临床研究

NK细胞联合Treg细胞对慢性粒细胞白血病患者酪氨酸激酶抑制剂停药的预测价值

  • 陈曦 ,
  • 王欢 ,
  • 李小龙 ,
  • 沈丽 ,
  • 刘洪涛 ,
  • 王碧薇 ,
  • 赵宏微
展开
  • 1.唐山市工人医院血液科 (河北 唐山 063000 )
    2.华北理工大学理学院 (河北 唐山 063210 )

收稿日期: 2024-04-01

  网络出版日期: 2024-11-05

基金资助

河北省医学科学研究课题计划(20240538)

The predictive value of NK cells combined with Treg cells for TKI discontinuation in patients with chronic myeloid leukemia

  • Xi CHEN ,
  • Huan WANG ,
  • Xiaolong LI ,
  • Li SHEN ,
  • Hongtao LIU ,
  • Biwei WANG ,
  • Hongwei ZHAO
Expand
  • *.Department of Hematology,Tangshan Workers Hospital,Tangshan 063000,Hebei,China

Received date: 2024-04-01

  Online published: 2024-11-05

摘要

目的 探讨NK细胞及Treg细胞在慢性粒细胞白血病(chronic myeloid leukemia, CML)应用酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)停药患者中的变化及二者对TKI停药的预测价值。 方法 随机选取确诊为CML的患者200例,分为停药组(n = 100)和未停药组(n = 100),停药组患者进一步分为复发组(n = 41)和未复发组(n = 59),对患者的临床资料及随访资料进行回顾性分析。Logistic回归分析各变量对停药后结局的影响,探讨患者停药后复发的独立影响因素。采用受试者工作特征(receiver operating characteristic, ROC)曲线分析NK细胞及Treg对TKI停药后结局的预测价值。 结果 停药组中应用干扰素治疗的患者比例显著高于未停药组(P < 0.05),而前者NK细胞(P < 0.05)及Treg细胞(P < 0.01)的数量显著高于后者。与复发组患者相比,未复发组患者中应用干扰素的比例显著高于前者(P < 0.05),TKI治疗时间及深度分子学反应(deep molecular response, DMR)持续时间均显著大于复发组患者(P < 0.05)。未复发组的NK细胞及Treg细胞的数量显著高于复发组(P < 0.01)。Logistic回归分析发现,是否应用干扰素(OR= 1.25, 95%CI: 1.11 ~ 2.03, P < 0.001)、DMR持续时间(OR = 1.16, 95%CI: 1.08 ~ 1.92, P < 0.05)、NK细胞(OR = 1.64, 95%CI: 1.14 ~ 2.28, P < 0.01)、Treg细胞(OR = 1.83, 95%CI: 1.15 ~ 2.42, P < 0.01)均是停药后患者是否复发的关键影响因素。ROC曲线分析结果表明,NK细胞联合Treg细胞预测TKI停药后是否复发的AUC = 0.892(95%CI: 0.857 ~ 0.927, P < 0.001)。 结论 NK细胞和Treg细胞在TKI停药未复发的患者中显著增加,二者联合对于CML患者停药是否复发具有良好的预测作用。

本文引用格式

陈曦 , 王欢 , 李小龙 , 沈丽 , 刘洪涛 , 王碧薇 , 赵宏微 . NK细胞联合Treg细胞对慢性粒细胞白血病患者酪氨酸激酶抑制剂停药的预测价值[J]. 实用医学杂志, 2024 , 40(20) : 2900 -2904 . DOI: 10.3969/j.issn.1006-5725.2024.20.013

