<strong>BCMA</strong>靶向的嵌合抗原受体<strong>T</strong>细胞治疗复发/难治多发性骨髓瘤患者发生肿瘤溶解综合征的危险因素

doi:10.3724/zdxbyxb-2022-0038

浙江大学学报（医学版）

2022, Vol. 51

Issue (2): 144-150 DOI: 10.3724/zdxbyxb-2022-0038

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发生肿瘤溶解综合征的危险因素

张棋琦^1,^2,^3,⁴,祖成^1,^2,^3,⁴,孟夜^1,^2,^3,⁴,吕雨琦^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

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy

ZHANG Qiqi^1,^2,^3,⁴,ZU Cheng^1,^2,^3,⁴,MENG Ye^1,^2,^3,⁴,LYU Yuqi^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：探究应用B细胞成熟抗原（BCMA）靶向的嵌合抗原受体（CAR）T细胞治疗的复发/难治多发性骨髓瘤（MM）患者发生肿瘤溶解综合征（TLS）的危险因素。方法：收集浙江大学医学院附属第一医院2018年7月至2021年12月共99例接受BCMA靶向的CAR-T细胞治疗MM患者的临床资料，通过单因素分析及多因素logistic回归分析患者接受BCMA靶向的CAR-T细胞治疗后发生TLS的危险因素。结果：99例患者中，17例发生TLS（TLS组），发生率为17.2%，发生时间为BCMA靶向的CAR-T细胞输注后（8.9±3.0）d。TLS组均出现TLS相关临床表现，其中出现肾功能不全17例，心律失常8例。TLS组均发生细胞因子释放综合征（CRS），发生时间为BCMA靶向CAR-T细胞输注后1.0（1.0，6.5）d，其中3~4级CRS 13例。TLS组治疗前血肌酐、血尿酸较非TLS组高，3~4级CRS患者的比例也高于非TLS组（P<0.01或P<0.05）。Logistic回归分析结果显示，高血肌酐水平（OR=1.015，P<0.01）和严重CRS（OR=9.371，P<0.01）是TLS发生的独立危险因素。结论：接受BCMA靶向的CAR-T细胞治疗的复发/难治MM患者具有较高的TLS发生率，高血肌酐水平和严重CRS是TLS的主要危险因素，临床可通过降低血肌酐、控制CRS严重程度预防TLS的发生。

关键词： 多发性骨髓瘤; 嵌合抗原受体T细胞; B细胞成熟抗原; 肿瘤溶解综合征; 危险因素

Abstract:

Objective: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. Method: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. Results: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0)?d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3–4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3–4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine (OR=1.015, P<0.01) and severe CRS (OR=9.371, P<0.01) were independent risk factors of TLS.Conclusions: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Key words: Multiple myeloma Chimeric antigen receptor T cell B cell maturation antigen Tumor lysis syndrome Risk factor

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: 胡永仙,黄河 E-mail: 1313016@zju.edu.cn

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引用本文:

张棋琦,祖成,孟夜,吕雨琦,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发生肿瘤溶解综合征的危险因素[J]. 浙江大学学报（医学版）, 2022, 51(2): 144-150.

ZHANG Qiqi,ZU Cheng,MENG Ye,LYU Yuqi,HU Yongxian,HUANG He. Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy. J Zhejiang Univ (Med Sci), 2022, 51(2): 144-150.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0038 或 https://www.zjujournals.com/med/CN/Y2022/V51/I2/144

