儿童急性淋巴细胞白血病第15天微小残留与预后的关系

doi:10.3969/j.issn.1004-583X.2024.01.008

摘要/Abstract

摘要：

目的分析儿童急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)第15天微小残留(minimal residual disease, MRD)与预后的关系,并以第15天MRD 0.01%、0.1%、1%这三个数值为临界值建立模型以评估其预测价值。方法收集广东医科大学附属医院儿童医学中心2016年01月至2020年10月共90例住院ALL患儿的临床资料,采用Cox回归模型分析各临床特征的独立预后价值。分别用0.01%、0.1%、1%作为第15天MRD临界值形成3个Cox回归模型,用似然比检验评估不同模型对数据的拟合效果。结果 90例ALL患儿的5年总生存率为(69.1±5.6)%,截至随访截止日期,总体死亡率为25.6%(23/90)。Cox多因素回归分析显示:当以MRD为0.01%和0.1%为阳性参考值时,第15天MRD是影响ALL儿童预后的独立危险因素( $P$ ＜0.05)。用似然比检验评估不同预后模型对数据的拟合效果显示:以0.1%为临界值构建预测模型其预测ALL临床结局的效能更佳。结论第15天MRD是影响患儿预后的独立危险因素,且以0.1%为临界值时更具临床预测价值。

关键词: 前体细胞淋巴母细胞白血病淋巴瘤, 儿童, 危险因素, 微小残留, 预后

Abstract:

Objective To analyze the relationship between minimal residual disease (MRD) on day 15 and prognosis in children with acute lymphoblastic leukemia (ALL), and to create a prediction model based on the cut-off values of MRD as 0.01%, 0.1% and 1% on day 15 to predict the prognosis of ALL in children. Methods The clinical data of 90 children with ALL from January 2016 to October 2020 in the Medical Center of Children, Affiliated Hospital of Guangdong Medical University were collected. The Cox regression model was used to analyze the independent prognostic value of each clinical feature. With 0.01%, 0.1%, and 1% of MRD on day 15 as the cut-off values, three Cox regression models were created and validated for the fitting effect via the likelihood ratio test. Results The 5-year survival of 90 children with ALL was 69.1%±5.6%. As of the last follow-up visit, the overall mortality was 25.6% (23/90). Cox multivariate regression analysis showed that MRD on day 15 was an independent risk factor for the prognosis of ALL children when MRD was 0.01% and 0.1% as positive reference values ( $P$ <0.05). The likelihood ratio test was used to evaluate the fitting effect of different prognostic models on the data. The results showed that the prediction model with 0.1% of MRD as the cut-off value had a better prediction efficacy for the clinical outcome of ALL. Conclusion On day 15, MRD is an independent risk factor for the prognosis of children with ALL, and the cut-off value of 0.1% is more valuable for clinical prediction.

Key words: precursor cell lymphoblastic leukemia-lymphoma, child, risk factors, minimal residue, prognosis

中图分类号:

R733.7

刘丽丽, 袁宇婷, 赖耿良, 田川, 蓝翔, 叶中绿. 儿童急性淋巴细胞白血病第15天微小残留与预后的关系[J]. 临床荟萃, 2024, 39(1): 47-52.

Liu Lili, Yuan Yuting, Lai Gengliang, Tian Chuan, Lan Xiang, Ye Zhonglv. The relationship between minimal residual disease on day 15 and prognosis in children with acute lymphoblastic leukemia[J]. Clinical Focus, 2024, 39(1): 47-52.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2024.01.008

https://huicui.hebmu.edu.cn/CN/Y2024/V39/I1/47

图/表 4

表1 90例ALL患儿临床特征及实验室检查[例(%)]

Tab.1 Clinical characteristics and laboratory examination of 90 children with ALL (cases [%])

临床特征	例数(%)
性别
男	54(60.0)
女	36(40.0)
年龄
<1岁	2(2.5)
1~9岁	80(88.8)
≥10	8(8.7)
初诊WBC
<10×10⁹/L	40(44.4)
10~50×10⁹/L	32(35.6)
50~300×10⁹/L	14(15.6)
≥300×10⁹/L	4(4.4)
免疫分型
B系	79(87.8)
T系	11(12.2)
危险度分级
低危	26(28.9)
中危	36(40.0)
高危	28(31. 1)
融合基因
BCR/ABL	5(6.0)
MLL重排	3(3.6)
E2A-PBX1	4(4.8)
TEL-AML1	16(19.3)
阴性	55(66.3)
未检测	7(7.8)
泼尼松试验反应
良好	72(80.0)
不良	18(20.0)
第15天骨髓涂片
M1	76(84.5)
M2	10(11.1)
M3	4(4.4)
第15天MRD(以0.01%为参考值)
≥0.01%	60(66.7)
<0.01%	30(33.3)
第15天MRD(以0.1%为参考值)
≥0.1%	59(65.6)
<0.1%	31(34.4)
第15天MRD(以1%为参考值)
≥1%	39(43.3)
<1%	51(56.6)
髓外浸润
中枢神经系统白血病	1(1.11)
睾丸白血病	1(1.11)

