigen Targeted Disease Patient Population Tisagenlecleucel CD19 B-cell acute lymphoblastic leukemia (ALL) Children and young adults with refractory or relapsed B-cell ALL B-cell non-Hodgkin lymphoma (NHL) Adults with relapsed or refractory B-cell NHL Axicabtagene ciloleucel CD19 B-cell NHL Adults with relapsed or refractory B-cell NHL Follicular lymphoma Adults with relapsed or refractory follicular lymphoma Brexucabtagene autoleucel CD19 Mantle cell lymphoma (MCL) Adults with relapsed or refractory MCL B-cell ALL Adults with refractory or relapsed B-cell ALL Lisocabtagene maraleucel CD19 B-cell NHL Adults with relapsed or refractory B-cell NHL Idecabtagene vicleucel BCMA Multiple myeloma Adults with relapsed refractory multiple myeloma myeloma Ciltacabtagene autoleucel BCMA Multiple myeloma Adults with relapsed refractory multiple myeloma myeloma
  • 17. Other Types of Immunotherapy IFN = interferon; TCR = T-cell receptor; IL = interleukin. Gupta et al, 2022; Kaplon et al, 2023; Koury et al, 2018; Sarnaik et al, 2021. Cytokine therapy High dose IL-2 IFN-𝛼 2b Monoclonal antibodies Rituximab Bispecific antibodies Blinatumomab Teclistimab, others Cancer vaccines Sipuleucel-T Oncolytic virus Talimogene laherparepvec Tumor-infiltrating lymphocytes Lifileucel (under FDA review) TCR-transduced T cells Clinical trials
  • 19. Risk Factors for IRAEs HER2i = human epidermal growth factor receptor 2 inhibitors; TKIs = tyrosine kinase inhibitors; AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; BMI = body mass index; ECOG = Eastern Cooperative Oncology Group Performance Status Scale; ILD = interstitial lung disease; RT = radiation therapy; COPD = chronic obstructive pulmonary disease; CKD = chronic kidney disease; eGRF = estimated glomerular filtration rate; PPI = proton pump inhibitors; NSAID = nonsteroidal anti-inflammatory drugs; ACEI =angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers Chennamadhavuni, et al, 2022.
  • 20. Risk Factors for IRAEs (cont.) Shimozaki et al, 2021; Liu et al, 2021; Chennamadhuvuni et al, 2022. Demographics: <60 years of age Men (PD-1/PD-L1) Woman (CTLA-4) ECOG 2 >50 pack-year smoking history or currently smoking Higher body mass index Sarcopenia Low muscle mass Medical history: History of an allergy Autoimmune disease Hypertension Cardiac history Pulmonary history or previous thoracic radiation Chronic kidney disease
  • 21. Risk Factors for IRAEs (cont.) Shimozaki et al, 2021; Liu et al, 2021; Chennamadhuvuni et al, 2022. Medications/vaccinations: PPIs & NSAIDs Diuretics & ACEI/ARD Anthracyclines, HER2 inhibitors, VEGF TKIs Antibiotics Influenza vaccinations Vitamin D deficiency Labs: Serum albumin >3.6 Neutrophil to lymphocyte ratio <3 Pre-existing autoantibodies Augmented expression of cytokines Gut microbiome Distinct human leukocyte antigen (HLA) HLA-DR4
  • 22. Tumor- and Agent-Specific Risk Factors for IRAEs aOdds ratio is from 2 different studies. OR = odds ratio. Chennamadhavuni, et al, 2022. Factor High risk of IRAE (odds ratio) Tumor-specific Non-specific • Higher disease burden (≥2 metastatic sites, OR=8.62), higher tumor mutational burden Melanoma • High risk for diarrhea (1.9/1.3) a , rash (1.8/1.6) a , pruritis (2.4/1.5) a , colitis colitis (4.2/not reported) a • Low risk for pneumonitis (0.4/0.3) a Breast cancer • Higher fatal adverse events in patients with PD-1 (3.1%) AML/MDS • High risk for dermatitis and hepatitis Agent-specific CTLA-4 inhibitors • In combination with PD-1 (vs PD-1/PD-L1) (1.53/1.88) a • Monotherapy (vs PD-1/PD-L1): organ-nonspecific (2.02); colitis (8.7); hypophysitis (6.5); and rash (2) PD-1 inhibitors • Pneumonitis (6.4), arthralgia, vitiligo (3.5), and hypothyroidism (4.3) vs. vs. CTLA-4 Organ-nonspecific • High risk when combined with chemotherapy (OR for grade 1-5, 2.67; OR 2.67; OR for grade 3-4, 1.83)
  • 23. Biomarkers for Predicting IRAEs a2 values represent results of 2 different studies; 2Cutoff values are not well established; GISpecific for gastrointestinal adverse events. ALC = absolute lymphocyte count; AMC = absolute monocyte count; AEC = absolute eosinophilic count; NLR = neutrophil-lymphocyte ratio; dNLR = derived NLR; PLR = platelet lymphocyte ratio; ANC = absolute neutrophil count; MLR = monocyte to lymphocyte ratio; TNFα = tumor necrosis factor alpha; CXCL = chemokine ligand; GNAL = guanine nucleotide-binding protein G subunit alpha; ITM2B = integral membrane protein 2B; BP = bullous pemphigoid; IgG = immunoglobulin G. Chennamadhavuni, et al, 2022. Circulating blood counts counts • ALC (>2.6 k/μL) • AEC a (>240/μL; >125/μL) • AMC (>0.29k/uL) • Platelet count (>145 k/μL) • NLR a (<3; <2.3) • dNLR (>3) • PLR a (< 534; < 180) • ANC (<6.5) • MLR (< 0.73) • Lower T-regulatory GI cells at the baseline (2.5% in IRAE group versus 8.4% in non-IRAE group) • CD8+ cells (clonal expansion >55) • Early T-cell receptor repertoire diversity • Drop-in white blood cell (WBC) count (by 59%) and relative lymphocytic count (by 32%) from baseline Cytokines • Lower baseline levels of TNF-α, IL-6, IL8, interferon γ-induced protein (IP)-10, CXCL9, CXCL10, CXCL11, and CXCL19. Post- Post-treatment significant rise in the levels of IL-6, CXCL5, CXCL9, and CXCL10 levels • Higher IL-7 at the baseline and exponential rise • Significant rise in granulocyte colony-stimulating factor (G-CSF) at 4 weeks compared to baseline • Serial interferon-gamma (IFN-γ), decrease to <10 IU/ml 3-6 weeks after starting ICI • A significant rise (mean rise from 8.4 mg/L to 52.7mg/L) C-reactive protein (CRP) Autoantibodies • Higher soluble CTLA-4 (>200 pg/ml) • Autoantibody detection: anti-GNAL, anti-ITM2B, and anti-CD74, rheumatoid factor, anti-nuclear and antithyroid antibody, antibody, antithyroid peroxidase antibody, antithyroglobulin antibody • Lower baseline (≤45μg/L) soluble major histocompatibility complex class I chain-related protein A (MICA), lower soluble CD25 CD25 (median level was 630 pg/ml in IRAE group), and a significant rise in soluble CD163 (± 21.3%) • Anti-BP180 IgG (median was 6.1 U/mL)
  • 24. Biomarkers for Predicting IRAEs (cont.) skin = specific for dermal adverse events. HLA = human leukocyte antigen; SNP = single nucleotide polvmorphisms; ECG = electrocardiogram. Chennamadhavuni, et al, 2022 Serum proteins • Higher baseline albumin (≥3.6 g/dl) • Significant drop in post-treatment leptin levels from baseline • Higher baseline thyroid-stimulating hormone levels (1.67 mIU/L) • Elevated troponin for cardiac IRAE • Lactate dehydrogenase (LDH) ≥245 U/L HLA genotypes • HLA types: HLA-DRB1*11:01 skin and HLA-DQB1*03:01 GI alleles • Predominance of HLA-DR4 • HLA-DR15, B52 and Cw12 IRAE-pituitary • HLA-DRB1*04: 05 for IRAE-arthritis • HLA-DPA1*02:02 and DPB1*05:01 in IRAE-diabetes MicroRNA and gene expression profiling • Increased IRAE risk: mapped to 1 variant A allele in GABRP SNP rs11743438; 1 variant A allele in GABRP SNP rs11743435; 1 variant allele A in the DSC2 SNP JHU_20.57183980; 1 variant allele G in the BAZ2B SNP rs56328422; 1 1 variant allele T in the SEMA5A SNP rs3026321 • Post-treatment (3-week) increased expression of CD177 GI (12.2-fold higher in IRAE group than non-IRAE group) and and CEACAM1 GI genes • Suppressed miR-146a gene (by SNP s2910164) • Reduced IRAE risk: mapped to RGMA, ANKRD42, PACRG, GLIS3, ROBO1 genes Intestinal microbiota GI • Abundant Bacteroidetes phylum, specifically Bacteroidaceae, Rikenellaceae, and Barnesiellaceae (deficient polyamine polyamine transport and vitamin B biosynthesis) • Abundant Faecalibacterium genus and other Firmicutes at baseline • At the phylum level, low Bacteroidetes/Firmicutes ratio; at the genus level, a relative abundance of Alistipes, low Bacteroides, and high Blautia, Lachnospiraceae, and Faecalibacterium Stool testing GI • Stool calprotectin (>150mcg/g) and positive lactoferrin in colitis-IRAE Cardiac workup • ECG abnormalities, and low echocardiographic global longitudinal strain (GLS) may predict cardiac-IRAE
  • 25. Risk Factors by Cancer Type and Treatment RCC = renal cell carcinoma; HIV = human immunodeficiency virus; BRAF = B-raf proto-oncogene; MEK = mitogen-activated protein kinase kinase; EGFR = epidermal growth factor receptor. Liu et al, 2021. Risk factor Cancer type Treatment IRAE Body composition parameters Low muscle attenuation Melanoma CTLA-4 inhibitor Grade 3-4 IRAE include rash, diarrhea, colitis, hypopituitarism, arthritis etc. Sex Female Melanoma CTLA-4 inhibitor Grade 3-4 IRAE include pruritus, diarrhea, diarrhea, hypophysitis etc. Tumor histology Melanoma compared to NSCLC CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of GI & skin IRAE ↓Risk of pneumonitis Melanoma compared to RCC CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of dermatitis, arthritis, myalgia ↓Risk of pneumonitis & dyspnea RCC compared to melanoma CTLA-4 inhibitor & PD-L1 inhibitor ↑Risk of pneumonitis & dyspnea Past medical history Pre-existing autoimmune disease (AD) Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Likely increased risk of IRAE, particularly patients on immunosuppressive therapy HIV infection Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Not increased Concurrent or sequential treatment High dose radiotherapy Solid tumors CTLA-4 inhibitors & PD-L1 inhibitors Likely increased risk of IRAE, particularly patients receiving higher radiation dose Vemurafenib Melanoma CTLA-4 inhibitors Hepatic toxicity Trametinib + vemurafenib Melanoma CTLA-4 inhibitors Severe colitis BRAF & MEK inhibitor Melanoma PD-L1 inhibitors Hepatic toxicity, pyrexia Crizotinib NSCLC PD-L1 inhibitors Hepatic toxicity EGFR-TKI except osimertinib NSCLC PD-L1 inhibitors Not increased Osimertinib prior to ICIs NSCLC PD-L1 inhibitors Grade 3-4 IRAEs include pneumonitis, hepatitis, colitis Osimertinib after ICIs NSCLC PD-L1 inhibitors Increased rate of ILD
  • 26. Risk Factors by Cancer Type and Treatment (cont.) s = soluble; REC = relative eosinophil count. Liu et al, 2021. Risk factor Cancer type Treatment IRAE Antibodies Pretreatment anti-thyroid antibody NSCLC PD-L1 inhibitors Thyroid dysfunction Pre-treatment rheumatoid factor Skin reaction, myasthenia Cytokine assays ↑Baseline IL-17 Melanoma CTLA-4 inhibitors Grade 3 colitis ↓IL-10 after treatment Urothelial carcinoma CTLA-4 inhibitors Ischemic papillopathy & optic neuritis ↓IL-10 and ↑IL-2 after treatment Melanoma CTLA-4 inhibitors IRAE ↑Baseline IL-6 (P<0.05) Melanoma CTLA-4 inhibitors Grade 3-4 IRAEs include rash, diarrhea, colitis, hypopituitarism, arthritis etc. ↓Baseline IL-6, IL-8, & sCD25 Melanoma CTLA-4 inhibitors Colitis ↑IL-6 after treatment Melanoma PD-L1 inhibitor Cutaneous IRAE ↓Baseline CXCL9, CXCL10, CXCL11 and CXCL19 ↑Post-treatment CXCL9 and CXCL10 Solid tumors PD-L1 inhibitor & CTLA-4 inhibitor Pneumonitis, thyroid, arthritis, dermatitis, etc. ↑Circulating sCD163 Melanoma PD-L1 inhibitor IRAE ↑Baseline sCTLA-4 level Melanoma CTLA-4 inhibitor Gastrointestinal IRAE Blood cells ↑WBC ↓RLC ↑RNC Melanoma PD-L1 inhibitor GI IRAE pulmonary IRAE ↑CD177 & CEACAM1 (neutrophil-activation markers) Melanoma CTLA-4 inhibitor GI IRAE ALC > 2,000; ↑Baseline AEC Solid tumors PD-L1 inhibitor IRAEs include rash, colitis, hepatitis, pneumonitis, pneumonitis, etc. ↑Baseline AEC at and REC after treatment Melanoma PD-L1 inhibitor Endocrine IRAEs Circulating T cells repertoire Prostate cancer CTLA-4 inhibitor IRAEs Clonal expansion of CD8 T cells clones in peripheral blood Prostate cancer CTLA-4 inhibitor IRAEs? Gut microbiome Faecalibaterium and other firmicutes Melanoma CTLA-4 inhibitor Colitis B. fragilis and Burkholderia cepacia Murine sarcoma CTLA-4 inhibitor ↓ Intestinal IRAE Bacteroidetes phylum Melanoma CTLA4 inhibitor ↓ Colitis Genetic variability Predominance of HLA-DR4 Solid-organ cancer PD-L1 inhibitor Diabetes Homozygous variant of PDCD1 804 C>T(rs2227981) NSCLC PD-L1 inhibitor ↓ IRAEs
