Kunadt Desiree, Kramer Michael, Dill Claudia, Altmann Heidi, Wagenführ Lisa, Mohr Brigitte, Thiede Christian, Röllig Christoph, Schetelig Johannes, Bornhäuser Martin, Schaich Markus, Stölzel Friedrich
Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Department of hematology, oncology and palliative care, Rems-Murr-Klinikum, Winnenden, Germany.
Biomark Res. 2020 Jun 12;8:20. doi: 10.1186/s40364-020-00200-9. eCollection 2020.
Lysyl oxidase (LOX) has been described as necessary for premetastatic niche formation in epithelium-derived malignancies and its expression level therefore correlates with risk of metastatic disease and overall survival. However, its role in acute myeloid leukemia (AML) has not been sufficiently analyzed.
We investigated LOX plasma expression in 683 AML patients (age 17-60 years) treated within the prospective AML2003 trial (NCT00180102). The optimal cut-off LOX value was determined using a minimal--value method dichotomizing patients into a LOX-high group (> 109 ng/mL, = 272, 40%) and a LOX-low group (≤ 109 ng/mL, = 411, 60%).
Higher LOX expression was associated with lower peripheral white blood cells, lower serum LDH, and a lower frequency of -ITD and mutations at diagnosis. Higher LOX expression was found significantly more frequently in patients with secondary AML and therapy-related AML, in patients with French-American-British M5 subtypes, and in patients with adverse-risk cytogenetics. Comparing patients in the LOX-high group and the LOX-low group revealed a 3-year overall survival (OS) of 47 and 53% ( = 0.022) and 3-year event-free survival (EFS) of 27 and 35% ( = 0.005), respectively. In the LOX-high group significantly more patients had extramedullary AML compared to the LOX-low group ( = 0.037). Combining extramedullary AML and LOX as interacting factors in a multivariate analysis resulted in an independent impact on survival for the LOX-high-extramedullary interaction for OS (HR = 2.25, = 0.025) and EFS (HR = 2.48, = 0.008). Furthermore, in patients with extramedullary disease ( = 59) the LOX level predicted survival. Patients within the LOX-low group had an OS of 43% and EFS of 36% as compared to the LOX-high group with an OS of 13% and EFS of 6% ( = 0.002 and = 0.008, respectively).
We hypothesize LOX expression to be a new potential biomarker to predict outcome in AML, specifically in AML subgroups such as the prognostic heterogeneous group of AML patients with extramedullary disease.
This retrospective study was performed with patient samples registered within the prospective AML2003 trial (NCT00180102). Patients were enrolled between December 2003 and November 2009.
赖氨酰氧化酶（LOX）被认为是上皮源性恶性肿瘤中形成前转移微环境所必需的，因此其表达水平与转移性疾病风险和总生存率相关。然而，其在急性髓系白血病（AML）中的作用尚未得到充分分析。
我们在一项前瞻性AML2003试验（NCT00180102）中，对683例年龄在17至60岁之间接受治疗的AML患者的血浆LOX表达进行了研究。采用最小值法确定最佳LOX临界值，将患者分为LOX高表达组（>109 ng/mL，n = 272例，40%）和LOX低表达组（≤109 ng/mL, n = 411例，60%）。
较高的LOX表达与较低的外周血白细胞计数、较低的血清乳酸脱氢酶水平以及诊断时较低的NPM1内部串联重复（-ITD）和FLT3突变频率相关。继发性AML和治疗相关AML患者、法国-美国-英国（FAB） M5亚型患者以及具有不良风险细胞遗传学的患者中LOX高表达更为常见。比较LOX高表达组和低表达组患者，3年总生存率（OS）分别为47%和53%（P = 0.022）, 3年无事件生存率（EFS）分别为27%和35%（P = 0.005）。与LOX低表达组相比，LOX高表达组中有髓外AML的患者明显更多（P = 0.037）。在多变量分析中，将髓外AML和LOX作为相互作用因素进行合并分析，结果显示LOX高表达-髓外相互作用对OS（HR = 2.25，P = 0.025）和EFS（HR = 2.48，P = 0.008）具有独立的生存影响。此外，在有髓外疾病的患者（n =59）中，LOX水平可预测生存情况。与LOX高表达组的OS为13%和EFS为6%相比，LOX低表达组患者的OS为43%，EFS为36%（P分别为0.002和0.008）。
我们推测LOX表达是预测AML预后的一种新的潜在生物标志物，特别是在AML亚组中，例如预后异质性的有髓外疾病的AML患者群体。
本回顾性研究使用了前瞻性AML2003试验（NCT00180102）中登记的患者样本。患者于2003年1月至2009年11月入组。
