两种CD19/CD22双靶点CAR-T细胞治疗策略在儿童PAX5基因变异复发/难治性B细胞急性淋巴细胞白血病中的疗效对比研究

doi:10.12372/jcp.2026.26e0038

Abstract

Abstract:

Objective Antigen escape, particularly CD19 loss, limits the efficacy of CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy in children with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). PAX5 gene variations have been shown to disrupt CD19 expression stability and increase relapse risk. This study aimed to compare the therapeutic efficacy of two CD19/CD22 dual-targeting CAR-T strategies, namely co-infusion versus bicistronic construct, in children with R/R B-ALL harboring PAX5 gene variations. Methods A retrospective analysis was conducted on the clinical data of R/R B-ALL children with PAX5 gene variation admitted to the hospital from November 5, 2019 to May 31, 2023. The patients were divided into a co-infusion group (Co group) and a bicistronic group (Bi group). All children received lymphodepletion conditioning followed by CAR-T cell infusion at a dose ranging from 2×10⁶ to 10×10⁶ cells/kg. The primary endpoints included the 30-day complete remission (CR) rate, minimal residual disease (MRD) negativity rate, relapse rate, survival outcomes, and treatment-related toxicity. The follow-up cutoff date was March 31, 2025. Results A total of 22 children with R/R B-ALL and PAX5 gene variations were included, including 18 cases (81.8%) of fusion variations, 2 cases (9.1%) of deletions, and 2 cases (9.1%) of missense variations. Six children (27.3%) had complex karyotypes (≥ 3 abnormalities). Among them, 8 patients received combined infusion of CAR-T treatment (Co group), and 14 received bicistronic CAR-T treatment (Bi group). The median age of the children at the time of treatment was 5.57 years (ranging from 1.31 to 14.85 years), and there were 13 boys and 9 girls. The CR rate of children in both the Co group and the Bi group was 100% 30 days after infusion, and the MRD was negative in both groups (MRD<0.01%). The median follow-up time was 26.5 months (range 5 to 66 months). Among the 22 patients, the 6-month, 12-month and 3-year overall survival (OS) rates were 95.45%, 90.91% and 63.64%, respectively. Meanwhile, the 6-month, 12-month and 3-year event-free survival (EFS) rates were 77.27%, 54.55% and 40.91%, respectively. The 6-month, 12-month, and 3-year OS rates in the Co group were 100%, 87.5%, and 50%, respectively, while those in the Bi group were 92.9%, 92.9%, and 71.4%, respectively. The 6-month, 12-month, and 3-year EFS rates in the Co group were 75%, 62.5%, and 37.5%, respectively, and those in the Bi group were 78.6%, 50%, and 42.9%, respectively. There were no statistically significant differences in OS and EFS rates between the two groups (P_OS=0.411, P_EFS=0.826). A total of 4 children received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T treatment. The 6-month, 12-month and 3-year OS rates in the transplantation group were 100%, 100% and 50.0%, respectively, while those in the non-transplantation group were 94.4%, 88.9% and 66.7%, respectively. The 6-month, 12-month and 3-year EFS rates in the transplantation group were 75.0%, 75.0% and 50.0%, respectively, while those in the non-transplantation group were 77.8%, 50.0% and 38.9%, respectively. There were no statistically significant differences in OS and EFS rates between the two groups (P_OS=0.693, P_EFS=0.553). Regarding toxicity, the incidence of grade ≥3 cytokine release syndrome (CRS) was 25.0% and 57.1% in the Co and Bi groups, respectively; the incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 25.0% and 21.4%, respectively. All adverse events were manageable and no treatment-related death occurred. Conclusions Both co-infusion and bicistronic CD19/CD22 dual-targeting CAR-T strategies exhibit favorable short-term efficacy and comparable safety profiles in pediatric R/R B-ALL with PAX5 variations. However, the 3-year EFS rate remains at a relatively low level, suggesting that the long-term prognosis still needs further improvement.

Key words: CD19/CD22 dual-targeting chimeric antigen receptor T-cell, relapsed/refractory B-cell acute lymphoblastic leukemia, PAX5 variation, allogeneic hematopoietic stem cell transplantation

CLC Number:

LI Yue, XIE Zhiwei, TANG Yanjing, LI Benshang. A comparative study on the efficacy of two CD19/CD22 dual-targeting CAR-T strategies in children with relapsed/refractory B-cell acute lymphoblastic leukemia with PAX5 gene variations[J].Journal of Clinical Pediatrics, 2026, 44(6): 508-517.

