异基因造血干细胞移植治疗儿童高危急性T淋巴细胞白血病23例临床研究

doi:10.12372/jcp.2025.25e1034

摘要/Abstract

摘要：

目的探讨异基因造血干细胞移植（allo-HSCT）治疗儿童高危急性T淋巴细胞白血病（T-ALL）的疗效及预后影响因素，比较不同治疗方案的疗效差异，探讨预处理方案对T-ALL患者allo-HSCT的影响。比较含克拉屈滨（Cla）与不含Cla（氟达拉滨，Flu）两种预处理方案在脐血移植（UCBT）中的效果，以及与基于全身照射（TBI）的外周血造血干细胞移植（PBSCT）方案的差异。方法回顾性分析2017年2月至2023年3月接受allo-HSCT的高危T-ALL患儿的临床资料。采用Kaplan-Meier法分析患儿3年的总生存（OS）率、无白血病生存（LFS）率、慢性移植物抗宿主病（cGVHD）累积发生率、累积复发率（CIR）、累积移植相关死亡率（TRM），采用Log-rank检验分析影响高危T-ALL患儿预后的因素。比较含克拉屈滨（Cla）预处理方案的UCBT组、含氟达拉滨（Flu）预处理方案的UCBT组和基于全身照射（TBI）预处理的外周血造血干细胞移植（PBSCT-TBI）组3组之间预处理相关毒性反应、移植后感染以及3年OS率差异。结果在23例高危T-ALL患儿中，男19例（82.6%）、女4例（17.4%），中位年龄为9.5（1.9~14）岁，诊断至移植的中位时间为7.5（6~29）个月。23例高危T-ALL患儿中性粒细胞均成功植入，UCBT患儿植入中位时间为18（12~38）d，PBSCT患儿植入中位时间12（11~15）d。UCBT患儿血小板植入中位时间为36（27~61）d，其中1例血小板未植入；PBSCT患儿血小板均植入，植入中位时间为13（9~25）d。5例（21.7%）患儿出现3级以上预处理相关毒性反应（主要表现为胃肠道反应、口腔黏膜炎、感染），14例为1~2级毒性反应，4例未发生毒性反应。23例患儿移植100天内无死亡发生，Ⅲ~Ⅳ度aGVHD发生率为26.1%（6/23），3年的cGVHD累积发生率为（27.15±13.33）%。共18例（78.3%）在移植后发生不同部位及不同程度的感染，以肺炎（10例）、BK多瘤病毒感染相关出血性膀胱炎（7例）以及侵袭性真菌感染（6例）为主。23例患儿移植后中位随访时间34（5~92）个月，LFS 18例、死亡5例。23例患儿3年OS为（77.5±8.9）%，LFS与OS一致。3年CIR及TRM分别为（13.04±7.19）%和（9.21±6.4）%。PBSCT-TBI组中性粒细胞及血小板植入时间均短于UCBT-Cla组和UCBT-Flu组（P<0.05）。UCBT-Cla组、UCBT-Flu组、PBSCT-TBI组之间预处理毒性反应，aGVHD及cGVHD发生率、移植后感染、3年OS率差异均无统计学意义（P>0.05）。Log-rank检验发现，初诊时中枢神经系统（CNS）受累可能为影响高危T-ALL患儿OS的高危因素（P<0.05）；年龄≥10岁、初诊时有CNS受累、移植前疾病状态为二次完全缓解（CR2）和符合难治性白血病可能为高危T-ALL移植后复发的高危因素（P<0.05）。结论 allo-HSCT可有效改善儿童高危T-ALL的长期生存，且TRM较低。初诊CNS受累是预后不良的重要标志。含Cla的预处理方案在UCBT中展现出降低复发率、提高生存率的潜力。UCBT-Cla方案可能是一种有前景的替代选择，值得进一步研究。

关键词: 异基因造血干细胞移植, 高危, 急性T淋巴细胞白血病, 克拉屈滨, 预处理方案, 儿童

Abstract:

