外周血CD4~+T淋巴细胞绝对数及CD4~+/CD8~+比值在套细胞淋巴瘤中的预后价值
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摘要
目的:探索外周血T淋巴细胞亚群计数在套细胞淋巴瘤(mantle cell lymphoma,MCL)患者中的分布、与临床特征的相关性及预后价值。方法:回顾性分析2006—2017年92例初诊MCL患者的临床资料。使用简化的MCL国际预后指数(s MI-PI)进行预后评分,采用流式细胞术分析T淋巴细胞亚群计数,包括CD4~+T淋巴细胞绝对数(ACD4C)和CD8~+T淋巴细胞绝对数(ACD8C)。Mann-Whitney U及Kruskal-Wallis检验分析T淋巴细胞亚群计数与其他临床指标的相关性。采用Kaplan-Meier法进行生存分析,Cox比例风险模型进行预后因素分析。结果:中位随访51个月(12～150个月),92例患者的中位总生存期(OS)是44个月。1年、3年、5年OS率分别为72%、45%、37%。ACD4C>0.5×10~9个/L的患者较ACD4C≤0.5×10~9个/L的患者的无进展生存期(PFS)和OS更长(P=0.009和P=0.004)。CD4~+/CD8~+比值>1.2的患者较≤1.2的患者有更长的PFS和OS(P=0.025和P=0.009)。单变量Cox回归分析显示:体力状态(ECOG评分)≥2分(P=0.021)、B症状(发热、盗汗或体重下降)(P=0.001)、升高的血清乳酸脱氢酶(LDH)(P=0.027)、高s MIPI评分(P=0.004)、低ACD4C(P=0.013)、低CD4~+/CD8~+比值(P=0.030)与较短的PFS相关。而较短的OS与B症状(P<0.001)、高s MIPI评分(P=0.004)、升高的LDH(P=0.040)、低ACD4C(P=0.006)和低CD4~+/CD8~+比值(P=0.012)相关。多因素Cox回归分析显示:B症状(P=0.006)、低ACD4C(P=0.001)是影响PFS的独立预后因素;B症状(P=0.003)、高sMIPI评分(P=0.047)、低ACD4C(P=0.001)、低CD4~+/CD8~+比值(P=0.031)是影响OS独立的预后因素。结论:低ACD4C、低CD4~+/CD8~+比值与MCL患者不良的预后相关,ACD4C水平、CD4~+/CD8~+比值可作为判断MCL患者预后方便且有效的指标。
Objective:To explore the distribution of T lymphocyte subsets in peripheral blood of patients with mantle cell lymphoma(MCL),and evaluate correlation with clinical baseline characteristics and its prognostic value.Methods:The clinical data of 92 newly diagnosed MCL patients from 2006 to 2017 were analyzed retrospectively.The prognostic stratification was performed using a simplified MCL international prognostic index s MIPI.The T lymphocyte subsets,including the absolute number of CD4+T lymphocytes(ACD4C)and the absolute number of CD8~+T lymphocytes(ACD8C)were analyzed by flow cytometry.Comparisons of T lymphocyte subsets as continuous parameters in different groups were described using Mann-Whitney U test and Kruskal-Wallis.Kaplan-Meier method was used to survival analysis,and the Cox proportional hazards models were used for the estimation of prognostic factors.Results:The median follow-up was 51 months(12-150 months),and the median overall survival(OS)in 92 patients was 44 months.The OS rate at 1,3 and 5 years was 72%,45%and 37%,respectively.In our cohort,patients with high ACD4C(>0.5×10~9/L)had longer PFS and OS(P=0.009,P=0.004),while patients with low CD4~+/CD8~+ratio(≤1.2)had unfavorable PFS and OS(P=0.025,P=0.009).Univariate Cox regression indicated that ECOG≥2(P=0.021),B symptoms(fever,night sweats or weight loss)(P=0.001),elevated LDH(P=0.027),high s MIPI score(P=0.004),low ACD4C(P=0.013)and low CD4~+/CD8~+ratio(P=0.030)correlated with shorter PFS,while the inferior OS was associated with B symptoms(P<0.001),high sMIPI score(P=0.004),elevated LDH(P=0.040),low ACD4C(P=0.006)and low CD4~-/CD8~+ratio(P=0.012).Multivariate Cox regression showed that B symptoms(P=0.006)and low ACD4C(P=0.001)were the independent prognostic factors of PFS;B symptoms(P=0.003),high sMIPI score(P=0.047),low ACD4C(P=0.001),low CD4~+/CD8~+ratio(P=0.031)were the independent prognostic factors of OS.Conclusion:Low ACD4C and low CD4~+/CD8~+ratio were associated with unfavorable prognosis in MCL patients.ACD4C level and CD4~+/CD8~+ratio proved to be convenient and effective predictors of prognosis in patients with MCL.
