急性B淋巴细胞白血病儿童化疗后微小残留病灶免疫表型改变的分析
|
摘要
目的:分析儿童急性B淋巴细胞白血病(B-cell acute lymphoblastic leukemia,B-ALL)化疗过程中首次微小残留病灶(minimal residual disease,MRD)免疫表型的变化规律及特点,为临床诊断及后续微小残留病的监测提供依据。方法:回顾性分析我院2013年1月至2018年4月收治的393例B-ALL患儿的免疫分型结果及诱导化疗第15天首次MRD数据。结果:(1)在393例白血病中,B-ALL相关特征性免疫表型的出现频率为:CD19+/CD10+/34+64.4%;CD19+/CD10+/34部分表达,15.5%;CD19+/CD34+/CD20+,58.5%;CD19+/CD10+/CD13+,13.2%;CD19+/CD10+/CD33+,5.9%;CD19+/CD10+/CD117+,0.7%;CD19+/CD10+/CD123+,50.1%;CD19+/CD10-/34±,5.9%;CD19+/CD10-/CD20-,2.5%;CD34bright,12.2%;(2)共有285例首次MRD检测结果呈阳性,有181例(63.5%)MRD检测结果至少有1个抗原荧光强度发生改变,其中出现一个抗原强度变化的为83例(29.1%),2个抗原荧光强度变化的为57例(20.0%),3个抗原荧光强度变化为31例(10.9%),4个及4个以上抗原荧光强度变化为10例(3.5%)。抗原荧光强度变化频率最高的依次为CD45、CD34、CD20;(3)共有7例患儿复发,复发时行免疫分型检测,其中4例与初发时有抗原荧光强度变化。结论:(1)儿童B-ALL远高于其他白血病类型,且具有独特的相关特征性免疫表型。初发B-ALL免疫分型结果不仅可完善白血病MICM分型,更是化疗后MRD监测的线索及客观依据;(2)在儿童B-ALL化疗过程中,免疫表型极有可能会发生变化,在后续的微小残留病灶检测过程中应注意对变化抗原的判断和追踪。
Objective: To review the flow immunophenotype results of the frist minimal residual disease(minimal residual disease, MRD) of 393 children with B-cell acute lymphoblastic leukemia(B-ALL), and compare with the results of immunophenotyping at the initial diagnosis. Analyze the surface antigen changes occurring in the B-ALL chemotherapy phase of the MRD, in order to understand the feature and changing characteristics of children's B-ALL immunophenotype and to provide evidence for clinical diagnosis and follow-up monitoring of MRD. Methods: A retrospective analysis of the immunophenotyping results and the first MRD data of induction chemotherapy for fifteenth days of 393 patients with B-ALL in our hospital from January 2013 to April 2018 was performed. Results:(1)in 393 cases of B-ALL, the frequency of leukaemia related immunophenotype(characterization of leukemia-associated immunotyping,LAIP) were: CD19+/CD10+/34+, 64.4 %; CD19+/CD10+/34 partial expression, 15.5 %; CD19+/CD34+/CD20+, 58.5 %; CD19+/CD10+/CD13+, 13.2 %; CD19+/CD10+/CD33+,5.9 %; CD10+/CD117+, 0.7 %; CD19+/CD10+/CD123+, 50.1 %; CD19+/CD10-/34+, 5.9 %;CD19+/CD10-/CD20-, 2.5 %; CD34 bright, 12.2 %;(2) A total of 285 first MRD tests were positive, 181(63.5 %) MRD detected at least 1 antigen fluorescence intensity changes, of which 1 antigen intensity change was 83 cases(29.1 %), 2 antigen fluorescence intensity changes were 57 cases(20 %), 3 antigen fluorescence intensity changes were 31 cases(10.9 %), 4 and more than 4 antigen fluorescence intensity changes were 10 cases(3.5 %). The highest frequency of antigen fluorescence intensity was CD45, CD34 and CD20.(3) A total of 7 children were recrudescence, of which 4 cases of antigen fluorescence intensity change compared with the initial stage. Conclusion:(1) children's B-ALL is much higher than other types of leukemia, and has a unique characteristic phenotype. The results of initial B-ALL immunophenotype can not only improve the MICM classification of leukemia, but also provide clues and objective evidence for MRD monitoring after chemotherapy.(2) Immunophenotype changes are most likely to occur during B-ALL treatment in children, and careful judgment and tracking should be made in the subsequent detection process of MRD.
