Chauhan Lata, Shin Miyoung, Wang Yi-Cheng, Loken Michael, Pollard Jessica, Aplenc Richard, Hirsch Betsy A, Raimondi Susana, Ries Rhonda E, Bernstein Irwin D, Gamis Alan S, Alonzo Todd A, Meshinchi Soheil, Lamba Jatinder K
University of Florida, Gainesville, FL.
Children's Oncology Group, Monrovia, CA.
JCO Precis Oncol. 2019 May 23;3. doi: 10.1200/PO.18.00387. eCollection 2019.
The US Food and Drug Administration recently announced reapproval of gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to develop strategies for effective use of GO. In light of our recent report showing prognostic significance of splicing single nucleotide polymorphisms (SNPs), the objective of this study was to comprehensively evaluate SNPs for accurate prediction of patients with AML who are more or less likely to respond to GO.
We investigated the five new SNPs (rs2455069, rs35112940, rs61736475, rs1803254, and rs201074739) for association with CD33 leukemic cell surface expression and clinical response in pediatric patients with AML enrolled in the Children's Oncology Group AAML0531 trial. We further developed a composite CD33 pharmacogenetics (PGx) score using six SNPs (CD33_PGx6_score) for association with clinical outcome.
Four SNPs were associated with cell surface CD33 levels and clinical response in the GO versus no-GO arms. Therefore, the CD33_PGx6_score was built using directional genotype scores for the previously reported splicing SNP and five new SNPs. Patients with a CD33_PGx6_score of 0 or higher had higher CD33 expression levels compared with patients with a score of less than 0 ( < .001). In addition, patients with a score of 0 or higher demonstrated an improved disease-free survival in the GO versus no-GO arms (62.5% ± 7.8% 46.8% ± 8.3%, respectively; = .008) and a reduced risk of relapse (28.3% ± 7.2% 49.9% ± 8.4%, respectively; < .001). No improvement from GO was observed in patients with a CD33-PGx6_score of less than 0. Consistent results were observed across the risk groups.
In this study, we report a composite CD33_PGx6_score using directional genotype scores of SNPs. Once validated, our findings hold promise for use of the CD33_PGx6_score to guide efficient use of GO in patients with AML. In addition, because the CD33_PGx6_score considers SNPs with varying abundance in different ethnic groups, it has potential for global application.
美国食品药品监督管理局最近宣布重新批准吉妥单抗奥唑米星（GO）用于治疗CD33阳性急性髓系白血病（AML），从而为制定有效使用GO的策略创造了机会。鉴于我们最近的报告显示剪接单核苷酸多态性（SNP）具有预后意义，本研究的目的是全面评估SNP，以准确预测对GO反应可能性大小不同的AML患者。
我们在儿童肿瘤学组AAML0531试验中，研究了5个新的SNP（rs2455069、rs35112940、rs61736475、rs1803254和rs201074739）与CD33白血病细胞表面表达及临床反应的相关性。我们进一步使用6个SNP开发了一个复合CD33药物遗传学（PGx）评分（CD33_PGx6_score），以评估其与临床结局的相关性。
4个SNP与GO治疗组和非GO治疗组的细胞表面CD33水平及临床反应相关。因此，CD33_PGx6_score是使用先前报道的剪接SNP和5个新SNP的定向基因型评分构建的。CD33_PGx6_score为0或更高的患者与评分低于0的患者相比，CD33表达水平更高（P<0.001）。此外，评分0或更高的患者在GO治疗组与非GO治疗组中无病生存率有所提高（分别为62.5%±7.8%和46.8%±8.3%；P = 0.008），复发风险降低（分别为28.3%±7.2%和49.9%±8.4%；P<0.001）。CD33-PGx6_score低于0的患者未观察到GO治疗带来的改善。在各风险组中观察到了一致的结果。
在本研究中，我们报告了使用SNP定向基因型评分的复合CD33_PGx6_score。一旦得到验证，我们的研究结果有望使用CD33_PGx6_score来指导AML患者有效使用GO。此外，由于CD33_PGx6_score考虑了不同种族中丰度不同的SNP，它具有全球应用的潜力。
