儿童急性淋巴细胞白血病化疗期间严重不良事件临床观察

doi:10.3969/j.issn.1004-583X.2023.02.009

摘要/Abstract

摘要：

目的总结儿童急性淋巴细胞白血病患儿接受儿童急性淋巴细胞白血病治疗协作组2016方案(SCCLG-ALL-2016方案)治疗过程中严重不良事件(severe adverse events, SAE)的发生情况,并分析发生SAE后死亡的相关危险因素。方法回顾性分析2017 年 12 月至 2021 年1月于广东医科大学附属医院儿科确诊并接受 SCCLG-ALL-2016 方案治疗的82 例急性淋巴细胞白血病患儿的临床特点,将化疗过程中发生SAE的患儿(n=21)分为死亡组(n=6)与存活组(n=15),分析化疗过程中发生SAE后导致死亡的相关危险因素。结果在各治疗阶段中,以诱导缓解治疗阶段(30.9%)记录到的SAE数最多。血液学相关SAE(60.3%)是主要的SAE。在发生的非血液学相关不良事件中,感染相关SAE占比最大(76.1%),其中又以呼吸系统感染事件的发生次数最多。在死亡组的6名患儿中,5名患儿因感染或合并明确感染因素死亡,占死亡原因的83.3%。结论 SCCLG-ALL-2016方案治疗儿童急性淋巴细胞白血病过程中发生的SAE主要发生在诱导缓解治疗阶段,以血液学相关SAE为主;在非血液学相关不良事件中,感染相关SAE占比最高,同时也是化疗期间死亡的重要原因。染色体检查结果阳性可能与死亡结局相关。

关键词: 前体细胞淋巴母细胞白血病淋巴瘤, 儿童, 严重不良反应, 感染, 危险因素

Abstract:

Objective To analyze the risk factors of severe adverse event(SAE)-related deaths in children with acute lymphoblastic leukemia (ALL) by summarizing the incidence of SAE during chemotherapy in patients receiving SCCLG-all-2016 regimen. Methods A retrospective analysis was performed on 82 ALL children admitted to the Department of Pediatrics of Affiliated Hospital of Guangdong Medical University, those children were treated with SCCLG-ALL-2016 regimen from December 2017 to January 2021, totally 21 children with SAE were assinged to death group (n=6) and survival group (n=15) to investigate the risk factors of SAE-related deaths during chemotherapy. Results Among the treatment stages, the largest number of SAEs was recorded in the stage of induction remission(30.9%). Hematology-related SAEs (60.3%) accounted for the majority of all SAEs. Among the non-hematology related SAEs, infection-related SAE accounted for the largest proportion (76.1%), and respiratory infection was the most frequent. Among the 6 children in the death group, 5 died of infection or co-infection factors, accounting for 83.3% of the causes of death. Conclusion For ALL children treated with SCCLG-ALL-2016 regimen, SAEs occurre mainly in the induced remission stage, mainly manifested as hematology-related SAE. Infection-related SAEs account for the highest proportion of non-hematology-related SAEs and are also important causes of death during chemotherapy. Positive chromosome results may be associated with death outcomes.

Key words: precursor cell lymphoblastic leukemia-lymphoma, child, severe adverse reactions, infection, risk factors

中图分类号:

R733.7

杜佳宜, 刘丽丽, 何永忠, 田川, 蓝翔, 叶中绿. 儿童急性淋巴细胞白血病化疗期间严重不良事件临床观察[J]. 临床荟萃, 2023, 38(2): 149-154.

Du Jiayi, Liu Lili, He Yongzhong, Tian Chuan, Lan Xiang, Ye Zhonglyu. Clinical observation of serious adverse events in children with acute lymphoblastic leukemia during chemotherapy[J]. Clinical Focus, 2023, 38(2): 149-154.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2023.02.009

https://huicui.hebmu.edu.cn/CN/Y2023/V38/I2/149

图/表 6

表1 各化疗阶段SAE发生情况

Tab. 1 The incidence of SAE in different chemotherapy stages

化疗阶段	平均发生事件数	最少事件数	最多事件数	SAE [例(%)]	死亡 [例(%)]
诱导缓解	13.67	6	20	287(30.9)	2(33.3)
巩固	11.29	3^*	34	237(25.5)	1(16.7)
再诱导	11	2^*	25	231(24.9)	2(33.3)
维持	8.24	2^*	26	173(18.6)	1(16.7)

