Genome-Wide Association Study of the Human Genetic Factors Influencing the Risk of Adverse Events during Idelalislib Therapy in Patients with Relapsed Indolent Lymphoma

Introduction: Idelalisib (IDELA) is a selective inhibitor of PI3Kδ that has demonstrated efficacy in indolent lymphoma. In the NCT01659021 (101-09) study in patients (pts) with previously treated iNHL, the ORR was 57%. However, in this heavily-treated and refractory population, 27.2% (34/125 pts) discontinued the study due to reported ≥ grade 3 adverse events (AEs). This analysis aims to investigate an underlying genetic molecular mechanism(s) that may contribute to IDELA associated AEs.

Methods: We performed a genome-wide association study (GWAS) to determine if common genetic factors influence the risk of AEs. We utilized available DNA samples from 66 subjects from the 101-09 clinical study to conduct genotyping at 2,088,393 single nucleotide polymorphisms (SNPs) using the Illumina HumanOmni2.5 high-density BeadArray chip. In parallel, we also conducted Illumina whole exome sequencing (WES) to identify causal functional variation, as well as to examine the role of rare functional variations that may influence the development of AEs. The phenotypic endpoints assessed in this GWAS analysis were: grade ≥3 any AE, diarrhea/colitis (DC), abnormal liver function test (LFT) and pneumonitis. True controls were defined as subjects with no reported AEs of any grade.

Results: Logistic regression analysis of the combined AE groups, DC, and pneumonitis status, identified no common SNPs among Caucasians, or any ethnic subgroups that exceeded the genome-wide threshold for statistical significance. For the abnormal LFT phenotype, a total of seven SNPs (four in the all ethnicity and three in the Caucasian subgroup analysis) were found to exceed the genome-wide threshold for statistical significance. Six of these SNPs were considered false positives resulting from the small sample size. The remaining SNP (rs1351623), located in intron 1 of the tachykinin receptor 3 (TACR3) gene, was present in 12 out of 23 controls (minor allele frequency of 28.3% vs. 17.6% in the general population), but was completely absent from the 9 pts in the abnormal LFT case group, suggesting that the minor allele may be protective against altered liver function. However, TACR3 does not have an obvious biological role in mediating liver function and we were unable to identify any potentially causal functional variants in TACR3 or any other genes in close proximity which could sufficiently explain the observed association. Follow-up analysis of this association using statistical tests more robust for rare data indicated that this association may much more likely be due to chance (p=0.0187; Firth logistic regression). Analyses of the WES dataset using single variant and gene-based collapsing tests showed no single nucleotide variants or genes that exceeded the threshold for statistical significance after correcting for multiple testing.

Conclusion: With the current dataset, no evidence was observed to support a role for human genetic variation of large effect size in influencing the risk of AEs during IDELA therapy. In pts with abnormal LFTs, we identified 7 SNPs that exceeded the genome-wide threshold for statistical significance. All but one of these associations were found to be false positives and there was no compelling evidence to support the remaining association with the rs1351623 SNP in TACR3. In both the GWAS and WES, significance scores from virtually all association analyses showed evidence of moderate p-value deflation, suggesting that the analyses were underpowered due to the limited sample size of the study. Therefore, further genetic studies using larger cohorts of patients treated with IDELA are needed to determine if genetic factors influence the risk of adverse events.