Chinese expert consensus on prevention and treatment of immunotherapeutic and molecular targeted agents-related infections in patients with hematological malignancies(2025 version): updates and key points
-
摘要: 抗体类和小分子靶向药物越来越广泛地应用于血液肿瘤，但这些新药对免疫系统也有不同程度的抑制作用，从而显著增加感染风险。2025年版《血液肿瘤免疫及靶向药物治疗相关性感染预防及诊治中国专家共识》在2021年版基础上进行了全面更新，细化了不同抗体类和小分子靶向药相关感染的风险评估，特别强调了新冠流行期的治疗策略，并提供了疫苗接种、感染防治及药物相互作用管理建议，为临床医生精准决策提供支持。Abstract: Antibodies or small molecule targeted compounds showed promising efficacy in treating hematological malignancies. However, these novel drugs significantly increase the risk of infections in patients due to their immunosuppressive effects. Based on the 2021 edition, the 2025 version of the Chinese expert consensus on prevention and treatment of immunotherapeutic and molecular targeted agents-related infections in patients with hematological malignancies has been comprehensively updated. This expert consensus revision focuses on the risk assessment of infections related to novel drugs, particularly emphasizing treatment strategies during the COVID-19 pandemic, and provides recommendations on vaccination, infection prevention and treatment, and drug interaction management, offering precise decision-making support for clinicians.
-
Key words:
- hematological malignancies /
- immunotherapy /
- molecular targeted agents /
- infection /
- consensus
-
-
表 1 抗体药物相关的感染
类别 免疫系统影响 感染事件 抗CD20单抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少肺炎(2.7%~4.0%)、结核、念珠菌、PcP、HBV再激活、CMV、VZV、JC病毒相关PML 抗CD38单抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少单药主要引起上呼吸道感染(21%)；联合治疗时，上呼吸道感染(2%~26%)，肺炎(8%~26%)，HBV、VZV再激活 抗CD19单抗 中性粒细胞减少 感染(73%，包括细菌、真菌和病毒)、≥ 3级肺炎(7%，中国人群25%) 抗CD30 ADC ①影响T细胞亚群比例平衡
②短暂的剂量依赖性中性粒细胞减少肺炎(10%)、PcP、HBV再激活、CMV、VZV、HSV(1%~10%)、JC病毒相关PML 抗CD79b ADC 中性粒细胞减少 单药肺炎(4.4%)；联合化疗，≥ 3级感染(14.0%~27.2%)；PcP、VZV、CMV、HBV再激活、JC病毒相关PML 抗CD22 ADC 中性粒细胞减少 单药≥ 3级感染(22.8%~40.0%)；联合化疗感染(17%~66%) 抗CD19 ADC 中性粒细胞减少 单药≥ 3级感染(10%)，包括败血症、肺炎、机会性感染；联合利妥昔时，严重感染(30%) 抗CD33 ADC 中性粒细胞减少 单药感染(42%)；联合标准化疗时，感染(36%~55%) 抗BCMA ADC ①B细胞减少
