ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial
ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial
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DOI：
10.1038/s41408-019-0211-y
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发表时间：
2019-05-21
影响因子：
12.8
通讯作者：
Lamba, Jatinder K.
中科院分区：
文献类型：
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作者：
Rafiee, Roya;Chauhan, Lata;Lamba, Jatinder K.
Gemtuzumab-ozogamicin（GO）是一种与毒素-加利车霉素-γ连接的人源化抗CD 33抗体，是一种重新出现的有前途的AML药物。加利车霉素是GO的关键成分，一旦连接的CD 33-抗体促进其摄取，就会诱导DNA损伤和细胞死亡。加利车霉素通过药物转运蛋白PgP-1的外排与GO反应有关，因此在本研究中，我们评估了ABCB 1-SNP对GO反应的影响。对942例随机接受加或不加GO标准治疗（COG-AAML 0531）的患者的基因组DNA样本进行ABCB 1-SNP基因分型。我们最有趣的结果显示，对于rs 1045642，在GO组中，与CC基因型患者相比，具有次要T等位基因（CT/TT）的患者具有更好的结局（无事件生存率-EFS：rho = 0.022;复发风险-RR，rho = 0.007）。相比之下，对于No-GO组内的任何临床终点，没有观察到基因型之间的差异（所有rho > 0.05）。当通过GO和No-GO臂比较基因型组时，获得了一致的结果。使用HL 60细胞的体外评价进一步证明了rs 1045642-T等位基因对加利车霉素诱导的DNA损伤和细胞活力的一致影响。我们的研究结果显示了ABCB 1 SNP对AML GO反应的重要性，并证明需要在其他队列中对此进行研究。一旦得到验证，ABCB 1-SNP与CD 33-SNP结合可以为个性化GO治疗提供机会。
Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-gamma 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: rho = 0.022; and risk of relapse-RR, rho = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all rho > 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.