Lo-Coco Francesco, Cuneo Antonio, Pane Fabrizio, Cilloni Daniela, Diverio Daniela, Mancini Marco, Testoni Nicoletta, Bardi Antonella, Izzo Barbara, Bolli Niccolò, La Starza Roberta, Fazi Paola, Iacobelli Simona, Piciocchi Alfonso, Vignetti Marco, Amadori Sergio, Mandelli Franco, Pelicci Pier Giuseppe, Mecucci Cristina, Falini Brunangelo, Saglio Giuseppe
Department of Biopathology, University Tor Vergata, via Montpellier 1, 00161 Rome, Italy.
Haematologica. 2008 Jul;93(7):1017-24. doi: 10.3324/haematol.12004. Epub 2008 May 27.
Recent advances in genetic characterization of acute myeloid leukemia indicate that combined cytogenetic and molecular analyses provide better definition of prognostic groups. The aim of this study was to verify this prospectively in a large group of patients.
Genetic characterization was prospectively carried out in 397 patients with acute myeloid leukemia (median age, 46 years) receiving uniform treatment according to the LAM99P protocol of the Italian GIMEMA group. The impact of genetic markers on response to therapy and outcome was assessed by univariate and multivariate analyses.
For induction response, conventional karyotyping identified three groups with complete remission rates of 92%, 67% and 39% (p<0.0001). Complete remission rates in NPM1 mutated (NPM1+) and wild-type (NPM1-) groups were 76% and 60%, respectively, for the whole population and 81% and 61% in the group with normal karyotype (p<0.001 and p=0.026, respectively). Multivariate analysis indicated that low risk karyotype and NPM1+ were independent factors favorably affecting complete remission. Multivariate analysis of overall and disease-free survival among 269 patients who achieved complete remission showed a significant impact of karyotype on both estimates and of FLT3 status on disease free-survival (FLT3-ITD vs. FLT3 wild-type, p=0.0001). NPM1 status did not significantly influence disease free-survival in either the whole population or in the patients with a normal karyotype in this series, probably due to the low number of cases analyzed.
These results reiterate the prognostic relevance of combining cytogenetic and mutational analysis in the diagnostic work up of patients with acute myeloid leukemia.
急性髓系白血病基因特征的最新进展表明，细胞遗传学和分子分析相结合能更好地定义预后分组。本研究旨在对一大组患者进行前瞻性验证。
对397例急性髓系白血病患者（中位年龄46岁）进行前瞻性基因特征分析，这些患者按照意大利GIMEMA组的LAM99P方案接受统一治疗。通过单因素和多因素分析评估基因标志物对治疗反应和预后的影响。
对于诱导缓解，传统核型分析确定了三组，完全缓解率分别为92%、67%和39%（p<0.0001）。在整个群体中，NPM1突变（NPM1+）组和野生型（NPM1-）组的完全缓解率分别为76%和60%，在核型正常的组中分别为81%和61%（分别为p<0.001和p=0.026）。多因素分析表明，低风险核型和NPM1+是有利于完全缓解的独立因素。对269例实现完全缓解的患者进行总生存期和无病生存期的多因素分析显示，核型对这两个评估指标均有显著影响，FLT3状态对无病生存期有显著影响（FLT3-ITD与FLT3野生型，p=0.0001）。在本系列研究中，NPM1状态在整个群体或核型正常的患者中均未对无病生存期产生显著影响，可能是由于分析的病例数较少。
这些结果再次强调了在急性髓系白血病患者诊断检查中结合细胞遗传学和突变分析的预后相关性。
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