Relations between Peripheral Blood Blast Clearance Time and Albumin Level at Initial Diagnosis during Induction Chemotherapy and Genetic Mutations and Prognosis in Patients with Acute Myeloid Leukemia
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摘要:
目的 探讨诱导化疗时外周血原始细胞清除 (PBBC) 时间和初诊时白蛋白 (ALB) 水平与急性髓系白血病(AML)患者基因突变及预后之间的关系。 方法 收集昆明医科大学第二附属医院2017年1月至2023年5月初诊的175例AML患者的临床资料进行回顾性分析,采用ROC曲线确定PBBC的最佳临界值为6.5 d,PBBC ≤ 6.5 d划分为外周血原始细胞清除短时间组 (EBC),PBBC > 6.5 d 分为外周血原始细胞清除长时间组 (DBC);以PBBC和初诊时ALB建立简易预后模型,可以将患者划分为a、b、c 3组,a组(PBBC ≤ 6.5 d、ALB > 34.45 g/L,无危险因素),b组(PBBC > 6.5 d、ALB > 34.45 g/L或PBBC ≤ 6.5 d、ALB ≤ 34.45 g/L,1个危险因素),c组(PBBC > 6.5 d、ALB ≤ 34.45 g/L,2个危险因素),对3组患者各基因突变情况及OS进行比较;采用t检验和卡方检验或秩和检验评估各种参数的差异性,Kaplan-Meier 法进行生存分析。 结果 对影响预后的因素进行COX回归分析显示PBBC和ALB是影响预后的独立因素,差异存在统计学意义 (P < 0.05);对abc 3组的OS进行组间比较发现,3组中位OS分别为未达到、1.86 a和0.93 a(a组vs b组,P < 0.001;a组vs c组,P < 0.001;b组vs c组,P = 0.001),差异具有统计学意义,得出无危险因素组的OS和PFS均优于1~2个危险因素者。发现3组间CEBPA双突变和NPM1基因突变无统计学意义 (P > 0.05),但C-KIT基因突变有统计学意义 (P < 0.05)。 结论 PBBC和ALB是AML患者预后的独立危险因素,以PBBC和ALB组成的简易预后模型可以为精准化、个体化诱导化疗方案的选择提供依据,为判断初诊AML患者的基因突变及预后提供参考。 Abstract:Objective To investigate the relationship between peripheral blood blast clearance (PBBC) time during induction chemotherapy and albumin (ALB) level at diagnosis and genetic mutation and prognosis in acute myeloid leukemia patients (AML). Methods Clinical data of 175 AML patients initially diagnosed from January 2017 to May 2023 at the Second Affiliated Hospital of Kunming Medical University were collected for a retrospective analysis. ROC curve was used to determine the optimal cut-off value of PBBC as 6.5 days. PBBC ≤ 6.5 days were classified as the Peripheral Blood Primitive Blood Cell Short-Term Clearance Group (EBC), and PBBC > 6.5 days were classified as the Peripheral Blood Primitive Blood Cell Long-Term Clearance Group (DBC). A simple prognostic model was established based on PBBC and ALB at initial diagnosis, dividing patients into groups a, b, and c: group A (PBBC ≤ 6.5 d, ALB > 34.45 g/L, no risk factors), group b (PBBC > 6.5 d, ALB > 34.45 g/L or PBBC ≤ 6.5 d, ALB ≤ 34.45 g/L, 1 risk factor), group c (PBBC > 6.5 d, ALB ≤ 34.45 g/L, 2 risk factors). Genetic mutations and OS were compared among the three groups of patients; differences in various parameters were evaluated using t-test and chi-squared test or rank sum test, and survival analysis was performed using the Kaplan-Meier method. Results COX regression analysis showed that PBBC and ALB were independent factors affecting prognosis, with statistical significance (P < 0.05). Comparison of OS among groups revealed median OS values of not reached, 1.86 a, and 0.93 a, respectively (a vs. b group, P < 0.001; a vs. c group, P < 0.001; b vs. c group, P = 0.001), with statistically significant differences indicating that the OS and PFS of the no-risk group were better than those with 1 to 2 risk factors.It was found that CEBPA double mutation and NPM1 gene mutation among the three groups were not statistically significant (P > 0.05), but C-KIT gene mutation was statistically significant (P < 0.05). Conclusion PBBC and ALB are independent risk factors for the prognosis of AML patients. A simple prognostic model composed of PBBC and ALB can provide a basis for the selection of precise and personalized induction chemotherapy regimens, and provide reference for determining gene mutations and prognosis in newly diagnosed AML patients. -