表2 90例ALL儿童临床预后因素分析

Tab.2 Analysis of clinical prognostic factors in 90 children with ALL

预后因素	单因素分析			多因素分析
预后因素	$P$ 值	$R R$ 值	95% $C I$	$P$ 值	$R R$ 值	95% $C I$
性别	0.169	1.810	0.777~4.216	0.953	0.965	0.294~3.171
免疫分型	0.278	0.439	0.099~1.943
年龄	0.482	1.049	0.917~1.201
危险度分级	0.188	3.083	0.922~10.315	0.132	2.552	0.660~9.872
初诊WBC	0.181	0.996	0.990~1.002	0.055	0.092	0.983~1.000
初诊血红蛋白	0.569	1.006	0.986~1.026
初诊血小板计数	0.296	0.997	0.993~1.002
融合基因
$T E L - A M L 1$	0.365	0.510	0.119~2.189
$B C R / A B L$	0.214	2.174	0.639~7.397
$E 2 A / P B X 1$	0.954	1.062	0.140~8.035
$M L L$ 重排	0.481	0.065	0.000~249.118
泼尼松试验	0.029	2.535	1.102~2.830	0.065	4.024	0.981~14.641
MRD1	0.078	2.996	0.886~10.133	0.039	0.070	0.006~0.871
MRD2	0.031	4.979	1.163~21.316	0.009	40.612	2.490~662.340
MRD3	0.311	1.527	0.673~3.462
中枢神经系统白血病	0.700	0.654	0.075~5.706
睾丸白血病	0.714	0.048	0.000~526218.723

表2 90例ALL儿童临床预后因素分析

Tab.2 Analysis of clinical prognostic factors in 90 children with ALL

预后因素	单因素分析			多因素分析
预后因素	$P$ 值	$R R$ 值	95% $C I$	$P$ 值	$R R$ 值	95% $C I$
性别	0.169	1.810	0.777~4.216	0.953	0.965	0.294~3.171
免疫分型	0.278	0.439	0.099~1.943
年龄	0.482	1.049	0.917~1.201
危险度分级	0.188	3.083	0.922~10.315	0.132	2.552	0.660~9.872
初诊WBC	0.181	0.996	0.990~1.002	0.055	0.092	0.983~1.000
初诊血红蛋白	0.569	1.006	0.986~1.026
初诊血小板计数	0.296	0.997	0.993~1.002
融合基因
$T E L - A M L 1$	0.365	0.510	0.119~2.189
$B C R / A B L$	0.214	2.174	0.639~7.397
$E 2 A / P B X 1$	0.954	1.062	0.140~8.035
$M L L$ 重排	0.481	0.065	0.000~249.118
泼尼松试验	0.029	2.535	1.102~2.830	0.065	4.024	0.981~14.641
MRD1	0.078	2.996	0.886~10.133	0.039	0.070	0.006~0.871
MRD2	0.031	4.979	1.163~21.316	0.009	40.612	2.490~662.340
MRD3	0.311	1.527	0.673~3.462
中枢神经系统白血病	0.700	0.654	0.075~5.706
睾丸白血病	0.714	0.048	0.000~526218.723

表3 临床预测模型分析

Tab.3 Analysis of clinical prediction model

	Model 1	Model 2	Model 3
$P$ 值	0.0455	0.0074	0.6139
loglik 值	-76.955	-75.379	-78.327
concordance	0.573	0.614	0.514

表3 临床预测模型分析

Tab.3 Analysis of clinical prediction model

	Model 1	Model 2	Model 3
$P$ 值	0.0455	0.0074	0.6139
loglik 值	-76.955	-75.379	-78.327
concordance	0.573	0.614	0.514

表4 不同临界值分组间临床特征比较

Tab.4 Comparison of clinical characteristics between groups with different cut-off values

