急性髓细胞白血病细胞遗传学与预后相关性的研究
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摘要
急性髓细胞性白血病(Acute myeloid leukemia,AML)是造血系统的恶性肿瘤,而肿瘤的发生发展与染色体的改变密切相关。研究表明,绝大多数白血病患者都有非随机的染色体畸变,它们对于白血病的诊断分型,预后估计,治疗方案的选择乃至发病机制的研究都有极为重要的价值。本文对我院2001-2006年期间132例AML患者(排除急性早幼粒细胞白血病患者)进行了染色体核型分析,对参与诱导治疗的101例患者进行生存随访,得出以下结论:(1)本组病例的染色体异常发生率为62.1%,染色体异常的形式广泛,但以结构异常为主。部分染色体异常和特定的FAB亚型相关,正因如此,根据以细胞遗传学/分子生物学特征为主线进行相应调整的WHO分型,更适合现代白血病治疗策略的制定。(2)急性髓细胞性白血病的细胞遗传学与预后具有相关性。inv(16)/del(16q)组缓解率高,生存期长,预后较好;不伴有t(8;21)的复杂核型、del(9q),-7,生存期短,预后差;未知组在生存期与缓解率上均与中危组无差异,预后中等。(3)t(8;21)的3个亚组,即单纯t(8;21)组,t(8;21)不伴del(9q)、复杂核型的附加组,伴del(9q)、复杂核型的t(8;21)附加组,之间比较,单纯t(8;21)组的缓解率,优于t(8;21)不伴del(9q)、复杂核型的附加组,两者的中位生存期分别为18.3个月、8.8个月,尽管无统计学差异,但单纯t(8;21)组生存时间明显较长。伴del(9q)、复杂核型的t(8;21)附加组与单纯t(8;21)比较,无论是缓解率或生存期均无明显差异,此结果与国内研究不符,但因该组样本量较小,并非确切结论。从t(8;21)各亚组的缓解率及生存期来看,随着样本量的扩大,有出现单纯t(8;21)组优于附加组的可能。
The incidence and development of tumors which maybe closely related to cytogenetic abnormalities. Acute myeloid leukemia (AML) is right a malignant tumor of hemopoietic system. It has been studied that the majority of patients with leukemia have non-random chromosome aberrations which may provide important information for typing, prognostic evaluation, options of treatment, and even the researches of pathogenesis. The purpose of this article is to study the distribution of karyotype and the relationship between chromosome abnormalities and prognostic in AML according to known domestic and international hierarchical cytogenetic classification. Karyotype analysis of 132 cases which were newly diagnosed as AML (excluding patients with acute promyelocytic leukemia) in our hospital from January 2001 to June 2006 were performed. The clinical data and survival state of 101 cases with induction therapy were recorded through a follow-up. Kaplan-Meier life-tables were constructed for survival data and were compared by means of the Log-rank test. Cox regression was used to analysis the several possible factors influencing survival of AML. The result shows: (1) In this study M2 is the most common type of AML. 82 patients presented clonal chromosome abnormalities, and rate of abnormality is 62.1%. (2) Forty-two kind of abnormalities were observed, including simply structural abnormalities, simply numerical abnormalities and compound abnormalities. The proportion of the three groups above are 41.5%, 28%, and 30.5% respectively. t (8; 21) (q22; q22) is the most common structural rearrangement, and rate is 28.8%. Inv (16)/del (16q), +21, -7, del (9q) are also observed frequently. (3) 101 patients with induction therapy were categorized into favorable, intermediate, unfavorable and unknown risk groups based on SWOG coding. Median overall survive time varied significantly between unfavorable risk group and all other three groups. There was similar significant heterogeneity of median disease-free survival time. Although there was no statistical difference in CR rates. (4) These 101 patients were also categorized into seven subgroups based on different hierarchical cytogenetic classifications. CR rate varied significantly between the simply t (8; 21) group and the t (8; 21) additional group without del (9q) and complex abnormalities, also between the latter and intermediate risk group. Median overall survive time varied significantly between the unfavorable risk group without t (8; 21) [del(9q), complex abnormalities without t (8; 21), -7] and all other six groups. (5) Median survival time was longer in the group with finally achieving complete remission (HR=0.0147). In the light of the analysis above, we can come to the following conclusions: (1) The rate of chromosome abnormalities is 62.1%. The kinds of cytogenetic abnormalities are varies, but structure abnormality is primary. Some abnormalities have been invariably associated with a specific FAB group; (2) Cytogenetic analysis is recognized as an important prognostic factor in acute leukemia. In this study, group with inv (16) /del (16q) has an superior CR and OS to others; The overall survival time of unfavorable risk group without t (8; 21) [del (9q), complex abnormalities without t (8; 21), -7] is shorter than others; (3) The simply t (8; 21) group has an superior CR to the t (8; 21) additional group without del (9q) and complex abnormalities. There was no statistical difference in survival time between intermediate risk group and group with t (8; 21), regardless of additional cytogenetic abnormalities. However, the overall survival time of the simply t (8; 21) group is longer. With the expansion of the sample, the simple t (8;21) group may be better than the t (8; 21) additional group.