  • 27. IRAEs-Toxicities in Every System DRESS = drug reaction with eosinophilia and systemic symptoms. Schneider et al, 2021; Martins et al, 2019; Puzanov et al, 2017.
  • 28. Most Common IRAEs Schneider et al, 2021; Puzanov et al, 2017; Trinh et al, 2019. Lung • Pneumonitis Cutaneous • Rash • Dermatitis • Pruritis Endocrine • Thyroid dysfunction • Hypophysitis Gastrointestinal • Colitis • Diarrhea • Hepatitis Musculoskeletal • Arthralgia • Myalgias
  • 29. Uncommon IRAEs Schneider et al, 2021; Puzanov et al, 2017; Trinh et al, 2019. Renal • Interstitial nephritis • Granulomatous nephritis Hematologic • Hemolytic anemia • Red cell aplasia • Thrombocytopenia • Myelodysplasia • Hemophilia Endocrine • Pancreatitis • Type 1 diabetes mellitus • Adrenal insufficiency Cardiac • Myocarditis • Pericarditis • Arrhythmias Neurologic • Encephalitis • Meningitis • Myasthenia gravis • Guillain-Barré syndrome • Peripheral neuropathies Ophthalmologic • Uveitis • Episcleritis • Blepharitis • Optic nerve swelling • Ulcerative keratitis • Vogt-Koyanagi-Harada
  • 30. Identifying Signs and Symptoms of IRAEs Yeung et al, 2020. Presenting symptom Warning signs Potential immune-related adverse effect Part A: neurological symptoms Headache Neck stiffness Meningitis Hypotension Hypophysitis Mental status change Neck stiffness Meningitis Weakness Respiratory failure Guillain-Barre syndrome, myasthenia gravis Paraplegia Transverse myelitis Mental status change Encephalitis Part B: cardiopulmonary symptoms Chest pain Peripheral edema Myocarditis Dyspnea on exertion, pulsus paradoxus, electric alternans alternans Pericarditis Cough Hypoxia Pneumonitis Shortness of breath Hypoxia Pneumonitis Peripheral edema Myocarditis Pulsus paradoxus, electric alternans Pericarditis Pale Hemolytic anemia, hemophagocytic lymphohistiocytosis Dehydration and tachypnea Diabetic ketoacidosis Palpitation/irregular tachycardia Thyrotoxicosis (Graves disease vs thyroiditis)
  • 31. Identifying Signs and Symptoms of IRAEs (cont.) Yeung et al, 2020. Presenting symptom Warning signs Potential immune-related adverse effect involved Part C: gastrointestinal symptoms Abdominal pain Mental status change, jaundice Hepatitis Nausea and vomiting Pancreatitis Diarrhea, dehydration Colitis Dehydration and tachypnea Diabetic ketoacidosis Diarrhea Dehydration, abdominal pain/tenderness Colitis Vomiting Stiff neck, mental status change Meningitis Abdominal pain Pancreatitis Jaundice Hepatitis Part D: miscellaneous symptoms Vision change Eye pain Uveitis Rash Bullae with Niklosky sign Pemphigus vulgaris Niklosky sign with mucosal involvement Steven-Johnson syndrome/toxic epidermal necrolysis necrolysis Fatigue Hypotension Adrenal insufficiency Hypophysitis Bradycardia Hypothyroidism Myocarditis Dehydration and tachypnea Diabetic ketoacidosis Splenomegaly Hemolytic anemia Hemophagocytic lymphohistiocytosis Joint pain Swelling, restricted movement Arthritis
  • 32. Toxicity Grading Scale for IRAEs ADL = activities of daily living; iADL = instrumental ADLs. NCI, 2017; Trinh et al, 2019. Treated and evaluated based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Asymptomatic Symptomatic Limits iADLs Severe symptoms Limits self-care ADLs Life-threatening Death No treatment indicated; clinical or lab observation Treatment indicated Hospitalization indicated Urgent interventions interventions needed needed Therapy should be continued Should hold treatment until IRAE has resolved and reinitiated, low dose dose corticosteroids can can be used (0.5-1.0 mg/kg/day) Treatment should be held or permanently discontinued & use of use of corticosteroids (1-2 mg/kg/day). Other immunosuppressants may be required if steroid refractory such as such as infliximab or mycophenolate
  • 33. Differences in Adverse Events Khan et al, 2018; Trinh et al, 2019; Magee et al, 2020. Meta-analysis found PD-1 inhibitors (nivolumab and pembrolizumab) had significantly fewer adverse events overall when compared to chemotherapy Chemotherapy was associated with increased neutropenia, anemia, alopecia, stomatitis, and myalgias Fatigue, nausea, decreased appetite, diarrhea, and asthenia were caused by both treatments but were more frequent with chemotherapy With PD-1 inhibitors, there were more hypothyroidism, hyperthyroidism, rash, and pneumonitis It has been noted that use of immunotherapy is associated with fewer AEs (65.82% for immunotherapy vs chemotherapy 85.26%) Treatment discontinuation was less with immunotherapy-treated patients (6.41%) vs chemotherapy (10.75%) Deaths are less with immunotherapy-treated patients (0.87%) vs chemotherapy (1.28%) Chemotherapy Versus Immunotherapy
  • 34. Guidelines Recommended for Nursing Management of Common IRAEs
  • 35. Endocrine IRAEs: Thyroid TSH = thyroid-stimulating hormone; FT4 = free thyroxine; FSH = follicle stimulating hormone. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Hyperthyroid: Symptoms: tachycardia, weight loss, heat intolerance, tremors, anxiety, diarrhea Rule out alternative etiology: Graves disease Labs TSH, FT4, TSH receptor antibody if Graves is suspected Hypothyroid: Symptoms: fatigue, weight gain, hair loss, cold intolerance, constipation, depression Rule out alternative etiology: if low FSH and low FT4, evaluate for hypophysitis Labs: TSH, FT4 Endocrinopathies are seen in approximately 10% Management: May need to hold, replacement of hormone, beta blocker Endocrine consultation based on presentation or grade
  • 36. Thyroid IRAEs: Hypothyroidism G1 = grade 1; G2 = grade 2; G3 = grade 3; G4 = grade 4. Schneider et al, 2021. Primary hypothyroidism Workup and evaluation • TSH, with the option of close including FT4, can be checked every 4-6 weeks as part of routine clinical monitoring for asymptomatic patients on ICI therapy • TSH and FT4 should be used for case detection in symptomatic patients • Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis • Commonly develops after thyroiditis Grading Management G1: TSH >4.5 and <10 and asymptomatic Should continue ICI with monitoring of TSH (option for FT4) every 4-6 weeks as part of routine care G2: Moderate symptoms, able to perform ADL. TSH persistently >10 mIU/L May continue or hold ICI until symptoms resolve to baseline Consider endocrine consultation for unusual clinical presentations, concern for central hypothyroidism, or difficulty titrating hormone therapy Prescribe thyroid hormone supplementation in symptomatic patients with any degree of TSH elevation or in asymptomatic patients with TSH levels that persist over 10 mIU/L G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform ADL Hold ICI until symptoms resolve to baseline with appropriate supplementation Endocrine consultation to assist with rapid hormone replacement Hospital admission for developing myxedema (bradycardia, hypothermia, and altered mental status) Inpatient endocrinology consultation can assist with IV levothyroxine dosing, steroids, and supportive care If there is uncertainty about whether primary or central hypothyroidism is present, hydrocortisone should be given before thyroid hormone is initiated Myxedema coma is a life-threatening emergency requiring admission and a high level of care Thyroid supplementation and reassessment as in G2 Additional considerations • For patients with risk factor (ie, <70 years old, not frail, and without cardiac disease or multiple comorbidities), full replacement can be estimated using ideal body weight for dose of approximately 1.6 approximately 1.6 mcg/kg/day • For those >70 years old and/or frail patients with multiple comorbidities (including cardiac disease), considering titrating up from a lower starting dose of 25-50 μg • Elevated TSH can be seen in the recovery phase of thyroiditis. In asymptomatic patients with FT4 that remains in the reference range, it is an option to monitor before treating to determine whether there is whether there is recovery to normal within 3-4 weeks. Progression or development of symptoms should be treated as per G2 • Development of a low TSH on therapy suggests overtreatment or recovery of thyroid function and dose should be reduced or discontinued with close follow-up
  • 37. Thyroid IRAEs: Thyrotoxicosis Schneider et al, 2021. Thyrotoxicosis Workup and evaluation • TSH can be checked every 4-6 weeks as part of routine clinical monitoring for asymptomatic patients on ICI therapy • TSH and FT4 should be used for case detection in symptomatic patients. T3 can be helpful in highly symptomatic patients with minimal FT4 elevations • Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis • Consider TSH receptor antibody testing if there are clinical features and suspicion of Graves disease (eg, ophthalmopathy and T3 toxicosis) Grading Management G1: Asymptomatic or mild symptoms Can continue ICI Beta-blocker (eg, atenolol or propranolol) for symptomatic relief Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch the transition to hypothyroidism, the most common outcome for transient transient subacute thyroiditis Treat transition to elevated TSH and low FT4 as for primary hypothyroidism For persistent thyrotoxicosis (>6 weeks) consider endocrine consultation for additional workup G2: Moderate symptoms, able to ADL Consider holding ICI until symptoms return to baseline Consider endocrine consultation Beta-blocker (eg, atenolol or propranolol) for symptomatic relief Hydration and supportive care For persistent thyrotoxicosis (>6 weeks) refer to endocrinology for additional workup and possible medical thyroid suppression G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL ADL Hold ICI until symptoms resolve to baseline with appropriate therapy Endocrine consultation for all patients Beta blocker (eg, atenolol or propranolol) Hydration and supportive care Consider hospitalizing patients in severe cases as inpatient endocrine consultation can guide the use of additional medical therapies including steroids, potassium potassium iodide (SSKI), or thionamide (methimazole or propylthiouracil) and possible surgery Additional considerations • Thyroiditis is self-limited and the initial hyperthyroidism generally resolves in weeks with supportive care, most often to primary hypothyroidism or occasionally to normal. Persistent or symptomatic symptomatic hypothyroidism developing after hyperthyroidism should be treated as above • Graves disease has not been reported with ICI specifically, but sporadic cases could occur. Graves disease is generally persistent and is treated with antithyroid medical therapy, radioactive iodine, or iodine, or surgery. Endocrine consultation is recommended if suspected • Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves disease and should prompt early endocrine referral