项目	以0.01%为临界值				以0.1%为临界值				以1%为临界值
项目	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]		MRD≥0.01% [例(%)]	χ²值		$P$ 值
总例数	30	60			31	59			51		39
性别
男女	20 10	34 26	0.833	0.361	20 11	34 25	0.402	0.526	32 19		22 17	0.370		0.543
年龄
<1岁	0	2			0	2			0		2
1~9岁	28	52	0.901	0.616	28	52	0.803	0.868	45		35	3.210		0.192
≥10岁	2	6			3	5			6		2
初诊WBC(×10⁹ /L)
<10	17	23			19	21			30		10
10~50	10	22	3.874	0.261	9	23	6.029	0.098	17		15	14.251		0.002
50~300	3	11			3	11			3		11
≥300	0	4			0	4			1		3
初诊血红蛋白
≤90 g/L >90 g/L	23 7	47 13	0.032	0.858	24 7	46 13	0.004	0.953	40 11		30 9	0.029		0.865
初诊血小板计数(×10⁹ /L)
≤100 >100	26 4	43 17	2.516	0.113	26 5	43 16	1.372	0.241	38 13		31 8	0.306		0.580
中枢神经系统白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
睾丸白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
危险度分型
低危	17	9			17	9			24		2
中危	5	31	18.430	0.000	7	29	15.716	0.000	18		18	20.959		0.000
高危	8	20			7	21			9		19
免疫分型
B系 T系	26 4	53 7	0.000	1.000	28 3	51 8	0.038	0.845	46 5		33 6	0.227		0.634
TEL-AML1
阳性阴性	8 22	8 52	2.432	0.119	10 21	6 53	6.783	0.009	12 39		4 35	2.664		0.103
BCR/ABL
阳性阴性	1 29	4 56	0.026	0.871	1 30	4 55	0.046	0.830	1 50		4 35	1.533		0.216
E2A/PBX1
阳性阴性	1 29	3 57	0.000	1.000	1 30	3 56	0.000	1.000	1 50		3 36	0.626		0.429
MLL重排
阳性阴性	0 30	3 57	0.388	0.533	1 30	2 57	0.000	1.000		1 50	2 37		0.056		0.813
泼尼松试验
良好不良	28 2	44 16	5.000	0.025	30 1	42 17	8.316	0.004		48 3	24 15		14.661		0.000
D15骨髓缓解状态
M1	29	47			30	46				50	26
M2	1	9	4.617	0.085	1	9	5.008	0.064		1	9		16.267		0.000
M3	0	4			0	4				0	4

表4 不同临界值分组间临床特征比较

Tab.4 Comparison of clinical characteristics between groups with different cut-off values

项目	以0.01%为临界值				以0.1%为临界值				以1%为临界值
项目	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]		MRD≥0.01% [例(%)]	χ²值		$P$ 值
总例数	30	60			31	59			51		39
性别
男女	20 10	34 26	0.833	0.361	20 11	34 25	0.402	0.526	32 19		22 17	0.370		0.543
年龄
<1岁	0	2			0	2			0		2
1~9岁	28	52	0.901	0.616	28	52	0.803	0.868	45		35	3.210		0.192
≥10岁	2	6			3	5			6		2
初诊WBC(×10⁹ /L)
<10	17	23			19	21			30		10
10~50	10	22	3.874	0.261	9	23	6.029	0.098	17		15	14.251		0.002
50~300	3	11			3	11			3		11
≥300	0	4			0	4			1		3
初诊血红蛋白
≤90 g/L >90 g/L	23 7	47 13	0.032	0.858	24 7	46 13	0.004	0.953	40 11		30 9	0.029		0.865
初诊血小板计数(×10⁹ /L)
≤100 >100	26 4	43 17	2.516	0.113	26 5	43 16	1.372	0.241	38 13		31 8	0.306		0.580
中枢神经系统白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
睾丸白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
危险度分型
低危	17	9			17	9			24		2
中危	5	31	18.430	0.000	7	29	15.716	0.000	18		18	20.959		0.000
高危	8	20			7	21			9		19
免疫分型
B系 T系	26 4	53 7	0.000	1.000	28 3	51 8	0.038	0.845	46 5		33 6	0.227		0.634
TEL-AML1
阳性阴性	8 22	8 52	2.432	0.119	10 21	6 53	6.783	0.009	12 39		4 35	2.664		0.103
BCR/ABL
阳性阴性	1 29	4 56	0.026	0.871	1 30	4 55	0.046	0.830	1 50		4 35	1.533		0.216
E2A/PBX1
阳性阴性	1 29	3 57	0.000	1.000	1 30	3 56	0.000	1.000	1 50		3 36	0.626		0.429
MLL重排
阳性阴性	0 30	3 57	0.388	0.533	1 30	2 57	0.000	1.000		1 50	2 37		0.056		0.813
泼尼松试验
良好不良	28 2	44 16	5.000	0.025	30 1	42 17	8.316	0.004		48 3	24 15		14.661		0.000
D15骨髓缓解状态
M1	29	47			30	46				50	26
M2	1	9	4.617	0.085	1	9	5.008	0.064		1	9		16.267		0.000
M3	0	4			0	4				0	4

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