②中性粒细胞减少症联合治疗时，≥ 3级感染(19.5%~49.0%)、肺炎(4.0%)、SARS-COV-2(1.0%) PD-1/PD-L1单抗 irAE合并使用免疫抑制剂增加感染风险 合并使用免疫抑制药物致机会性感染(7.3%)、结核、组织胞浆菌病、李斯特菌病感染 CD19×CD3双抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少治疗相关感染(17.8%~45.0%)、真菌感染罕见，长期连续输注期间(2~4周)需关注静脉导管相关感染 CD20×CD3双抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少严重感染(15.0%~18.2%)，以病毒性感染为主，包括EBV、SARS-COV-2、VZV；IFD相对罕见 BCMA×CD3双抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少单药≥ 3级感染(22.4%~39.8%)；SARS-COV-2、腺病毒、CMV再激活；PcP GPRC5D×CD3双抗 ①B细胞减少相关低丙种球蛋白血症
②中性粒细胞减少单药≥ 3级感染(15.0%~20.0%)，致命感染(3.2%)，包括SARS-COV-2、败血症和真菌感染，而机会性感染发生率较低；联合达雷妥尤时，≥ 3级感染(27.5%~28.6%) 注：PML：多病灶脑白质病；HSV：单纯疱疹病毒。 
下载: 导出CSV
表 2 小分子靶向药物相关性感染
类别 免疫系统影响 感染事件 TKI ①抑制非靶向激酶，造成CD4+和CD8+细胞增殖受抑制
②抑制B细胞功能
③中性粒细胞减少肺炎；PcP；结核；CMV、VZV、EBV、HBV再激活 蛋白酶体抑制剂 ①选择性耗竭T细胞
②中性粒细胞减少肺炎(4.0%~18.0%)；VZV(6.0%~22.3%)；流感住院率为66.7%，重症监护病房住院率为41.6%；机会性感染如诺卡菌病、原藻病或PcP；HBV再激活 BTK抑制剂 ①抑制B细胞发育、低丙种球蛋白血症
②抑制Toll样受体介导的感染最常见为上呼吸道感染，严重感染为肺炎；中枢真菌感染；VZV、EBV、HBV再激活；PcP；感染风险可随靶点特异性增加而下降 HDAC抑制剂 抑制Toll样受体介导的树状突细胞和巨噬细胞功能(传感、吞噬、细胞因子产生、黏附) 均见于联合用药，感染轻中度并可控 JAK激酶抑制剂 ①抑制树突状细胞及CD4+T细胞功能，降低Treg数量
②抑制NK细胞细菌感染；真菌感染(2.0%~3.4%)；VZV(最常见，且感染发生率随治疗时机延迟增加)、EBV、CMV、HBV再激活；PcP BCL-2抑制剂 中性粒细胞减少 ≥ 3级感染(淋巴瘤治疗：17.7%~19.0%；髓系肿瘤治疗：72.0%~74.0%)；≥ 3级IFD(8.0%)；中国患者感染风险略低 FLT3抑制剂 ①中性粒细胞减少
②抑制树状突细胞功能，特别是异基因移植患者中单药肺炎(1.0%~23.0%)、严重感染(1.2%)、IFD(3.0%)；联合治疗时，肺炎(12.0%~21.0%，严重4.0%~13.9%)、IFD(25.0%) PI3K抑制剂 ①作用于T细胞和NK细胞，易引起免疫抑制
②中性粒细胞减少严重感染(17.2%~21.0%)、严重肺炎(12.0%)；PcP(0.6%)；CMV、HBV、VZV再激活 IDH抑制剂 无特异性免疫抑制相关报道 单药不增加感染风险；联合强化疗，≥ 3级感染(5.0%~6.5%) SMO抑制剂 无特异性免疫抑制相关报道 单药不增加感染风险；联合小剂量阿糖胞苷时，肺炎(28.6%)；联合强化疗时，肺炎(20.4%) DNA甲基转移酶抑制剂 中性粒细胞减少 单药地西他滨，肺炎(20.6%)；单药阿扎胞苷，肺炎(6.4%)；阿扎胞苷联合维奈克拉，肺炎(26.0%)、败血症(7.0%) XPO1抑制剂 与中性粒细胞减少相关性需要进一步研究 机会性感染包括但不限于IFD和病毒
下载: 导出CSV
表 3 SARS-COV-2感染期间抗肿瘤治疗的管理策略
患者类型 感染程度 暂停时间 重启指征 主要条件 次要条件 非紧急治疗需求患者 无症状 暂停10 d 持续无症状 连续两次实时聚合酶链反应检测阴性(间隔≥ 24 h) 轻-中度 暂停至少14 d 症状好转，无退烧药下退热≥ 24 h 重症-危重症 暂停至少21~28 d 症状好转，无退烧药下退热≥ 72 h 需紧急启动治疗患者 由血液病专家判断是否立即治疗 可治愈的新诊断或复发侵袭性患者 根据病情直接治疗，不建议延迟 惰性或不可治愈性患者 根据肿瘤负荷进行观察随访，或选择免疫抑制较弱及住院需求少的方案
下载: 导出CSV
-
[1] Maschmeyer G, De Greef J, Mellinghoff SC, et al. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia(ECIL)[J]. Leukemia, 2019, 33(4): 844-862. doi: 10.1038/s41375-019-0388-x
[2] NCCN. Clinical practice guidelines in oncology: prevention and treatment of cancer-related infections(version 2.2023)[EB/OL]. [2025-02-05].
https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf .[3] 中华医学会血液学分会感染学组, 中华医学会血液学分会淋巴细胞疾病学组, 中国临床肿瘤学会(CSCO)抗淋巴瘤联盟. 血液肿瘤免疫及靶向药物治疗相关性感染预防及诊治中国专家共识(2021年版)[J]. 中华血液学杂志, 2021, 42(9): 717-727.