  • 38. Endocrine IRAEs: Pituitary Hypophysitis Diagnosis/evaluation Frequency: endocrinopathies are seen in approximately 10% Symptoms: headaches, fatigue, visual changes, loss of libido, mood changes, oligomenorrhea Rule out alternative etiology: pituitary mass, Addison’s or adrenal hemorrhage Labs to include 8 am cortisol, ACTH, TSH, FT4, electrolytes, consider LH/testosterone in males and FSH and estrogen in females, MRI of the brain with pituitary or sellar cuts Management: Replacement of deficient hormones High-dose steroids may be needed if MRI findings of pituitary enlargement May need to consider holding until stabilized Endocrine consultation based on grade ACTH = adrenocorticotropic hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021; Chang & Yialamas, 2018.
  • 39. Pituitary IRAEs: Hypophysitis EMS = emergency medical services; HPA = hypothalamic pituitary adrenal; Q = every. Schneider et al, 2021. Pituitary—Hypophysitis Workup and evaluation • Evaluate ACTH (am), cortisol (am), TSH, FT4, and electrolytes • Consider standard-dose ACTH stimulation testing for indeterminate results (am cortisol >3 µg/dL and <15 µg/dL) • Consider evaluation LH and testosterone in males, FSH, and estrogen in premenopausal females with fatigue, loss of libido and mood changes, or oligomenorrhea • Consider MRI brain with or without contrast with pituitary or sellar cuts in all patients with new hormonal deficiencies and particularly those with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes • Perform MRI brain with or without contrast with pituitary or sellar cuts for all patients presenting with diabetes insipidus (Diabetes insipidus is most commonly from metastatic disease) Grading Management All grades Referral to endocrinology Education on steroid stress dosing, emergency injections, and a medical alert bracelet or necklace, accessory, or system G1: or mild symptoms symptoms Consider holding ICI until patient is stabilized or replacement hormones Endocrine consultation Corticosteroid replacement for adrenal insufficiency with preference for hydrocortisone (15-20 mg in divided doses) Initiate other hormone replacement only after any needed adrenal replacement to avoid precipitating adrenal crisis • Thyroid hormone replacement if needed using dosing as above for primary hypothyroidism, with a goal FT4 in the upper half of the reference range (TSH is not accurate in central hypothyroidism) • Testosterone or estrogen therapy if needed in those without contraindications (eg, prostate cancer, breast cancer, or history of deep vein thrombosis (DVT) G2: Moderate symptoms, able to to perform ADL Consider holding ICI until patient is stabilized or replacement hormones Endocrine consultation Clinic evaluation to assess need for steroids and volume repletion Consider oral pulse dose therapy in patients with MRI findings of swelling or threatened optic chiasm compression [prednisone 1 mg/kg/day (or equivalent)]. Taper over 1-2 weeks and transition to physiologic maintenance therapy once down to 5 mg once down to 5 mg prednisone equivalent Hormonal supplementation as in G1 G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform perform ADL Hold ICI until patient is stabilized on replacement hormones Endocrine consultation Hospitalize or make an emergency department (ED) referral for: • Normal saline (at least 2L) or monitored free water replacement if diabetes insipidus • Intravenous (IV) Stress dose steroids. Hydrocortisone 50-100 mg Q 6-8 hours initial dosing • Oral pulse dose therapy with prednisone 1-2 mg/kg/day (or equivalent) tapered over at least 1-2 weeks to physiologic maintenance in patients with significant swelling on MRI, optic chiasm compression, severe headache, or visual changes changes Taper stress dose corticosteroids down to oral maintenance doses over 5-7 days Maintenance therapy as in G1 Additional considerations • Please be aware of the need to start corticosteroids first when planning hormone replacement therapy for multiple deficiencies as other hormones accelerate the clearance of cortisol and can precipitate adrenal crisis • ACTH stimulation can give a false-negative result early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost. In the presence of clinical uncertainty, opt for replacement and test for ongoing need at 3 months • If prednisone or equivalent is started for mild or moderate symptoms, consider lower doses (average daily dose over 2 months <7.5 mg) because of report of reduced survival on higher doses • All patients need education on stress dosing for sick days, use of emergency steroid injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet for adrenal insufficiency to trigger stress dose corticosteroids by EMS EMS • Steroid use for other IRAEs can cause isolated central adrenal insufficiency with a low ACTH. In a patient with adrenal insufficiency, a recent history of treatment with corticosteroids, and no other central hormone deficiencies, the HPA axis should be tested for recovery tested for recovery after 3 months of maintenance therapy with hydrocortisone • Laboratory confirmation of adrenal insufficiency (AI) should not be attempted in patients given high-dose corticosteroids for other IRAEs until treatment is ready to be discontinued • AM cortisol in a patient on corticosteroids is not diagnostic as the measurement of therapeutic steroids in the assay for cortisol varies. Hydrocortisone needs to be held for 24 hours and other steroids for longer before endogenous function is assessed. Consider consulting Consider consulting endocrinology for recovery and weaning protocols using hydrocortisone in patients with symptoms of AI after wearing off corticosteroids
  • 40. Pulmonary IRAEs: Pneumonitis Schneider et al, 2021; Brahmer et al, 2021; Puzanov et al, 2017; Naidoo et al, 2016. Diagnosis/evaluation: Frequency: ranges from 0%-10% Symptoms: worsening shortness of breath, cough, wheezing, chest pain, new or increasing oxygen requirements Rule out alternative etiology: disease progression, infection, pulmonary embolism Labs to consider blood cultures, urine culture, sputum culture, nasal swab, sensitivity for COVID-19, and imaging with computed tomography, pulse oximetry Management: Prompt intervention is imperative Patient symptom reporting will be key Based on grade corticosteroids may need to be initiated If steroid refractory, additional immunosuppression may be needed Pulmonary and infectious disease referral if necessary
  • 41. Pulmonary IRAEs: Pneumonitis (cont.) CT = computed tomography; CXR = chest X-ray; DLCO = diffusing capacity of lung for carbon monoxide; BAL = bronchoalveolar lavage; IVIG = intravenous immune globulin Schneider et al, 2021. Pneumonitis Workup and evaluation • Should include the following: pulse oximetry and CT chest preferably with contrast if concerned for other etiologies such as pulmonary embolus • For G2 or higher, may include the following infectious workup: nasal swab, sputum culture and sensitivity, blood culture and sensitivity, urine culture and sensitivity • COVID-19 evaluations—per institutional guidelines where relevant Grading Management G1: Asymptomatic; confined to one lobe of the or <25% of lung parenchyma, clinical or diagnostic diagnostic observations only Hold ICI or proceed with closing monitoring Monitor patients weekly with history and physical examination, pulse oximetry; may also offer chest imaging (CXR, CT) if uncertain diagnosis and/or to and/or to follow progress Repeat chest imaging in 3-4 weeks or sooner if patient becomes symptomatic In patients who have had baseline testing, may offer a repeat spirometry or DLCO in 3-4 weeks May resume ICI with radiographic evidence of improvement or resolution if held. If no improvement, should treat as G2 G2: Symptomatic; involves more than one lobe of the lung or 25%-50% of lung parenchyma; medical medical intervention indicated; limiting instrumental instrumental ADL Hold ICI until clinical improvements to ≤G1 Prednisone 1-2 mg/kg/d and taper over 4-6 weeks Consider bronchoscopy with BAL ± transbronchial biopsy Consider empiric antibiotics if infection remains in the differential diagnosis after workup Monitor at least once per week with history and physical examination, pulse oximetry, consider radiologic imaging; if no clinical improvement after 48-72 improvement after 48-72 hours of prednisone, treat as grade 3 Pulmonary and infectious disease consults if necessary G3: Severe symptoms; hospitalization required; involves all lung lobes or >50% of lung parenchyma; limiting self-care ADL; oxygen indicated Permanently discontinue ICI Empiric antibiotics may be considered Methylprednisone IV 1-2 mg/kg/d If no improvement after 48 hours, may add immunosuppressive agent. Options include infliximab or mycophenolate mofetil IV or IVIG or cyclophosphamide. Taper corticosteroids over 4-6 weeks Pulmonary and infectious disease consults if necessary May consider bronchoscopy with BAL ± transbronchial biopsy if patient can tolerate G4: Life-threatening respiratory compromise; intervention indicated (intubation)
  • 42. Gastrointestinal IRAEs: Colitis Brahmer et al, 2021; Trinh et al, 2019; Schneider et al, 2021; Geukes Foppen et al, 2018. Diagnosis/evaluation: Frequency: 8%-27% but can be as high as 54% with CTLA-4 inhibitors Symptoms: diarrhea, abdominal pain, rectal bleeding, mucus in stool Rule out alternative etiology: infection Labs for stool studies for Clostridium difficile, cytomegalovirus, DNA polymerase chain reaction (PCR), stool ova and parasites, fecal calprotectin, fecal occult blood, endoscopy Management: Close monitoring and dietary changes Loperamide Hold treatment for grade ≥2 Grade ≥3: corticosteroids, consider hospitalization; additional immunosuppression may be needed Consider referral to gastroenterology for grade ≥2
  • 43. Gastrointestinal IRAEs: Colitis (cont.) CBC = complete blood count; CMP = comprehensive metabolic panel; CMV = cytomegalovirus. Schneider et al, 2021. Colitis workup and evaluation G2 • Workup of blood (CBC, CMP, and TSH) and stool (culture, C. diff, parasite, CMV, or other viral etiology, ova and parasite if appropriate) should be performed for the initial for the initial presentation, and also considered for immunosuppressant refractory cases • Consider testing for fecal lactoferrin (for patient stratification to determine who needs more urgent endoscopy) and calprotectin (to follow up on disease activity) activity) • Screening labs (HIV, hepatitis A and B, and tuberculous testing), repeated annually in patients who require biologic treatment, eg, infliximab or vedolizumab for >1 year for >1 year until treatment is completed • Consider reviewing concomitant medications that could alter the gut microbiome and their indications for prolonged use (eg, proton pump inhibitors, antibiotics, and antibiotics, and probiotics) • Imaging, eg, CT scan of abdomen and pelvis for colitis-related symptoms (abdominal pain and bleeding) to rule out colitis-related complications, including typhlitis and typhlitis and bowel perforation or abscess • GI endoscopy or colonoscopy with biopsy for patients who have positive stool inflammatory markers or colitis-related symptoms should be considered as there is evidence there is evidence showing the presence of ulceration in the colon can predict steroid refractory course, which may require early infliximab • Repeat colonoscopy may be considered for cases G≥2 for disease activity monitoring to document complete remission, especially if there is a plan to resume ICI. Mucosal ICI. Mucosal healing on repeat endoscopy and/or fecal calprotectin level ≤116 µg/g can be considered the treatment target to guide decisions on when to stop biologic stop biologic treatment and when to resume ICI therapy G3-4 • Complete all recommendations as above and consider inpatient care Management All patients Counsel all patients to be aware of and inform their health care provider immediately if they experience abdominal pain, nausea, cramping, blood cramping, blood or mucus in stool, or changes in bowel habits, fever, abdominal distention, or constipation For G ≥2, consider permanently discontinuing CTLA-4 agents and may restart PD-1 or PD-L1 agents if patients recover to G≤1; concurrent concurrent immunosuppressant maintenance therapy should be considered only if clinically indicated in individual cases
