CD19 靶向的嵌合抗原受体 T 细胞治疗急性 B 淋巴细胞白血病伴髓外复发患者的疗效和安全性

doi:10.3724/zdxbyxb-2022-0036

浙江大学学报（医学版）

2022, Vol. 51

Issue (2): 151-159 DOI: 10.3724/zdxbyxb-2022-0036

专题报道

CD19 靶向的嵌合抗原受体 T 细胞治疗急性 B 淋巴细胞白血病伴髓外复发患者的疗效和安全性

黄荦^1,^2,^3,⁴,张明明^1,^2,^3,⁴,魏国庆^1,^2,^3,⁴,赵厚力^1,^2,^3,⁴,胡永仙^1,^2,^3,^4,*(

),黄河^1,^2,^3,^4,*(

)

1.浙江大学医学院附属第一医院骨髓移植中心，浙江杭州 310003
2.浙江大学医学中心良渚实验室，浙江杭州 311121
3.浙江大学血液学研究所，浙江杭州 310058
4.浙江省干细胞与细胞免疫治疗工程实验室，浙江杭州 310058

Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse

HUANG Luo^1,^2,^3,⁴,ZHANG Mingming^1,^2,^3,⁴,WEI Guoqing^1,^2,^3,⁴,ZHAO Houli^1,^2,^3,⁴,HU Yongxian^1,^2,^3,^4,*(

),HUANG He^1,^2,^3,^4,*(

)

1. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China;
3. Institute of Hematology, Zhejiang University, Hangzhou 310058, China;
4. Zhejiang Provincial Laboratory for Stem Cell and Immunity Therapy, Hangzhou 310058, China

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摘要：

目的： 评估CD19靶向的嵌合抗原受体（CAR）T细胞治疗急性B淋巴细胞白血病（B-ALL）伴髓外复发患者的疗效和安全性。 方法： 回顾性收集2016年1月至2021年10月在浙江大学医学院附属第一医院接受CD19靶向的CAR-T细胞治疗的 15例 B-ALL伴髓外复发患者的资料。采用Kaplan?Meier分析法评估患者的总存活率和无白血病存活率，观察不同部位的髓外病灶对CD19靶向的CAR-T细胞治疗的反应，并对CD19靶向的CAR-T细胞治疗期间细胞因子释放综合征（CRS）、血液学毒性、免疫效应细胞相关神经毒性综合征（ICANS）等不良反应进行统计分析。 结果： 15例患者中位随访时间为7（3~71）个月，最佳疗效为完全缓解11例（73.3%），中位完全缓解持续时间为6（2~27）个月；部分缓解3例（20.0%）；疾病进展1例（6.7%）。CD19靶向的CAR-T细胞治疗总反应率达93.3%（14/15），随访终点总存活率为80.0%（12/15）。15例患者累计复发率和复发病死率分别为40.0%（6/15）和20.0%（3/15），目前9例（60.0%）患者无病生存。15例患者中，13例（86.7%）发生CRS，其中1~2级 7例， 3级6例；1例（6.7%）出现可逆性ICANS；15例（100.0%）出现B细胞发育不全； 12例（80.0%）发生严重血液学不良反应；2例（13.3%）出现肝功能异常；1例（6.7%）出现肾功能异常；4例（26.7%）发生感染。上述不良反应均控制良好。 结论： CD19靶向的CAR-T细胞治疗复发/难治B-ALL伴髓外复发患者疗效明确，不良反应控制良好。

关键词： 急性B淋巴细胞白血病; 嵌合抗原受体T细胞; 复发/难治；; 髓外复发; CD19; 疗效; 安全性

Abstract:

Objective: To evaluate the efficacy and safety of CD19 chimeric antigen receptor (CAR) T cell therapy for patients with B cell acute lymphoblastic leukemia (B-ALL) involving extramedullary relapse. Methods: Fifteen patients with B-ALL involving extramedullary relapse who received CD19 CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2016 to October 2021 were enrolled in this study. The overall survival and leukemia-free survival of patients were analyzed using Kaplan-Meier curves, and the response of extramedullary lesions in different locations following the CD19 CAR-T cell therapy was observed. Cytokine release syndrome (CRS), hematological toxicity, and immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T cell therapy were analyzed. Results: The median follow-up time was 7 (3–71)?months, and 11 cases (73.3%) achieved complete response, median duration of complete response was 6 (2–27)?months; 3 cases (20.0%) achieved partial response; 1 case (6.7%) got progressive disease. The overall response rate was 93.3% (14/15), and the overall survival rate was 80.0% (12/15) at the end of follow-up. The cumulative incidence of relapse was 40.0% (6/15) and relapse mortality rate was 20.0% (3/15). Until last follow-up date, 9 cases (60.0%) were still in disease-free survival. Among the 15 patients, 13 cases (86.7%) developed cytokine release syndrome (CRS) after cell infusion, including 7 cases with grade 1–2 CRS, 6 cases with grade 3 CRS; 1 case suffered from reversible ICANS; 15 cases (100.0%) developed B cell dysplasia; 12 cases (80.0%) developed severe hematologic adverse reactions; 2 cases (13.3%) had abnormal liver function; 1 case (6.7%) had abnormal renal function; 4 cases (26.7%) developed infection. The adverse reactions mentioned above were well controlled. Conclusion: CD19 CAR-T cell therapy shows explicit efficacy and controllable adverse reactions for B-ALL patients with extramedullary relapse.

