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

Abstract

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

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.

Figures/Tables 3

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)

References 24

[1]	Zheng R, Peng X, Zeng H, et al. Incidence, mortality and survival of childhood cancer in China during 2000-2010 period: a population-based study[J]. Cancer Lett, 2015, 363(2): 176-180. doi: 10.1016/j.canlet.2015.04.021 pmid: 25917566
[2]	Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014[J]. CA Cancer J Clin, 2014, 64(2): 83-103. doi: 10.3322/caac.21219
[3]	Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia[J]. Haematologica, 2020, 105(11): 2524-2539. doi: 10.3324/haematol.2020.247031 pmid: 33054110
[4]	Kato M, Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia[J]. Pediatr Int, 2018, 60(1): 4-12. doi: 10.1111/ped.13457 pmid: 29143423
[5]	张之南, 沈悌. 血液病诊断及疗效标准[M]. 北京: 科学出版社, 2007.
[6]	李宗儒, 赵婷, 刘艳荣, 等. 微小残留病在高危Ph阴性急性淋巴细胞白血病中的意义[J]. 中华血液学杂志, 2019, 40(7): 554-560.
[7]	Xue YJ, Wang Y, Jia YP, et al. The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia[J]. Int J Hematol, 2021, 113(4): 547-555. doi: 10.1007/s12185-020-03063-w
[8]	Inaba H, Pui CH. Advances in the diagnosis and treatment of pediatric acute lymphoblastic leukemia[J]. J Clin Med, 2021, 10(9): 1926. doi: 10.3390/jcm10091926
[9]	Cui L, Li ZG, Chai YH, et al. Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: the first nation-wide prospective multicenter study in China[J]. Am J Hematol, 2018, 93(7): 913-920. doi: 10.1002/ajh.25124 pmid: 29675840
[10]	朱嘉莳, 李红, 邵静波, 等. 急性淋巴细胞白血病儿童治疗失败原因的分析[J]. 上海交通大学学报(医学版), 2021, 41(6): 764-769.
[11]	Jaime-Pérez JC, Pinzón-Uresti MA, Jiménez-Castillo RA, et al. Relapse of childhood acute lymphoblastic leukemia and outcomes at a reference center in Latin America: organomegaly at diagnosis is a significant clinical predictor[J]. Hematology, 2018, 23(1): 1-9. doi: 10.1080/10245332.2017.1333294 pmid: 28580844
[12]	Oskarsson T, Söderhäll S, Arvidson J, et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome[J]. Haematologica, 2016, 101(1): 68-76. doi: 10.3324/haematol.2015.131680 pmid: 26494838
[13]	高伟, 蒋梦影, 高莉, 等. 儿童急性淋巴细胞白血病治疗失败的相关因素分析[J]. 中国实验血液学杂志, 2021, 29(3): 661-668.
[14]	Gaudichon J, Jakobczyk H, Debaize L, et al. Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: reconciling biological concepts and clinical issues[J]. Blood Rev, 2019, 36: 40-56. doi: S0268-960X(18)30078-X pmid: 31010660
[15]	Lenk L, Alsadeq A, Schewe DM. Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data[J]. Cancer Metastasis Rev, 2020, 39(1): 173-187. doi: 10.1007/s10555-020-09848-z
[16]	Yu X, Zhang H, Yuan M, et al. Identification and characterization of a murine model of BCR-ABL1⁺ acute B-lymphoblastic leukemia with central nervous system metastasis[J]. Oncol Rep, 2019, 42(2): 521-532.
[17]	Liao C, Xu X, Shen D, et al. Minimal residual disease-guided risk restratification and therapy improves the survival of childhood acute lymphoblastic leukemia: experience from a tertiary children's hospital in China[J]. J Pediatr Hematol Oncol, 2019, 41(6): e346-e354. doi: 10.1097/MPH.0000000000001412
[18]	Campana D, Pui CH. Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia[J]. Blood, 2017, 129(14): 1913-1918. doi: 10.1182/blood-2016-12-725804 pmid: 28167658
[19]	冯静, 陈晓娟, 刘晓明, 等. 多参数流式细胞术检测的微小残留病与儿童急性B淋巴细胞白血病预后的相关性研究[J]. 中华血液学杂志, 2019, 40(8): 678-680.
[20]	Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232[J]. Blood, 2015, 126(8): 964-971. doi: 10.1182/blood-2015-03-633685 pmid: 26124497
[21]	Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study[J]. Lancet Oncol, 2015, 16(4): 465-474. doi: 10.1016/S1470-2045(15)70082-3
[22]	Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic leukemia[J]. Cancer Metastasis Rev, 2019, 38(4): 595-610. doi: 10.1007/s10555-019-09834-0
[23]	O'Connor D, Bate J, Wade R, et al. Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003[J]. Blood, 2014, 124(7): 1056-1061. doi: 10.1182/blood-2014-03-560847 pmid: 24904116
[24]	Inaba H, Pei D, Wolf J, et al. Infection-related com-plications during treatment for childhood acute lymphoblastic leukemi a[J]. Ann Oncol, 2017, 28(2): 386-392. doi: 10.1093/annonc/mdw557 pmid: 28426102

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

Clinical analysis of treatment failure in children with acute lymphoblastic leukemia

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