  • 44. Gastrointestinal IRAEs: Colitis (cont.) EGD = esophagogastroduodenoscopy; JAK = Janus kinase. Schneider et al, 2021. Grading Management G1: Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline Continue ICI. Alternatively, ICI may be held temporarily and resumed if toxicity does not exceed grade 1 or resolves May also include supportive care with medications such as loperamide if infection has been ruled out in patients with diarrhea only and not colitis-related symptoms as a temporary measure Monitor for dehydration and recommend dietary changes Patient should be closely monitored by phone or electronic medical system for symptoms changes by clinical providers every 3 days or more frequently if needed until stabilized May obtain gastroenterology consult for prolonged G1 cases and consider endoscopy with biopsies G2: Increase of 4-6 stools per day over baseline; moderate moderate increase in ostomy ostomy output compared with with baseline Hold ICI at least until recovery to G1—see last bullets May also include supportive care with medications such as loperamide if infection has been ruled out in patients with diarrhea only and not colitis-related symptoms as a temporary measure Consider consult with gastroenterology for ≥G2 Administer corticosteroids, unless diarrhea is transient, starting with initial dose of 1 mg/kg/day prednisone or equivalent until symptoms improve to G1, and then start taper over 4-6 weeks Consider narrower-spectrum or more potent agents, including anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) antibody to patients whose colitis is corticosteroid-refractory (ie, no decrease (ie, no decrease by one grade in 72 hours) or dependent or with high-risk endoscopic features on initial endoscopy examination When symptoms improve to ≤G1, taper corticosteroids over 4-6 weeks; may consider shorter tapers in patients also treated with biologics Endoscopic evaluation with EGD or colonoscopy is highly recommended for cases grade ≥2 to stratify patients for early treatment of biologics based on endoscopic findings Resuming ICI after symptoms improve to ≤G1 may be considered when steroid taper is completed, risk and benefits reviewed if maintained on biologics, and/or if endoscopic and histologic remissions are remissions are achieved. Fecal calprotectin ≤116 µg/g may be considered as a surrogate for endoscopic and histologic remission Resuming PD-1/PD-L1 agent is associated with lower risk of flare-up; however, CTLA-4 inhibitor can still be considered in selected cases, such as in patients who have not yet responded or whose response whose response is deemed inadequate G3: Increase of ≥7 stools per day over baseline; incontinence; hospitalization hospitalization indicated; severe increase in ostomy output compared with baseline; and limiting self- care ADL Follow G2 recommendations as listed, with the following additions for G3: Administer corticosteroids (initial dose of 1-2 mg/kg/day prednisone or equivalent) until symptoms improve to G1, and then start taper over 4-6 weeks. Consider IV methylprednisolone, especially if concern for especially if concern for concurrent upper GI inflammation Consider early introduction of infliximab or vedolizumab in addition to steroids in patients with high-risk endoscopic features on initial endoscopy examination or inadequate response to steroids (persistent steroids (persistent symptoms after 3 days) Consider hospitalization for patients with dehydration or electrolyte imbalance Consider repeat colonoscopy in patients who are immunosuppression-refractory Should consider permanently discontinuing CTLA-4 agents G4: Life-threatening consequences; urgent intervention indicated Follow G2-3 recommendations as listed, with the following additions for G4: Permanently discontinue treatment Should provide inpatient care Administer 1-2 mg/kg/day methylprednisolone or equivalent until symptoms improve to G1, and then start taper over 4-6 weeks Consider early biologics (infliximab or vedolizumab) if inadequate response to steroids after 3 days. Consider lower GI endoscopy if symptoms refractory, despite treatment or there is concern of new of new infections Additional considerations • May consider fecal microbiota transplant, JAK inhibitor tofacitinib, or IL-12–blocking antibody ustekinumab in patients who are refractory to the previous immunosuppressants • Patients with both IRAE-related hepatitis and IRAE-related colitis are less common, and management may include permanently discontinuing ICI and offering other immunosuppressant agents (eg, prednisone and mycophenolate) that mycophenolate) that works systemically for both conditions. Infliximab is contraindicated for hepatic IRAE • Currently, enteritis and/or gastritis alone as the cause of GI toxicity is uncommon and endoscopy with biopsy is recommended as the evaluation tool. It may be managed similarly to colitis including steroid and/or biologics etc biologics etc
  • 45. Gastrointestinal IRAEs: Hepatitis ANA = antinuclear antibody; ASMA = anti–smooth muscle antibodies; ANCA = antineutrophil cytoplasmic antibody; GTT = gamma-glutamyl transferase; ALKP = alkaline phosphatase; CK = creatine kinase. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: 2%-10%; in combination with ICI+ICI, can be up to 25%-30% for all grades Symptoms: diagnosed with increase in serum liver function test (LFT), alanine transaminase (ALT) and aspartate transaminase (AST) Rule out alternative etiology: rule out viral causes, hepatoxic medications and hepatic dysfunction that is drug related, progression of the liver Labs for viral hepatitis, alcohol history, imaging and blood work to rule liver metastasis, ANA/ASMA/ANCA, GTT (if ALKP alone elevated), CK (for isolated transaminases) Management: Hold treatment/discontinue for grade ≥2 Start corticosteroids If no improvement in 2 days, consider alternative immunosuppression, mycophenolate Consider referral to hepatology for grade ≥2
  • 46. Gastrointestinal IRAEs: Hepatitis (cont.) ULN = upper limit of normal; NASH = nonalcoholic steatohepatitis. Schneider et al, 2021. Hepatitis Workup and evaluation • Monitor patient for abnormal blood tests: AST, ALT, and bilirubin before each infusion and/or consider weekly if grade 1 LFT elevations. No treatment is recommended for grade 1 LFT abnormality • Review medications and supplements that may cause hepatotoxicity and rule out abnormal liver enzymes from development or progression of liver metastases • Liver biopsy should be considered if the patient is steroid-refractory or if concern for other differential diagnoses that would alter medical management • For grade ≥2: workup for other causes of elevated liver enzymes (eg, viral hepatitis, alcohol history, iron studies, thromboembolic event, or potential liver metastasis from primary malignancy) by doing blood work and imaging and imaging (ultrasound and cross-sectional imaging). If suspicion for primary autoimmune hepatitis is high, can consider ANA/ASMA/ANCA. If patients with elevated ALKP alone, GGT should be tested. For isolated elevation of isolated elevation of transaminases, consider checking CK for other etiologies Grading Management G1: Asymptomatic (AST or ALT >ULN 3.0x ULN and/or total bilirubin >ULN >ULN to 1.5x ULN) Continue ICI with close monitoring; consider alternate etiologies Consider monitoring labs 1-2 times weekly Manage with supportive care for symptom control G2: Asymptomatic (AST or ALT >3.0 ≤5x ULN and/or total bilirubin >1.5 to to ≤3x ULN) Hold ICI temporarily Patients should be advised to stop unnecessary medications and any known hepatotoxic drugs. Temporarily hold other potentially hepatotoxic oncologic agents For G2 hepatic toxicity, may administer steroid (0.5-1 mg/kg/day prednisone) or equivalent if no improvement is seen after 3-5 days Increase frequency of monitoring to every 3 days If inadequate improvement after 3 days, consider adding mycophenolate mofetil May initiate steroid taper when symptoms improve to ≤G1 and may resume ICI treatment when steroid ≤10 mg/day. Taper over at least 1 month G3: AST or ALT 5-20x ULN and/or bilirubin 3-10x ULN, or symptomatic symptomatic liver dysfunction; fibrosis fibrosis by biopsy; compensated cirrhosis; and reactivation of chronic chronic hepatitis Follow G2 recommendations as listed, with the following additions for G3: Consider permanently discontinuing ICI if asymptomatic; permanently discontinue if symptomatic Immediately start steroid 1-2 mg/kg methylprednisolone or equivalents. If steroid refractory, consider liver biopsy to rule out NASH, tumor, cholestatic variants, other drug-related hepatic related hepatic inflammation, infection, or other autoimmune entity and consider adding azathioprine or mycophenolate if infectious cause is ruled out Labs daily or every other day; consider inpatient monitoring for patients with AST/ALT > 8x ULN and/or elevated total bilirubin 3x >ULN If no improvement is achieved with steroid for patients on ICI therapy combined with novel agents, with chemotherapy, or with targeted therapy, refer to hepatologist for further pathologic pathologic evaluation of hepatitis Steroid taper can be attempted around 4-6 weeks when ≤ G1, re-escalate if needed, optimal duration unclear Consider transfer to tertiary care facility if necessary G4: AST or ALT >20x ULN and/or bilirubin >10x ULN or decompensated decompensated liver function (eg, ascites, coagulopathy, encephalopathy, and coma) Follow G3 recommendations as listed, with the following additions for G4: Administer 2 mg/kg/d methylprednisone equivalents Additional considerations: Infliximab is contraindicated for immune-related hepatitis
  • 47. Dermatologic IRAEs: Rash/Pruritus/Dermatitis Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: reported up to 71.5% Symptoms: pruritis, maculopapular rash, atopic dermatitis, eczema, acneiform, lichenoid rash Rule out alternative etiology: infection, adverse effect of another drug or unrelated primary skin disorder Labs to include blood count, complete metabolic panel, consider skin biopsy, consider follow-up with serial clinical photography Management: Starting topical steroids, rich emollients May considering holding and starting oral corticosteroids depending on grade Referral to dermatology for grade 4
