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

CF Xu, T Johnson, X Wang, C Carpenter… - Clinical Cancer …, 2016 - AACR
CF Xu, T Johnson, X Wang, C Carpenter, AP Graves, L Warren, Z Xue, KS King, DJ Fraser…
Clinical Cancer Research, 2016AACR
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 …
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. Clin Cancer Res; 22(6); 1371–7. ©2015 AACR.
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