Lamba Jatinder K, Chauhan Lata, Shin Miyoung, Loken Michael R, Pollard Jessica A, Wang Yi-Cheng, Ries Rhonda E, Aplenc Richard, Hirsch Betsy A, Raimondi Susana C, Walter Roland B, Bernstein Irwin D, Gamis Alan S, Alonzo Todd A, Meshinchi Soheil
Jatinder K. Lamba, Lata Chauhan, and Miyoung Shin, University of Florida, Gainesville, FL; Michael R. Loken, Hematologics Inc; Rhonda E. Ries, Irwin D. Bernstein, and Soheil Meshinchi, Fred Hutchinson Cancer Research Center; Roland B. Walter and Soheil Meshinchi, University of Washington, Seattle, WA; Jessica A. Pollard, Maine Medical Center, Portland, ME; Jessica A. Pollard, Tufts University, Boston, MA; Yi-Cheng Wang, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Richard Aplenc, Children's Hospital of Philadelphia, Philadelphia, PA; Betsy A. Hirsch, University of Minnesota, Minneapolis, MN; Susana C. Raimondi, St Jude Children's Research Hospital, Memphis, TN; and Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO.
J Clin Oncol. 2017 Aug 10;35(23):2674-2682. doi: 10.1200/JCO.2016.71.2513. Epub 2017 Jun 23.
Purpose Gemtuzumab 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 Methods CD33 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. Results The 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 < 1.0E) and with lower diagnostic leukemic cell surface CD33 intensity ( P < 1.0E). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.
目的 吉妥珠单抗奥唑米星（GO）是一种靶向CD33的免疫偶联物，是一种重新出现的急性髓系白血病（AML）治疗方法。剪接增强子区域的CD33单核苷酸多态性rs12459419 C>T可调节缺少外显子2的可变剪接CD33异构体（D2-CD33）的表达，从而消除了作为GO抗体结合位点的CD33 IgV结构域以及诊断性免疫表型分析。我们旨在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。
患者与方法 根据儿童肿瘤学组AAML0531试验，对新诊断的AML患者进行CD33剪接单核苷酸多态性评估，这些患者被随机分配接受单纯标准五疗程化疗（无GO组，n = 408）或在诱导期和强化期各加用两剂GO的化疗（GO组，n = 408）。
结果 415例患者（51%）的rs12459419基因型为CC，316例患者（39%）为CT，85例患者（10%）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转录本显著相关（P < 1.0E），与较低的诊断性白血病细胞表面CD33强度显著相关（P < 1.0E）。CC基因型患者在GO组的复发风险显著低于无GO组（26%对49%；P < .001）。然而，在CT或TT基因型患者中，使用GO并不影响复发风险（39%对40%；P = .85）。GO组中CC基因型患者的无病生存率高于无GO组（分别为65%对46%；P = .004），但在CT或TT基因型患者中未观察到加用GO的这种益处。
结论 我们的结果表明，rs12459419基因型为CC的患者对GO有显著反应，使其成为选择可能对GO有显著反应患者的潜在生物标志物。