Objective To explore the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of high-risk acute T-lymphoblastic leukemia (T-ALL) in children, compare the efficacy differences of different treatment regimens, and explore the influence of pretreatment regimens on allo-HSCT in T-ALL patients. To compare the effects of two conditioning regimens, one containing cladribine (Cla) and the other without (fludarabine, Flu), in umbilical cord blood transplantation (UCBT), as well as the differences between this and the peripheral blood hematopoietic stem cell transplantation (PBSCT) based on total body irradiation (TBI). Methods A retrospective analysis was conducted on the clinical data of children with high-risk T-ALL who underwent allo-HSCT from February 2017 to March 2023. The Kaplan-Meier method was used to analyze the 3-year overall survival (OS) rate, leukemia-free survival (LFS) rate, cumulative incidence of chronic graft-versus-host disease (cGVHD), cumulative incidence of relapse (CIR), and cumulative transplant-related mortality (TRM) of the children. The Log-rank test was used to analyze the factors influencing the prognosis of high-risk T-ALL children. The differences in pre-treatment related toxic reactions, post-transplant infections, and 3-year OS rates among different pre-treatment regimens (UCBT-Cla group, UCBT-Flu group, and PBSCT-TBI group) were compared. Results Among the 23 children with high-risk T-ALL, 19 were boys (82.6%) and 4 were girls (17.4%), with a median age of 9.5 (1.9-14) years, and the median time from diagnosis to transplantation was 7.5 (6-29) months. Among the 23 high-risk T-ALL children, neutrophil engraftment was successfully achieved in all cases. The median time to engraftment was 18 (12 - 38) days for UCBT patients and 12 (11 - 15) days for PBSCT patients. The median time to platelet engraftment was 36 (27-61) days in UCBT recipients, with one case failing to achieve platelet engraftment; all PBSCT recipients achieved platelet engraftment, with a median time of 13 (9-25) days. Five children (21.7%) experienced grade ≥3 conditioning-related toxicities (primarily manifested as gastrointestinal reactions, oral mucositis, and infections), 14 had grade 1-2 toxicities, and 4 had no toxicities. No deaths occurred within 100 days post-transplantation among the 23 children. The incidence of grade Ⅲ-Ⅳ aGVHD was 26.1% (6/23). The 3-year cumulative incidence of cGVHD was (27.15 ± 13.33) %. Eighteen children (78.3%) experienced infections of varying severity and locations after transplantation, primarily pneumonia (10 cases), BK polyomavirus-associated hemorrhagic cystitis (7 cases), and invasive fungal infections (6 cases). The median post-transplant follow-up time was 34 (5-92) months. LFS was observed in 18 children, and 5 children died. The 3-year OS and LFS rate were both (77.5 ± 8.9) %. The 3-year CIR and TRM were (13.04 ± 7.19) % and (9.21 ± 6.4)%, respectively. The neutrophil and platelet engraftment times in the PBSCT-TBI group were significantly shorter than those in the UCBT-Cla and UCBT-Flu groups (P<0.05). No statistically significant differences were observed among the UCBT-Cla, UCBT-Flu, and PBSCT-TBI groups in terms of conditioning-related toxicities, incidence of aGVHD and cGVHD, post-transplant infections, or 3-year OS rate (P>0.05). The log-rank test revealed that central nervous system (CNS) involvement at initial diagnosis may be a high-risk factor affecting the overall survival (OS) of children with high-risk T-ALL (P<0.05). Age≥10 years, CNS involvement at initial diagnosis, pre-transplant disease status in second complete remission (CR2), and meeting the criteria for refractory leukemia may be high-risk factors for post-transplant relapse in high-risk T-ALL (P<0.05). Conclusions Allo-HSCT can effectively improve long-term survival in children with high-risk T-ALL and is associated with low TRM. CNS involvement at initial diagnosis is an important marker of poor prognosis. The cla-containing conditioning regimen in UCBT demonstrates potential for reducing relapse rates and improving survival outcomes. The Cla-containing conditioning regimen demonstrates potential in UCBT to reduce relapse rates and improve survival. The UCBT-Cla regimen may be a promising alternative option worthy of further investigation.