  • 48. Dermatologic IRAEs Schneider et al, 2021. Rash or Inflammatory Dermatitis Workup and evaluation • Pertinent history and physical examination including examination of the oral mucosa, assessment for blister formation, and assessment of BSA involved • Review full list of patient medications to rule out other drug-induced cause of photosensitivity • Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, including prior or other recent cancer therapies, or a skin condition linked to another systemic disease or systemic disease or unrelated primary skin disorder • Recent or new complete blood count and comprehensive metabolic panel (if needed for skin differential diagnosis) • Consider referral to dermatologist if autoimmune skin disease is suspected • Consider skin biopsy • Consider clinical monitoring with use of serial clinical photography Grading Management G1: Rash covering <10% BSA, which may or may not be associated with symptoms of pruritis or tenderness Continue ICI Treat with topical emollients and/or mild-moderate potency topical corticosteroids Counsel patients to avoid skin irritants G2: Rash covering 10%-30% BSA with or without (eg, pruritis, burning, and tightness); limiting instrumental instrumental ADL; rash covering >30% BSA with or without mild symptoms Consider holding ICI and monitor weekly for improvement. If skin toxicity is not improved after 4 weeks, then regrade toxicity as G3 In addition, treat with topical emollients, oral antihistamines, and medium-to-high potency topical corticosteroids Consider initiating prednisone (or equivalent) at dosing 0.5-1 mg/kg, tapering over 4 weeks. In patients with pruritus without rash, consider topical consider topical anti-itch remedies (eg, refrigerated menthol and pramoxine) G3: Rash covering >30% BSA with moderate or severe symptoms; limiting self-care ADL Hold ICI therapy and consult with dermatology to determine appropriateness of resuming Treat with topical emollients, oral antihistamines, and high-potency topical corticosteroids. May also consider phototherapy to treat severe pruritus severe pruritus Initiate oral prednisone or equivalent (1 mg/kg/d) tapering over at least 4 weeks Once downgraded to ≤G1 and prednisone (or equivalent) below 10 mg/d, clinicians may consider resuming ICI therapy with close monitoring and monitoring and follow-up with dermatology in certain cases such as psoriasis In patients with pruritus without rash, may treat with gabapentin, pregabalin, aprepitant, or dupilumab G4: Severe consequences requiring hospitalization or intervention indicated or life-threatening consequences consequences Immediately hold ICI May admit patient immediately with direct oncology involvement and with an urgent consult by dermatology Systemic steroids: IV methylprednisolone (or equivalent) dosed at 1-2 mg/kg with slow tapering when the toxicity resolves Monitor closely for progression to severe cutaneous adverse reaction (SCAR) Consider alternative antineoplastic therapy over resuming ICIs if the skin IRAE does not resolve to ≤G1. If ICIs are the patients only option, option, consider restarting once these side effects have resolved to a G1 level with close dermatology follow-up
  • 49. Musculoskeletal IRAEs: Arthralgia / Myalgia RF = rheumatoid factor; CCP = citrullinated protein antibody; ESR = erythrocyte sedimentation rate. Trinh et al, 2019; Puzanov et al, 2017; Schneider et al, 2021; Brahmer et al, 2021. Diagnosis/evaluation: Frequency: reported up to 40% Symptoms: arthralgia, myalgia, large joint reactive arthritis, polyarthritis Rule out alternative etiology: degenerative joint disease, osteoarthritis, gout, pseudogout, septic arthritis, rotator cuff tendinitis, Labs to consider ANA, RF, anti-CCP, ESR, CRP, X-ray or MRI imaging of affected joint Management: Initiate acetaminophen ± NSAIDS for analgesia May considering holding and starting oral corticosteroids depending on grade Referral to Rheumatology for grade >2
  • 50. Musculoskeletal IRAEs Schneider et al, 2021. Inflammatory Arthritis Workup and evaluation 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 or imaging to exclude metastases and evaluate joint damage (erosions) if appropriate • Consider autoimmune panel including ANA, RF, anti-CCP, and inflammatory markers (ESR and CRP) if symptoms persist. If symptoms are suggestive of reactive reactive arthritis or affect the spine, consider HLA B27 testing G2 • Complete history and examination as above; laboratory tests as above • Consider ultrasound ± MRI imaging of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment, and suspicion for differential diagnoses diagnoses such as metastatic lesions or septic arthritis). Consider arthrocentesis if septic arthritis or crystal-induced arthritis is suspected • Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms persist >4 weeks G3 • As for grade 2 • Seek rheumatologist advice and review • Test for viral hepatitis B, C, and latent or active tuberculous test before disease-modifying antirheumatic drug (DMARD) treatment. Repeated screening labs annually in annually in patients who require biologic treatment for >1 year until treatment is completed Monitoring Patients with inflammatory arthritis should be monitored with serial rheumatologic examinations, including inflammatory markers, every 4-6 weeks after treatment is instituted treatment is instituted Additional considerations Early recognition is critical to avoid erosive joint damage Corticosteroids can be used as part of initial therapy therapy in inflammatory arthritis, but because of likely likely prolonged treatment requirements, physicians physicians should consider starting steroid-sparing sparing agents earlier than one would with other IRAEs Oligoarthritis can be treated early on with intra- articular steroids, consider early referral Grading Management All grades Clinicians should follow reports of new joint pain to determine if IA is present. Question whether symptoms are new since receiving ICI G1: Mild pain with inflammation, erythema, or joint swelling Continue ICI; initiate analgesia with acetaminophen and/or NSAIDs G2: Moderate pain associated with signs inflammation, erythema, or joint swelling; swelling; limiting instrumental ADL Consider holding ICI; escalate analgesia and consider higher doses of NSAIDs as needed If inadequately controlled, initiate prednisone 10-20 mg/d or equivalent If improvement, slow taper according to response during the next 4-6 weeks, if no improvement after initial 4 weeks treat as G3 If unable to lower corticosteroid dose to below 10 mg/d after 6-8 weeks, consider DMARD Consider inter-articular steroid injections for large joints Referral to rheumatology G3-4: Severe pain associated with signs of inflammation, erythema, or joint swelling; swelling; irreversible joint damage; disabling; and limiting self-care ADL Hold ICI temporarily and may resume in consultation with rheumatology, if recover to ≤G1 Initiate oral prednisone 0.5-1 mg/kg If failure of improvement after 2 weeks or worsening in meantime, consider synthetic or biologic DMARD • Synthetic: methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine alone or in combination • Biologic: consider anticytokine therapy such as TNF⍺ or IL-6 antagonists. Referral to rheumatology
  • 51. Guidelines Recommended for Nursing Management of Uncommon IRAEs
  • 52. Endocrine IRAEs: Diabetes DM = diabetes mellitus; PCP = primary care physician. Schneider et al, 2021. Diabetes Workup and evaluation • Monitor patients for symptoms of new or worsening diabetes mellitus (polyuria, polydipsia, and fatigue) • Monitor glucose at baseline and with each treatment cycle while on therapy and at follow-up visits for at least 6 months • Laboratory evaluation in suspected checkpoint inhibitor–associated diabetes mellitus (CIADM) should include: o Urine and/or serum ketones o Anion gap on a metabolic panel o Anti-glutamic acid decarboxylase (GAD) or anti-islet cell antibodies o C-peptide levels Grade Management G1: Asymptomatic or mild symptoms; type 2 DM with fasting glucose value >ULN to mg/dL (>ULN to 8.9 mmol/L). No evidence of CIADM such as ketoacidosis or laboratory evidence of pancreatic autoimmunity Can continue ICI with close clinical follow-up and laboratory evaluation Refer to PCP for additional management or: • May initiate oral therapy for those with new-onset type 2 DM • Intensify medical therapy for those with worsening type 2 DM G2: Moderate symptoms, able to perform ADL; type 2 DM with fasting glucose value >150-250 mg/dL (>8.9 to 13.9 mmol/L). No ketoacidosis or metabolic derangements derangements but other evidence of CIADM at any glucose level May hold ICI until glucose control is obtained Urgent endocrine consultation for any patient with new-onset CIADM Initiate insulin for CIADM (or as default therapy if there is any questions about the diagnosis) Referral to ED or hospital admission if unable to initiate therapy, urgent outpatient specialist evaluation is not available, developing ketoacidosis, or other ketoacidosis, or other concern for CIADM G3-4: Severe symptoms, medically significant or life-threatening consequences, to perform ADL; G3: >250-500 mg/dL (>13.9 to 27.8 mmol/L); G4: >500 mg/dL (>27.8 mmol/L). Ketoacidosis or other metabolic abnormality Hold ICI until glucose control is obtained with reduction of toxicity to ≤G1 Admit for inpatient management of diabetic ketoacidosis, volume and electrolyte resuscitation, and insulin initiation Endocrine consultation for all patients Insulin therapy appropriate for all patients Additional considerations • Insulin therapy should be used in any case with significant hyperglycemia pending additional diagnostic workup if mechanism of DM is not known • Long-acting insulin therapy alone is not sufficient for CIADM because of the absence of pancreatic function after beta-cell destruction • Starting total daily requirement can be estimated at 0.3-0.4 units/kg/day • Half of daily requirements are typically given in divided doses as prandial coverage, while half should be administered as once-daily long-acting homolog. This requires self-monitoring 4 or more times daily or the use of continuous glucose continuous glucose monitor • Sliding scale insulin can be used in conjunction with multiple daily injection regimens to accommodate the variability in glucose levels • Decreased requirements after the initial acute admission for diabetic ketoacidosis are commonly seen in the so-called honeymoon period • Education is critical to learn skills like responding to hypoglycemia, anticipating exercise, monitoring for diabetic ketoacidosis, or carbohydrate counting, and to transition to technologies such as insulin pumps. Early endocrinology endocrinology consultation is a high priority for all patients • Type 2 DM patients will need to increase the frequency of self-monitoring as therapy intensifies and agents that can cause hypoglycemia are added to their regimen • Steroids can exacerbate postprandial hyperglycemia, and endocrinology consult should be considered for initiating or managing insulin in patients with Type 2 DM being started on high-dose steroids. If insulin is used, the doses generally doses generally needs to be adjusted again as steroids are tapered down
