What are the adverse effects of Tyrosine Kinase Inhibitors (TKIs)?

Adverse Effects of Tyrosine Kinase Inhibitors (TKIs)

Hematological Toxicities

Myelosuppression is the most common hematological adverse effect of TKIs, occurring predominantly in the first weeks to months of treatment and representing an expression of efficacy rather than true toxicity. 1

• Neutropenia occurs in 17.3% (grade 3/4) with first-line imatinib 400 mg daily, 34.4% with imatinib 800 mg daily, 14.8% with nilotinib 300 mg twice daily, 19.4% with dasatinib 100 mg daily, and 10.8% with bosutinib 500 mg daily 1
• Thrombocytopenia occurs in 10.2% (grade 3/4) with first-line imatinib 400 mg daily, 15.0% with nilotinib 300 mg twice daily, 17.4% with dasatinib 100 mg daily, and 14.1% with bosutinib 500 mg daily 1
• Anemia occurs in 4.9% (grade 3/4) with first-line imatinib 400 mg daily, 3.4% with nilotinib 300 mg twice daily, 11.5% with dasatinib 100 mg daily, and 6.0% with bosutinib 500 mg daily 1
• In second-line therapy, myelosuppression rates increase substantially: thrombocytopenia reaches 47.2% and neutropenia 45.8% with dasatinib 70 mg twice daily or 140 mg daily 1
• Hematologic toxicities are dose-dependent, reversible on treatment cessation or dose reduction, and affect all three lineages to variable degrees 1
• Grade 1-2 hematological adverse events generally do not require specific intervention during the first 3 months of treatment; use red blood cell transfusion support, erythropoietin, or granulocyte stimulating factors if necessary to maximize early therapeutic response 1

Cardiovascular Toxicities

Arterial occlusive events (AOE) represent the most serious cardiovascular complication, with ponatinib carrying the highest risk, followed by nilotinib, while other TKIs show substantially lower risk. 1

• Ponatinib has the highest excess risk of arterial occlusive events including myocardial infarction, stroke, and peripheral arterial disease, with FDA black box warnings for serious heart-related events, blood clots, and death 1
• Nilotinib carries significant cardiovascular risk, making previous or concomitant arteriovascular disease a strong contraindication to first-line use 1
• Hypertension is common with VEGFR-targeting TKIs (sorafenib, sunitinib) and requires antihypertensive management 2, 3
• Congestive heart failure has been reported with imatinib and sunitinib therapy, though this may relate to patient selection 2
• Pleural effusion is primarily associated with dasatinib, with a 5-year cumulative incidence of 37%; risk factors include older age, twice daily dosing, previous or concomitant cardiac disease, autoimmune disorders, hypertension, hypercholesterolemia, and advanced phase CML 1
• Pericardial effusion and pulmonary edema are very rare in pediatric patients with CML-CP, mainly grade 2 1
• QTcF should be measured by electrocardiography prior to commencing any TKI and subsequently before using any other agent known to increase the QT interval 1

Dermatological Toxicities

EGFR-TKI agents (erlotinib, gefitinib) display the broadest spectrum of adverse effects on skin and hair, with acneiform eruptions occurring in more than 50% of patients. 1, 2

• Acneiform rash is the most common dermatological adverse effect of EGFR-TKIs, manifesting as folliculitis, skin fissure, xerosis, and paronychia 1
• Hand-foot skin reaction (HFSR) is a dose-limiting dermatological toxicity particularly associated with sunitinib 1
• Rash/desquamation occurs in 38.1% (all grades) with imatinib 400 mg and 49.8% with imatinib 800 mg in GIST patients 4
• Erlotinib and gefitinib cause folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of frontal alopecia 2
• Sorafenib and sunitinib are associated with subungual splinter hemorrhages but less commonly cause folliculitis 2
• Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI, potentially leading to non-compliance, dose reduction, or therapy discontinuation 1, 3

Gastrointestinal Toxicities

Gastrointestinal symptoms are among the most frequently reported adverse effects across all TKIs, with diarrhea being particularly common with bosutinib. 1

• Nausea occurs in 58.1% (all grades) with imatinib 400 mg and 64.5% with imatinib 800 mg in GIST patients 4
• Diarrhea occurs in 56.2% (all grades) with imatinib 400 mg and 58.2% with imatinib 800 mg in GIST patients; it is particularly common with bosutinib but usually self-limited and may be less problematic with 400 mg dose once daily and with concurrent or pre-emptive treatment with loperamide 1, 4
• Vomiting occurs in 37.4% (all grades) with imatinib 400 mg and 40.6% with imatinib 800 mg in GIST patients 4
• Abdominal pain/cramping occurs in 57.2% (all grades) with imatinib 400 mg and 55.2% with imatinib 800 mg in GIST patients 4
• Mild gastrointestinal symptoms are the most commonly reported non-hematological adverse events with imatinib 1

Hepatotoxicity

Ponatinib has a 56% incidence of ALT/AST elevations, the highest among all TKIs, with documented cases of hepatitis, hepatic failure, and fatal outcomes. 5

• Ponatinib hepatotoxicity has characteristically rapid onset, occurring within 1 week of treatment initiation, notably faster than other TKIs like imatinib or bosutinib 5
• Fatal liver injury has been documented in ponatinib-treated patients, distinguishing it from safer alternatives like dasatinib, which has no reported fatal hepatic failure cases 5
• Monitor liver function tests every 2 weeks during the first 3 months of ponatinib treatment, then monthly thereafter or as clinically indicated 5
• For Grade 2 hepatotoxicity, withhold ponatinib until toxicity improves to Grade 2 or better, and increase monitoring frequency to every 3 days 5
• For Grade 3 hepatotoxicity, immediately discontinue ponatinib, obtain urgent hepatology consultation, and consider methylprednisolone 1-2 mg/kg/day if no improvement after 3-5 days 5
• For Grade 4 hepatotoxicity or hepatic decompensation, immediate hospitalization at a liver center is mandatory with permanent discontinuation of ponatinib, and initiate methylprednisolone 2 mg/kg/day with planned 4-6 week taper 5
• Hepatotoxicity may occur with any TKI, but particularly with bosutinib and nilotinib 1
• Patients with Gilbert's syndrome require special consideration, as nilotinib can cause unconjugated hyperbilirubinemia through UGT1A1 inhibition 5

