Adverse Reactions to Immuno-Oncology

Background

Introduction

Immune checkpoint inhibitors (ICI) used in oncology can improve progression-free survival (e.g. 3-5 years1 in non small cell lung cancer) and overall survival in some cancer patients with advanced malignancies. Some cancers can acquire immune checkpoints so that the tumour cells are not recognised by the immune system. Inhibiting the checkpoints therefore enables the tumour cells to be recognised and allows an immune response to be activated against them.2
These therapies can occasionally cause auto-immune attacks on non-cancerous tissue, causing severe and, rarely, fatal adverse events [called immune-related adverse events (irAEs)], especially if not promptly recognized and treated.3
The risk, clinical manifestations, and severity of irAEs is variable across ICI regimen and cancer type, and incidence can range from 15 to 90%.4 IrAEs typically represent a medical emergency, with patients appearing in the emergency department. These adverse events often appear infectious, when in fact they result from the immune toxicity caused by immune checkpoint therapy. IrAEs can occur in any organ system, but adverse events in dermatologic (e.g. rash), gastrointestinal (e.g. diarrhea, colitis), endocrine (e.g. thyroid dysfunction), and respiratory (e.g. pneumonitis) systems are among the most common5,6. High clinical suspicion, timely evaluation and multi-disciplinary management provide the foundation for optimal clinical outcomes4. IrAEs are primarily treated with corticosteroids, which suppress the overactive immune response that is secondary to the treatment. Physicians should be familiar with IrAEs and screen for ICI use for all patients presenting to the ED.
The following notes provide physicians with a guide to the management of IrAEs, based on currently available treatment guidelines. The goal of this program is to assist physicians in rapidly making treatment decisions at crucial points during the management of patients with IrAEs.

References
  1. Domagała-Kulawik J. Immune checkpoint inhibitors in non-small cell lung cancer – towards daily practice. Adv Respir Med. 2018;86(3). doi:10.5603/ARM.2018.0022
  2. Ardolino L, Joshua A. Immune checkpoint inhibitors in malignancy. Aust Prescr. 2019;42(2):62-67. doi:10.18773/austprescr.2019.012
  3. Esfahani K, Meti N, Miller WH, Hudson M. Adverse events associated with immune checkpoint inhibitor treatment for cancer. CMAJ. 2019;191(2):E40-E46. doi:10.1503/cmaj.180870
  4. Connolly C, Bambhania K, Naidoo J. Immune-Related Adverse Events: A Case-Based Approach. Front Oncol. 2019;9. doi:10.3389/fonc.2019.00530
  5. Simmons D, Lang E. The Most Recent Oncologic Emergency: What Emergency Physicians Need to Know About the Potential Complications of Immune Checkpoint Inhibitors. Cureus. October 2017. doi:10.7759/cureus.1774
  6. Myers G. Immune-related adverse events of immune checkpoint inhibitors: a brief review. Current Oncology. 2018;25(5). doi:10.3747/co.25.4235
  7. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. New England Journal of Medicine. 2018;378(2):158-168. doi:10.1056/NEJMra1703481
Acronyms

ED: Emergency department
IrAEs: immune-related adverse events
CTLA-4: cytotoxic T-lymphocyte antigen 4
PD-1: Programmed cell death 1
PD-L1: Programmed cell death ligand 1

Scenarios

Scenario 1: Colitis

  • 67 y/o male, retired bank executive was enjoying a family dinner last night when he began to experience crampy lower abdominal pain and bloody diarrhea (5 bouts), as well as nausea.
  • In his third month of Durvalamab treatment for metastatic bladder cancer involving retroperitoneum.
  • Disease stable for 18 months on standard chemotherapeutic agents, but due to recent spread first noted 4 months ago, immune checkpoint therapy was initiated.
  • No travel and no infectious contacts; no recent antibiotic use.
  • Told to present to ED by oncology if any bleeding or infection noted.
    • Metastatic bladder cancer on Durvalamab for 6 months
  • Examination
  • Actions
  • Pale, in significant discomfort, diaphoretic.
  • BP 90 / 70, HR 120, RR 16, Temp 38.2.
  • Diffuse mild tenderness on abdominal exam, especially LLQ; rectal deferred pending labs; mucous and blood in stool. Pain score 8/10.
  • Hgb 95 (baseline 110), WBC 17, PLT 300. Chemistry profile normal including renal indices.
  • Lactate 2.4.

