儿童急性淋巴细胞白血病长期随访生存分析
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摘要
目的探讨儿童急性淋巴细胞白血病(ALL)的诊断和治疗对预后的影响,提高诊治水平。方法收集我院2005年6月至2016年12月年间收治的114例初诊ALL儿童患者,回顾分析不同化疗方案、危险度分组、是否有完整MICM诊断、是否有微小残留病灶(MRD)监测、诱导化疗是否规范,诱导后继续化疗是否延期对患者5年无事件生存率(EFS)的影响,运用COX回归比例风险模型分析影响预后的因素。结果 08方案治疗组患者的5年EFS为(80.3±5.9)%,高于06方案治疗组(51.9±9.6)%和05方案治疗组(45.0±11.1)%患者,差异有统计学意义(x~2=7.23,P=0.007;x~2=5.58,P=0.018)。高危组患者5年EFS为(19.9±12.4)%,低于标危组(70.8%±8.9%)和中危组(67.0%±6.9%),差异有统计学意义(x~2=8.938P,P=0.003;x~2=9.365,P=0.002)。有MRD监测的患者其5年EFS为(80.2±5.9)%,高于无MRD监测的患者(46.7±7.3)%,差异有统计学意义(x~2=11.568,P=0.001)。诱导化疗不规范患者5年EFS为(32.8±12.2)%,低于诱导化疗规范患者(72.1±5.2)%,差异有统计学意义(x~2=8.886,P=0.003)。诱导后继续化疗有延迟的患者,其5年EFS与无延迟的患者差异无统计学意义(x~2=1.806,P=0.179)。无完整MICM诊断的患者5年EFS与有完整MICM诊断的患者差异无统计学意义(x~2=3.37,P=0.66)。多因素危险分析显示,危险度分组为高危、无MRD监测、诱导化疗不规范是儿童ALL患者预后不良的危险因素。结论危险度分组、诱导治疗的规范性及根据MRD调整治疗强度是影响儿童ALL患者预后的重要因素。基于细胞遗传学及分子生物水平的诊断、监测及规范、个体化的化疗是提高生存的有效手段。
Objective To investigate the effect of diagnosis and treatment of childhood acute lymphoblastic leukemia( ALL) on prognosis and to improve the level of diagnosis and treatment.Methods Collect 114 children patients with first visit ALL from June 2005 to December 2016,and make retrospective analysis on different chemotherapy regimens,risk grouping,whether there were complete MICM diagnosis,whether there were minimal residual disease( MRD) monitoring,whether induction chemotherapies were conventional,and the effect of whether continued chemotherapy delayed after induction on 5-year event-free survival( EFS),and COX proportional hazards regression model was used to analyze the factors affecting prognosis.Results The 5-year EPS of patients in 08 treatment group was( 80. 3 ± 5. 9) %,higher than 06 treatment group( 51. 9 ± 9. 6) % and 05 treatment group( 45. 0 ±11. 1) %,and the difference was significant( x~2= 7. 23,P = 0. 007; x~2= 5. 58,P = 0. 018).The 5-year EFS of high risk group was( 19. 9±12. 4) %,lower than standard risk group( 70. 8% ±8. 9%) and medium risk group( 67. 0% ±6. 9%),and the difference was statistically significant(x~2= 8. 938,P = 0. 003; x~2= 9. 365,P = 0. 002).The 5-year EFS of patients with MRD monitoring was( 80. 2±5. 9) %,higher than patients without MRD monitoring( 46. 7±7. 3) %,and the difference was statistically significant( x~2= 11. 568,P = 0. 001).The 5-year EFS of the patients with nonstandard induction chemotherapy were( 32. 8±12. 2) %,less than standard induction chemotherapy patients( 72. 1±5. 2) %,and the difference was statistically significant(x~2 = 8. 886,P = 0. 003).Patients with delayed chemotherapy after induction had no statistically significant difference between the 5-year EFS of the patients without delay(x~2 = 1. 806,P =0. 179).There was no statistically significant difference of 5-year EFS between the patients with incomplete MICM diagnosis and the patients with complete MICM diagnosis(x~2 = 3. 37,P = 0. 66). Multivariate risk analysis showed that high risk degree in risk grouping,no MRD monitoring,and nonstandard induction chemotherapy were the risk factors for children ALL patients with poor prognosis.Conclusion The risk grouping and standardization of induction therapy and the adjustment of treatment intensity according to MRD are important factors affecting the prognosis of children ALL patients.The diagnosis,monitoring and standardization based on cytogenetics and molecular biological level are the effective means to improve survival.