The incidence and development of tumors which maybe closely related to cytogenetic abnormalities. Acute myeloid leukemia (AML) is right a malignant tumor of hemopoietic system. It has been studied that the majority of patients with leukemia have non-random chromosome aberrations which may provide important information for typing, prognostic evaluation, options of treatment, and even the researches of pathogenesis. The purpose of this article is to study the distribution of karyotype and the relationship between chromosome abnormalities and prognostic in AML according to known domestic and international hierarchical cytogenetic classification. Karyotype analysis of 132 cases which were newly diagnosed as AML (excluding patients with acute promyelocytic leukemia) in our hospital from January 2001 to June 2006 were performed. The clinical data and survival state of 101 cases with induction therapy were recorded through a follow-up. Kaplan-Meier life-tables were constructed for survival data and were compared by means of the Log-rank test. Cox regression was used to analysis the several possible factors influencing survival of AML. The result shows: (1) In this study M2 is the most common type of AML. 82 patients presented clonal chromosome abnormalities, and rate of abnormality is 62.1%. (2) Forty-two kind of abnormalities were observed, including simply structural abnormalities, simply numerical abnormalities and compound abnormalities. The proportion of the three groups above are 41.5%, 28%, and 30.5% respectively. t (8; 21) (q22; q22) is the most common structural rearrangement, and rate is 28.8%. Inv (16)/del (16q), +21, -7, del (9q) are also observed frequently. (3) 101 patients with induction therapy were categorized into favorable, intermediate, unfavorable and unknown risk groups based on SWOG coding. Median overall survive time varied significantly between unfavorable risk group and all other three groups. There was similar significant heterogeneity of median disease-free survival time. Although there was no statistical difference in CR rates. (4) These 101 patients were also categorized into seven subgroups based on different hierarchical cytogenetic classifications. CR rate varied significantly between the simply t (8; 21) group and the t (8; 21) additional group without del (9q) and complex abnormalities, also between the latter and intermediate risk group. Median overall survive time varied significantly between the unfavorable risk group without t (8; 21) [del(9q), complex abnormalities without t (8; 21), -7] and all other six groups. (5) Median survival time was longer in the group with finally achieving complete remission (HR=0.0147). In the light of the analysis above, we can come to the following conclusions: (1) The rate of chromosome abnormalities is 62.1%. The kinds of cytogenetic abnormalities are varies, but structure abnormality is primary. Some abnormalities have been invariably associated with a specific FAB group; (2) Cytogenetic analysis is recognized as an important prognostic factor in acute leukemia. In this study, group with inv (16) /del (16q) has an superior CR and OS to others; The overall survival time of unfavorable risk group without t (8; 21) [del (9q), complex abnormalities without t (8; 21), -7] is shorter than others; (3) The simply t (8; 21) group has an superior CR to the t (8; 21) additional group without del (9q) and complex abnormalities. There was no statistical difference in survival time between intermediate risk group and group with t (8; 21), regardless of additional cytogenetic abnormalities. However, the overall survival time of the simply t (8; 21) group is longer. With the expansion of the sample, the simple t (8;21) group may be better than the t (8; 21) additional group.
引文
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[3] David Grimwade, Helen Walker, Fiona Oliver, et al. The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1, 612 Patients Entered Into the MRC AML 10 Trial [J]. Blood, 1998,92(7):2322-2333.
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[5] Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t (8; 21) (q22; q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia, 1996;10:1288-1295.
[6] Nishi K, Usui E, Katayama N, et al. Characteristics of t (8; 21) acute myeloid leukemia (AML) with additional chromosomalabnormality: concomitant trisomy 4 may constitute a distinctive subtype of t (8; 21) AML. Leukemia, 2003,17:731-737.
[7] Second International Workshop on Chromosomes in Leukemia 1979. Cytogenetic, morphologic and clinical correlations in acute nonlymphocytic leukemia with t (8q2; 21q+).Cancer Genet Cytogenet; 1980;2:99-102.
[8] Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t (8; 21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML intergroup. Blood, 2002;99:3517-3523.
[9] Marcucci G, Mrózek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t (8; 21) differ from those of patients with inv (16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705-5717.
[10] 石红霞, 江滨, 丘镜莹, 等. 成人t (8; 21) 急性髓系白血病M2型治疗方案及预后分析[J]. 中华血液学杂志, 2005,26:481-484.
[11] 赖悦云, 邱镜滢, 江滨, 等. T (8; 21) 急性髓性白血病72例的特征分析. 北京大学学报, 2005,37:245-248.
[12] De Botton S, Chevret S, Sanz M, et al. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial[J]. Br J hematol, 2000 Dec; 111(3):801-6.
[13] Marilyn L, Slovak, Kenneth J. Kopey, Peter A. Cassileth, et al.Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study[J]. Blood, 2000,96(13):4075-4083.
[14] Hiorn LR, Swansbury GJ, Mehta J, et al. Additional chromosome abnormalities confer worse prognosis in acute promyelocytic [J]. Br J hematol, 1997,96:314-321.
[15] 程淑琴, 裴仁治, 马俊霞, 等. 急性早幼粒细胞白血病附加染色体异常与预后的关系. 浙江医学, 2000,22:385-387.
[16] Romayne Holmes, Michael J. Keating, et al. A Unique Pattern of Central Nervous System Leukemia in Acute Myelomonocytic Leukemia Associated With inv (16) (p13q22). Blood, 1985;65: 1071-1077.
[17] Krzysztof Mrózek, Clara D. Bloomfield, Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia. Hematology, 2006 (1):169-177.
[18] Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98:1312-1320.
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