表 1 BCMA靶向的CAR-T细胞治疗期间发生肿瘤溶解综合征患者的临床症状及实验室检查结果

表 2 BCMA靶向的CAR-T细胞治疗期间是否发生TLS患者的细胞因子峰值比较

表 3 BCMA靶向的CAR-T细胞治疗期间是否发生TLS患者的临床特征比较

表 4 复发/难治MM患者BCMA靶向的CAR-T细胞治疗期间发生肿瘤溶解综合征的多因素logistic回归分析结果

1	RODRIGUEZ-OTERO P, PAIVA B, SAN-MIGUEL J F. Roadmap to cure multiple myeloma[J]. Cancer Treat Rev, 2021, 100: 102284
2	HIDESHIMA T, MITSIADES C, TONON G, et al. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets[J]. Nat Rev Cancer, 2007, 7(8): 585-598
3	GANDOLFIS, LAUBACHJ P, HIDESHIMAT, et al.The proteasome and proteasome inhibitors in multiplemyeloma[J]Cancer Metastasis Rev, 2017, 36( 4): 561-584. doi: 10.1007/s10555-017-9707-8
4	RAZAS, SAFYANR A, LENTZSCHS. Immunomodulatory drugs (IMiDs) in multiple myeloma[J]Curr Cancer Drug Targets, 2017, 17( 9): 846-857. doi: 10.2174/1568009617666170214104426
5	LONIALS, WEISSB M, USMANIS Z, et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial[J]Lancet, 2016, 387( 10027): 1551-1560. doi: 10.1016/S0140-6736(15)01120-4
6	RICHARDSONP G, MOREAUP, LAUBACHJ P, et al.Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma[J]Pharmacol Res, 2017, 185-191. doi: 10.1016/j.phrs.2016.11.020
7	GROSICKIS, SIMONOVAM, SPICKAI, et al.Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial[J]Lancet, 2020, 396( 10262): 1563-1573. doi: 10.1016/S0140-6736(20)32292-3
8	MUNSHIN C, ANDERSON JR.L D, SHAHN, et al.Idecabtagene vicleucel in relapsed and refractory multiple myeloma[J]N Engl J Med, 2021, 384( 8): 705-716. doi: 10.1056/NEJMoa2024850
9	ZHANGM, ZHOUL, ZHAOH, et al.Risk factors associated with durable progression-free survival in patients with relapsed or refractory multiple myeloma treated with anti-BCMA CAR T-cell therapy[J]Clin Cancer Res, 2021, 27( 23): 6384-6392. doi: 10.1158/1078-0432.CCR-21-2031
10	CAILLETEAUA, TOUZEAUC, JAMETB, et al.Cytokine release syndrome and tumor lysis syndrome in a multiple myeloma patient treated with palliative radiotherapy: a case report and review of the literature[J]Clin Transl Radiat Oncol, 2022, 24-28. doi: 10.1016/j.ctro.2021.11.004
11	SINGHA, GUPTAS, YIMB, et al.Tumor lysis syndrome in multiple myeloma: an increasingly recognized risk——a report of seven cases[J]Ind J Hematol Blood Transfus, 2017, 33( 1): 41-44. doi: 10.1007/s12288-016-0731-6
12	CASTELLONC, ONKARAPPA MANGALAY, PEREZ RODRIGUEZA, et al.First case report of tumor lysis syndrome and acute renal failure after selinexor use in multiple myeloma[J]Leuk Lymphoma, 2021, 62( 14): 3536-3539. doi: 10.1080/10428194.2021.1961230
13	FASSASA B T, DESIKANK R, SIEGELD, et al.Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma[J]Br J Haematology, 1999, 105( 4): 938-941. doi: 10.1046/j.1365-2141.1999.01467.x
14	NAYMAGONL, ABDUL-HAYM. Novel agents in the treatment of multiple myeloma: a review about the future[J]J Hematol Oncol, 2016, 9( 1): 52. doi: 10.1186/s13045-016-0282-1
15	HOWARDS C, TRIFILIOS, GREGORYT K, et al.Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review[J]Ann Hematol, 2016, 95( 4): 563-573. doi: 10.1007/s00277-015-2585-7
16	HOWARDS C, JONESD P, PUIC H. The tumor lysis syndrome[J]N Engl J Med, 2011, 364( 19): 1844-1854. doi: 10.1056/NEJMra0904569
17	ZAFRANIL, CANETE, DARMONM. Understanding tumor lysis syndrome[J]Intensive Care Med, 2019, 45( 11): 1608-1611. doi: 10.1007/s00134-019-05768-x
18	CAIROM S, COIFFIERB, REITERA, et al.Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus[J]Br J Haematology, 2010, 149( 4): 578-586. doi: 10.1111/j.1365-2141.2010.08143.x
19	DARMONM, VINCENTF, CAMOUSL, et al.Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. A prospective multicentre study from the Groupe de Recherche en Réanimation Respiratoire et Onco-Hématologique[J]Br J Haematol, 2013, 162( 4): 489-497. doi: 10.1111/bjh.12415
20	FRIGAULTM J, DIETRICHJ, MARTINEZ-LAGEM, et al.Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma[J]Blood, 2019, 134( 11): 860-866. doi: 10.1182/blood.2019001694
21	NEELAPUS S, LOCKEF L, BARTLETTN L, et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma[J]N Engl J Med, 2017, 377( 26): 2531-2544. doi: 10.1056/NEJMoa1707447
22	JASKIEWICZA D, HERRINGTONJ D, WONGL. Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia[J]Pharmacotherapy, 2005, 25( 12): 1820-1825. doi: 10.1592/phco.2005.25.12.1820
23	OIWAK, MORITAM, KISHIS, et al.High risk of tumor lysis syndrome in symptomatic patients with multiple myeloma with renal dysfunction treated with bortezomib[J]Anticancer Res, 2016, 36( 12): 6655-6662. doi: 10.21873/anticanres.11274
24	KONDOM, HOTTAY, YAMAUCHIK, et al.Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: a retrospective study[J]BMC Cancer, 2020, 20( 1): 1117. doi: 10.1186/s12885-020-07592-9
25	HANDE K R, GARROW G C. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma[J]. Am J Med, 1993, 94(2): 133-139
26	MONTESINOS P, LORENZO I, MARTIN G, et al. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model[J]. Haematologica, 2008, 93(1): 67-74
27	VAISBANE, ZAINAA, BRAESTERA, et al.Acute tumor lysis syndrome induced by high-dose corticosteroids in a patient with chronic lymphatic leukemia[J]Ann Hematol, 2001, 80( 5): 314-315. doi: 10.1007/s002770000276
28	DUZOVAA, CETINM, GÜMRÜKF, et al.Acute tumour lysis syndrome following a single-dose corticosteroid in children with acute lymphoblastic leukaemia[J]Eur J Haematology, 2001, 66( 6): 404-407. doi: 10.1034/j.1600-0609.2001.066006404.x

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