Can Ribociclib (a cyclin-dependent kinase 4/6 inhibitor) cause transaminitis (elevations in liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST)) in patients, particularly those with pre-existing liver conditions?

Ribociclib and Transaminitis

Yes, ribociclib causes transaminitis and hepatotoxicity, with Grade 3 or 4 elevations in ALT occurring in 8% of early breast cancer patients and 11% of advanced breast cancer patients, making routine liver enzyme monitoring mandatory during treatment. 1

Incidence and Severity

Ribociclib-induced hepatotoxicity is well-documented and occurs with significant frequency:

• In early breast cancer (NATALEE trial): Grade 3 or 4 ALT elevations occurred in 8% of patients, with Grade 4 elevations in 1.5%, and AST elevations of Grade 3 or 4 in 4.7% of patients 1
• In advanced/metastatic breast cancer (MONALEESA trials): Grade 3 or 4 ALT and AST elevations occurred in 11% and 8% of patients respectively 1
• Drug-induced liver injury (DILI): Occurred in 0.4% of early breast cancer patients, with 8 clinically confirmed Hy's Law cases (0.3%), indicating severe hepatotoxicity with concurrent bilirubin elevation 1

The median time to onset of Grade ≥3 ALT/AST elevation is 92 days, with median time to resolution to Grade ≤2 being 21 days after dose modification or discontinuation 1

Clinical Presentation and Patterns

Ribociclib-induced hepatotoxicity presents in several distinct patterns:

• Hepatocellular injury pattern: Most common presentation with isolated transaminase elevations, typically ALT > AST 1, 2
• Hy's Law cases: Concurrent ALT or AST >3× ULN with total bilirubin >2× ULN and normal alkaline phosphatase occurred in 1% of patients in MONALEESA-2 and MONALEESA-3, indicating severe hepatocellular injury with risk of acute liver failure 1
• Fulminant hepatitis: Rare but documented cases of biopsy-proven fulminant toxic hepatitis with massive hepatocellular necrosis (up to 30% parenchymal necrosis) have been reported 2, 3

Monitoring Requirements

The FDA mandates specific monitoring protocols for ribociclib:

• Baseline: Perform liver function tests before initiating treatment 1
• First 2 cycles: Monitor LFTs every 2 weeks 1
• Cycles 3-6: Monitor LFTs at the beginning of each cycle 1
• Ongoing: Continue monitoring as clinically indicated 1

Management Based on Severity

Grade 1 (ALT/AST >ULN to 3× ULN):

• Continue ribociclib at current dose 4
• Monitor LFTs every 1-2 weeks 4

Grade 2 (ALT/AST >3× to 5× ULN):

• Hold ribociclib until recovery to Grade ≤1 1
• Resume at reduced dose (400 mg if starting dose was 600 mg, or 200 mg if starting dose was 400 mg) 1
• Monitor every 3 days 4

Grade 3 (ALT/AST >5× to 20× ULN):

• Hold ribociclib until recovery to Grade ≤1 1
• Resume at reduced dose by one level 1
• If Grade 3 recurs, discontinue permanently 1
• Consider hepatology consultation and liver biopsy if steroid-refractory or diagnostic uncertainty 4

Grade 4 (ALT/AST >20× ULN) or Hy's Law:

• Permanently discontinue ribociclib 1
• Immediate hospitalization, preferably at a liver center 4
• Consider corticosteroid therapy (methylprednisolone 2 mg/kg/day) for severe necroinflammation 4, 3

Important Clinical Considerations

Pre-existing liver disease:

• Ribociclib should be used with extreme caution in patients with baseline hepatic impairment 1
• For patients with abnormal baseline transaminases, use multiples of individual baseline rather than absolute ULN values for dose modifications 4

Persistent hepatotoxicity:

• In rare cases, transaminase elevations persist despite ribociclib discontinuation, requiring investigation for alternative causes including autoimmune hepatitis, viral hepatitis, and other hepatotoxic medications 5, 2
• Liver biopsy may be necessary to confirm drug-induced liver injury and guide corticosteroid therapy 2, 3

Cross-reactivity with other CDK4/6 inhibitors:

• Switching to palbociclib after ribociclib-induced hepatotoxicity has been successful in some cases, with normalization of transaminases 6
• However, close monitoring remains essential as class effect cannot be excluded 6

Critical Pitfalls to Avoid

• Do not assume hepatotoxicity will resolve immediately after ribociclib discontinuation - some cases show persistent or worsening transaminase elevation requiring additional investigation and treatment 5, 2
• Do not overlook Hy's Law criteria - concurrent ALT >3× ULN with bilirubin >2× ULN requires permanent discontinuation and urgent hepatology consultation 1
• Do not delay liver biopsy in cases of severe or persistent hepatotoxicity - biopsy can confirm drug-induced liver injury and guide corticosteroid therapy 2, 3
• Do not restart ribociclib after Grade 4 hepatotoxicity or Hy's Law - permanent discontinuation is mandatory 1