表2 各化疗阶段血液学相关SAE发生例次比较[例(%)]

Tab. 2 Comparison of the incidence of hematology-related SAEs in different chemotherapy stages [cases (%)]

化疗阶段	例次	中性粒细胞绝对计数减少	血小板减少	贫血	纤维蛋白原减少	活化部分凝血活酶时间延长	溶血
诱导缓解	197	67(34.0)	60(30.5)	54(27.4)	14(7.1)	1(0.5)	1(0.5)
巩固	155	64(41.3)	46(29.7)	36(23.2)	8(5.2)	1(0.6)	0(0)
再诱导	126	41(32.5)	46(36.5)	35(27.8)	4(3.2)	0(0)	0(0)
维持	82	57(69.5)	15(18.3)	8(9.8)	1(1.2)	0(0)	1(1.2)

表3 各化疗阶段发生感染性SAE例次比较[例(%)]

Tab. 3 Comparison of cases of infectious SAE in different chemotherapy stages [cases (%)]

化疗阶段	例次	呼吸系统	消化系统	泌尿系统	败血症	发热性中性粒细胞减少	其他部位
诱导缓解	68	23(33.8)	7(10.3)	2(2.9)	4(5.9)	26(38.3)	6(8.8)
巩固	62	24(38.7)	4(6.5)	7(11.2)	4(6.5)	19(30.6)	4(6.5)
再诱导	76	20(26.3)	6(7.9)	6(7.9)	7(9.2)	30(39.5)	7(9.2)
维持	74	51(68.9)	2(2.7)	5(6.7)	3(4.1)	11(14.9)	2(2.7)

表4 两组发生SAE例次比较[例(%)]

Tab. 4 Comparison of SAE cases between groups [cases (%)]

组别	例数	导缓解阶段	巩固阶段	再诱导阶段	维持阶段
死亡组	6	97(38.8)^*	81(32.4)^#	46(18.4)	26(10.4)
存活组	15	190(28.0)^*	156(23.0)^#	185(27.3)	147(21.7)
χ²值		0.008	12.037	1.611	19.410
$P$ 值		0.927	0.000	0.204	0.000

表4 两组发生SAE例次比较[例(%)]

Tab. 4 Comparison of SAE cases between groups [cases (%)]

组别	例数	导缓解阶段	巩固阶段	再诱导阶段	维持阶段
死亡组	6	97(38.8)^*	81(32.4)^#	46(18.4)	26(10.4)
存活组	15	190(28.0)^*	156(23.0)^#	185(27.3)	147(21.7)
χ²值		0.008	12.037	1.611	19.410
$P$ 值		0.927	0.000	0.204	0.000

表5 两组血液学相关SAE发生例次比较[例(%)]

Tab. 5 Comparison of the occurrence of hematology-related SAE between groups [cases (%)]

组别	例数	诱导缓解	巩固	再诱导	维持
死亡组	5	65(44.8)^*	51(35.2)^#	14(9.7)	15(10.3)
存活组	15	132(31.8)^*	104(25.1)^#	112(27.0)	67(16.1)
χ²值		0.000	18.563	2.135	6.119
$P$ 值		0.986	0.000	0.144	0.013

表5 两组血液学相关SAE发生例次比较[例(%)]

Tab. 5 Comparison of the occurrence of hematology-related SAE between groups [cases (%)]

组别	例数	诱导缓解	巩固	再诱导	维持
死亡组	5	65(44.8)^*	51(35.2)^#	14(9.7)	15(10.3)
存活组	15	132(31.8)^*	104(25.1)^#	112(27.0)	67(16.1)
χ²值		0.000	18.563	2.135	6.119
$P$ 值		0.986	0.000	0.144	0.013

表6 发生SAE后死亡的单因素分析[例(%)]

Tab. 6 Single factor analysis of SAE-related deaths [cases (%)]