Initial Management:

  • Opioids and anti-emetics provided along with 1500 cc Normal Saline.
  • Three views of the abdomen unremarkable, no evidence of toxic megacolon.
  • Stool for WBC and culture and ova and parasite analysis sent.
  • GI consulted – will arrange for scope in 24 hours when more stable.
  • No bowel motility agents ordered.

Follow-up:

  • Reduced pain and BP 100 / 60; HR 90; pain 3 / 10.
  • Bloody diarrhea and cramps persisting.
  • Internal Medicine resident consulting and considering broad spectrum antibiotics.
  • Possibility of immune-checkpoint-induced enterocolitis entertained and endorsed in discussion between ED MD and oncologist on call.
  • Methylprednisolone Sodium Succinate (Solu-Medrol) 120 mg IV Q8h ordered with improved symptoms noted within 6 hours.

Treatment:

  • Methylprednisolone Sodium Succinate (Solu-Medrol) 1-2 mg/kg IV.
  • R/O alternative infectious causes.
  • Colonoscopy to grade severity of toxicity (ulceration is an indication for rapid introduction of biologics) and to rule out alternative causes.

References:

  1. Soularue, E. et al. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 67, 2056-2067, doi:10.1136/gutjnl-2018-316948 (2018).
  2. Brahmer, J. R. et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, JCO2017776385, doi:10.1200/JCO.2017.77.6385 (2018).
  3. Haanen, J. et al. Management of toxicities from immunotherapy: European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, doi:10.1093/annonc/mdy162 (2018).

Acronyms:
ED: Emergency department
HR: Heart rate
LLQ: Lower left quadrant
PLT: Platelets
R/O: Ruled out

Scenario 2: Hypophysitis

  • 41-year-old male presents to the ED with excessive fatigue and lethargy, 10 days following the third cycle of treatment for renal cell carcinoma with pulmonary metastasis.
  • He reports sleeping more than 16 hours in the day, and not having enough energy to perform simple activities of daily living.
  • Past medical history:
    • Patient is on first-line treatment with ipilimumab and nivolumab.
    • He reports no infectious symptoms.
    • No other relevant past medical history.
    • No other medications.
  • Examination
  • Actions
  • 92/78, HR 102, 38.2 temperature rectal, normal oxygen saturation.
  • Normal neurological, cardiac, respiratory, and abdominal examination.

Initial Management:

  • ABCs, obtain IV access.
  • Septic workup sent (urine and bacterial culture). CXR shows nil acute.
  • Bloodwork: Normal CBC. Electrolytes normal, except for K+ at 3.0. Na+ 130.

Further Management:

  • IV hydration and electrolyte replacement.
  • MRI of the head shows diffuse pituitary inflammation, consistent with hypophysitis.
  • TSH and random cortisol both supressed.

Practice Considerations:

  • Excessive fatigue, lethargy, hypokalemia or hypotension in the absence of other causes in a patient on cancer immunotherapy should trigger a full pituitary-adrenal axis investigation (TSH, T4, Cortisol) and an MRI of the pituitary whenever available.
  • Unlike other immune-related adverse events, endocrine adverse events only require physiologic replacement of the deficient hormone. High dose corticosteroids in this specific setting is associated with worse cancer outcomes and survival.

Treatment:

  • Levothyroxine (Synthroid) adjusted to weight (1.6 mcg/kg/day)
  • Physiologic doses of hydrocortisone (e.g. 10-5-5 mg per day)
  • Consider short-term stress-dose corticosteroids if other concomitant illness, such as sepsis.

References:

  1. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018:JCO2017776385.
  2. Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018.
  3. Puzanov I, Diab A, Abdallah K, Bingham CO, 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95.
  4. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018;124(18):3706-14.

Acronyms:
ABCs: Airway, Breathing, and Circulation
CXR: Chest X-Ray
TSH: Thyroid stimulating hormone
T4: Thyroxine

Scenario 3: Myocarditis

  • 48 y/o male presents to the ED with syncopal episode at home.
  • Reports poor sleep for the last 3 nights, feeling anxious and short of breath.
  • EMS is called after a second episode at home following regaining consciousness and standing.
  • Patient found moderately hypotensive with a BP of 90 systolic and EKG showing marked ventricular ectopy and bigeminy.
  • Past medical history:
    • Stable on pembrolizumab for metastatic melanoma for 2 years.
    • Normal activities of daily living, married with two young children.
  • Examination
  • Actions
  • Sallow complexion, poor capillary refill, short of breath.
  • BP 110/80 after EMS fluid bolus.
  • Pulse 110 with significant ectopy.
  • Respiratory rate 24 / oxygen sat 88%.
  • Fine bibasilar creps on exam.
  • Limited ability to hear heart sounds.
  • Stat portable CXR reveals vascular redistribution and cardiomegaly.
  • EKG and monitor shows salvos of VT and non-specific ST-T abnormalities.
  • Swab for COVID 19 (due to shortness of breath).

