Final results of the UGT1A1-based dose modification of irinotecan and its impact on rates of severe neutropenia and hospitalization.

Abstract

461 Background: UGT1A1 7/7 genotype has been associated with a 3-fold increase in severe neutropenia for patients treated with irinotecan (IRI) (Mcleod 2010, Liu 2013). UGT1A1 determination may tailor IRI therapy and reduce toxicities. However, the impact of the FDA-recommended IRI dose modification on outcomes is unclear. Methods: UGT1A1 genotyping was done for patients with various cancers wherein IRI therapy was planned and who consented to 1 of 3 IRB-approved registries. For patients with UGT1A1 7/7, a reduction in IRI doses was recommended per FDA and toxicities monitored during the first 2 doses. Results: 323/341 patients registered had UGT1A1 determined, of which 13% (42/323) had the 7/7 or 7/8 genotypes. Notably, a significantly higher proportion of African-Americans (AA) harbor these genotypes compared to Caucasians (C) (26.32% vs 10.08%, p=0.001). Among the 251 evaluable for toxicities, the incidence of grade 3-5 ANC for patients with 7/7 was not significantly different than those with 6/6 or 6/7 (Kendall's Tau-b coefficient p=0.494) (see Table). Among the 7/7 patients, 23/33 were treated at IRI doses of 150 mg/m2 or higher. 30% of patients treated at the higher dosages still developed grade 3-5 neutropenia compared to 17-21% for those with other genotypes. 38 of 251 patients were hospitalized during their first 2 cycles of therapy. The proportion of hospitalized patients with 7/7 genotype was not significantly different than those with 6/6 or 6/7 (15% vs 17% vs 12.6%). Conclusions: UGT1A1 can be used to tailor IRI therapy and reduce toxicities. The incidence of severe neutropenia and rate of hospitalization is comparable among patients with all UGT1A1 genotypes when IRI dose is adjusted for those with UGT1A1 7/7. There is a higher incidence of UGT1A1 7/7 genotype among African-Americans comnpared to Caucasians, which warrants further evaluation. [Table: see text]