Key words: allogeneic hematopoietic stem cell transplantation, high-risk, T-cell acute lymphoblastic leukemia, cladribine, conditioning regimen, child

中图分类号:

吴正宙, 詹丽萍, 徐宏贵, 李欣瑜, 王茵, 阙丽萍, 方建培, 黄科. 异基因造血干细胞移植治疗儿童高危急性T淋巴细胞白血病23例临床研究[J]. 临床儿科杂志, 2025, 43(12): 947-959.

WU Zhengzhou, ZHAN Liping, XU Honggui, LI Xinyu, WANG Yin, QUE Liping, FANG Jianpei, HUANG Ke. Clinical study of allogeneic hematopoietic stem cell transplantation in 23 children with high-risk T-cell acute lymphoblastic leukemia[J]. Journal of Clinical Pediatrics, 2025, 43(12): 947-959.

图/表 9

表1

表2

23例高危T-ALL患儿造血干细胞移植的实施情况及结局"

患儿	HLA配型	干细胞来源	单个核细胞数 (UCB×10⁷/kg， PBSC×10⁸/kg)	CD34⁺细胞 (UCB×10⁵/kg， PBSC×10⁶/kg)	预处理方案	GVHD预防方案
例1	10/10	UCB	3.70	2.10	Flu方案	CSA+MMF
例2	8/10	UCB	5.81	1.68	Flu方案	FK506+MMF
例3	9/10	UCB	9.10	1.80	Flu方案	FK506+MMF
例4	9/10	UCB	16.30	3.27	Flu方案	CSA+MMF
例5	10/10	PBSC,同胞	12.87	6.82	TBI方案	CsA+MMF+MTX
例6	10/10	PBSC,同胞	10.47	11.20	TBI方案	CsA+MMF+MTX
例7	3/6	BM+PBSC,父亲单倍体	10.87	7.02	BuCy方案	CsA+MMF+MTX
例8	10/10	PBSC,同胞	10.20	4.39	TBI方案	CsA+MMF+MTX
例9	8/10	UCB	5.60	1.96	Flu方案	CSA+MMF
例10	7/10	UCB	5.00	3.65	Flu方案	CSA+MMF
例11	8/10	UCB	8.60	1.98	Flu方案	CSA+MMF
例12	8/10	UCB	3.30	2.26	Cla方案	CsA+MMF
例13	9/10	UCB	7.47	3.38	Cla方案	CsA+MMF
例14	9/10	UCB	5.05	7.07	Cla方案	CsA+MMF
例15	8/10	UCB	3.02	0.94	Cla方案	CsA+MMF
例16	8/10	UCB	4.70	2.26	Cla方案	CsA+MMF
例17	9/10	UCB	4.28	2.30	Cla方案	CsA+MMF
例18	9/10	UCB	4.40	4.20	Cla方案	CsA+MMF
例19	10/10	UCB	2.70	3.67	Cla方案	CsA+MMF
例20	9/10	UCB	6.21	3.01	Cla方案	CsA+MMF
例21	7/10	BM+PBSC,父亲单倍体	11.62	4.03	Cla方案	CsA+MMF+MTX
例22	9/10	PBSC,非亲缘	12.2	6.34	Cla方案	CsA+MMF+MTX
例23	9/10	PBSC,非亲缘	12.67	10.26	TBI 方案	CsA+MMF+MTX
患儿	中性粒细胞植入时间/天	血小板植入时间/天	d28STR/%	aGVHD	cGVHD	结局
例1	17	40	100	是	是	LFS
例2	14	36	100	否	否	LFS
例3	19	33	100	是	否	LFS
例4	12	32	100	是	否	LFS
例5	12	13	100	是	是	LFS
例6	11	9	100	否	否	LFS
例7	13	24	100	否	否	LFS
例8	12	13	100	否	是	LFS
例9	22	53	99.78	否	否	因骨髓及中枢复发死亡
例10	19	61	99.78	否	否	因骨髓复发死亡
例11	38	未植入	99.80	是	否	因TMA死亡
例12	22	45	100	是	是	LFS
例13	14	32	100	是	否	LFS
例14	14	27	100	是	否	LFS
例15	18	33	100	是	否	LFS
例16	18	36	100	是	是	中枢复发、严重感染死亡
例17	18	30	100	是	否	LFS
例18	16	38	100	是	否	LFS
例19	19	46	100	是	否	LFS
例20	23	50	100	否	否	LFS
例21	12	25	100	是	是	LFS
例22	15	16	100	否	是	LFS
例23	11	12	100	是	是	因肺纤维化、呼吸衰竭死亡

