CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531
CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531
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DOI：
10.1200/jco.2016.71.2513
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发表时间：
2017-08-10
影响因子：
45.3
通讯作者：
Meshinchi, Soheil
中科院分区：
文献类型：
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作者：
Lamba, Jatinder K.;Chauhan, Lata;Meshinchi, Soheil
目的吉妥珠单抗奥佐米星 (GO) 是一种靶向 CD33 的免疫偶联物，是一种重新出现的治疗急性髓系白血病 (AML) 的疗法。剪接增强子区域中的 CD33 单核苷酸多态性 rs12459419 C>T 调节缺乏外显子 2 的选择性剪接 CD33 同工型 (D2-CD33) 的表达，从而消除 CD33 IgV 结构域（GO 以及诊断免疫表型组的抗体结合位点）。我们的目的是确定这种剪接多态性的基因型对接受含 GO 化疗的 AML 患者的影响。 患者和方法 在新诊断的 AML 患者中评估 CD33 剪接单核苷酸多态性，这些患者被随机分配接受标准五疗程单独化疗（No-GO 组，n = 408）或化疗加两剂 GO，一次在诱导期间，一次在诱导期间添加一次。 根据儿童肿瘤组 AAML0531 试验，强化（GO 组，n = 408）。 结果 rs12459419 基因型在 415 名患者 (51%) 中为 CC，在 316 名患者 (39%) 中为 CT，在 85 名患者 (10%) 中为 TT，次要等位基因频率为 30%。 T 等位基因与较高水平的 D2-CD33 转录物显着相关 (P
PurposeGemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy.Patients and MethodsCD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial.ResultsThe rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript (P