儿童急性B淋巴细胞白血病诱导治疗第8天外周血微小残留病的临床意义

魏圣洁; 窦留瑞; 刘炜; 时明月; 肖梦宇; 李丹; 牛晓娜; 牛俊伟; 白炎亮; 孙恺

doi:10.7619/jcmp.20220480

儿童急性B淋巴细胞白血病诱导治疗第8天外周血微小残留病的临床意义

1.
郑州大学人民医院, 河南郑州, 450003
2.
河南省儿童医院血液肿瘤科, 河南郑州, 450000
3.
河南省人民医院血液科, 河南郑州, 450003

基金项目:

国家自然科学基金项目 81971508

详细信息

通讯作者:
孙恺, E-mail: sunkai@cellscience.org

中图分类号: R733.71;R552
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- 文章访问数: 182
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出版历程
- 收稿日期: 2022-02-16
- 网络出版日期: 2022-08-22

Clinical significance of peripheral blood minimal residual disease detection at the eighth day of induction therapy in children with B-cell acute lymphoblastic leukemia

1.
People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003
2.
Department of Hematology and Oncology, Henan Children's Hospital, Zhengzhou, Henan, 450000
3.
Department of Hematology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003

摘要

摘要:
目的
基于TARGET数据库分析诱导治疗第8天外周血微小残留病(MRD)检测在急性B淋巴细胞白血病(B-ALL)患儿预后评估中的临床意义。
方法
下载TARGET数据库中2000—2010年诱导治疗第8天外周血MRD和第29天骨髓MRD资料完整的359例B-ALL患儿的数据。采用Spearman相关分析法探讨第8天外周血MRD与同期骨髓细胞形态学的相关性。采用Kaplan-Meier曲线分析第8天外周血MRD与无事件生存(EFS)的关系, 并分析第8天外周血MRD联合第29天骨髓MRD与EFS率的关系。采用Cox回归分析探讨B-ALL患儿预后的危险因素。
结果
Spearman相关分析显示，第8天外周血MRD与同期骨髓原始细胞占比呈正相关(r=0.620, P < 0.001)。生存曲线显示，第8天外周血MRD < 0.01%、0.01%~ < 0.10%、0.10%~ < 1.00%、≥1.00%患儿的5年EFS率比较，差异有统计学意义(P < 0.001)。第8天外周血MRD与第29天骨髓MRD检测结果双阴性者预后最佳，单阳性者次之，双阳性者预后最差，差异有统计学意义(P < 0.001)。第29天骨髓MRD阴性患儿中，第8天外周血MRD阴性者的5年EFS率高于第8天外周血MRD阳性者，差异有统计学意义(P=0.009)。Cox回归分析显示，第8天外周血MRD≥0.10%(HR=1.967, 95%CI为1.234~3.134, P=0.004)、第29天骨髓MRD≥0.01%(HR=2.076, 95%CI为1.423~3.027, P < 0.001)均为B-ALL患儿EFS的独立危险因素。
结论
诱导治疗第8天外周血MRD在儿童B-ALL预后评估中具有重要的临床意义，可作为第29天骨髓MRD的强有力补充。
- 儿童 /
- 急性B淋巴细胞白血病 /
- 外周血 /
- 微小残留病 /
- 无事件生存 /
- TARGET数据库
Abstract:
Objective
To analyze clinical significance of peripheral blood minimal residual disease (MRD) detection at the eighth day of induction therapy in evaluating prognosis of children with B-cell acute lymphoblastic leukemia (B-ALL) based on the TARGET database.
Methods
Data of 359 B-ALL children with peripheral blood MRD at the eighth day of induction therapy and bone marrow MRD at 29th day of induction therapy from year 2000 to 2010 were downloaded from TARGET database. Spearman correlation analysis was used to explore the association between peripheral blood MRD at the eighth day and morphology of bone marrow cells in the same period. Kaplan-Meier curve was used to analyze the relationship between peripheral blood MRD at the eighth day and event free survival (EFS), and further analyze the relationship of combined detection of peripheral blood MRD at the eighth day and bone marrow MRD at 29th day with EFS. Cox regression model was used to analyze the risk factors for prognosis in B-ALL children.
Results
Spearman correlation analysis showed that the level of peripheral blood MRD at the eighth day was positively correlated with the proportion of bone marrow blasts at day 8 (r=0.620, P < 0.001). Survival analysis showed that there were significant differences in 5-year EFS rates of MRD < 0.01%, 0.01% to 0.10%, 0.10% to 1.00% and ≥ 1.00% in peripheral blood at the eighth day(P < 0.001). Double-negative patients with peripheral blood MRD at the 8th day and bone marrow MRD at the 29th day had the best prognosis, followed by single-positive patients, and double-positive patients had the worst prognosis, the differences were statistically significant (P < 0.001). The combined MRD at both time points showed that the prognosis was best in the double-negative group, followed by the single-positive group and worst in the double-positive group (P < 0.001). In children with negative bone marrow MRD at day 29, the 5-year EFS rate of children negative for MRD in peripheral blood at the eighth day was significantly higher than those positive for MRD in peripheral blood at the eighth day(P=0.009). Cox regression analysis showed that MRD ≥ 0.10% in peripheral blood on day 8(HR=1.967; 95%CI, 1.234 to 3.134; P=0.004), MRD ≥ 0.01% in bone marrow on day 29 (HR=2.076; 95%CI, 1.423 to 3.027; P < 0.001) were independent risk factors for EFS in B-ALL children.
Conclusion
Peripheral blood MRD at day 8 of induction therapy has important clinical significance in prognosis assessment in children with B-ALL, and can be used as a strong supplement for the prognosis assessment of B-ALL children with bone marrow MRD at day 29.
- children /
- B-cell acute lymphoblastic leukemia /
- peripheral blood /
- minimal residual disease /
- event free survival /
- TARGET database

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图 1 诱导治疗第8天不同外周血MRD水平B-ALL患儿的生存曲线

下载: 全尺寸图片幻灯片

图 2 诱导治疗第29天不同骨髓MRD水平B-ALL患儿的生存曲线

下载: 全尺寸图片幻灯片

图 3 第8天外周血MRD与第29天骨髓MRD联合检测不同结果患儿的生存曲线

下载: 全尺寸图片幻灯片

图 4 第29天骨髓MRD阴性患儿第8天外周血MRD阳性、阴性者的生存曲线

下载: 全尺寸图片幻灯片

图 5 第29天骨髓MRD阳性患儿第8天外周血MRD阳性、阴性者的生存曲线

下载: 全尺寸图片幻灯片

表 1 359例B-ALL患儿的临床特征分析

特征	分类	[n(%)]
性别	男	219(61.0)
	女	140(39.0)
年龄	< 10岁	176(49.0)
	≥10岁	183(51.0)
白细胞	< 50×10⁹/L	219(61.0)
	≥50×10⁹/L	140(39.0)
TCF3-PBX1基因	阴性	321(89.4)
	阳性	38(10.6)
ETV6-RUNX1基因	阴性	324(90.3)
	阳性	35(9.7)
4号和10号染色体三倍体	阴性	324(90.3)
	阳性	35(9.7)
MLL基因重排	阴性	337(93.9)
	阳性	22(6.1)
BCR-ABL1基因	阴性	353(98.3)
	阳性	6(1.7)
DNA指数	< q1.16	308(85.8)
	≥1.16	51(14.2)
第8天骨髓原始细胞占比	< 20%	219(61.0)
	≥20%	140(39.0)
第29天骨髓原始细胞占比	< 5%	349(97.2)
	≥5%	10(2.8)
第8天外周血MRD	< 0.01%	45(12.5)
	0.01%~ < 0.10%	65(18.1)
	0.10%~ < 1.00%	114(31.8)
	≥1.00%	135(37.6)
第29天骨髓MRD	< 0.01%	227(63.2)
	0.01%~ < 0.10%	47(13.1)
	0.10%~ < 1.00%	54(15.0)
	≥1.00%	31(8.6)
MRD: 微小残留病。

下载: 导出CSV

表 2 B-ALL患儿EFS的单因素和多因素Cox回归分析

变量	单因素分析			多因素分析
变量	HR	95%CI	P	HR	95%CI	P
年龄	1.205	0.859~1.688	0.280	—	—	—
白细胞	1.466	1.047~2.053	0.026	1.287	0.914~1.813	0.149
DNA指数	0.330	0.162~0.675	0.002	0.250	0.087~0.716	0.010
ETV6-RUNX1基因	0.412	0.192~0.881	0.022	0.540	0.250~1.170	0.118
4号和10号染色体三倍体	0.427	0.200~0.914	0.028	1.541	0.501~4.736	0.450
MLL基因重排	1.560	0.841~2.894	0.159	—	—	—
TCF3-PBX1基因	1.253	0.744~2.112	0.396	—	—	—
BCR-ABL1基因	1.622	0.516~5.095	0.407	—	—	—
第8天骨髓原始细胞占比	1.866	1.332~2.613	< 0.001	1.070	0.731~1.567	0.726
第29天骨髓原始细胞占比	4.404	2.236~8.676	< 0.001	2.636	1.309~5.307	0.007
第8天外周血MRD	2.502	1.609~3.890	< 0.001	1.967	1.234~3.134	0.004
第29天骨髓MRD	2.720	1.937~3.820	< 0.001	2.076	1.423~3.027	< 0.001
MRD: 微小残留病。

下载: 导出CSV

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