  • 53. Endocrine IRAEs: Adrenal NA = sodium; K = potassium. Schneider et al, 2021. Adrenal–Primary Adrenal insufficiency (AI) Workup and evaluation • Evaluate am levels of ACTH (if >2x ULN) and cortisol level (if <3 µg/dL) • Basic metabolic panel (Na K, CO2, and glucose) • Renin and aldosterone • Consider standard dose ACTH stimulation test for indeterminate results (am cortisol >3 µg/dL and <15 µg/dL) • Evaluate for precipitating cause of crisis such as infection • Adrenal CT for metastasis or hemorrhage (most common causes of primary AI) Grading Management All grades Referral to endocrinology Education on steroid stress dosing, emergency injections, and medical alert bracelet or necklace, accessory, or system G1: Asymptomatic or mild symptoms Consider holding ICI until patient is stabilized or replacement hormone Endocrine consultation Initiate replacement therapy with hydrocortisone (15-20 mg in divided doses) Titrate hydrocortisone to maximum of 30 mg daily total dose for residual symptoms of AI Reduce maintenance dosing for symptoms of iatrogenic Cushings’ syndrome (eg, bruising, thin skin, edema, weight gain, hypertension, and hyperglycemia) Most primary AI will also require fludrocortisone (starting dose 0.5-1 mg/d). Adjust based on volume status, sodium level, and renin response (target upper half of the reference range) G2: Moderate symptoms, able to perform ADL Consider holding ICI until patient is stabilized on replacement hormone Endocrine consultation See in clinic to assess need for hydration, supportive care, and hospitalization Initiate outpatient corticosteroid treatment at 2-3 times maintenance (eg, hydrocortisone 30-50 mg total dose or prednisone 20 mg daily) to manage acute symptoms Initiate fludrocortisone (0.5-1 mg/day) Decrease stress dose corticosteroids down to maintenance doses after 2 days Maintenance therapy as in G1 G3-4: Severe symptoms, medically significant or life- life-threatening consequences, unable to perform ADL Hold ICI until patient is stabilized on replacement hormone Endocrine consultation Inpatient management may be needed to provide: • Normal saline (at least 2L) • IV stress dose steroids: hydrocortisone 50-100 mg Q 6-8 hours initial dosing Taper stress dose corticosteroids down to oral maintenance doses over 5-7 days 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 hypophysitis for secondary (central) adrenal insufficiency • Using hydrocortisone allows for recreation of the diurnal rhythm of cortisol. Typically, 2/3 of the dose is given in the morning and 1/3 in the early afternoon. Long-acting steroids such as prednisone, rather than short-acting hydrocortisone, carry risk of over hydrocortisone, carry risk of over replacement but can be used in special circumstances, for example, if a patient is not able to adhere to a short-acting steroid regimen. Hydrocortisone 20 mg is equivalent to prednisone 5 mg • Dehydroepiandrosterone (DHEA) replacement is controversial but deficiency can be tested and replacement considered in women with low libido and/or energy who are judged to be otherwise well replaced • All patients need education on stress dosing for sick days, use of emergency injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet or necklace for adrenal insufficiency to trigger stress dose corticosteroids corticosteroids by emergency medical personnel. Therefore, early endocrinology consultation is appropriate • Endocrine consultation should be part of planning before surgery or high-stress treatments such as cytotoxic chemotherapy at any time during a patient’s care
  • 54. Renal IRAEs hpf = high power field. Schneider et al, 2021. Renal Toxicities Nephritis and renal dysfunction—diagnosis and monitoring Clinical presentation and diagnosis • Definite ICI-related nephritis or acute kidney injury • Kidney biopsy-confirmed diagnosis compatible with ICI nephritis or acute kidney injury, and after clinical review of risk factors • Probably ICI-related nephritis or acute renal failure: o BOTH of the following:  Sustained increase in serum creatinine ≥50% on at least two consecutive values or need for renal replacement therapy, after clinical review of risk factors risk factors  Absence of an alternative plausible etiology o AND at least 1 of the following:  Sterile pyuria (≥5 WBCs/hpf)  Concomitant or recent extrarenal IRAE-eosinophilia (≥500 cells per µL) • Possible ICI-related nephritis or acute renal failure: o BOTH of the following:  Increase in serum creatinine ≥50%  Need for renal replacement therapy nephritis or acute kidney injury is not readily attributable to alternative causes Monitoring • Monitor patients for elevated serum creatinine before every dose • Routine urinalysis is not necessary, other than to rule out urinary tract infections, etc • For any suspected immune-mediated adverse reactions, exclude other causes (see below) • For suspected renal IRAE obtain urinalysis, consider referral to nephrology • For patients receiving combination therapy with ICIs and other agents, assess the potential contribution of the non-ICI treatment to the renal failure • Assess for concomitant medications, prescribed and over the counter, herbals, vitamins, nephrotoxic agents, or contrast media • If no potential alternative cause of acute kidney injury is identified, then one can assume it is ICI-related and should forego biopsy • Swift treatment of autoimmune-component is important
  • 55. Renal IRAEs: Nephritis or Acute Kidney Injury Schneider et al, 2021. Grading Management G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5–2.0x above baseline Consider temporarily holding ICI and/or other potential contributing agents in combination regimens, pending consideration of consideration of potential alternative etiologies (recent IV contrast, medications, fluid status, and urinary tract infection) and infection) and baseline renal function. A change that is still <1.5 ULN could be meaningful G2: Creatinine 2–3x above baseline Hold ICI temporarily Consult nephrology Evaluate for other causes (recent IV contrast, medications, and fluid status) if other etiologies are ruled out, administer 0.5–1 administer 0.5–1 mg/kg/day prednisone equivalents If worsening or no improvement after 1 week, increase to 1–2 mg/kg/day prednisone equivalents and permanently discontinue ICI If improved to G ≥1, taper steroids over at least 4 weeks If no recurrence of chronic renal insufficiency discuss resumption of ICI with patient after taking into account the risks and risks and benefits. Resumption of ICI can be considered once steroids have been successfully tapered to ≤10 mg/day or mg/day or discontinued G3: Creatinine >3x baseline or >4.0 mg/dL; hospitalization indicated Permanently discontinue ICI if ICI is directly implicated in renal toxicity Consult nephrology Evaluate for other causes (recent IV contrast, medications, fluid status, and urinary tract infection) Administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent) G4: Life-threatening consequences; dialysis indicated; creatinine 6x above above baseline Additional considerations • Monitor creatinine weekly • Reflex kidney biopsy should be discouraged until steroid treatment has been attempted
  • 56. Nephritis or Acute Kidney Injury: Follow-Up Schneider et al, 2021. Renal IRAEs Grading Management G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5–2.0x above baseline If improved to baseline: resume routine creatinine monitoring G2: Creatinine 2–3x above baseline If improved to G1: taper corticosteroids over at least 4 weeks before resuming treatment with routine routine creatinine monitoring If elevations persist >7 days or worsen and no other cause found, treat as G3 G3: Creatinine >3x baseline or >4.0 mg/dL; hospitalization indicated If improved to G1: taper corticosteroids over at least 4 weeks If elevations persist >3–5 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate) G4: Life-threatening consequences; dialysis indicated; creatinine 6x above above baseline If improved to G1: taper corticosteroids at least 4 weeks If elevations persist >2–3 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate)
  • 57. Neurologic IRAEs: Myasthenia Gravis AChR = acetylcholine receptor; MuSK = muscle-specific kinase; LPR4 = lipoprotein-related 4; MGFA = Myasthenia Gravis Foundation of America; PO = by mouth. Schneider et al, 2021. Myasthenia Gravis Workup and evaluation • AChR and antistriated muscle antibodies in blood If AChR antibodies are negative, consider MuSK and LPR4 antibodies in blood—while presence of antibodies is confirmatory, the absence of antibodies of antibodies does not rule out the syndrome • Pulmonary function assessment with negative inspiratory force (NIF) and vital capacity (VC) • Creatine phosphokinase (CPK), aldolase, ESR, and CRP for possible concurrent myositis • Consider MRI brain and/or spine depending on symptoms to rule out central nervous system (CNS) involvement by disease or alternate diagnosis • Troponin, ECG, and consider transthoracic echocardiogram and/or cardiac MRI to evaluate concomitant myocarditis • Electrodiagnosis studies, under neurologic consultation, including neuromuscular junction testing with repetitive stimulation and/or jitter studies, nerve conduction study (NCS) to exclude neuropathy, and neuropathy, and needle electromyography (EMG) to evaluate for concomitant myositis • Inflammatory markers (ESR and CRP) • Consider paraneoplastic workup • Review and stop medications with known risk of worsening myasthenia: beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics Grading Management All grades All grades warrant workup and intervention given potential for progressive myasthenia gravis to lead to respiratory compromise. Inpatient admission may be may be appropriate at all grades No G1 NA G2: Some symptoms interfering with ADLs. MGFA severity class I (ocular symptoms and findings only) and MGFA severity class II (mild generalized weakness) Hold ICI and may resume in G2 patients (MGFA 1 and 2) only if symptoms resolve and steroid taper completed Neurology consultation Strongly consider inpatient care as patients can deteriorate quickly Pyridostigmine starting at 30 mg PO 3x a day and gradually increase to maximum of 120 mg PO 4x a day as tolerated and based on symptoms and wean based on wean based on improvement. These procedures should be done in close collaboration with the neurologist Administer corticosteroids (prednisone 0.5 mg/kg orally daily). Wean based on symptom improvement G3-4: Limiting self-care and aids warranted, weakness limiting walking, walking, ANY dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms or MGFA severity class III-V III-V (moderate to severe generalized generalized weakness to myasthenic crisis Follow G2 recommendations as listed, with the following additions for G3-4: Permanently discontinue ICI Admit patient, may need intensive care unit (ICU) level monitoring Continue steroids, taper should begin 3-4 weeks after initiation then wean based on symptom improvement Initiate IVIG 2 G/kg IV over 5 days (0.4 G/kg/day) or plasmapheresis x 5 days Consider adding rituximab if refractory to IVIG or plasmapheresis Frequent pulmonary function assessment Daily neurologic review