变量	存活组( $n$ =15)	死亡组( $n$ =5)	$P$ 值	$O R$ 值	95% $C I$
变量	存活组( $n$ =15)	死亡组( $n$ =5)	$P$ 值	$O R$ 值	下限	上限
年龄
>10岁 1~10岁	14(93.3) 1(6.7)	4(80.0) 1(20.0)	0.999	0.000	0.000	0.000
性别
男女	12(80.0) 3(20.0)	2(40.0) 3(60.0)	0.109	6.000	0.671	53.681
危险分层
标危中/高危	5(33.3) 10(66.7)	0(0) 5(100.0)	0.206	2.000	0.000	0.000
基因检查是否阳性
是否	8(53.3) 7(46.7)	2(40.0) 3(60.0)	0.608	1.714	0.219	13.406
染色体检查是否阳性
是否	0(0) 15(100.0)	2(40.0) 3(60.0)	0.011	5.000	0.000	0.000
初诊时白细胞计数
≤50×10⁹/L >50×10⁹/L	10(66.7) 5(33.3)	5(100.0) 0(0)	0.206	2.000	0.000	0.000
初诊时是否有肝脾肿大
是否	10(66.7) 5(33.3)	4(80.0) 1(20.0)	0.518	0.500	0.044	5.737
初诊时是否有多处(≥3)淋巴结肿大
是否	5(33.3) 10(66.7)	1(20.0) 4(80.0)	1.0	1.000	0.080	12.557
d15MRD
≥0.1% <0.1%	10(66.7) 5(33.3)	4(80.0) 1(20.0)	0.578	5.000	0.440	5.737
化疗过程是否出现败血症
是否	9(60.0) 6(40.0)	5(100.0) 0(10.0)	0.999	0.000	0.000	0.000

表6 发生SAE后死亡的单因素分析[例(%)]

Tab. 6 Single factor analysis of SAE-related deaths [cases (%)]

变量	存活组( $n$ =15)	死亡组( $n$ =5)	$P$ 值	$O R$ 值	95% $C I$
变量	存活组( $n$ =15)	死亡组( $n$ =5)	$P$ 值	$O R$ 值	下限	上限
年龄
>10岁 1~10岁	14(93.3) 1(6.7)	4(80.0) 1(20.0)	0.999	0.000	0.000	0.000
性别
男女	12(80.0) 3(20.0)	2(40.0) 3(60.0)	0.109	6.000	0.671	53.681
危险分层
标危中/高危	5(33.3) 10(66.7)	0(0) 5(100.0)	0.206	2.000	0.000	0.000
基因检查是否阳性
是否	8(53.3) 7(46.7)	2(40.0) 3(60.0)	0.608	1.714	0.219	13.406
染色体检查是否阳性
是否	0(0) 15(100.0)	2(40.0) 3(60.0)	0.011	5.000	0.000	0.000
初诊时白细胞计数
≤50×10⁹/L >50×10⁹/L	10(66.7) 5(33.3)	5(100.0) 0(0)	0.206	2.000	0.000	0.000
初诊时是否有肝脾肿大
是否	10(66.7) 5(33.3)	4(80.0) 1(20.0)	0.518	0.500	0.044	5.737
初诊时是否有多处(≥3)淋巴结肿大
是否	5(33.3) 10(66.7)	1(20.0) 4(80.0)	1.0	1.000	0.080	12.557
d15MRD
≥0.1% <0.1%	10(66.7) 5(33.3)	4(80.0) 1(20.0)	0.578	5.000	0.440	5.737
化疗过程是否出现败血症
是否	9(60.0) 6(40.0)	5(100.0) 0(10.0)	0.999	0.000	0.000	0.000