Objective To investigate the effect of diagnosis and treatment of childhood acute lymphoblastic leukemia( ALL) on prognosis and to improve the level of diagnosis and treatment.Methods Collect 114 children patients with first visit ALL from June 2005 to December 2016,and make retrospective analysis on different chemotherapy regimens,risk grouping,whether there were complete MICM diagnosis,whether there were minimal residual disease( MRD) monitoring,whether induction chemotherapies were conventional,and the effect of whether continued chemotherapy delayed after induction on 5-year event-free survival( EFS),and COX proportional hazards regression model was used to analyze the factors affecting prognosis.Results The 5-year EPS of patients in 08 treatment group was( 80. 3 ± 5. 9) %,higher than 06 treatment group( 51. 9 ± 9. 6) % and 05 treatment group( 45. 0 ±11. 1) %,and the difference was significant( x~2= 7. 23,P = 0. 007; x~2= 5. 58,P = 0. 018).The 5-year EFS of high risk group was( 19. 9±12. 4) %,lower than standard risk group( 70. 8% ±8. 9%) and medium risk group( 67. 0% ±6. 9%),and the difference was statistically significant(x~2= 8. 938,P = 0. 003; x~2= 9. 365,P = 0. 002).The 5-year EFS of patients with MRD monitoring was( 80. 2±5. 9) %,higher than patients without MRD monitoring( 46. 7±7. 3) %,and the difference was statistically significant( x~2= 11. 568,P = 0. 001).The 5-year EFS of the patients with nonstandard induction chemotherapy were( 32. 8±12. 2) %,less than standard induction chemotherapy patients( 72. 1±5. 2) %,and the difference was statistically significant(x~2 = 8. 886,P = 0. 003).Patients with delayed chemotherapy after induction had no statistically significant difference between the 5-year EFS of the patients without delay(x~2 = 1. 806,P =0. 179).There was no statistically significant difference of 5-year EFS between the patients with incomplete MICM diagnosis and the patients with complete MICM diagnosis(x~2 = 3. 37,P = 0. 66). Multivariate risk analysis showed that high risk degree in risk grouping,no MRD monitoring,and nonstandard induction chemotherapy were the risk factors for children ALL patients with poor prognosis.Conclusion The risk grouping and standardization of induction therapy and the adjustment of treatment intensity according to MRD are important factors affecting the prognosis of children ALL patients.The diagnosis,monitoring and standardization based on cytogenetics and molecular biological level are the effective means to improve survival.
引文
[1]Zheng R,Peng X,Zeng H,et al.Incidence,mortality and survival of childhood cancer in China during 2000-2010 period:A populationbased study[J].Cancer Lett,2015,363(2):176-80
[2]Hunger SP,Lu X,Devidas M,et al.Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and2005:a report from the children's oneology group[J].J Clin Oncol,2012,30(14):1663-1669.
[3]Pui CH.Recent advances in acute lymphoblastic leukemia[J].Oncology,2011,25(4):341,346-347.
[4]Schmiegelow K,Forestier E,Hellebostad M,et al.Long-term results of NOPH0 ALI-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia[J].Leukemia,2010,24(2):345-354.
[5]汤静燕,顾龙君,薛惠良,等.ALL-2005方案治疗158例儿童急性淋巴细胞白血病诱导缓解期疗效评价及中期随访报告[J].中华血液学杂志,2009,30(5):289-293.
[6]中华医学会儿科学分会血液学组,中华儿科杂志编辑委员会.儿童急性淋巴细胞白血病诊疗建议(第三次修订草案)[J].中华儿科杂志,2006,44(5):392-395.
