What are the cardiovascular toxicities associated with Sprycel (dasatinib)?

Cardiovascular Toxicities of Sprycel (Dasatinib)

Dasatinib is associated with several significant cardiovascular toxicities including pulmonary arterial hypertension, pleural and pericardial effusions, and cardiac dysfunction, which require careful monitoring and prompt management to reduce morbidity and mortality.

Major Cardiovascular Toxicities

Pulmonary Arterial Hypertension (PAH)

• Dasatinib can cause pulmonary arterial hypertension, which may occur any time after initiation, including after more than 1 year of treatment 1
• The incidence of PAH with dasatinib is estimated to be 0.45%, though the DASISION study reported pulmonary hypertension in 5% of patients treated with dasatinib compared to <1% with imatinib 2
• PAH is largely reversible upon discontinuation of dasatinib, although normal right heart hemodynamics may not be fully restored 2
• Clinical manifestations include dyspnea, fatigue, hypoxia, and fluid retention 1
• The mechanism may involve inhibition of SRC kinase, which regulates smooth muscle proliferation and vasoconstriction 2

Pleural and Pericardial Effusions

• Pleural effusion is a common adverse effect of dasatinib, occurring in 28-33% of patients in clinical studies 2
• Risk factors for developing pleural effusions include:
  • Prior cardiac history
  • Hypertension
  • Twice-daily dosing of dasatinib (70 mg twice daily has higher risk than 100 mg once daily)
  • Advanced age 2
• Pleural effusion can lead to dose interruption (in 83% of affected patients) and dose reduction (in 71% of affected patients) 2
• Pericardial effusion can also occur and may be part of the fluid retention syndrome associated with dasatinib 2

Cardiac Dysfunction

• Dasatinib can cause various forms of cardiac dysfunction 1
• After 5 years of follow-up in newly diagnosed chronic phase CML patients, the following cardiac adverse reactions were observed:
  • Cardiac ischemic events (3.9% with dasatinib vs 1.6% with imatinib)
  • Cardiac-related fluid retention (8.5% with dasatinib vs 3.9% with imatinib)
  • Conduction system abnormalities, primarily arrhythmias and palpitations (7% with dasatinib vs 5% with imatinib) 2, 1
• Dasatinib may cause QT interval prolongation, particularly in patients with hypokalemia, hypomagnesemia, congenital long QT syndrome, or those taking medications that prolong QT 1
• Mechanistically, dasatinib may cause cardiotoxicity through targeting c-Src kinase, which can lead to inhibition of the RAF/MEK/ERK pro-survival pathway in cardiac myocytes 3, 4

Monitoring and Management Strategies

Monitoring for PAH

• Baseline assessment should include:
  • Evaluation of risk factors for PAH
  • Assessment of NYHA/WHO functional class
  • Consider 6-minute walk test and NT-proBNP measurement
  • Echocardiographic assessment of pulmonary arterial pressure 2
• Surveillance strategy:
  • Assess NYHA/WHO functional class every 3 months
  • Assess echocardiographic level of pulmonary arterial pressure every 3 months
  • Consider right heart catheterization for suspected PAH 2
• Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during treatment with dasatinib 1

Management of Cardiovascular Toxicities

• For PAH:

  • If confirmed, dasatinib must be permanently discontinued 2, 1
  • Consider alternative TKIs and targeted therapy for PAH (sildenafil, endothelin antagonist, or calcium channel blocker) 2
  • Monthly follow-up with echocardiogram for serial assessment of pulmonary artery pressure 2

• For fluid retention events (pleural/pericardial effusion):

  • Manage with diuretics and supportive care
  • For significant symptoms, consider short course of steroids (prednisone 20 mg/day for 3 days)
  • Dose interruption may be necessary; when resolved, reduce dose by one level 2
  • For severe cases, thoracentesis and oxygen therapy may be required 2

• For cardiac dysfunction:

  • Monitor patients for signs or symptoms of cardiac dysfunction
  • Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration 1
  • Consider dose reduction or treatment interruption for severe cardiac events 1

Special Considerations

Dose Adjustments

• The occurrence of pleural effusion is significantly reduced with dasatinib 100 mg once daily compared with 70 mg twice daily 2
• For patients with clinically significant intolerance to dasatinib 100 mg once daily, consider reducing to 50 mg (or 20 mg with careful monitoring in selected patients) to avoid serious adverse events 2

Drug Interactions

• Concomitant use of medications that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided or monitored closely for toxicity 2
• Medications that prolong QT interval should be used with caution in patients receiving dasatinib 1

Pediatric Patients

• Acute cardiovascular adverse events including pericardial effusions, electrocardiographic abnormalities, and premature ventricular contractions can occur after long-term use in pediatric patients 2
• Regular electrocardiogram and echocardiographic assessments are recommended in pediatric patients 2

Conclusion

Cardiovascular toxicities associated with dasatinib require vigilant monitoring and prompt intervention to minimize morbidity and mortality. The most serious cardiovascular toxicity is pulmonary arterial hypertension, which necessitates permanent discontinuation of dasatinib if confirmed. Other significant toxicities include pleural and pericardial effusions and cardiac dysfunction, which may require dose modifications or treatment interruptions.