  • 58. Neurologic IRAEs: Guillain-Barré Syndrome CSF = cerebrospinal; NCS = nerve conduction study; NIF = negative inspiratory force; VC = vital capacity; ICU = intensive care unit. ANNA-1 = antineuronal nuclear antibody type 1. Schneider et al, 2021. Guillain-Barré Syndrome Workup and evaluation • Neurologic consultation • MRI spine with or without contrast (rule out compressive lesion and evaluate for nerve root enhancement/thickening) • Lumbar puncture: CSF analysis for cell count and differential, cytology for malignant cells, protein, glucose, and viral/bacterial cultures. Note that CSF typically has elevated protein and protein and often elevated WBC as well, although this not typically seen in classical Guillain-Barré Syndrome (GBS) • Consider paraneoplastic workup eg ANNA-1 antibody testing • Serum antiganglioside antibody tests for GBS and its subtypes (eg, anti-GQ1b for Miller Fisher variant associated with ataxia and ophthalmoplegia) • Flow cytometry in patients with hematologic malignancies • Electrodiagnostic studies (NCS and EMG) to evaluate polyneuropathy • Pulmonary function (NIF or VC) • Frequent neuro checks Grading Management All grades warrant workup and intervention given potential for progressive GBS to lead to respiratory compromise. Note, there is no G1 toxicity G2: Moderate: some interference with ADLs, symptoms concerning concerning to patient Discontinue ICI Neurology consultation Admission to inpatient unit with capability of rapid transfer to ICU-level monitoring Start IVIG (0.4 G/kg/day for 5 days for a total dose of 2 G/kg) or plasmapheresis. Note: plasmapheresis immediately after IVIG will remove immunoglobulin Corticosteroids are usually not recommended for idiopathic GBS; however, in ICI-related forms, a trial is reasonable (methylprednisolone 16 mg/kg/d), mg/kg/d), followed by slow steroid taper. Pulse steroid dosing (methylprednisolone 1 g daily for 5 days) may also be considered for G3-4 along with along with IVIG or plasmapheresis. After pulse steroids, taper steroids over 4-6 weeks Frequent neuro checks and pulmonary function monitoring Monitor for concurrent autonomic dysfunction Nonopioid management of neuropathic pain, for example, pregabalin, gabapentin, or duloxetine Treatment of constipation/ileus G3-4: Severe: limiting self-care and aids warranted, weakness limiting walking, ANY dysphagia, dysphagia, facial weakness, respiratory muscle weakness, or or rapidly progressive symptoms Additional considerations • Extreme caution with rechallenging for severe cases after complete resolution of symptoms and tapered off immunosuppression
  • 59. Neurologic IRAEs: Peripheral Neuropathy HbA1c = hemoglobin A1c; RNP = ribonucleoprotein; dsDNA = double stranded DNA; ab = antibody; MAG = myelin-associated glycoprotein. Schneider et al, 2021. Peripheral Neuropathy Workup and evaluation G1 • Consider neurology consultation to guide neuropathy phenotype determination and workup • Serum testing for reversible neuropathy causes: HbA1c, vitamin B12, TSH, vitamin B6, folate, serum protein electrophoresis, and immunofixation, CPK • Consider additional testing guided by neuropathy phenotype: ANA, ESR, CRP, ANCA, anti-smooth muscle, Sjögren’s syndrome A/Sjögren’s syndrome B, RNP, anti- anti-dsDNA, ganglioside ab, anti-MAG, anti-Hu (ANNA-1 ab), thiamine, Lyme, hepatitis B or C, and HIV • Consider MRI spine with or without contrast G2: In addition to the above • MRI spine advised, MRI brain if cranial nerve involvement, and MRI plexus if concern for plexus involvement • Consider lumbar puncture: CSF analysis for cell count and differential, cytology for malignant cells, protein, glucose, and viral or bacterial cultures • Consider EMG or NCS G3-4: go to GBS algorithm Grading Management G1: Mild: no interference with function and symptoms not concerning patient. Note: any cranial nerve problem should be managed as moderate Low threshold to hold ICI and monitor symptoms for a week. If to continue, monitor very closely for closely for any symptom progression G2: Moderate: some interference with ADLs, symptoms concerning to patient (ie, pain but not weakness or gait limitation) Hold ICI and resume once return to ≤G1 Initial observation OR initiate prednisone 0.5–1 mg/kg/day (if progressing from mild) Gabapentin, 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, and rapidly ascending sensory changes). Severe may be GBS and should should be managed as such Permanently discontinue ICI Admit patient Neurology consultation Initiate IV methylprednisolone 2–4 mg/kg/day and proceed as per GBS management
  • 60. Neurologic IRAEs: Autonomic Neuropathy Schneider et al, 2021. Autonomic Neuropathy Workup and evaluation • An evaluation by neurologist or relevant specialist depending on organ system, with testing that may include: o Screen for other causes of autonomic dysfunction: diabetic screen, adrenal insufficiency, HIV, paraproteinemia, amyloidosis, and amyloidosis, and botulism; consider chronic diseases such as Parkinson’s and other autoimmune screen o Orthostatic vital signs o Consider electrodiagnostic studies (NCS and EMG) to evaluate for concurrent polyneuropathy o Consider paraneoplastic autoimmune dysautonomia antibody testing (eg, antiganglionic AChR, ANNA-1, and N-type voltage- voltage-gated calcium channel antibodies) Grading Management G1: Mild: no interference with function and symptoms not concerning to patient Low threshold to hold ICI and monitor symptoms for a week. If to continue, continue, monitor very closely for any symptom progression G2: Moderate: some interference with ADLs, concerning to patient Hold ICI and resume once return to ≤G1 and off prednisone if used Initial observation OR initiate prednisone 0.5–1 mg/kg/day (if progressing from from mild) Neurology consultation G3-4: Severe: limiting self-care and aids warranted Permanently discontinue ICI Admit patient Initiate methylprednisolone 1 g daily x 3 days followed by oral steroid taper taper Neurology consultation
  • 61. Neurologic IRAEs: Aseptic Meningitis HSV = herpes simplex virus. Schneider et al, 2021. Aseptic Meningitis Workup and evaluation • MRI brain with or without contrast with pituitary or sellar cuts protocol • Am cortisol, ACTH to rule out adrenal insufficiency • Strongly consider lumbar puncture with CSF analysis for opening pressure, cell count and differential, cytology for malignant cells that could could indicate leptomeningeal metastases, protein, glucose, gram stain, viral or bacterial cultures, PCR for HSV, and other viral PCRs depending depending on suspicion • May see elevated WBC in CSF with normal glucose, normal culture, and gram stain. May see reactive lymphocytes, neutrophils, or histiocytes on histiocytes on cytology Grading Management G1: Mild: no interference with function and symptoms not concerning to patient. Note: any cranial nerve problem problem should be managed as moderate Hold ICI and discuss resumption with patient only after taking into account the risks and risks and benefits Consider neurology consult Consider empiric antiviral (IV acyclovir) and antibacterial therapy until CSF results results Once bacterial and viral infection negative, may closely monitor off corticosteroids or corticosteroids or consider oral prednisone 0.5–1 mg/kg/day or IV methylprednisolone 1 methylprednisolone 1 mg/kg/day if moderate or severe symptoms Steroids can be tapered after 2-4 weeks, monitoring for symptom recurrence Consider hospitalization for G3-4 G2: Moderate: some interference with ADLs, symptoms concerning to patient (ie, pain but no weakness or gait gait limitation) G3-4: Severe: limiting self-care and aids warranted
  • 62. Neurologic IRAEs: Encephalitis FLAIR = fluid-attenuated inversion recovery; EEG = electroencephalogram; TPO = thyroid peroxidase. Schneider et al, 2021. Encephalitis Workup and evaluation • Neurologic consultation • MRI brain with or without contrast may reveal T2/FLAIR changes typical of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal normal • Lumbar puncture with CSF analysis for opening pressure, cell count and differential, cytology for malignant cells that could indicate leptomeningeal metastases, protein, metastases, protein, glucose, gram stain, viral or bacterial cultures, PCR for HSV and other viral PCRs depending on suspicion, oligoclonal bands, autoimmune autoimmune encephalopathy, and paraneoplastic panels • May see elevated WBC with lymphocytic predominance and/or elevated protein • EEG to evaluate for subclinical seizures • Serum studies: chem panel, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and thyroglobulin, am cortisol and ACTH, GQ1b antibodies (Bickerstaff encephalitis and rhombencephalitis), celiac antibody panel, and paraneoplastic and autoimmune encephalitis panels • 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 Hold ICI 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/day Neurology consultation If severe or progressing symptoms or oligoclonal bands present, consider pulse corticosteroids (methylprednisolone (methylprednisolone 1 g IV daily for 3-5 days) plus IVIG 2 g/kg over 5 days (0.4 g/kg/day) or plasmapheresis plasmapheresis Taper steroids following acute management at least 4-6 weeks If positive for autoimmune encephalopathy or paraneoplastic antibody or limited or no improvement, consider consider rituximab in consultation Admit patient for G3-4 G2: Moderate: some interference with ADLs, concerning to patient (ie, pain but no weakness or gait gait limitation) G3-4: Severe: limiting self-care and aids warranted
  • 63. Neurologic IRAEs: Demyelinating Diseases Schneider et al, 2021. Demyelinating Diseases, Including Multiple Sclerosis, Transverse Myelitis, Acute-Disseminated Encephalomyelitis, Optic Neuritis, and Neuromyelitis Optica Workup and evaluation • Neurologic consultation • Ophthalmic or neuro-ophthalmic evaluation if ocular involvement • MRI with contrast of brain, orbit, cervical, and thoracic spinal cord (tailor to examination finding) • Lumbar puncture with CSF analysis including autoimmune encephalitis panel and oligoclonal bands, CNS demyelinating disease antibodies (aquaporin 4 and myelin oligodendrocyte oligodendrocyte glycoprotein), and viral PCRs especially John Cunningham virus PCR to exclude progressive multifocal leukoencephalopathy • Serum studies: B12, HIV, rapid plasma regain (RPR), ANA, Ro/La, TSH, aquaporin-4 IgG, paraneoplastic panel or anti-HU and anti–CRMP5-CV2, thyroid panel including TPO and and thyroglobulin, am cortisol and ACTH, and paraneoplastic autoimmune encephalitis panels • Evaluation for urinary retention and constipation • EEG to evaluate for subclinical seizures • Although less common, biopsy may provide definitive evidence of CNS demyelination Grading Management G1: Asymptomatic or mild symptoms; clinical or diagnostic observations only Intervention not indicated Continue immunotherapy unless symptoms worsen or do not improve G2: Moderate symptoms; minimal, limiting age-appropriate instrumental ADL Stop ICI Neurology consultation Start prednisone 1 mg/kg/day and taper over 1 month Rule out infection G3: Severe or medically significant symptoms but not immediately life-threatening; limiting self-care ADL Permanently discontinue ICI Neurology consultation Nonopioid management of neuropathic pain, for example, pregabalin, gabapentin, or duloxetine Admit patient for methylprednisolone pulse dose 1 g/day and consider IVIG or plasmapheresis if no improvement or or symptoms worsen after 3 days G4: Life-threatening consequences Permanently discontinue ICI Neurology consultation ICU level inpatient care Start methylprednisolone pulse dosing 1 g/day and consider IVIG or plasmapheresis if no improvement or symptoms worsen symptoms worsen after 3 days