表2

图1

表3

图2

图3

图4

图5

表4

23例高危T-ALL患儿预后影响因素的单因素分析"

项目	例数	OS				复发
项目	例数	18个月OS率/%	3年OS率/%	χ²值	P	18个月复发率/%	3年复发率/%	χ²值	P
性别				1.15	0.284			0.70	0.404
男	19	78.6	73.0			16.4	16.4
女	4	100.0	100.0			0	0
年龄				3.01	0.083			4.13	0.042
<10岁	13	92.3	92.3			0	0
≥10岁	10	70.0	58.3			30.0	30.0
中枢受累				8.47	0.004			5.19	0.023
否	19	89.2	89.2			5.3	5.3
是	4	50.0	25.0			50.0	50.0
携带基因变异				0.40	0.529			0.02	0.889
否	7	71.4	71.4			16.7	16.7
是	16	87.1	79.8			12.5	12.5
NOTCH1变异				0.16	0.689			0.34	0.562
阴性	11	75.0	75.0			9.1	9.1
阳性	12	90.9	79.5			17.5	17.5
FBXW7变异				0.87	0.351			0.23	0.630
阴性	18	83.0	83.0			11.5	11.5
阳性	5	80.0	60.0			20.0	20.0
NOTCH1与FBXW7共同变异				0.87	0.351			0.23	0.630
否	18	83.0	83.0			11.5	11.5
是	5	80.0	60.0			20.0	20.0
移植前疾病状态				0.80	0.372			3.86	0.049
CR1	21	85.7	80.4			10.0	10.0
CR2	2	50.0	50.0			50.0	50.0
d84 MRD				3.45	0.063			0.72	0.395
阴性	19	89.2	83.2			10.5	10.5
阳性	4	50.0	50.0			33.3	33.3
移植前MRD				0.55	0.458			0.31	0.577
阴性	21	80.7	75.3			14.8	14.8
阳性	2	100.0	100.0			0	0
难治白血病				2.31	0.129			5.97	0.015
否	19	89.5	83.5			5.6	5.6
是	4	50.0	50.0			50.0	50.0
HLA相合度				1.66	0.198			0.92	0.337
全相合	5	100.0	100.0			0	0
不全相合	18	77.4	70.9			17.4	17.4
预处理方案				1.68	0.195			0.34	0.562
含Cla	11	90.9	90.9			9.1	9.1
不含Cla	12	75.0	66.7			17.5	17.5
预处理方案				0.00	0.993			0.72	0.395
含TBI	4	100.0	75.0			0	0
不含TBI	19	78.6	78.6			17.0	17.0
移植方式				0.48	0.488			1.48	0.225
脐血移植	16	74.5	74.5			19.6	19.6
非脐血移植	7	100.0	85.7			0	0
aGVHD				0.09	0.760			0.40	0.528
否	11	80.8	80.8			18.2	18.2
是	12	83.3	75.0			9.1	9.1
cGVHD				0.01	0.906			0.01	0.924
否	15	79.4	79.4			13.8	13.8
是	8	87.5	75.0			12.5	12.5

表4

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项目	UCBT-Cla组(n=9)	UCBT-Flu组(n=7)	PBSCT-TBI组(n=4)	P¹⁾
感染	8（88.9）	6（85.7）	2（50.0）	0.359
肺炎	4（44.4）	5（71.4）	1（25.0）	0.395
侵袭性真菌感染	2（22.2）	3（42.9）	1（25.0）	0.818
菌血症	3（33.3）	1（14.3）	0（0）	0.480
BKV-HC	4（44.4）	2（28.6）	0（0）	0.313
CMV血症	2（22.2）	2（28.6）	0（0）	0.792
EBV血症	1（11.1）	0（0）	1（25.0）	0.668