Key words: Relapsed/refractory B cell acute lymphoblastic leukemia Extramedullary relapse Chimeric antigen receptor T cell CD19 Efficacy Safety

收稿日期: 2022-02-14 出版日期: 2022-08-02

CLC:

R733

基金资助: 国家自然科学基金（81730008，81870153）

通讯作者: 胡永仙,黄河 E-mail: 1313016@zju.edu.cn

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引用本文:

黄荦,张明明,魏国庆,赵厚力,胡永仙,黄河. CD19 靶向的嵌合抗原受体 T 细胞治疗急性 B 淋巴细胞白血病伴髓外复发患者的疗效和安全性[J]. 浙江大学学报（医学版）, 2022, 51(2): 151-159.

HUANG Luo,ZHANG Mingming,WEI Guoqing,ZHAO Houli,HU Yongxian,HUANG He. Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse. J Zhejiang Univ (Med Sci), 2022, 51(2): 151-159.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0036 或 https://www.zjujournals.com/med/CN/Y2022/V51/I2/151

表 1 15例接受CD19靶向的嵌合抗原受体T细胞治疗的急性B淋巴细胞白血病伴髓外复发患者基线资料

图 1 15例急性B淋巴细胞白血病伴髓外复发患者CD19靶向的嵌合抗原受体T细胞治疗后总存活率和无白血病存活率

图 2 15例急性B淋巴细胞白血病伴髓外复发患者CD19靶向的嵌合抗原受体 T细胞治疗前后的髓外病灶

图 3 1例急性B淋巴细胞白血病伴髓外复发患者CD19靶向的CAR-T细胞治疗前后的PET-CT显像患者12在CD19靶向的CAR-T细胞治疗前PET-CT提示肝、双肾、子宫、多发淋巴结浸润，无骨髓累及；治疗2个月后PET-CT提示完全缓解，治疗 103 d 后髓内复发，完全缓解持续时间为 49 d. CAR：嵌合抗原受体；PET-CT：正电子发射体层成像-计算机断层扫描术.

图 4 1例CD19靶向的CAR-T细胞治疗期间发生3级CRS患者细胞因子水平变化患者6的细胞因子水平在CAR-T细胞输注 2 d 后开始升高， 4~5 d 达到峰值. IL：白介素；CAR：嵌合抗原受体.

例序	CAR-T细胞数（×10 ⁶ /kg）	治疗后		CRS		血液学毒性			B细胞发育不全持续时间（月）	其他不良反应	预后
例序	CAR-T细胞数（×10 ⁶ /kg）	髓内	髓外	分级	托珠单抗或糖皮质激素治疗	重度中性粒细胞减少	重度血小板减少	重度贫血	B细胞发育不全持续时间（月）	其他不良反应	主要事件	复发后治疗	结局
1	5.00	CR	CR	0	否	否	否	否	3	无	术后第143天睾丸复发	二次CD19CAR-T细胞	存活
2	3.00	CR	PR	3	否	是	是	是	14	无	术后第184天乳腺复发	化疗	死亡
3	5.00	CR	PD	2	否	是	否	否	5	无	术后第50天腹股沟区进展	二次CD19CAR-T细胞	死亡
4	2.30	CR	PR	3	否	是	是	是	4	无	术后第303天骨髓股骨髋骨复发	二次CD19CAR-T细胞	死亡
5	3.64	CR	CR	3	是	是	是	是	6	ICANS	术后第154天骨髓、中枢复发	化疗	存活
6	2.80	CR	CR	3	是	是	是	是	6	无	—	未复发	存活
7	2.40	CR	CR	3	是	否	是	否	7	无	—	未复发	存活
8	3.04	CR	PR	1	否	是	否	否	3	无	术后第123天续贯CD22 ?CAR-T细胞治疗	未复发	存活
9	4.44	CR	CR	2	是	否	否	否	4	肝功能异常	术后第83天异基因造血干细胞移植	未复发	存活
10	3.58	CR	CR	2	是	是	是	是	9	肾功能异常、感染	术后第89天异基因造血干细胞移植	未复发	存活
11	4.48	CR	CR	1	否	是	否	否	7	无	—	未复发	存活
12	2.24	CR	CR	2	是	是	是	是	2	感染	术后第103天骨髓复发	化疗	存活
13	3.64	CR	CR	2	否	是	是	是	3	感染	—	未复发	存活
14	2.50	CR	CR	3	是	是	是	是	5	肝、肾功能异常，感染	—	未复发	存活
15	2.90	CR	CR	0	否	否	否	否	4	无	术后第133天续贯CD22? CAR-T细胞治疗	未复发	存活

表 2 15例急性B淋巴细胞白血病伴髓外复发患者CD19靶向的CAR-T细胞治疗的疗效及安全性资料

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