Endocrine Toxicities

Thyroid abnormalities are common with TKIs, detected in 25% of patients treated with imatinib, 55% with nilotinib, and 70% with dasatinib, with hypothyroidism being more common than hyperactivity. 1

• Hypothyroidism responds to hormone supplementation 1
• Hypercholesterolemia and hypertriglyceridemia have been reported with lorlatinib 3
• Gynecomastia has been reported in 6% of patients with imatinib, mostly associated with diminution of testosterone levels, and with dasatinib 1

Fluid Retention and Edema

Periorbital edema is a common adverse effect of imatinib, while superficial edema occurs in the majority of TKI-treated patients and can be managed with diuretics or dose reduction. 4, 2

• Edema occurs in 76.7% (all grades) with imatinib 400 mg and 86.1% with imatinib 800 mg in GIST patients, with severe (CTC Grade 3/4) edema observed in 11.1% of patients 4
• Superficial edema, most frequently periorbital or lower extremity edema, is managed with diuretics, other supportive measures, or by reducing the dose of imatinib 4
• Periorbital edema occurred in 33.3% of DFSP patients treated with imatinib 4

Renal Toxicities

Both acute and chronic renal failure have been reported with TKIs including gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. 3

• Imatinib should be withheld in patients with significant renal impairment 1
• Renal/genitourinary toxicity occurs in 14.2% (all grades) with imatinib 400 mg and 13.6% with imatinib 800 mg in GIST patients 4

Musculoskeletal Toxicities

• Myalgia occurs in 32.2% (all grades) with imatinib 400 mg and 30.2% with imatinib 800 mg in GIST patients 4
• Arthralgia occurs in 13.6% (all grades) with imatinib 400 mg and 12.3% with imatinib 800 mg in GIST patients 4
• Rare grade 3-4 musculoskeletal pain may warrant treatment switch with imatinib 1

Respiratory Toxicities

• Dyspnea occurs in 13.6% (all grades) with imatinib 400 mg and 14.2% with imatinib 800 mg in GIST patients 4
• Pulmonary hypertension is very rare in pediatric patients with CML-CP 1
• Respiratory failure and previous or concomitant pleuro-pulmonary disease are strong contraindications to dasatinib first line 1

Infectious Complications

TKIs used as monotherapy do not require antimicrobial prophylaxis, as they do not cause significant immunosuppression, distinguishing them from truly immunosuppressive therapies. 6

• Imatinib shows a low incidence (2%) of opportunistic infections in large series 6
• Second-generation TKIs (nilotinib, dasatinib, bosutinib) in first-line therapy show no significantly increased infection rates compared to imatinib 6
• Hepatitis B reactivation has been associated with TKIs (imatinib, nilotinib), though this risk is substantially lower than with B-cell depleting agents (rituximab) or high-dose corticosteroids 6
• No systemic antimicrobial prophylaxis is recommended when TKIs are given as monotherapy 6
• Reserve prophylaxis for combination regimens that include cytotoxic chemotherapy 6

Constitutional Symptoms

• Fatigue/lethargy, malaise, asthenia occurs in 69.3% (all grades) with imatinib 400 mg and 74.9% with imatinib 800 mg in GIST patients 4
• Fever in absence of neutropenia occurs in 13.2% (all grades) with imatinib 400 mg and 12.9% with imatinib 800 mg in GIST patients 4
• Headache is a common non-hematological symptom with dasatinib, reported in fewer than 5% as grade 3-4 1

Management Principles

Most TKI toxicities are mild to moderate, reversible after interruption or reduction of the TKI dose, but a switch to another TKI is needed when there is severe or recurrent toxicity. 1

• Determination of TKI plasma concentration may be helpful in detecting excessive exposure to the drug in the event of persistent or recurrent adverse events 1
• During the first 3 months of treatment, avoid discontinuing or reducing the dose of TKIs to maximize achievement of early therapeutic response 1
• Drug discontinuation for adverse reactions occurs in approximately 5.4% of patients 4
• Most side effects occur early within the treatment course and are typically manageable through drug dose reduction or treatment interruption 7
• The criteria for choice of second-line TKI depend on age, comorbidities, and toxicity of prior TKI 1

Drug-Drug Interactions

Almost all TKIs undergo metabolism by CYP3A4, creating substantial potential for interactions with drugs that modulate this metabolic pathway, with co-prescribing rates for DDI drugs ranging from 23-74%. 1

• Co-prescribing rates for DDI drugs that may decrease TKI effectiveness range from 23-57%, while co-prescribing rates with drugs that may increase TKI toxicity range from 24-74% 1
• Avoid concomitant use of CYP3A4 inducers that may increase toxic metabolite formation, particularly with ponatinib 5
• Concomitant use of CYP3A4 inhibitors increases risk of dermatological toxicities with sunitinib due to decreased ability to metabolize the parent compound 1

Special Populations

• In pediatric patients, imatinib has demonstrated a good long-term safety profile 1
• Hematologic and non-hematologic adverse events in children are usually mild to moderate and reversible after interruption or reduction of the TKI dose 1
• No cardiac toxicities have been reported with imatinib in pediatric populations 1