Marzac Christophe, Teyssandier I, Calendini Ors'Anton, Perrot Jean-Yves, Faussat Anne-Marie, Tang Ruoping, Casadevall Nicole, Marie Jean-Pierre, Legrand Ollivier
Université Pierre et Marie Curie-Paris 6, UMRS 736, Les Cordeliers, INSERM, Paris F-75006, France.
Clin Cancer Res. 2006 Dec 1;12(23):7018-24. doi: 10.1158/1078-0432.CCR-06-0641.
Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification.
We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols.
ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, Pgp-ITD- group), mutually exclusive in 73 of 171 (43%, Pgp-ITD+ and Pgp+ITD- groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P < 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P < 0.0001), WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITD- (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus Pgp- patients. In the Pgp-ITD- group (41 of 95), CR rates were 70% versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P < 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-Pgp-ITD- group were not significantly different from the favorable cytogenetic group.
Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.
具有中等细胞遗传学特征的成年急性髓系白血病（AML）患者仍是一个异质性群体，个体预后差异很大。新的分子标志物有助于完善细胞遗传学分层。
我们评估了P-糖蛋白（Pgp）活性和Flt3内部串联重复（ITD+），因为它们已知具有预后价值，且可能有助于靶向治疗。我们对171例按照欧洲癌症研究与治疗组织方案接受治疗的成年AML患者进行了多变量分析。
在所有患者中，分别有171例中的26例（15%）检测到ITD+，171例中的55例（32%）检测到高Pgp活性（Pgp+）。171例中有94例（55%，Pgp-ITD-组）的ITD和Pgp活性均为阴性，171例中有73例（43%，Pgp-ITD+和Pgp+ITD-组）二者相互排斥，只有171例中的4例（2%，Pgp+ITD+组）患者二者均为阳性。在多变量分析中，Pgp+ITD+（P<0.0001）和年龄（P = 0.0022）是实现完全缓解（CR）的独立预后因素。总生存期（OS）、CR实现情况（P<0.0001）、世界卫生组织体能状态（P = 0.0007）和Pgp+ITD+状态（P = 0.0014）也是独立预后因素。在95例具有中等细胞遗传学特征的患者中，ITD+患者的CR率为40%，而ITD-患者为62%（P = 0.099）；Pgp+患者为41%，Pgp-患者为67%（P = 0.014）。在Pgp-ITD-组（95例中的41例）中，CR率为70%，其他组为44%（P = 0.012），OS分别为48%和16%（P<0.0001），无病生存期分别为56%和27%（P = 0.024）。此外，中等细胞遗传学-Pgp-ITD-组的OS曲线与良好细胞遗传学组无显著差异。
Flt3/ITD和Pgp活性是独立且相加的预后因素，可提供有力的风险分类，可常规用于对具有中等细胞遗传学特征的AML患者进行治疗分层。应考虑对ITD+和Pgp+患者进行靶向治疗。
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