参考文献 23

[1]	Miller KD, Fidler-Benaoudia M, Keegan TH, et al. Cancer statistics for adolescents and young adults, 2020[J]. CA Cancer J Clin, 2020, 70(6):443-459. doi: 10.3322/caac.v70.6 URL
[2]	Malard F, Mohty M. Acute lymphoblastic leukaemia[J]. Lancet, 2020, 395(10230):1146-1162. doi: S0140-6736(19)33018-1 pmid: 32247396
[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]	Suarez A, Piña M, Nichols-Vinueza DX, et al. A strategy to improve treatment-related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays[J]. Pediatr Blood Cancer, 2015, 62(8):1395-1402. doi: 10.1002/pbc.25510 pmid: 25808195
[5]	Loeffen EAH, Knops RRG, Boerhof J, et al. Treatment-related mortality in children with cancer: Prevalence and risk factors[J]. Eur J Cancer, 2019, 121:113-122. doi: S0959-8049(19)30468-X pmid: 31569066
[6]	Gibson P, Pole JD, Lazor T, et al. Treatment-related mortality in newly diagnosed pediatric cancer: A population-based analysis[J]. Cancer Med, 2018, 7(3):707-715. doi: 10.1002/cam4.2018.7.issue-3 URL
[7]	Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: A retrospective analysis from the Ponte di Legno study group[J]. Blood, 2014, 123(1):70-77. doi: 10.1182/blood-2013-06-509463 pmid: 24222333
[8]	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
[9]	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
[10]	许凤玲, 管贤敏, 温贤浩, 等. 儿童急性淋巴细胞白血病化疗相关严重不良反应的临床分析[J]. 中国当代儿科杂志, 2020, 22(8):828-833.
[11]	高萌, 傅云峰, 赵国胜, 等. 急性淋巴细胞白血病患儿血小板输注疗效及影响因素分析[J]. 中国循证儿科杂志, 2017, 12(1):45-48.
[12]	马军, 沈志祥, 朱军, 等. 培门冬酶治疗急性淋巴细胞白血病和恶性淋巴瘤中国专家共识[J]. 中国肿瘤临床, 2015, 42(24):1149-1158.
[13]	Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in Neutropenia[J]. J Immunol, 2015, 195(4):1341-1349. doi: 10.4049/jimmunol.1500861 pmid: 26254266
[14]	Suttitossatam I, Satayasai W, Sinlapamongkolkul P, et al. Predictors of severe adverse outcomes in febrile neutropenia of pediatric oncology patients at a single institute in Thailand[J]. Pediatr Hematol Oncol, 2020, 37(7):561-572. doi: 10.1080/08880018.2020.1767243 URL
[15]	Taicz M, Pérez MG, Reijtman V, et al. Epidemiologíay factores de riesgo de internación prolongada en niños con leucemia y bacteriemia. Estudio de cohorte [Epidemiology and risk factors for prolonged hospital length of stay in children with leukemia and bacteremia. Cohort study][J]. Rev Chilena Infectol, 2018, 35(3):233-238. doi: 10.4067/s0716-10182018000300233 URL
[16]	沈子园, 康海全, 桑威, 等. 白血病合并感染患者细菌分布、耐药情况及死亡危险因素分析[J]. 临床荟萃, 2021, 36(12):1092-1096.
[17]	Elseady NSM, Khamis NAGA, AbdelGhani S, et al. Antibiotic sensitivity/resistance pattern of hospital acquired blood stream infection in children cancer patients: A retrospective study[J]. Int J Clin Pract, 2021, 75(10):e14617.
[18]	Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update[J]. J Clin Oncol, 2017, 35(18):2082-2094. doi: 10.1200/JCO.2016.71.7017 pmid: 28459614
[19]	Ariza-Heredia EJ, Chemaly RF. Update on infection control practices in cancer hospitals[J]. CA Cancer J Clin, 2018, 68(5):340-355. doi: 10.3322/caac.21462 URL
[20]	Alexander S, Fisher BT, Gaur AH, et al. Effect of levofloxacin prophylaxis on bacteremia in children with acute leukemia or undergoing hematopoietic stem cell transplantation: A randomized clinical trial[J]. JAMA, 2018, 320(10):995-1004. doi: 10.1001/jama.2018.12512 pmid: 30208456
[21]	Safavi S, Paulsson K. Near-haploid and low-hypodiploid acute lymphoblastic leukemia: Two distinct subtypes with consistently poor prognosis[J]. Blood, 2017, 129(4):420-423. doi: 10.1182/blood-2016-10-743765 pmid: 27903530
[22]	Molina O, Bataller A, Thampi N, et al. Near-haploidy and low-hypodiploidy in B-cell acute lymphoblastic leukemia: When less is too much[J]. Cancers (Basel), 2021, 14(1):32. doi: 10.3390/cancers14010032 URL
[23]	Schmiegelow K, Attarbaschi A, Barzilai S, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: A Delphi consensus[J]. Lancet Oncol, 2016, 17(6):e231-e239. doi: 10.1016/S1470-2045(16)30035-3 pmid: 27299279