379P Impact of MGMT and ABCB1 single nucleotide polymorphisms on temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma

Abstract

Chemo-induced thrombocytopenia is a limiting adverse event in glioblastoma patients receiving temozolomide (TMZ). Constitutional single nucleotide polymorphisms (SNP) of genes involved in the pharmacodynamics and pharmacokinetics of TMZ were described to be associated with increased risk of TMZ-induced myelotoxicity in retrospective cohorts. We prospectively investigate the risk of thrombocytopenia (<100G/L) regarding MGMT rs2308327 and ABCB1 rs1045642. A total of 100 newly-diagnosed glioblastoma patients, receiving standard treatment (concomitant TMZ and radiotherapy [RT] followed by TMZ maintenance phase), were included in the study. Loss of function allelic variants rs2308327 of the MGMT gene; and rs1045642 of the ABCB1 gene were characterized using Taqman® PCR. Using univariate and multivariate logistic regression we investigated the association between SNPs and TMZ-induced thrombocytopenia occurrence along first-line treatment schedule and overall survival. This study is ancillary to the ongoing prospective phase 2 GLIOPLAK trial (NCT02617745). Overall, 23/100 patients experienced TMZ-induced thrombocytopenia: 11 patients during the RT-TMZ phase and 12 other patients during the TMZ maintenance phase. Among them, 7 patients experienced severe thrombocytopenia <50 G/l. Observed allele frequencies were in accordance with those reported for Caucasians (11% for MGMT rs2308327 and 47.5% for ABCB1 rs1045642). Harboring rs2308327 or rs1045642 was not associated with TMZ-induced thrombocytopenia: odds ratio (OR) 1.1 [CI 95% 0.3-3.2, p=0.56] and OR 1.01 [0.49-2.09, p=0.55] respectively. Severe thrombocytopenia (<50 G/L, n=7 patients) were not associated with any of the two SNPs. Wild-type versus heterozygous or homozygous SNP did not influence overall survival, log-rank test p=0.19 and p=0.34 respectively. Occurrence of thrombocytopenia <100 G/l induced an underexposure to TMZ in maintenance phase: median 3 cycles vs 5 in the no thrombocytopenia group. rs2308327 and rs1045642 were not associated with TMZ-related thrombocytopenia in a prospective population of glioblastoma.