Figures/Tables 5

Table 1

Clinical characteristics of the patients and the situation of CAR-T treatment"

组别	患儿	性别	年龄	基因变异	入组指征	CAR-T治疗前使用 blinatumomab	CAR-T治疗前 allo-HSCT	复发部位
Co组	例1	女	5.1	PAX5-C20orf112	一次复发	否	否	骨髓、睾丸
	例2	男	3.8	PAX5-C20orf112	一次复发	否	否	骨髓、CNS
	例3	女	14.9	PAX5 DEL CDKN2A	三次复发	－	－	骨髓、睾丸
	例4	女	7.0	PAX5-TCRA; TCRA-PAX5	一次复发	否	否	骨髓
	例5	男	6.8	PAX5-AUTS2	难治	否	否	骨髓
	例6	女	2.4	PAX5-ZNF521	一次复发	否	否	骨髓
	例7	女	11.3	MIR4475-PAX5	难治	否	否	骨髓
	例8	女	5.6	PAX5-NOL4L	一次复发	否	否	骨髓
Bi组	例9	女	1.3	ZCCHC7-PAX5	一次复发	否	否	骨髓
	例10	男	5.5	PAX5 DEL	三次复发	否	是	骨髓
	例11	女	4.4	PAX5-ZCCHC7;PAX5-NOL4L	一次复发	否	否	骨髓、CNS
	例12	女	5.1	PAX5-AUTS2;	一次复发	否	否	骨髓、CNS
	例13	男	4.7	PAX5-ZNF521	一次复发	否	否	骨髓
	例14	男	5.7	PAX5-CD99	一次复发	否	否	骨髓
	例15	男	11.1	PAX5-GLIPR2	二次复发	否	否	骨髓、CNS
	例16	女	3.6	PAX5-ZNF521	一次复发	否	否	骨髓
	例17	女	8.5	PAX5:S247fs	一次复发	否	否	骨髓、睾丸
	例18	女	6.5	PAX5-HNRNPDL	一次复发	否	否	骨髓、睾丸
	例19	男	4.1	PAX5-FAM208A	一次复发	否	否	骨髓、睾丸
	例20	男	12.1	PAX5:G338_E9splice	二次复发	否	否	骨髓
	例21	男	6.0	PAX5-FBRSL1	一次复发	否	否	骨髓
	例22	女	2.2	PAX5:R31W	二次复发	否	否	CNS
组别	患儿	性别	CAR-T输注前MRD/%		总CAR-T输注剂量/×10⁶·kg^-1	19CAR⁺/%	22CAR⁺/%	第30天疾病状态
Co 组	例1	女	34.5		8.7	49.0	34.0	MRD 阴性
	例2	男	8.0		6.0	48.3	44.2	MRD 阴性
	例3	女	0.1		4.9	30.0	38.0	MRD 阴性
	例4	女	22.9		3.2	67.2	62.9	MRD 阴性
	例5	男	0.8		5.9	58.7	58.4	MRD 阴性
	例6	女	66.5		1.8	30.0	20.0	MRD 阴性
	例7	女	1.4		5.1	42.8	40.2	MRD 阴性
	例8	女	17.6		2.2	68.1	75.0	MRD 阴性
Bi 组	例9	女	10.0		5.2	27.3	20.3	MRD 阴性
	例10	男	5.0		6.3	35.2	46.6	MRD 阴性
	例11	女	9.4		4.0	50.3	62.2	MRD 阴性
	例12	女	－		8.0	37.8	49.8	MRD 阴性
	例13	男	8.1		4.5	40.8	51.9	MRD 阴性
	例14	男	20.0		10.0	43.7	43.7	MRD 阴性
	例15	男	0.2		2.9	46.7	50.1	MRD 阴性
	例16	女	12.6		5.1	62.0	75.0	MRD 阴性
	例17	女	35.5		3.4	40.4	61.9	MRD 阴性
	例18	女	1.9		2.4	34.0	44.0	MRD 阴性
	例19	男	<0.01		2.3	38.0	47.0	MRD 阴性
	例20	男	0.8		6.9	29.7	42.4	MRD 阴性
	例21	男	53.6		8.1	57.0	69.0	MRD 阴性
	例22	女	－		5.7	31.0	36.0	MRD 阴性

Table 1

Figure 1

Table 2

Figure 2

Figure 3

References 30

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A comparative study on the efficacy of two CD19/CD22 dual-targeting CAR-T strategies in children with relapsed/refractory B-cell acute lymphoblastic leukemia with PAX5 gene variations

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组别	患儿	CRS等级	CRS持续时间/d	ICANS等级	ICANS 持续时间/d	接受托珠单抗	皮质类固醇使用	B细胞再生障碍直至末次随访/d	最后状态
Co组	例1	2	－	0	－	是	否	100	存活
	例2	4	6	4	1	是	是	126	存活
	例3	0	－	0	－	否	否	150	死亡
	例4	2	4	0	－	是	否	303	死亡
	例5	1	4	0	－	是	否	190	存活
	例6	1	8	0	－	是	否	191	死亡
	例7	3	3	2	2	是	是	110	死亡
	例8	1	2	0	－	否	否	183	存活
Bi组	例9	3	9	0	－	是	否	－	存活
	例10	2	4	0	－	是	否	1 098	存活
	例11	3	8	3	13	是	是	93	死亡
	例12	3	6	0	－	否	否	67	存活
	例13	2	5	0	－	是	否	－	死亡
	例14	2	2	0	－	否	否	－	存活
	例15	1	9	1	7	是	否	27	死亡
	例16	4	8	0	－	是	是	721	存活
	例17	3	6	3	2	是	是	61	存活
	例18	1	4	0	－	否	否	31	死亡
	例19	0	－	0	－	否	否	176	存活
	例20	3	4	0	－	是	否	32	存活
	例21	3	7	0	－	否	否	148	存活
	例22	3	9	0	－	是	否	371	存活

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