Key words:
- Acute myeloid leukemia /
- Peripheral blood blast clearance /
- Albumin /
- Gene mutation /
- Prognosis
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表 1 175例AML患者的临床资料[n(%)/($ \bar x \pm s $)/M(QL,QU)]
Table 1. Clinical data of 175 AML patients [n(%)/($ \bar x \pm s $)/M(QL,QU)]
因素 PBBC(d) P ALB(g/L) P EBC组(n=108) DBC组(n=67) 低ALB组(n=68) 正常ALB组(n=107) 年龄(岁) 48±17 53±16 0.070 51±16 50±17 0.417 性别 0.501 0.039* 男 54(50.00) 37(55.20) 42(61.80) 49(45.80) 女 54(50.00) 30(44.80) 26(38.20) 58(54.20) WBC(×109/L) 5.9 (2.10,31.10) 8.47(1.85,37.51) 0.962 6.65(1.64,33.88) 6.6(2.10,32.00) 0.910 NEU(×109/L) 0.6(0.20,2.00) 0.57(0.11,2.70) 0.739 0.31(0.04,1.60) 0.8(0.30,2.50) 0.004* Hb(g/L) 81±25 80±24 0.918 75±21 84±25 0.022* PLT(×109/L) 39 (24,69) 50 (22,95) 0.310 38.00(24,65) 42(24,85) 0.375 骨髓原始细胞(%) 59.5(31.30,77.13) 46(26.00,76.00) 0.294 68.00(34.00,82.00) 49(26.00,72.00) 0.016* LDH(U/L) 320(222,589) 386(243,954) 0.244 374.00(233,897) 334(227,594) 0.318 ALB(g/L) 37.1(33.00,41.20) 35.40±6.70 0.075 诱导治疗后 <0.001* 0.104 CRc 98(90.70) 25(37.30) 43(63.20) 80(74.80) 未缓解 10(9.30) 42(62.70) 25(36.80) 27(25.20) FAB分型(个) 0.167 0.038* M1 14(13.00) 8(11.90) 12(17.60) 10(9.30) M2 38(35.20) 19(28.40) 18(26.50) 39(36.40) M4 15(13.90) 9(13.40) 5(7.40) 19(17.80) M5 25(23.10) 10(14.90) 14(20.60) 21(19.60) M6 0(0.00) 0(0.00) 0(0.00) 0(0.00) M7 1(0.90) 1(1.50) 0(0.00) 2(1.90) 未分型 15(13.90) 20(29.90) 19(27.90) 16(15.00) 细胞遗传学分组 <0.001* 0.004* 低危 20(18.50) 0(0.00) 4(5.90) 16(15.00) 中危 51(47.20) 18(26.90) 19(27.90) 47(43.90) 高危 37(34.30) 51(76.10) 45(66.20) 44(41.10) 融合基因突变 CEBPA双突变 32(29.60) 15(22.40) 0.293 17(25.00) 30(28.00) 0.659 NPM1+ 38(35.20) 16(29.60) 0.251 16(28.60) 40(43.90) 0.055 C-KIT+ 27(49.10) 18(26.90) 0.020* 34(50.00) 21(19.60) <0.001* 是否移植 0.027* 0.178 是 19(17.60) 4(6.00) 6(8.80) 17(15.90) 否 89(82.40) 63(94.00) 62(91.20) 90(84.10) *P < 0.05。 表 2 OS单因素和多因素COX回归分析
Table 2. OS univariate and multivariate COX regression analysis
因素 单因素分析 多因素分析 HR 95%CI P HR 95%CI P 男性 0.990 0.648~1.512 0.962 年龄≥60岁 1.010 0.997~1.024 0.133 WBC≥30×109/L 1.003 1.000~1.007 0.086 PLT<100×109/L 0.997 0.993~1.000 0.073 LDH>245U/L 1.000 1.000~1.001 0.022* 骨髓原始细胞(%) 0.700 0.307~1.597 0.397 PBBC>6.5 d 5.477 3.466~8.657 <0.001* 5.132 3.240~8.129 <0.001* ALB<34.45 g/L 0.497 0.323~0.765 0.001* 0.589 0.382~0.910 0.017* *P < 0.05。 表 3 不同危险因素分组中患者各基因突变人数及百分比统计[n(%)]
Table 3. Statistics on the number and percentage of patients with various gene mutations in different risk factor groups[ n (%)]
组别 CEBPA双突变 P NPM1 P C-KIT P 阴性 阳性 阴性 阳性 阴性 阳性 a组 50(71.40) 20(28.60) 0.382 43(61.40) 27(38.60) 0.099 56(80.00) 14(20.00) <0.001* b组 53(70.70) 22(29.30) 51(68.00) 24(32.00) 55(73.30) 20(26.70) c组 25(83.30) 5(16.70) 25(83.30) 5(16.70) 9(30.00) 21(70.00) a组:PBBC ≤ 6.5 d、ALB > 34.45 g/L,无危险因素;b组:PBBC > 6.5 d、ALB > 34.45 g/L或PBBC ≤ 6.5 d、ALB ≤ 34.45 g/L,1个危险因素;c组:PBBC > 6.5 d、ALB ≤ 34.45 g/L,2个危险因素;*P < 0.05。 -