[7]鲍亮,吴南海,吴敏媛,等.CCLG-ALL2008方案治疗儿童急性淋巴性白血病单中心疗效分析[J].中国小儿血液与肿瘤杂志,2016,2l(2):66-72
[8]Pieters R,de Groot-Kruseman H,va Il der Velden V,et al.Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring:Study ALL10From the Dutch Childhood Oncology Group[J].J Clin 0ncol,2016,34(22):2591-2601.
[9]张乐萍.积极开展儿童急性淋巴细胞白血病微小残留病的定量监测[J].山东医药,2009,49(44):1-3.
[10]肖志坚,郝玉书.急性白血病诱导缓解治疗期间残留白血病检测的重要意义[J].中华血液学杂志,2003,24(1):5
[11]阙丽萍,黄科.儿童急性淋巴细胞白血病复发机制的研究进展[J].中国小儿血液与肿瘤杂志,2016,21(6):322-326.
[12]儿童急性淋巴细胞性白血病诊疗研究协作组.上海儿童医学中心急性淋巴细胞性白血病2005方案疗效多中心研究[J].中华儿科杂志,2013,51(7):495-501.
[13]张艳清,王叨,秦好奇,等.两种方案治疗儿童急性淋巴细胞白血病的疗效分析[J].中国实用医刊,2015,42(7):37-38.
[14]赵贝贝,李捷,李祯萍,等.MRD监测下88例儿童急性B淋巴细胞白血病长期疗效的分析[J].中国小儿血液与肿瘤杂志,2014,19(3):147-150.
[15]张珏,张艳丽,李欣,等.CCLG-ALL-2008方案治疗1 69例儿童急性淋巴细胞白血病长期随访结果[J].华中科技大学学报(医学版),2016,45(4):411-414,419.
[16]Biondi A,Schrappe M,De Lorenzo P,et al.Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia(Es Ph ALL):a randomised,open-label,intergroup study[J].Lance t Oncol,2012,13(9):936-945.
[17]Van der Sligte NE,Scherpen FJ,Ter Elst A,et al.Effect of IKZFl deletions on signal transduction pathways in Philadelphia chromosome negatlve pediatric B-cell precursor acute lymphoblastic 1eukemia(BCP-AIl)[J].Exp Hematol 0ncol,2015,4:23.
[18]Den Boer ML,van Slegtenhorst M,De Menezes RX,et al.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome:a genome-wide classification study[J].Lancet Oncology,2009,10(2):125-134.
[19]Maude SL,Tasian SK,Vincent T,et al.Targeting JAK1/2 and m TOR in murine xenograft models of Ph-like acute lymphoblastic leukemia[J].Blood,2012,120(17):3510-3518.
[20]Roberts KG,Li Y,Payne-Turner D,et al.Targetable Kinase-Activating Lesions in Ph-like acute Lymphoblastic Leukemia[J].N Engl J Med,2014,371(11):1005-1015.
[21]Gómez-Gómez Y,Organista-Nava J,Rangel-Rodriguez CA,et al.Effect of folylpolyglutamate synthase A22G polymorphism on the risk and survival of patients with acute lymphoblastic leukemia[J].Oncol Lett,2014,8(2):731-735.
[22]Jamroziak K,Mlynarski W,Balcerczak E,et al.Functional C3435T polymorphism of MDR1 gene:an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia[J].Eur J Haematol,2004,72(5):314-321.
[23]Fernandez CA,Smith C,Yang W,et al.HLA—DRB1*07:01 is associated with a higher risk of asparaginase allergies[J].Blood,2014,124(8):1266-1276.
[24]Li B,Li H,Bai Y,et al.Negative feedback-defective PRPSl mutants drive thiopurine resistance in relapsed childhood ALL[J].Nat Med,2015,21(6):563-571.
[2]Hunger SP,Lu X,Devidas M,et al.Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and2005:a report from the children's oneology group[J].J Clin Oncol,2012,30(14):1663-1669.
[3]Pui CH.Recent advances in acute lymphoblastic leukemia[J].Oncology,2011,25(4):341,346-347.
[4]Schmiegelow K,Forestier E,Hellebostad M,et al.Long-term results of NOPH0 ALI-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia[J].Leukemia,2010,24(2):345-354.
