奥佐美星
医学
卡奇霉素
内科学
单核苷酸多态性
肿瘤科
药物基因组学
依托泊苷
柔红霉素
队列
SNP公司
诱导化疗
髓系白血病
化疗
药理学
生物
基因型
遗传学
干细胞
川地34
CD33
基因
作者
Vivek M. Shastri,Lata Chauhan,Mohammed Gbadamosi,Todd A. Alonzo,Yi-Cheng Jim Wang,Richard Aplenc,Betsy A. Hirsch,E. Anders Kolb,Alan S. Gamis,Soheil Meshinchi,Jatinder K. Lamba
标识
DOI:10.1158/1078-0432.ccr-23-2073
摘要
Comprehensive pharmacogenomics (PGx) evaluation of calicheamicin-pathway to identify predictive PGx markers of response to gemtuzumab ozogamicin (GO) treatment in acute myeloid leukemia (AML).Single nucleotide polymorphisms (SNPs) in DNA-damage response (DDR) pathway genes were tested for association with event-free survival (EFS), overall-survival (OS), risk of relapse after induction 1 (RR1) in patients treated with standard chemotherapy consisting of Ara-C, Daunorubicin and Etoposide (ADE) with or without addition of GO on COG-AAML03P1 and COG-AAAML0531 trials (ADE+GO, n=755; ADE n=470). SNPs with significant association with any endpoint within ADE+GO arm but not in the ADE arm were tested using multi-SNP modeling to develop DDR_PGx7 Score.Patients with low-DDR_PGx7 score (<0) had significantly worse EFS (HR=1.51, 95%CI (1.21-1.89), P<0.001), worse OS (HR=1.59, 95%CI (1.22-2.08), P<0.001), and higher RR1 (HR=1.87, 95%CI(1.41-2.47), P<0.0001) compared to patients with high-DDR_PGx7 score (≥0) when treated with GO (ADE+GO cohort). However, no difference between low and high DDR_PGx7 score groups was observed for EFS, OS, and RR1 (all P>0.3) in patients treated on ADE arm.Our results suggest that DDR pathway-based pharmacogenomic score holds potential to predict outcome in patients treated with GO which consists of DNA damaging cytotoxin, calicheamicin. The potential clinical relevance for this score to personalize GO in AML requires further validation in independent and expanded cohorts.
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