文章：

ABCB1单核苷酸多态性可预测接受吉妥珠单抗奥佐米星治疗的急性髓系白血病患者预后：来自儿童肿瘤协作组AAML0531试验的报告

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children’s Oncology Group AAML0531 Trial

原文发布日期：2019-05-21

DOI: 10.1038/s41408-019-0211-y

类型: Article

开放获取: 是

英文摘要：

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.
 

摘要翻译： 

吉姆单抗-奥佐米星（GO）是一种与毒素卡奇霉素γ连接的人源化抗CD33抗体，是急性髓系白血病（AML）治疗中重新涌现且前景广阔的药剂。作为GO的关键组分，卡奇霉素在连接的CD33抗体促进其内化后，可诱导DNA损伤与细胞死亡。既往研究提示药物转运蛋白PgP-1介导的卡奇霉素外排与GO疗效相关，故本研究评估了ABCB1基因单核苷酸多态性（SNPs）对GO疗效的影响。我们对942例随机接受标准治疗（联合或不联合GO）患者的基因组DNA样本（COG-AAML0531试验）进行了ABCB1-SNPs分型。最值得关注的结果显示：在GO治疗组中，rs1045642位点携带次要T等位基因（CT/TT）的患者较CC基因型患者预后更优（无事件生存期EFS：p=0.022；复发风险RR：p=0.007）。相反，在非GO治疗组中，所有临床终点指标均未观察到基因型间差异（所有p>0.05）。通过治疗组间基因型比较获得了一致结论。利用HL60细胞进行的体外实验进一步证实rs1045642-T等位基因对卡奇霉素诱导的DNA损伤及细胞活力存在一致性影响。本研究揭示了ABCB1 SNPs对AML患者GO疗效的重要意义，有必要在其他队列中深入验证。若获证实，ABCB1-SNPs与CD33-SNPs的联合检测将为GO个体化治疗开辟新途径。

原文链接：

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children’s Oncology Group AAML0531 Trial