Initial Management:

  • Electrical instability treated with metoprolol 5 mg IV x 2 with good result. Ectopy resolved.
  • Furosemide 20 IV with good response and no further oxygen requirements.
  • BNP reported at 6000 and hsTnT 600 ng/L.
  • Cardiology paged and cath lab activated for NSTEMI with possible early cardiogenic shock.

Follow-up:

  • Normal coronaries but EF < 30%.
  • Immune-checkpoint induced myocarditis and cardiomyopathy suspected.
  • Methylprednisolone sodium succinate (Solu-Medrol) 1g IV DIE x 3 days after consultation with oncologist on call.

Clinical pearls:

  • Myocarditis from immune checkpoint therapy has a mortality of up to 50%.
  • Rapid administration of high dose pulse steroids in the setting of critical/unstable patients can be lifesaving.
  • Major complications include heart block requiring pacemaker, tachy-brady arrythmias, or pump failure.

References:

  1. Palaskas, N., Lopez-Mattei, J., Durand, J. B., Iliescu, C. & Deswal, A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc 9, e013757, doi:10.1161/JAHA.119.013757 (2020).

Acronyms:
BNP: B-type natriuretic peptide
BP: Blood pressure
DIE: “bis in die” (Latin) for twice a day
ED: Emergency department
EF: Ejection Fraction
EKG: Electrocardiogram
EMS: Emergency medical services
hsTnT: High-sensitivity troponin T
NSTEMI: Non-ST-elevation myocardial infarction
VT: Ventricular tachycardia

Scenario 4: Pneumonitis

  • 55-year-old male presents to the ED with significant shortness of breath, not associated with any cough, fever, or sputum production.
  • Past medical history:
    • Metastatic non-small cell lung cancer, with multiple bilateral pulmonary nodules.
    • On first-line treatment with carboplatin-pemetrexed and pemrolizumab.
    • No other relevant past medical history, medications, sick contacts, occupational exposure or travel history.
    • Not known for COPD and former smoker x 4 years.
    • Social isolation observed for COVID 19.
  • Examination
  • Actions
  • BP 123/64, HR 100, RR 32 80% saturation on room air, 93% on 5L oxygen by nasal prongs. Temperature 37.5 rectal.
  • Normal cardiac exam. Respiratory exam is clear, without any adventitious sounds.

Initial Management:

  • Blood tests: Normal CBC, and extended electrolytes.
  • Nasopharyngeal swab for COVID 19 – High risk age group.
  • CXR: Diffuse bilateral interstitial infiltrates. No clear consolidation. No pleural effusion.
  • CT-angiogram: No evidence of pulmonary embolism. Metastatic lung lesions are stable. New bilateral interstitial infiltrates with a broad differential diagnosis including infectious, inflammatory or lymphangitic carcinomatosis.
  • Septic workup, including blood and sputum cultures.
  • Bronchoscopy and alveolar lavage, if patient’s condition permits.

Practice Considerations:

  • There are no characteristic radiographic features that are diagnostic for immune-related pneumonitis. A chest x-ray should always be performed first. However, chest computed tomography (CT) is the preferred imaging modality, as routine chest radiography will miss the diagnosis in almost one-fourth of cases.
  • Infectious causes must be ruled out, preferably with a bronchoscopy and alveolar lavage, as both conditions can overlap.
  • Corticosteroids and antibiotics should be initiated in tandem, until infectious causes are ruled out.

Treatment:

  • Methylprednisolone sodium succinate (Solu-Medrol) 2 mg/kg IV DIE.
  • If no improvement within 48-72 hours, need second line immunosuppression (either mycophenolate mofetil, infliximab or tocilizumab).
  • Early involvement of a multidisciplinary team of oncologists, pulmonary and infectious disease specialists.

References:

  1. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018:JCO2017776385.
  2. Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2017;35(7):709-17.
  3. Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018.
  4. Puzanov I, Diab A, Abdallah K, Bingham CO, 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95.

Acronyms:
COPD: Chronic obstructive pulmonary disease
CT: Chest computed tomography
CXR: Chest Xray
DIE: Twice daily

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