Can venetoclax (venetoclax) and azacitidine (azacitidine) cause jaundice?

Can Venetoclax and Azacitidine Cause Jaundice?

Yes, venetoclax and azacitidine can cause jaundice, though this is not a commonly reported adverse effect in the major clinical trials and guidelines for these agents. The primary hepatotoxicity concerns with this combination relate to drug-induced liver injury rather than direct jaundice as a frequent complication.

Evidence for Hepatotoxicity

Azacitidine-Related Hepatotoxicity

• Azacitidine can cause drug-induced liver injury (DILI), though the specific incidence of jaundice is not well-characterized in the literature 1
• In inflammatory bowel disease literature, azathioprine (a related thiopurine) has been documented to cause severe cholestatic jaundice that may not improve despite drug withdrawal 1
• The mechanism of thiopurine-related hepatotoxicity includes cholestatic patterns and vascular endothelial damage 1

Venetoclax-Related Hepatotoxicity

• Venetoclax is predominantly metabolized by the liver through CYP3A4/5 pathways, making hepatic function critical for drug clearance 2, 3
• In patients with severe hepatic impairment (Child-Pugh C), venetoclax exposure increases 2.3- to 2.7-fold with a doubled half-life compared to normal hepatic function 2
• A 50% dose reduction is recommended for patients with severe hepatic impairment to account for these pharmacokinetic changes 2

Clinical Trial Safety Data

Major Adverse Events from Combination Therapy

The pivotal VIALE-A trial and related studies show the following toxicity profile for venetoclax plus azacitidine 4, 1:

• Hematologic toxicities are predominant: grade ≥3 thrombocytopenia (45%), neutropenia (42%), and febrile neutropenia (42%) 4
• Infections occur in 84-85% of patients (any grade), with serious infections being common 4, 1
• Gastrointestinal effects: nausea in 44% of patients 4
• Jaundice is not listed among the common or serious adverse events in the major registration trials 4, 1

Specific Hepatic Monitoring

• In a phase 1b study of venetoclax with azacitidine in relapsed/refractory MDS, the most common grade ≥3 adverse events were febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%), with no specific mention of jaundice or hepatotoxicity 5
• Pneumonia (23%) was the most common grade ≥3 infection, but hepatobiliary complications were not highlighted 5

Clinical Context and Risk Factors

When to Suspect Drug-Induced Jaundice

If jaundice develops in a patient receiving venetoclax and azacitidine, consider 1:

• Timing: Drug-induced liver injury typically manifests within the first few months of treatment 1
• Pattern: Check if bilirubin elevation is conjugated (cholestatic pattern) or unconjugated 1
• Alternative causes: Rule out sepsis (22% of jaundice cases), malignancy-related biliary obstruction, hemolysis, or pre-existing liver disease 1
• Concomitant medications: CYP3A4 inhibitors (azole antifungals) increase venetoclax exposure and may theoretically increase hepatotoxicity risk 1, 3

Important Caveats

• Sepsis is a more common cause of jaundice in AML patients than direct drug hepatotoxicity, occurring in 22% of hospitalized patients with new-onset jaundice 1
• Tumor lysis syndrome can cause metabolic derangements but does not typically present as isolated jaundice 6, 3
• Baseline liver disease: Patients with pre-existing hepatic impairment require dose adjustments and closer monitoring 2

Practical Management Approach

If Jaundice Develops

1. Obtain hepatic panel immediately: differentiate conjugated vs unconjugated hyperbilirubinemia, check ALT/AST, alkaline phosphatase, and GGT 1
2. Rule out biliary obstruction: ultrasound is the initial imaging modality of choice 1
3. Assess for infection/sepsis: blood cultures, clinical evaluation for cholangitis or systemic infection 1
4. Review all medications: consider drug-drug interactions, particularly CYP3A4 inhibitors 1, 3
5. Consider dose interruption: hold venetoclax if severe hepatotoxicity is suspected pending evaluation 2

Dose Modifications for Hepatic Impairment

• Mild to moderate hepatic impairment: no dose adjustment required 2
• Severe hepatic impairment (Child-Pugh C): reduce venetoclax dose by 50% 2
• Azacitidine: no specific dose adjustments are recommended in the literature for hepatic impairment, but monitor closely 4

Bottom Line

While venetoclax and azacitidine can theoretically cause jaundice through drug-induced liver injury mechanisms, this is not a frequently reported adverse event in clinical practice or major trials 4, 1. The combination's toxicity profile is dominated by myelosuppression and infections rather than hepatobiliary complications. If jaundice occurs, a thorough evaluation for alternative etiologies—particularly sepsis, biliary obstruction, and hemolysis—is essential before attributing it to the medications 1.