Abstract
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.
Highlights
Gemtuzumab ozogamicin (GO), a CD33-antibody conjugated to cytotoxin-calicheamcin[1] is a re-emerging and promising drug in AML treatment
Given that riskgroups impact clinical responses to GO and allele-frequency of rs1045642 SNP differ by risk-group classification (Supplementary Table 2), we evaluated ABCB1 SNPs within low, standard and high-risk group patients by treatment arms
We evaluated whether the most studied SNPs within ABCB1 have an influence on treatment outcome in patients receiving GO based therapy in the randomized AAML0531 clinical trial. rs1045642, commonly referred to as C3435T is a synonymous change (Ile1145Ile) in exon[27] of ABCB1 and has been shown to occur in partial LD with two coding SNPs rs1128503 (Gly412Gly) and rs2032582 (Ser893Ala/ Thr). rs1045642-T allele has been shown to be associated with lower ABCB1 expression in several studies[18,19,20,21,22], and with higher expression in one study[23]
Summary
Gemtuzumab ozogamicin (GO), a CD33-antibody conjugated to cytotoxin-calicheamcin[1] is a re-emerging and promising drug in AML treatment. In light of encouraging results from several randomized studies[2,3,4,5,6,7,8], recent re-approval of GO by FDA is a big step in treatment of AML. Given the anticipated increase in GO use, there is an urgent unmet need to identify biomarkers that can improve our ability to personalize GO. We recently reported a splicing-polymorphism in CD33, with significant impact on GO response[9], these encouraging results prompted us to investigate additional biomarkers that can impact GO-response. Since anti-leukemic effects of GO are due to calicheamicin-induced DNA damage, intracellular abundance of calicheamicin is critical for its anti-leukemic effect. PgP1, encoded by ABCB1, influences the accumulation of calicheamicin and its expression levels has been
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