HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer

Abstract

Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.

Experimental design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.

Results: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.

Conclusions: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.

Figure 1.

Association between HLA-B*57:01 carriage and maximum on-treatment ALT in pazopanib-treated patients from the combined data (N = 2,190).

Figure 2.

Cumulative incidence of ALT > 3× ULN (A) and ALT > 5× ULN events (B) by HLA-B*57:01 carriage status in pazopanib-treated patients from the combined data (N = 2,190). The x-axis was truncated at 100 days.

Figure 3.

A model of pazopanib (light pink carbons) bound to HLA-B*57:01. Abacavir (orange carbons) from the crystal structure of abacavir bound to HLA-B*57:01 is overlaid for reference. Crystallographic water molecules retained in the model are represented as red spheres. Protein-ligand interactions are represented by dashed lines. The binding site surface is colored green for hydrophobic regions, blue for mild polar regions, and magenta for hydrogen-bonding regions. Image produced using Molecular Operating Environment software version 2012.10; Chemical Computing Group Inc.