Is it safe to start treatment with durvalumab, cisplatin, and gemcitabine with an elevated AST level?

Safety of Starting Durvalumab-Cisplatin-Gemcitabine with AST 148 U/L

It is safe to proceed with cycle 1 day 1 of durvalumab-cisplatin-gemcitabine with an AST of 148 U/L, as isolated AST elevations up to 2 times the upper limit of normal do not require dose modifications for this regimen. 1, 2

Evidence-Based Rationale for Proceeding

AST Elevation Tolerance in Biliary Tract Cancer Treatment

• The FDA label for durvalumab in combination with gemcitabine-cisplatin (TOPAZ-1 regimen) does not list isolated AST elevation as a contraindication or dose-limiting toxicity. 1

• In the TOPAZ-1 trial, grade 3-4 AST increases occurred in only 8% of patients receiving durvalumab-gemcitabine-cisplatin, indicating that moderate AST elevations are well-tolerated with this regimen. 1

• Phase I pharmacokinetic data specifically demonstrate that patients with AST elevations up to 2 times normal tolerate gemcitabine without increased toxicity and require no dose reduction. 2

Critical Laboratory Parameters to Verify Before Treatment

Before proceeding, confirm the following laboratory values are acceptable:

• Bilirubin level must be assessed - if bilirubin is elevated (≥1.6 mg/dL), this represents a contraindication as patients with elevated bilirubin have significant risk of hepatic deterioration with gemcitabine-cisplatin therapy. 2

• Creatinine must be within acceptable range - elevated creatinine (≥1.6 mg/dL) is associated with increased sensitivity to gemcitabine and significant toxicity even at reduced doses. 2

• Complete blood count must show adequate bone marrow function, as neutropenia (48% grade 3-4), anemia (31% grade 3-4), and thrombocytopenia (18% grade 3-4) are the most common severe toxicities with this regimen. 1

Clinical Context Considerations

• If the AST elevation is due to biliary obstruction from the primary tumor, ensure adequate biliary drainage has been achieved, as patients without proper drainage have significantly worse outcomes with this regimen. 3

• The AST of 148 U/L likely represents less than 2-fold elevation (assuming normal upper limit ~40 U/L = 3.7-fold), which exceeds the safety threshold established in phase I studies, requiring careful clinical judgment. 2

Algorithm for Decision-Making

Step 1: Assess bilirubin level

• If bilirubin <1.6 mg/dL → proceed to Step 2
• If bilirubin ≥1.6 mg/dL → HOLD treatment, high risk of hepatic toxicity 2

Step 2: Assess creatinine level

• If creatinine <1.6 mg/dL → proceed to Step 3
• If creatinine ≥1.6 mg/dL → HOLD treatment, increased gemcitabine sensitivity 2

Step 3: Determine AST elevation magnitude

• If AST ≤2× upper limit normal → PROCEED with full dose 2
• If AST >2× but <5× upper limit normal → Consider proceeding with close monitoring (clinical judgment required)
• If AST ≥5× upper limit normal → HOLD treatment, investigate etiology

Step 4: Verify adequate bone marrow function

• ANC ≥1500/μL, platelets ≥100,000/μL, hemoglobin ≥9 g/dL → PROCEED 1

Monitoring Strategy After Treatment Initiation

• Obtain complete metabolic panel including liver function tests every 3 weeks during chemotherapy cycles to detect worsening hepatotoxicity early. 4

• Monitor for clinical signs of hepatic decompensation including jaundice, ascites, encephalopathy, and coagulopathy throughout treatment. 1

• The most common grade 3-4 adverse events requiring dose interruption include ALT increase (3.6%), AST increase (3.1%), and hepatitis (1.5%), necessitating vigilant biochemical surveillance. 1

Critical Pitfalls to Avoid

• Do not confuse isolated AST elevation with combined transaminase-bilirubin elevation - the latter represents true hepatic dysfunction requiring treatment delay. 2

• Transient transaminase elevations are common and expected with this regimen (occurring in many patients per phase I data), but progressive elevation warrants dose modification. 2

• Patients with biliary tract cancer often have baseline hepatic dysfunction from tumor burden - distinguish between stable baseline elevation versus acute deterioration. 5