儿童急性淋巴细胞白血病治疗失败相关因素分析

doi:10.12372/jcp.2023.22e0067

摘要/Abstract

摘要：

目的探讨儿童急性淋巴细胞白血病（ALL）治疗失败的相关因素。方法随访2013年1月至2017年12月收治的初诊ALL患儿，对124例治疗失败患儿的临床资料进行回顾性分析，比较不同临床特征与复发时间及部位的关系，以及治疗失败的可能危险因素。结果 124例治疗失败患儿中男82例、女42例，初诊时中位年龄为8.0（3.3~13.0）岁，中位随访时间24.0（14.0~43.5）月。治疗失败原因包括复发（104例）、非复发性死亡（19例）及第二肿瘤（1例）。104例复发患儿的中位复发时间为17.7（3.0~57.2）月，其中复发时间以极早期复发为主（52例），复发部位以单纯骨髓复发为主（84例）。复发时间与初诊白细胞计数、免疫分型、不同融合基因及危险度分层相关（P<0.05）；复发部位与初诊白细胞计数、免疫分型有关（P<0.05）。第33天的MRD水平是影响治疗失败生存（TFS）率和总生存（OS）率的独立危险因素（P<0.05）。结论复发是儿童ALL治疗失败的最主要原因，密切监测早期治疗反应，积极预防、治疗极早期复发可降低治疗失败发生率，提高患儿OS率。

关键词: 急性淋巴细胞白血病, 治疗失败, 复发, 微小残留病, 儿童

Abstract:

Objective To explore the related factors of treatment failure in children with acute lymphoblastic leukemia (ALL). Methods The clinical data of 124 newly diagnosed ALL children with treatment failure admitted from January 2013 to December 2017 were retrospective analyzed. The association of different clinical features with recurrence time and sites was compared and the possible risk factors for treatment failure was analyzed. Results By April 15, 2020, the median follow-up time was 24.0 (14.0-43.5) months. Among the 124 children who failed treatment, 82 were boys and 42 were girls. The median age at first diagnosis was 8.0 (3.3-13.0) years. The reasons for treatment failure included recurrence (104 cases), non-recurrent death (19 cases) and secondary tumor (1 case). Totally 104 ALL children relapsed, whose median recurrence time was 17.7 (3.0-57.2) months. Very early recurrence (52 cases) was the commonest recurrence time, and bone marrow (84 cases) was the commonest recurrence site. The recurrence time was correlated with initial white blood cell count, immunophenotyping, different fusion genes and risk stratifications (P<0.05). The recurrence site was correlated with initial white blood cell count and immunophenotyping (P<0.05). MRD level on day 33 was an independent risk factor for treatment failure survival rate (TFS) and overall survival (OS) rate (P<0.05). Conclusions Recurrence is the main cause of treatment failure in children with ALL. Close monitoring of early treatment response, active prevention and treatment of very early recurrence can reduce the incidence of treatment failure and improve the OS rate of children with ALL.

Key words: acute lymphoblastic leukemia, treatment failure, recurrence, minimal residual disease, child

薛玉娟, 陆爱东, 王毓, 贾月萍, 左英熹, 张乐萍. 儿童急性淋巴细胞白血病治疗失败相关因素分析[J]. 临床儿科杂志, 2023, 41(3): 204-209.

XUE Yujuan, LU Aidong, WANG Yu, JIA Yueping, ZUO Yingxi, ZHANG Leping. Clinical analysis of treatment failure in children with acute lymphoblastic leukemia[J]. Journal of Clinical Pediatrics, 2023, 41(3): 204-209.

图/表 3

表1

104例复发ALL患儿临床特征与复发相关性 [n (%)]"

