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浙江大学学报(医学版)  2022, Vol. 51 Issue (2): 160-166    DOI: 10.3724/zdxbyxb-2022-0039
专题报道     
BCMA 靶向的嵌合抗原受体 T 细胞治疗复发/难治多发性骨髓瘤患者并发噬血细胞综合征临床观察
祖成1,2,3,4,王柯馨1,2,3,4,张棋琦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
Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma
ZU Cheng1,2,3,4,WANG Kexin1,2,3,4,ZHANG Qiqi1,2,3,4,HU Yongxian1,2,3,4,HUANG He1,2,3,4,*()
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: 研究以B细胞成熟抗原(BCMA)为靶点的嵌合抗原受体(CAR)T细胞治疗复发/难治多发性骨髓瘤(MM)后并发噬血细胞综合征(carHLH)患者的临床特点和治疗方案。 方法: 回顾性分析2018年7月至2021年12月浙江大学医学院附属第一医院BCMA靶向的CAR-T细胞治疗Ⅰ期单中心临床试验(注册号:ChiCTR1800017404)中的99例复发/难治MM患者(包括3例浆细胞白血病患者)的临床资料。收集carHLH组和非carHLH组的临床资料,比较两组临床特点、疗效、CAR-T细胞扩增特点、血清细胞因子水平等差异,并总结carHLH患者的治疗方案及转归。 结果: 99例患者中,发生carHLH20例,carHLH发生率为20.20%,carHLH发生的中位时间为细胞因子释放综合征(CRS)后的第7天(第0~19天),集中发生于CRS后第5~10天。与非carHLH患者比较,carHLH患者中男性患者比例、CAR-T细胞治疗前骨髓浆细胞比例、治疗期间发生3~4级CRS的患者比例均更高(均 P <0.05);CAR-T细胞扩增高峰更高( P <0.01);血清细胞因子白介素(IL)-6、IL-10和γ干扰素水平更高(均 P <0.01);国际标准化比值和D-二聚体峰值更高,纤维蛋白原谷值更低(均 P <0.01)。20例发生carHLH的患者中,单独使用托珠单抗治疗 7例, 单独使用糖皮质激素治疗5例,同时使用托珠单抗和糖皮质激素治疗6例,均好转。MM客观缓解率17例接受疗效评估的carHLH患者为100.00%,78例接受疗效评估的非carHLH患者为94.87%( P >0.05)。 结论: 接受BCMA靶向的CAR-T细胞治疗的MM患者carHLH发生率较高,治疗前骨髓浆细胞比例越大越容易发生carHLH,且治疗后CAR-T细胞扩增程度及细胞因子水平与carHLH发生密切相关。并发carHLH者在接受以托珠单抗和糖皮质激素为主的治疗后疗效大多较好。

关键词: 多发性骨髓瘤嵌合抗原受体T细胞浆细胞白血病B细胞成熟抗原噬血细胞综合征    
Abstract:

Objective : To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma. Methods : Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed. Results : CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0–19)?d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3–4), and robust expansion of CAR-T cells in the peripheral blood (all P <0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P <0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P >0.05]. Conclusions: The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

Key words: Multiple myeloma    Chimeric antigen receptor T cell    Plasma cell leukemia    B cell maturation antigen    Hemophagocytic syndrome
收稿日期: 2022-02-15 出版日期: 2022-08-02
CLC:  R733  
基金资助: 国家自然科学基金(81730008)
通讯作者: 黄河     E-mail: huanghe@zju.edu.cn
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引用本文:

祖成,王柯馨,张棋琦,胡永仙,黄河. BCMA 靶向的嵌合抗原受体 T 细胞治疗复发/难治多发性骨髓瘤患者并发噬血细胞综合征临床观察[J]. 浙江大学学报(医学版), 2022, 51(2): 160-166.

ZU Cheng,WANG Kexin,ZHANG Qiqi,HU Yongxian,HUANG He. Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. J Zhejiang Univ (Med Sci), 2022, 51(2): 160-166.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0039        https://www.zjujournals.com/med/CN/Y2022/V51/I2/160

组 别

n

年龄(岁)

性别(男/女)

难治或复发

骨髓浆细胞比例(%) *

化疗疗程数

重链类型

轻链类型

难治

复发

IgG

IgA

IgD

轻链型

不分泌型

κ

λ

不分泌型

carHLH组

20

63(41~75)

16/4

7

13

38.5(0.0~89.0)

3(2~8)

3

6

2

8

1

6

13

1

非carHLH组

79

59(16~74)

41/38

19

60

8.0(0.0~83.0)

3(1~9)

35

23

7

14

0

44

35

0

χ 2 / T

801

1030

616

8.286

5.660

?

P

>0.05

<0.05

>0.05

<0.05

>0.05

>0.05

>0.05

?

组 别

n

高危细胞遗传学特征

CRS等级

输注后客观缓解 (是/否/无法评估)

t(4;14)

t(14;16)

t(14;20)

染色体17p缺失

染色体1q获得

至少1种 #

0

1

2

3

4

carHLH组

20

6

0

3

7

14

17

0

0

2

15

3

17/0/3

?

非carHLH组

79

15

16

13

10

3

1

3

14

34

27

1

74/4/1

χ 2 / T

22.814

?

P

>0.05

>0.05

>0.05

>0.05

>0.05

>0.05

<0.01

>0.05

?
表 1  是否发生carHLH患者的基线临床特点和疗效比较
图 1  是否发生carHLH患者BCMA靶向的CAR-T细胞输注后外周血中CAR-T/CD3 T细胞比例的变化 + 与非carHLH组比较, <0.05. BCMA:B细胞成熟抗原;CAR:嵌合抗原受体;carHLH:CAR-T细胞相关噬血细胞综合征.

组别

n

IL-2 (pg/mL)

IL-4(pg/mL)

IL-6(pg/mL)

IL-10(pg/mL)

IL-17A(pg/mL)

TNF-α(pg/mL)

carHLH组

20

7.82(0.10~30.75)

3.61(0.10~7.80)

5?863(278~34?696)

565(122~38?821)

14.55(0.10~135.81)

7.98(0.10~231.72)

非carHLH组

79

4.41(0.10~1226.57)

2.37(0.10~22.22)

636(17~40?739)

161(7.5~65?373.0)

9.25(0.10~94.08)

3.82(0.10~188.94)

T

799

860

1057

1226

879

872

P

>0.05

>0.05

<0.01

<0.01

>0.05

>0.05

组别

n

γ干扰素(pg/mL)

三酰甘油(mmol/L)

INR

D-二聚体(μg/L)

纤维蛋白原(g/L)

C反应蛋白(mg/L)

carHLH组

20

2060.5(361.5~13?097.2)

3.0(1.3~5.3)

1.4(1.1~4.5)

49?255(2091~88?000)

3.4(2.5~5.5)

114(67~240)

非carHLH组

79

159.3(0.2~9020.5)

2.4(0.9~8.5)

1.2(1.0~3.3)

12?330(539~88?000)

4.4(2.4~12.4)

109(13~417)

T

1330

860

1130

1066

362

790

P

<0.01

>0.05

<0.01

<0.01

<0.01

>0.05

表 2  是否发生carHLH患者CAR-T细胞输注后血清细胞因子和其他血清学标志物水平比较
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doi: 10.1182/blood.V126.23.LBA-3.LBA-3
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