  • 64. Hematologic IRAEs: Hemolytic Anemia DIC = disseminated intravascular coagulation; PT = prothrombin time; INR = international normalized ratio; PTT = partial thromboplastin time; PNH = paroxysmal nocturnal hemoglobinuria; Hgb = hemoglobin; LLN = lower limit of normal; RBC = red blood cell; SAE = serious adverse events. Schneider et al, 2021. Hemolytic Anemia Workup and evaluation • History and physical examination (with special consideration of history of new drugs, insect, spider, or snake bites) • Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear, LDH, haptoglobin, bilirubin, reticulocyte count, and free hemoglobin • DIC panel, which could include PT or INR or PTT, and infectious causes • Autoimmune serology • PNH screening • Direct and indirect bilirubin, direct agglutinin test, and if no obvious cause, bone marrow analysis, and cytogenetic analysis to evaluate MDS • Evaluation for viral or bacterial (mycoplasma etc.) causes of hemolysis studies • Workup for bone marrow failure syndrome if refractory including B12, folate, copper, parvovirus, iron, and thyroid, infection • Glucose-6-phosphate dehydrogenase level • Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine or quinidine, fludarabine, ciprofloxacin, lorazepam, and diclofenac) • Assessment of methemaglobinemia Grading Management G1: Hgb <LLN to 10.0 g/dL; <LLN to 6.2 mmol/L; LLN to 100 g/L Continue ICI with close clinical follow-up and laboratory evaluation G2: Hgb <10.0 to 8.0 g/dL; <6.2 to 4.9 mmol/L; <100 to 80 g/L Hold ICI and strongly consider permanent discontinuation Administer 0.5-1 mg/kg/d prednisone equivalents G3: Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated Permanently discontinue ICI; should use clinical judgement and consider admitting the patient; Hematology consult Prednisone 1-2 mg/kg/d (oral or IV equivalent depending on symptoms or speed of development 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 or to return to a patient to a safe hemoglobin range (7-8 g/dL instable, noncardiac inpatients) Should offer patients supplementation with folic acid 1 mg daily G4: Life-threatening consequences; urgent intervention indicated Permanently discontinue ICI; admit patient; hematology consult IV prednisone corticosteroids 1-2 mg/kg/day If no improvement on or if worsening on corticosteroids or severe symptoms on presentation, initiate other immunosuppressive drugs, such as rituximab, IVIG, IVIG, cyclosporine, infliximab, mycophenolate mofetil, or antithymocyte globulin (ATG) RBC transfusion per existing guidelines. Discuss with blood bank team before transfusions that a patient with possible ICI SAE is in the hospital Additional considerations Monitor hemoglobin levels weekly until the steroid tapering process is complete. Thereafter, less frequent testing is needed
  • 65. Hematologic IRAEs: Acquired TTP TTP = thrombotic thrombocytopenic purpura; ADAMS13 = a disintegrin and metalloprotease with thrombospondin type motifs 13; PEX = plasma exchange. Schneider et al, 2021. Acquired TTP Workup and evaluation • History with specific questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, oxymorphone, antibiotics, and quinine) • Hematology consult • Physical examination, peripheral smear to check for schistocytes • ADAMTS13 activity level and inhibitor titer • LDH, haptoglobin, reticulocyte count, bilirubin, and urinalysis to rule out other causes • Prothrombin time, activated partial thromboplastin time, and fibrinogen • Blood group and antibody screen, and direct antiglobulin test • Consider CT or MRI brain, echocardiogram, electrocardiogram • Cytomegalovirus serology • Note: this disorder is usually associated with severe drop in platelets and hemolysis or anemia precipitously (microangiopathy) 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 consult should immediately be called, as delay in identification is associated with increased mortality or morbidity Initially, the patient should be stabilized, and any critical organ dysfunction stabilized G1: Evidence of RBC destruction (schistocytosis) without renal insufficiency, or thrombocytopenia clinically G2: Evidence of RBC destruction (schistocytosis) without clinical consequence with G2 anemia and thrombocytopenia Hold ICI and discuss resumption with patient only after taking into account the risks and benefits, nothing that there are currently no data to currently no data to recommend restarting ICI therapy Administer 0.5–1 mg/kg/day prednisone G3: Laboratory findings with clinical consequences (G3 thrombocytopenia, anemia, and renal insufficiency >2) G4: Life-threatening consequences (eg, CNS hemorrhage or thrombosis or embolism or renal failure) Hold ICI and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to currently no data to recommend restarting ICI therapy In conjunction with hematology, initiate therapeutic PEX according to existing guidelines with further PEX dependent on clinical progress progress Administer methylprednisolone 1 g IV daily for 3 days, with the first dose typically administered immediately after the first PEX. For patients For patients who has an initial platelet count response, discontinue PEX May offer rituximab Consider caplacizumab if ADAMTS13 activity level is <10 IU/dL or <10% of normal, with an inhibitor or elevated anti-ADAMTS13 IgG ADAMTS13 IgG If no exacerbation within 3-5 days after stopping PEX, taper steroids over 2-3 weeks, complete course of rituximab (if receiving), and and discontinue caplacizumab (if receiving)
  • 66. C = complement protein; MCV = mean corpuscular volume; EBV = Epstein Barr virus; CMV = cytomegalovirus; HHV6 = human herpesvirus 6. Schneider et al, 2021. Hematologic IRAEs: Hemolytic Uremic Syndrome Hemolytic Uremic Syndrome (HUS) Workup and evaluation • 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 or methylmalonic acid • Complement testing C3, C4, and CH50 (complement inhibitory antibodies for suspected familial) • Evaluate reticulocyte-count and MCV • Evaluation of infectious cause including screening for viral EBV, CMV, and HHV6 • Evaluation for nutritional causes of macrocytosis (B12 and folate) • Pancreatic enzymes • Evaluation for diarrheal causes, shiga toxin, and Escherichia coli 0157 • Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia • Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, and sirolimus) • Evaluation for neurologic changes (alteration in consciousness, concurrent confusion, seizures, pyramidal syndrome, and extrapyramidal syndrome with hypertonia) Grading Management G1-2: Evidence of RBC destruction (schistocytosis) without clinical consequences of anemia, and thrombocytopenia grade 2 Continue ICI with close clinical follow-up and laboratory evaluation Supportive care G3: Laboratory findings with clinical consequences (eg, renal insufficiency and petechiae) Permanently discontinue ICI Hematology consult Begin therapy with eculizumab (anti-C5 antibody) 900 mg weekly x4 doses, 1,200 mg Week 5, then 1,200 mg every 2 weeks Red blood transfusion according to existing guidelines G4: Life-threatening consequences, (eg, CNS thrombosis or or renal failure)
  • 67. BM = bone marrow. Schneider et al, 2021. Hematologic IRAEs: Aplastic Anemia Aplastic Anemia Workup and evaluation • History and physical examination (close attention to medications, exposure to radiation, toxins, and recent viral infections) • CBC, smear, and reticulocyte count • Viral studies including CMV, HHV6, EBV, and parvovirus • Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, and vitamin D • Serum LDH and renal function • Evaluation for infectious causes • Identify marrow hypo/aplasia • BM biopsy and BM aspirate analysis • Peripheral blood analysis including neutrophil count, proportion of Glycosyl-phosphatidylinositol (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: Mild: >0.5 PMNs x 109/L hypocellular marrow, marrow cellularity <25%, peripheral platelet count count >20,000, reticulocyte count >20,000 Hold ICI, provide growth factor support, and close clinical follow-up and laboratory evaluation Supportive transfusions as per local guidelines G2: Moderate: hypocellular marrow <25% and two of the following ANC <500, peripheral platelet <20,000 <20,000 and reticulocyte <20,000 Hold ICI and provide growth factor support and close clinical laboratory evaluations daily Hematology consult Administer horse ATG plus cyclosporine Supportive transfusions as per local guidelines. All blood products should be irradiated and filtered HLA typing and evaluation for bone marrow transplantation if patient is a candidate G3-4: Severe: ANC <200, platelet count <20,000, reticulocyte count of <20,000, plus hypocellular marrow <25% As per G2 Hold ICI and monitor weekly for improvement. If not resolved, discontinue treatment until AE has reverted to G1 If no response, repeat immunosuppression with rabbit ATG plus cyclosporine, and cyclophosphamide For refractory patients, consider eltrombopag plus supportive care
  • 68. Hematologic IRAEs: Lymphopenia Lymphopenia Workup and evaluation • History (special attention to nutritional status and for lymphocyte depleting therapy such as fludarabine, ATG, steroids, cytotoxic chemotherapy, chemotherapy, and radiation exposure, as well as history of autoimmune disease [AD] and family history of AD) • Physical examination with special attention to spleen size • CBC with differential, peripheral smear, and reticulocyte count • CXR for evaluation of presence of thymoma • Bacterial cultures and evaluation for infection (fungal, bacterial, and viral—specifically CMV or HIV) Grading Management All grades No specific action is required for lymphopenia G1-G3 and ICI therapy should be continued For G4 (<250 PB lymphocyte count), continue ICI therapy and initiate Mycobacterium avium complex prophylaxis and and Pneumocystis jirovecii prophylaxis, CMV screening. HIV or hepatitis screening if not already done May consider EBV testing if evidence of lymphadenopathy or hepatitis, fevers, and hemolysis occur consistent with lymphoproliferative disease occurs PB = peripheral blood. Schneider et al, 2021.

Notas do Editor

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  2. -Sipuleucel-T for metastatic prostate cancer -Talimogene laherparepvec: for Tx of Melanoma Lifileucel: FDA accepted BLA and has a 6 month priority review for melanoma -
  3. HLA-DR4 predominance among patients treated with ICIs who developed autoimmune, insulin-dependent diabetes 
  4. Link for figure: https://www.mdpi.com/1718-7729/29/2/74#