Objective:To explore the distribution of T lymphocyte subsets in peripheral blood of patients with mantle cell lymphoma(MCL),and evaluate correlation with clinical baseline characteristics and its prognostic value.Methods:The clinical data of 92 newly diagnosed MCL patients from 2006 to 2017 were analyzed retrospectively.The prognostic stratification was performed using a simplified MCL international prognostic index s MIPI.The T lymphocyte subsets,including the absolute number of CD4+T lymphocytes(ACD4C)and the absolute number of CD8~+T lymphocytes(ACD8C)were analyzed by flow cytometry.Comparisons of T lymphocyte subsets as continuous parameters in different groups were described using Mann-Whitney U test and Kruskal-Wallis.Kaplan-Meier method was used to survival analysis,and the Cox proportional hazards models were used for the estimation of prognostic factors.Results:The median follow-up was 51 months(12-150 months),and the median overall survival(OS)in 92 patients was 44 months.The OS rate at 1,3 and 5 years was 72%,45%and 37%,respectively.In our cohort,patients with high ACD4C(>0.5×10~9/L)had longer PFS and OS(P=0.009,P=0.004),while patients with low CD4~+/CD8~+ratio(≤1.2)had unfavorable PFS and OS(P=0.025,P=0.009).Univariate Cox regression indicated that ECOG≥2(P=0.021),B symptoms(fever,night sweats or weight loss)(P=0.001),elevated LDH(P=0.027),high s MIPI score(P=0.004),low ACD4C(P=0.013)and low CD4~+/CD8~+ratio(P=0.030)correlated with shorter PFS,while the inferior OS was associated with B symptoms(P<0.001),high sMIPI score(P=0.004),elevated LDH(P=0.040),low ACD4C(P=0.006)and low CD4~-/CD8~+ratio(P=0.012).Multivariate Cox regression showed that B symptoms(P=0.006)and low ACD4C(P=0.001)were the independent prognostic factors of PFS;B symptoms(P=0.003),high sMIPI score(P=0.047),low ACD4C(P=0.001),low CD4~+/CD8~+ratio(P=0.031)were the independent prognostic factors of OS.Conclusion:Low ACD4C and low CD4~+/CD8~+ratio were associated with unfavorable prognosis in MCL patients.ACD4C level and CD4~+/CD8~+ratio proved to be convenient and effective predictors of prognosis in patients with MCL.
引文
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[15]Kiraz Y,Baran Y,Nalbant A,et al. T cells in tumor micro-environment[J]. Tumor Biol,2016,37(1):39-45
[16] Yang ZZ,Ansell SM. The tumor microenvironment in fol-licular lymphoma[J]. Clin Adv Hematol Oncol,2012,10(12):810-818
[17] Kusano Y,Yokoyama M,Terui Y,et al. Low absolute pe-ripheral blood CD4+T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lym-phoma[J]. Blood Cancer J,2017,7(4):e558
[18] Judd J,Dulaimi E,Li T,et al. Low level of blood CD4+T cells is an independent predictor of inferior progression-free survival in diffuse large B-cell lymphoma[J]. Clin Lymphoma Myeloma Leuk,2017,17(2):83-88
[19] He L,Liang JH,Wu JZ,et al. Low absolute CD4+Tcell counts in peripheral blood are associated with inferior sur-vival in follicular lymphoma[J]. Tumor Biol,2016,37(9):12589-12595
[20]Nunes C,Wong R,Mason M,et al. Expansion ofa CD8+PD-1+replicative senescence phenotype in early stage CLLpatients is associated with inverted CD4:CD8 ratios and diseaseprogression[J]. Clin Cancer Res,2012,18(3):678-687
[21] Sakaguchi S. Naturally arising CD4+regulatory T cells for immunologic self-tolerance and negative control of im-mune responses[J]. Annu Rev Immunol,2004,22(1):531-562
[22]赵启航,梁瑞,李丹,等. Foxp3+调节性T细胞分化发育及其功能稳定性研究进展[J].南京医科大学学报(自然科学版),2017,37(1):1-9
[23]Christopoulos P,Pfeifer D,BartholoméK,et al. Definition and characterization of the systemic T cell dysregulation in untreated Indolent B-cell lymphoma and very early CLL[J]. Blood,2011,117(14):3836-3846
[24] Rakhra K,Bachireddy P,Zabuawala T,et al. CD4+T cells contribute to the remodeling of the microenvironment re-quired for sustained tumor regression upon oncogene inac-tivation[J]. Cancer Cell,2010,18(5):485-498
[25] Wang L,Qian J,Lu Y,et al. Immune evasion of mantle cell lymphoma:expression of B7-H1 leads to inhibited T cell response to and killing of tumor cells[J]. Haematolog-ica,2013,98(9):1458-1466
