Background
New agents, new toxicities
Agent | Target | Indications | Toxicities |
---|---|---|---|
Monoclonal antibodies | |||
Rituximab Ofatumumab Obinutuzumab | CD20 | B-cell lymphomas and leukemias | CRS Immunodeficiency |
Trastuzumab | HER2neu | Breast cancer | Cardiac disease |
Cetuximab | EGFR | Colorectal cancer | Diarrhea Exanthema |
Bevacizumab | VEGF | Colorectal cancer Breast cancer Renal cell cancer NSCLC | Hypertension GI bleeding or perforation Thromboembolism |
Ramucirumab | VEGFR | Gastric cancer | |
Tyrosine kinase inhibitors | |||
Imatinib Dasatinib | BCR-ABL | CML ALL | Pleural/pericardial effusions Pulmonary hypertension |
Ponatinib | Thromboembolism | ||
Erlotinib | EGFR | NSCLC Pancreatic cancer | Exanthema, diarrhea GI bleeding or perforation |
Idelalisib | PI3K | B-cell lymphoma | Pneumonitis Colitis, hepatosis |
Trametinib | MEK | Melanoma | Diarrhea, edema Decrease of LVEF |
Aflibercept Axitinib | VEGF VEGFR | Colorectal cancer Renal cell cancer | Hypertension GI bleeding or perforation Thromboembolism PRES |
Sorafenib Sunitinib Pazopanib | Multiple kinases | Renal cell cancer GIST Soft tissue sarcoma | Decrease of LVEF Hypertension |
Bispecific antibodies (BAB) | |||
Blinatumomab | CD3/CD19 | ALL B-cell lymphomas | CRS Neurotoxicity (e.g., convulsions) Liver toxicity (transaminitis) |
Checkpoint inhibitors | |||
Ipilimumab | CTLA-4 | Melanoma | IRAEs: Diarrhea, colitis Hypophysitis Immunhepatitis Polyarthritis |
Nivolumab Pembrolizumab | PD-1 | Melanoma NSCLC RCC Hodgkin’s lymphoma | |
Cellular treatments | |||
CAR T cells | CD19 | ALL B-cell lymphomas | CRS Neurotoxicity (e.g., convulsions, encephalopathy, or ischemia) |
Cytokine-release syndrome
Constitutional | |
Fever, chills, headache, asthenia, myalgia, arthralgia, back or abdominal pain | |
Organ related | |
Oliguria, bronchospasm, dyspnea, hypotension, tachycardia, arrhythmia, confusion, erythema, urticarial reaction, pruritus | |
Lab tests | |
Hypokalemia, increased urea, decreased glomerular filtration rate, altered blood counts and/or coagulation tests, elevation of C-reactive protein and/or procalcitonin |
Tocilizumab 4 to 8 mg/kg i.v. (1-h infusion, maximum 800 mg) | |
---|---|
(1) Decrease of LVEF <40% assessed by echocardiogram | |
(2) Increase of creatinine >2.5-fold compared to baseline | |
(3) Norepinephrine support (>2 μg/min) for 48 h since start of vasopressors (even if non-continuous administration) | |
(4) Decrease of systolic blood pressure <90 mmHG despite vasopressor support | |
(5) Severe dyspnea potentially requiring mechanical ventilation | |
(6) APTT >2× UNL | |
(7) Persisting elevation (>5× UNL) of creatinine kinase longer than 48 h |
Central nervous system events
Immune-related adverse events
Basic evaluation |
(1) When was the treatment with checkpoint inhibitor started and how many doses has the patient already received? |
(2) Which is/are the leading symptom/s and when did it/they start? |
(3) Which grading definition(s) according to NCI CTCAE is fulfilled? |
(4) Rule out important differential diagnosis: pre-existing autoimmune condition, complication of underlying malignancy, infection |
(5) What is the patient’s prognosis due to malignancy? |
Initial management |
(1) ICU monitoring, venous/arterial access, fluid load, vasopressors and oxygen supplementation, ultrasound, and/or CT scan as indicated |
(2) Check common laboratory tests: hematology, chemistry (including renal and liver function tests), coagulation, endocrine function, microbial and viral infections, autoantibodies (e.g., ANA, AMA, SMA, LKM1, pANCA, TPOAb, TRAb, TGAb) |
(3) If diagnosis of IRAEs is established, initiate steroid therapy at 1–2 mg/kg of body weight OR, if patient is already on steroids, consider increase of dose (up to 5 mg/kg or equivalent) |
(4) Involve organ specialists: gastroenterology, endocrinology, and neurology, surgery (if perforation or ileus is suspected) |
Advanced support |
(1) If symptoms do not improve after 5–7 days, discuss additional immunosuppressive intervention (mycophenolate mofetil, tacrolimus) |
(2) Consider endoscopy and colonic biopsies for patients with diarrhea/colitis, or liver biopsy in selected cases |
(3) Evaluate specific recommendations for organ dysfunction: -Hormone replacement in endocrine disorders -Infliximab in severe colitis |
(4) In responding events slowly taper steroids over 4 weeks; discuss duration of alternative immunosuppression (if needed) with organ specialist |
(5) Checkpoint inhibition should be discontinued definitively after grade 3/4 IRAEs |
Interstitial pneumonia and pneumonitis
Events associated with impaired angiogenesis
Bevacizumab |
→ Arterial hypertension |
Decreased endothelial production of nitric oxide with consecutive vasoconstriction Cholesterol embolization syndrome |
→ Congestive heart failure |
Disruption of physiological coronary angiogenesis Impaired response to pressure overload |
→ Arterial thromboembolism |
Reduction of anti-inflammatory effects and atherosclerotic instability Impaired proliferation and repair of endothelial cells Endothelial cell dysfunction and exposure of subendothelial collagen Direct platelet activation Inhibition of collateral circulation |
Dasatinib |
→ Pulmonary hypertension |
Reduced hypoxic vasoconstriction Induction of pulmonary endothelial cell apoptosis Induction of reactive oxygen species and consecutive endothelial dysfunction |
Dasatinib, nilotinib, ponatinib |
→ Cardiovascular events |
Metabolic effects: hyperglycaemia, hyperlipidemia Interaction with VEGF receptors Inhibition of KIT and PDGF receptor Inhibition of discoidin domain receptor 1 |