Abstract

Objective To investigate the dynamics of NK cells and Treg cells, as well as their potential prognostic significance in relation to TKI discontinuation among patients diagnosed with chronic myeloid leukemia (CML). Methods In this study, a total of 200 patients diagnosed with CML were randomly selected and divided into two groups: the discontinuation group (n = 100) and the non-discontinuation group (n = 100). Within the discontinuation group, patients were further categorized into a recurrence subgroup (n = 41) and a non-recurrence subgroup (n = 59). Clinical data and follow-up information of these patients were retrospectively analyzed. Logistic regression analysis was performed to investigate the impact of various variables on patient outcomes following drug discontinuation, as well as to explore independent factors influencing recurrence in these individuals. Receiver operating characteristic (ROC) curve analysis was employed to assess the predictive value of NK cells and Treg cells for TKI discontinuation outcomes. A significance level of P < 0.05 was considered statistically significant. Results The proportion of patients treated with interferon in the discontinuation group was significantly higher than that in the non-discontinuation group (P < 0.05). Moreover, the former group exhibited a significantly higher number of NK cells (P < 0.05) and Treg cells (P < 0.01) compared to the latter group. Compared to the recurrence group, there was a significant increase in the proportion of patients using interferon in the non-recurrence group (P < 0.05), along with longer durations of TKI treatment and deep molecular response (DMR) duration (P < 0.05). The number of NK cells and Treg cells in the non-recurrence group was significantly higher than that in the recurrence group (P < 0.01). Logistic regression analysis found that the use of interferon (OR = 1.25, 95% CI: 1.11 ~ 2.03, P < 0.001), duration of DMR (OR = 1.16, 95% CI: 1.08 ~ 1.92, P < 0.05), NK cells (OR = 1.64, 95% CI: 1.14 ~ 2.28, P < 0.01), and Treg cells (OR = 1.83, 95% CI: 1.15 ~ 2.42, P < 0.01) were all influencing factors for the recurrence of patients after drug discontinuation. The results of ROC curve analysis showed that the AUC of NK cells combined with Treg cells for predicting the recurrence of TKI after discontinuation was 0.892 (95% CI: 0.857 ~ 0.927, P < 0.001). Conclusion The frequencies of NK cells and Treg cells were significantly elevated in patients who remained recurrence-free following TKI discontinuation, highlighting the potential predictive value of combined NK cell and Treg cell analysis for drug cessation in CML patients.