临床特征	例数	复发时间					复发部位
临床特征	例数	极早期	早期	晚期	χ²值	P	骨髓	中枢神经系统	骨髓+中枢神经系统	其他髓外复发	χ²值	P
性别					2.25	0.324					-	0.619¹⁾
男	73	33(45.2)	27(37.0)	13(17.8)			58(79.5)	5(6.8)	8(11.0)	2(2.7)
女	31	19(61.3)	8(25.8)	4(12.9)			26(83.9)	3(9.7)	1(3.2)	1(3.2)
年龄/岁					0.43	0.808					-	0.791¹⁾
≥10	44	23(52.3)	15(34.1)	6(13.6)			34(77.3)	4(9.1)	5(11.4)	1(2.3)
1~10	60	29(48.3)	20(33.3)	11(18.3)			50(83.3)	4(6.7)	4(6.7)	2(3.3)
初诊WBC×10⁹·L^-1					7.53	0.023					-	0.011¹⁾
≥50.0	33	23(69.7)	7(21.2)	3(9.1)			23(69.7)	3(9.1)	7(21.2)	0(0.0)
<50.0	71	29(40.8)	28(39.4)	14(19.7)			61(85.9)	5(7.0)	2(2.8)	3(4.2)
免疫分型					-	0.019¹⁾					-	0.016¹⁾
B-ALL	88	39(44.3)	32(36.4)	17(19.3)			74(84.1)	7(8.0)	4(4.5)	3(3.4)
T-ALL	16	13(81.3)	3(18.8)	0(0.0)			10(62.5)	1(6.3)	5(31.3)	0(0.0)
融合基因					-	0.022¹⁾					-	0.545¹⁾
ETV6-RUNX1⁺	6	0(0.0)	4(66.7)	2(33.3)			5(83.3)	0(0.0)	0(0.0)	1(16.7)
MLL⁺	2	1(50.0)	0(0.0)	1(50.0)			2(100.0)	0(0.0)	0(0.0)	0(0.0)
E2A-PBX1⁺	8	4(50.0)	1(12.5)	3(37.5)			6(75.0)	2(25.0)	0(0.0)	0(0.0)
BCR-ABL1⁺	9	7(77.8)	2(22.2)	0(0.0)			7(77.8)	1(11.1)	1(11.1)	0(0.0)
其他	79	40(50.6)	28(35.4)	11(13.9)			64(81.0)	5(6.3)	8(10.1)	2(2.5)
第15天骨髓原始幼稚淋巴细胞/%					1.71	0.426					-	0.819¹⁾
<5.0	44	21(47.7)	13(29.5)	10(22.7)			34(77.3)	4(9.1)	5(11.4)	1(2.3)
≥5.0	46	27(58.7)	13(28.3)	6(13.0)			39(84.8)	3(6.5)	3(6.5)	1(2.2)
未检测	14	4(28.6)	9(64.3)	1(7.1)			11(78.6)	1(7.1)	1(7.1)	1(7.1)
第33天MRD/%					3.35	0.780					-	0.879¹⁾
≥1.0	21	11(52.4)	7(33.3)	3(14.3)			17(81.0)	1(4.8)	2(9.5)	1(4.8)
0.1~1.0	24	14(58.3)	5(20.8)	5(20.8)			22(91.7)	1(4.2)	1(4.2)	0(0.0)
0.01~0.1	10	4(40.0)	5(50.0)	1(10.0)			9(90.0)	0(0)	1(10.0)	0(0.0)
<0.01	49	23(46.9)	18(36.7)	8(16.3)			36(73.5)	6(12.2)	5(10.2)	2(4.1)
第90天MRD/%					-	0.129¹⁾					-	0.336¹⁾
≥0.1	17	13(76.5)	3(17.6)	1(5.9)			16(94.1)	0(0.0)	0(0.0)	1(5.9)
0.01~0.1	10	6(60.0)	2(20.0)	2(20.0)			10(100.0)	0(0.0)	0(0.0)	0(0.0)
<0.01	77	33(42.9)	30(39.0)	14(18.2)			58(75.3)	8(10.4)	9(11.7)	2(2.6)
复发部位					-	0.321¹⁾					-	-
骨髓	84	45(53.6)	25(29.8)	14(16.7)			-	-	-
中枢神经系统	8	3(37.5)	3(37.5)	2(25)			-	-	-
骨髓+中枢神经系统	9	4(44.4)	4(44.4)	1(11.1)			-	-	-
其他髓外复发	3	0(0.0)	3(100.0)	0(0.0)
危险度					-	0.029¹⁾					-	0.053¹⁾
标危	11	2(18.2)	7(63.6)	2(18.2)			8(72.7)	0(0.0)	1(9.1)	2(18.2)
中危	52	23(44.2)	18(34.6)	11(21.2)			41(78.8)	7(13.5)	4(7.7)	0(0.0)
高危	41	27(65.9)	10(24.4)	4(9.8)			35(85.4)	1(2.4)	4(9.8)	1(2.4)

表1

表2

图1

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预后因素	失败例数	3年OS率/%	χ²值	P	3年TFS率/%	χ²值	P
性别			0.25	0.621		1.91	0.167
男	82	87.2±1.7			81.7±2.0
女	42	87.0±2.1			84.9±2.3
年龄/岁			15.00	0.001		11.82	0.003
≥10	54	79.3±2.9			75.3±3.1
1~10	70	90.6±1.4			86.3±1.6
初诊WBC×10⁹·L^-1			10.41	0.001		10.60	0.001
≥50.0	39	77.9±3.6			73.6±3.8
<50.0	85	89.7±1.4			85.5±1.6
免疫分型			12.98	<0.001		7.04	0.008
T-ALL	23	72.8±5.1			70.3±5.2
B-ALL	101	89.1±1.3			84.7±1.5
融合基因			38.42	<0.001		38.85	<0.001
ETV6/RUNX1⁺	6	97.8±1.6			95.7±2.1
MLL⁺	3	91.7±5.6			91.7±5.6
E2A/PBX1⁺	11	89.7±4.9			79.5±6.5
BCR/ABL1⁺	13	77.7±5.9			74.0±6.2
其他	91	85.6±1.8			81.1±2.0
伴髓外浸润			7.42	0.006		3.69	0.055
是	13	74.4±6.7			74.4±6.7
否	111	88.0±1.4			83.6±1.5
第15天骨髓原始幼稚淋巴细胞/%¹⁾			23.63	<0.001		32.23	<0.001
≥5.0	55	78.2±3.2			70.5±3.5
<5.0	52	92.0±1.4			89.4±1.6
第33天MRD/%²⁾			80.00	<0.001		76.43	<0.001
≥1.0	27	55.9±7.0			52.0±7.1
0.1~1.0	25	77.6±5.1			70.1±5.6
0.01~0.1	10	89.3±3.8			87.1±4.0
<0.01	59	92.3±1.3			88.3±1.5
90天MRD/%³⁾			47.29	<0.001		55.68	<0.001
≥0.1	18	53.1±8.8			46.9±8.8
0.01~0.1	10	76.0±8.5			68.0±9.3
<0.01	92	90.1±1.3			86.2±1.5
危险度分层			53.46	<0.001		47.01	<0.001
标危	13	97.0±1.3			93.6±1.9
中危	60	88.7±1.8			84.0±2.1
高危	51	70.8±3.8			66.7±4.0