[1] Thoms J,Beck D,Pimanda J E. Transcriptional networks in acute myeloid leukemia[J]. Genes Chromosomes Cancer,2019,58(12):859-874. doi: 10.1002/gcc.22794 [2] Arellano M,Pakkala S,Langston A,et al. Early clearance of peripheral blood blasts predicts response to induction chemotherapy in acute myeloid leukemia[J]. Cancer,2012,118(21):5278-5282. doi: 10.1002/cncr.27494 [3] Soeters P B,Wolfe R R,Shenkin A. Hypoalbuminemia: Pathogenesis and clinical significance[J]. Journal of Parenteral and Enteral Nutrition,2019,43(2):181-193. doi: 10.1002/jpen.1451 [4] Hohloch K,Ziepert M,Truemper L,et al. Low serum albumin is an independent risk factor in elderly patients with aggressive B-cell lymphoma: Results from prospective trials of the German high-grade non-Hodgkin's lymphoma study group[J]. eJHaem,2020,1(1):181-187. doi: 10.1002/jha2.61 [5] Zhang L,Fang Y,Li L,et al. Human serum albumin-based drug-free macromolecular therapeutics: Apoptosis induction by coiled-coil-mediated cross-linking of CD20 antigens on lymphoma B cell surface[J]. Macromol Biosci,2018,18(11):e1800224. doi: 10.1002/mabi.201800224 [6] 中华医学会血液学分会白血病淋巴瘤学组. 成人急性髓系白血病(非急性早幼粒细胞白血病)中国诊疗指南(2023年版). 中华血液学杂志,2023,44(9): 705-712. [7] Pelcovits A,Niroula R. Acute myeloid leukemia: A review[J]. R I Med J (2013),2020,103(3): 38-40. [8] Infante M S,Piris M Á,Hernández-Rivas J Á. Molecular alterations in acute myeloid leukemia and their clinical and therapeutical implications[J]. Med Clin (Barc),2018,151(9):362-367. doi: 10.1016/j.medcli.2018.05.002 [9] Konopleva M,Letai A. BCL-2 inhibition in AML: An unexpected bonus?[J]. Blood,2018,132(10):1007-1012. doi: 10.1182/blood-2018-03-828269 [10] Pei S,Pollyea D A,Gustafson A,et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia[J]. Cancer Discov,2020,10(4):536-551. doi: 10.1158/2159-8290.CD-19-0710 [11] Holtzman N G,El Chaer F,Baer M R,et al. Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia[J]. British Journal of Haematology,2020,188(6):881-887. doi: 10.1111/bjh.16261 [12] Holowiecki J,Grosicki S,Giebel S,et al. Cladribine,but not fludarabine,added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: A multicenter,randomized phase III study[J]. J Clin Oncol,2012,30(20):2441-2448. doi: 10.1200/JCO.2011.37.1286 [13] Wang H,Mao L,Yang M,et al. Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: A multicentre,single-arm,phase 2 trial[J]. The Lancet Haematology,2022,9(6):415-424. doi: 10.1016/S2352-3026(22)00106-5 [14] Sevindik O G,Guc Z,Kahraman S,et al. Hypoalbuminemia is a surrogate biomarker of poor prognosis in myelodysplastic syndrome even when adjusting for comorbidities[J]. Leuk Lymphoma,2015,56(9):2552-2555. doi: 10.3109/10428194.2015.1014362 [15] Yokus O,Sunger E,Cinli TA,et al. Serum albumin and ferritin levels: A practical indicator of prognosis in acute myeloid leukemia over 50 years of age?[J]. American Journal of Blood Research,2022,12(3):97-104. [16] Heath E M,Chan S M,Minden M D,et al. Biological and clinical consequences of NPM1 mutations in AML[J]. Leukemia,2017,31(4):798-807. doi: 10.1038/leu.2017.30 [17] Ayatollahi H,Shajiei A,Sadeghian M H,et al. Prognostic importance of C-KIT mutations in core binding factor acute myeloid leukemia: A systematic review[J]. Hematol Oncol Stem Cell Ther,2017,10(1):1-7. doi: 10.1016/j.hemonc.2016.08.005 [18] Abdellateif M S,Bayoumi A K,Mohammed M A. C-Kit receptors as a therapeutic target in cancer: Current Insights[J]. Onco Targets Ther,2023,16:785-799. [19] Deng D X,Zhu H H,Liu Y R,et al. Minimal residual disease detected by multiparameter flow cytometry is complementary to genetics for risk stratification treatment in acute myeloid leukemia with biallelic CEBPA mutations[J]. Leuk Lymphoma,2019,60(9):2181-2189. doi: 10.1080/10428194.2019.1576868 [20] Yuan J,He R,Alkhateeb H B. Sporadic and familial acute myeloid leukemia with CEBPA mutations[J]. Curr Hematol Malig Rep,2023,18(5):121-129. doi: 10.1007/s11899-023-00699-3 -