参考文献

1 刘孝荣, 何悦, 陈妍, 等. 利用慢病毒载体构建过表达人TCRP1基因的慢性髓系白血病K562细胞系及其生物学功能检[J].实用医学杂志, 2023,39(19): 2456-2460.
2 HADDAD F G, KANTARJIAN H. Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors[J]. J Natl Compr Canc Netw,2024,22(1):e237116. doi:10.6004/jnccn.2023.7116
3 BOWER H, BJORKHOLM M, DICKMAN P W,et al. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population[J]. J Clin Oncol,2016,34(24): 2851-2857. doi:10.1200/jco.2015.66.2866
4 STEEGMANN J L, BACCARANI M, BRECCIA M,et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia[J]. Leukemia,2016,30(8): 1648-1671. doi:10.1038/leu.2016.104
5 丁宇轩,郭沥泞,沈佳怡,等. 放疗联合PD-1抑制剂及酪氨酸激酶抑制剂治疗MSS型结直肠癌肝转移疗效及安全性[J]. 实用医学杂志,2024,40(9):1293-1297. doi:10.3969/j.issn.1006-5725.2024.09.019
6 HOCHHAUS A, BACCARANI M, SILVER R T, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia[J]. Leukemia,2020,34(4): 966-984. doi:10.1038/s41375-020-0776-2
7 CHEN K K, DU T F, XIONG P S, et al. Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia With Losing Major Molecular Response as a Definition for Molecular Relapse: A Systematic Review and Meta-Analysis[J]. Front Oncol,2019, 9(3): 372. doi:10.3389/fonc.2019.00372
8 INZOLI E, AROLDI A, PIAZZA R, et al. Tyrosine Kinase Inhibitor discontinuation in Chronic Myeloid Leukemia: eligibility criteria and predictors of success[J]. Am J Hematol,2022, 97(8): 1075-1085. doi:10.1002/ajh.26556
9 GAMBACORTI-PASSERINI C. Part I: Milestones in personalised medicine-imatinib[J]. Lancet Oncol,2008, 9(6): 600. doi:10.1016/s1470-2045(08)70152-9
10 SAVAS E M, YILMAZ S, BASER DIKYAR A A,et al. Long-term Results of Imatinib Discontinuation in Patients with Chronic-phase Chronic Myeloid Leukemia: A National Multicenter Prospective Study[J]. Turk J Haematol,2023,40(4): 236-241. doi:10.4274/tjh.galenos.2023.2023.0194
11 DEININGER M W, SHAH N P, ALTMAN J K,et al. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw,2020, 18(10): 1385-1415.
12 SCHEICH F, DUYSTER J, PESCHEL C, et al. The immunogenicity of Bcr-Abl expressing dendritic cells is dependent on the Bcr-Abl kinase activity and dominated by Bcr-Abl regulated antigens[J]. Blood,2007, 110(7): 2556-2560. doi:10.1182/blood-2007-01-071001
13 HSIEH Y C, KIRSCHNER K, COPLAND M. Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape[J]. Leukemia,2021,35(5): 1229-1242. doi:10.1038/s41375-021-01238-w
14 HUGHES A, YONG A S M. Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission[J]. Front Immunol,2017,8(1): 469. doi:10.3389/fimmu.2017.00469
15 贾王强,倪红谚,袁龙. FGL-1作为LAG-3主要的免疫抑制配体在恶性肿瘤中的研究进展[J]. 实用医学杂志,2021,37(4):547-551. doi:10.3969/j.issn.1006-5725.2021.04.026
16 姚磊,颜巍,闫宇博,等. 驱动基因阴性非小细胞肺癌患者新辅助免疫治疗手术后预后的影响因素[J]. 实用医学杂志,2021,37(21):2748-2751,2756.
17 BACHY E, BERNAUD J, ROY P, et al. Quantitative and functional analyses of CD4(+) CD25(+) FoxP3(+) regulatory T cells in chronic phase chronic myeloid leukaemia patients at diagnosis and on imatinib mesylate[J]. Br J Haematol,2011,153(1): 139-143. doi:10.1111/j.1365-2141.2010.08453.x
18 HUGHES A, CLARSON J, TANG C,et al. CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors[J]. Blood,2017,129(9): 1166-1176. doi:10.1182/blood-2016-10-745992
19 BRUCK O, BLOM S, DUFVA O,et al. Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML[J]. Leukemia,2018, 32(7): 1643-1656. doi:10.1038/s41375-018-0175-0
20 KIM J, PARK J, MOON Y,et al. Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis[J]. Int J Hematol,2019, 110(6): 683-689. doi:10.1007/s12185-019-02744-5
21 ILANDER M, OLSSON-STROMBERG U, SCHLUMS H,et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia[J]. Leukemia,2017,31(5): 1108-1116. doi:10.1038/leu.2016.360
22 REA D, HENRY G, KHAZNADAR Z,et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study[J]. Haematologica,2017,102(8): 1368-1377. doi:10.3324/haematol.2017.165001
23 OKADA M, IMAGAWA J, TANAKA H,et al. Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment[J]. Clin Lymphoma Myeloma Leuk,2018, 18(5): 353-360. e351. doi:10.1016/j.clml.2018.03.004
24 IRANI Y D, HUGHES A, CLARSON J,et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells[J]. Br J Haematol,2020,191(3): 433-441. doi:10.1111/bjh.16718
25 VIGON L, LUNA A, GALAN M,et al. Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission[J]. J Clin Med,2020,10(1): 42-51. doi:10.1182/blood-2019-130017
26 CAYSSIALS E, JACOMET F, PICCIRILLI N,et al. Sustained treatment-free remission in chronic myeloid leukaemia is associated with an increased frequency of innate CD8(+) T-cells[J]. Br J Haematol,2019, 186(1): 54-59. doi:10.1111/bjh.15858
27 MUSTJOKI S, AUVINEN K, KREUTZMAN A,et al. Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy[J]. Leukemia,2013,27(4): 914-924. doi:10.1038/leu.2012.348
28 HUGHES T P, SAGLIO G, KANTARJIAN H M,et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib[J]. Blood,2014, 123(9): 1353-1360. doi:10.1182/blood-2013-06-510396
29 CORTES J E, SAGLIO G, KANTARJIAN H M,et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial[J]. J Clin Oncol,2016, 34(20): 2333-2340. doi:10.1200/jco.2015.64.8899
文章导航

/