[2] Cheah CY,Seymour JF,Wang ML. Mantle cell lymphoma[J]. J Clin Oncol,2016,34(11):1256-1269
[3] Herrmann A,Hoster E,Zwingers T,et al. Improvement of overall survival in advanced stage mantle cell lymphoma[J]. J Clin Oncol,2009,27(4):511-518
[4] Hoster E,Dreyling M,Klapper W,et al. A new prognostic index(MIPI)for patients with advanced-stage mantle cell lymphoma[J]. Blood,2008,111(2):558-565
[5] Hoster E,Klapper W,Hermine O,et al. Confirmation of the mantle cell lymphoma international prognostic index in randomized trials of the european mantle cell lympho-ma network[J]. J Clin Oncol,2014,32(13):1338-1346
[6] Klapper W,Hoster E,Determann O,et al. Ki-67 as a prog-nostic marker in mantle cell lymphoma:Consensus guide-lines of the pathology panel of the European MCL Network[J]. J Hematop,2009,2(2):103-111
[7] Aukema SM,Hoster E,Rosenwald A,et al. Expression of TP53 is associated with outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL network[J].Blood,2018,131(4):417-420
[8] Yoo C,Yoon DH,Kim S,et al. Serum beta-2 microglobu-lin as a prognostic biomarker inpatients with mantle cell lymphoma[J]. Hematol Oncol,2016,34(1):22-27
[9] Sarkozy C,TerréC,Jardin F,et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival,independent of the MCL international prognostic index[J]. Genes Chromo-som Cancer,2014,53(1):106-116
[10] Burger JA,Ford RJ. The microenvironment in mantle cell lymphoma:cellular and molecular pathways and emerging targeted therapies[J]. Semin Cancer Biol,2011,21(5):308-312
[11] Nygren L,Wasik AM,Baumgartner-Wennerholm S,et al.T cell levels are prognostic in mantle cell lymphoma[J].Clin Cancer Res,2014,20(23):6096-6104
[12] Swerdlow SHCE,Campo E,Harris N,et al. WHO classifi-cation of tumours of the haematopoeitic and lymphoid tis-sues[M]. 4th ed. Lyon:International Agency for Re-search on Cancer,2008:438-441
[13] Coupland SE.The challenge of the microenvironment in B-cell lymphomas[J]. Histopathology,2011,58(1):69-80
[14] Zhang L,Yang J,Qian J,et al. Role of the microenviron-ment in mantle cell lymphoma:IL-6 is an important sur-vival factor for the tumor cells[J]. Blood,2012,120(18):3783-3792
[15]Kiraz Y,Baran Y,Nalbant A,et al. T cells in tumor micro-environment[J]. Tumor Biol,2016,37(1):39-45
[16] Yang ZZ,Ansell SM. The tumor microenvironment in fol-licular lymphoma[J]. Clin Adv Hematol Oncol,2012,10(12):810-818
[17] Kusano Y,Yokoyama M,Terui Y,et al. Low absolute pe-ripheral blood CD4+T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lym-phoma[J]. Blood Cancer J,2017,7(4):e558
[18] Judd J,Dulaimi E,Li T,et al. Low level of blood CD4+T cells is an independent predictor of inferior progression-free survival in diffuse large B-cell lymphoma[J]. Clin Lymphoma Myeloma Leuk,2017,17(2):83-88
[19] He L,Liang JH,Wu JZ,et al. Low absolute CD4+Tcell counts in peripheral blood are associated with inferior sur-vival in follicular lymphoma[J]. Tumor Biol,2016,37(9):12589-12595
[20]Nunes C,Wong R,Mason M,et al. Expansion ofa CD8+PD-1+replicative senescence phenotype in early stage CLLpatients is associated with inverted CD4:CD8 ratios and diseaseprogression[J]. Clin Cancer Res,2012,18(3):678-687
[21] Sakaguchi S. Naturally arising CD4+regulatory T cells for immunologic self-tolerance and negative control of im-mune responses[J]. Annu Rev Immunol,2004,22(1):531-562
[22]赵启航,梁瑞,李丹,等. Foxp3+调节性T细胞分化发育及其功能稳定性研究进展[J].南京医科大学学报(自然科学版),2017,37(1):1-9
[23]Christopoulos P,Pfeifer D,BartholoméK,et al. Definition and characterization of the systemic T cell dysregulation in untreated Indolent B-cell lymphoma and very early CLL[J]. Blood,2011,117(14):3836-3846
[24] Rakhra K,Bachireddy P,Zabuawala T,et al. CD4+T cells contribute to the remodeling of the microenvironment re-quired for sustained tumor regression upon oncogene inac-tivation[J]. Cancer Cell,2010,18(5):485-498
[25] Wang L,Qian J,Lu Y,et al. Immune evasion of mantle cell lymphoma:expression of B7-H1 leads to inhibited T cell response to and killing of tumor cells[J]. Haematolog-ica,2013,98(9):1458-1466