[5]汤静燕,顾龙君,薛惠良,等.ALL-2005方案治疗158例儿童急性淋巴细胞白血病诱导缓解期疗效评价及中期随访报告[J].中华血液学杂志,2009,30(5):289-293.
[6]中华医学会儿科学分会血液学组,中华儿科杂志编辑委员会.儿童急性淋巴细胞白血病诊疗建议(第三次修订草案)[J].中华儿科杂志,2006,44(5):392-395.
[7]鲍亮,吴南海,吴敏媛,等.CCLG-ALL2008方案治疗儿童急性淋巴性白血病单中心疗效分析[J].中国小儿血液与肿瘤杂志,2016,2l(2):66-72
[8]Pieters R,de Groot-Kruseman H,va Il der Velden V,et al.Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring:Study ALL10From the Dutch Childhood Oncology Group[J].J Clin 0ncol,2016,34(22):2591-2601.
[9]张乐萍.积极开展儿童急性淋巴细胞白血病微小残留病的定量监测[J].山东医药,2009,49(44):1-3.
[10]肖志坚,郝玉书.急性白血病诱导缓解治疗期间残留白血病检测的重要意义[J].中华血液学杂志,2003,24(1):5
[11]阙丽萍,黄科.儿童急性淋巴细胞白血病复发机制的研究进展[J].中国小儿血液与肿瘤杂志,2016,21(6):322-326.
[12]儿童急性淋巴细胞性白血病诊疗研究协作组.上海儿童医学中心急性淋巴细胞性白血病2005方案疗效多中心研究[J].中华儿科杂志,2013,51(7):495-501.
[13]张艳清,王叨,秦好奇,等.两种方案治疗儿童急性淋巴细胞白血病的疗效分析[J].中国实用医刊,2015,42(7):37-38.
[14]赵贝贝,李捷,李祯萍,等.MRD监测下88例儿童急性B淋巴细胞白血病长期疗效的分析[J].中国小儿血液与肿瘤杂志,2014,19(3):147-150.
[15]张珏,张艳丽,李欣,等.CCLG-ALL-2008方案治疗1 69例儿童急性淋巴细胞白血病长期随访结果[J].华中科技大学学报(医学版),2016,45(4):411-414,419.
[16]Biondi A,Schrappe M,De Lorenzo P,et al.Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia(Es Ph ALL):a randomised,open-label,intergroup study[J].Lance t Oncol,2012,13(9):936-945.
[17]Van der Sligte NE,Scherpen FJ,Ter Elst A,et al.Effect of IKZFl deletions on signal transduction pathways in Philadelphia chromosome negatlve pediatric B-cell precursor acute lymphoblastic 1eukemia(BCP-AIl)[J].Exp Hematol 0ncol,2015,4:23.
[18]Den Boer ML,van Slegtenhorst M,De Menezes RX,et al.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome:a genome-wide classification study[J].Lancet Oncology,2009,10(2):125-134.
[19]Maude SL,Tasian SK,Vincent T,et al.Targeting JAK1/2 and m TOR in murine xenograft models of Ph-like acute lymphoblastic leukemia[J].Blood,2012,120(17):3510-3518.
[20]Roberts KG,Li Y,Payne-Turner D,et al.Targetable Kinase-Activating Lesions in Ph-like acute Lymphoblastic Leukemia[J].N Engl J Med,2014,371(11):1005-1015.
[21]Gómez-Gómez Y,Organista-Nava J,Rangel-Rodriguez CA,et al.Effect of folylpolyglutamate synthase A22G polymorphism on the risk and survival of patients with acute lymphoblastic leukemia[J].Oncol Lett,2014,8(2):731-735.
[22]Jamroziak K,Mlynarski W,Balcerczak E,et al.Functional C3435T polymorphism of MDR1 gene:an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia[J].Eur J Haematol,2004,72(5):314-321.
[23]Fernandez CA,Smith C,Yang W,et al.HLA—DRB1*07:01 is associated with a higher risk of asparaginase allergies[J].Blood,2014,124(8):1266-1276.
[24]Li B,Li H,Bai Y,et al.Negative feedback-defective PRPSl mutants drive thiopurine resistance in relapsed childhood ALL[J].Nat Med,2015,21(6):563-571.
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