[4] Contejean A, Janssen C, Orsini-Piocelle F, et al. Increased risk of infection reporting with anti-BCMA bispecific monoclonal antibodies in multiple myeloma: A worldwide pharmacovigilance study[J]. Am J Hematol, 2023, 98(12): E349-E353.
[5] Yang L, Zheng Z, Li N, et al. Efficacy and safety of rituximab biosimilars or reference product as first-line treatment in patients with low-tumour-burden follicular lymphoma: A systematic review and meta-analysis[J]. J Clin Pharm Ther, 2022, 47(12): 1923-1931. doi: 10.1111/jcpt.13799
[6] Hammons L, Szabo A, Janardan A, et al. The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody(bsAb)therapy in patients with relapsed refractory multiple myeloma[J]. Haematologica, 2024, 109(3): 906-914.
[7] Lancman G, Parsa K, Kotlarz K, et al. IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies[J]. Blood Cancer Discov, 2023, 4(6): 440-451. doi: 10.1158/2643-3230.BCD-23-0049
[8] Shankar B, Zhang J, Naqash AR, et al. Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer[J]. JAMA Oncol, 2020, 6(12): 1952-1956. doi: 10.1001/jamaoncol.2020.5012
[9] Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/Ⅱ PCYC-1102 Study[J]. Clin Cancer Res, 2020, 26(15): 3918-3927. doi: 10.1158/1078-0432.CCR-19-2856
[10] Song Y, Malpica L, Cai Q, et al. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma(JACKPOT8 Part B): a single-arm, multinational, phase 2 study[J]. Lancet Oncol, 2024, 25(1): 117-125. doi: 10.1016/S1470-2045(23)00589-2
[11] Rozkiewicz D, Hermanowicz JM, Kwiatkowska I, et al. Bruton's Tyrosine Kinase Inhibitors(BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials[J]. Molecules, 2023, 28(5): 2400. doi: 10.3390/molecules28052400
[12] Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management[J]. Signal Transduct Target Ther, 2023, 8(1): 262. doi: 10.1038/s41392-023-01469-6
[13] Bedaj M, Bonilha CS, McInnes IB, et al. Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis[J]. Clin Exp Rheumatol, 2022, 40(7): 1313-1323.
[14] Wu WC, Shiu C, Tong TK, et al. Suppression of NK Cell Activation by JAK3 Inhibition: Implication in the Treatment of Autoimmune Diseases[J]. J Immunol Res, 2023, 2023: 8924603.
[15] Ohashi Y, Yatabe M, Niijima D, et al. Importance of Compliance With Guidelines for the Prevention of Varicella-Zoster Virus Reactivation in Multiple Myeloma[J]. In Vivo, 2021, 35(6): 3289-3296. doi: 10.21873/invivo.12624
[16] Häselbarth L, Karow A, Mentz K, et al. Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib[J]. Cancer Immunol Immunother, 2023, 72(6): 1661-1672. doi: 10.1007/s00262-022-03361-8
[17] Levis M, Perl AE. Gilteritinib: potent targeting of FLT3 mutations in AML[J]. Blood Adv, 2020, 4(6): 1178-1191. doi: 10.1182/bloodadvances.2019000174
[18] Pagano L, Salmanton-García J, Marchesi F, et al. Breakthrough COVID-19 in vaccinated patients with hematologic malignancies: results from the EPICOVIDEHA survey[J]. Blood, 2022, 140(26): 2773-2787. doi: 10.1182/blood.2022017257
[19] Bertini CD Jr, Khawaja F, Sheshadri A. Coronavirus Disease-2019 in the Immunocompromised Host[J]. Clin Chest Med, 2023, 44(2): 395-406. doi: 10.1016/j.ccm.2022.11.012
[20] Wang J, Shao L, Liang J, et al. Chinese expert consensus on the management of patients with hematologic malignancies infected with SARS-CoV-2[J]. J Cancer Res Ther, 2023, 19(6): 1495-1500. doi: 10.4103/jcrt.JCRT_782_23
[21] 巨春蓉, 王梅英, 袁静, 等. 免疫缺陷人群新型冠状病毒感染诊治策略中国专家共识(2023. V2版)[J]. 中国感染控制杂志, 2023, 22(12): 1411-1424.
[22] Stelljes M, Raffel S, Alakel N, et al. Inotuzumab Ozogamicin as Induction Therapy for Patients Older Than 55 Years With Philadelphia Chromosome-Negative B-Precursor ALL[J]. J Clin Oncol, 2024, 42(3): 273-282. doi: 10.1200/JCO.23.00546
-
计量
- 文章访问数: 91
- 施引文献: 0