Objective: To review the flow immunophenotype results of the frist minimal residual disease(minimal residual disease, MRD) of 393 children with B-cell acute lymphoblastic leukemia(B-ALL), and compare with the results of immunophenotyping at the initial diagnosis. Analyze the surface antigen changes occurring in the B-ALL chemotherapy phase of the MRD, in order to understand the feature and changing characteristics of children's B-ALL immunophenotype and to provide evidence for clinical diagnosis and follow-up monitoring of MRD. Methods: A retrospective analysis of the immunophenotyping results and the first MRD data of induction chemotherapy for fifteenth days of 393 patients with B-ALL in our hospital from January 2013 to April 2018 was performed. Results:(1)in 393 cases of B-ALL, the frequency of leukaemia related immunophenotype(characterization of leukemia-associated immunotyping,LAIP) were: CD19+/CD10+/34+, 64.4 %; CD19+/CD10+/34 partial expression, 15.5 %; CD19+/CD34+/CD20+, 58.5 %; CD19+/CD10+/CD13+, 13.2 %; CD19+/CD10+/CD33+,5.9 %; CD10+/CD117+, 0.7 %; CD19+/CD10+/CD123+, 50.1 %; CD19+/CD10-/34+, 5.9 %;CD19+/CD10-/CD20-, 2.5 %; CD34 bright, 12.2 %;(2) A total of 285 first MRD tests were positive, 181(63.5 %) MRD detected at least 1 antigen fluorescence intensity changes, of which 1 antigen intensity change was 83 cases(29.1 %), 2 antigen fluorescence intensity changes were 57 cases(20 %), 3 antigen fluorescence intensity changes were 31 cases(10.9 %), 4 and more than 4 antigen fluorescence intensity changes were 10 cases(3.5 %). The highest frequency of antigen fluorescence intensity was CD45, CD34 and CD20.(3) A total of 7 children were recrudescence, of which 4 cases of antigen fluorescence intensity change compared with the initial stage. Conclusion:(1) children's B-ALL is much higher than other types of leukemia, and has a unique characteristic phenotype. The results of initial B-ALL immunophenotype can not only improve the MICM classification of leukemia, but also provide clues and objective evidence for MRD monitoring after chemotherapy.(2) Immunophenotype changes are most likely to occur during B-ALL treatment in children, and careful judgment and tracking should be made in the subsequent detection process of MRD.
引文
[1]王朦,贾国存.儿童急性淋巴细胞白血病的诊治现状与预后[J].齐齐哈尔医学院学报,2015,(11):1666-1668
[2]Borowitz MJ,Devidas M,Hunger SP,et al.Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors:a Children's Oncology Group study[J].Blood,2008,111(12):5477-5485
[3]赵旸.儿童难治复发急性淋巴细胞白血病的新治疗策略[J].临床儿科杂志,2018,36(8):639-642
[4]胡淑芬,谭冬梅,黎毓光.急性B淋巴细胞白血病微小残留病的监测[J].白血病·淋巴瘤,2013,22(4):248-250
[5]Setiadi A,Owen D,Tsang A,et al.The significance of peripheral blood minimal residual disease to predict early disease response in patients with B-cell acute lymphoblastic leukemia[J].International journal of laboratory hematology,2016,38(5):527-534
[6]王月芳,江咏梅,高举,等.原血细胞对于儿童急性B淋巴细胞白血病预后判断的价值[J].中国当代儿科杂志,2016,18(4):292-296
[7]Baraka A,Sherief LM,Kamal NM,et al.Detection of minimal residual disease in childhood B-acute lymphoblastic leukemia by 4-color flowcytometry[J].International journal of hematology,2017,105(6):784-791
[8]Fossat C,Roussel M,Arnoux I,et al.Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia:A French multicenter study[J].Cytometry B Clin Cytom,2014:1
[9]Fossat C,Roussel M,Arnoux I,et al.Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia:A French multicenter study[J].Cytometry B Clin Cytom,2015,88(1):21-29
[10]Vinhas E,Lucena-Silva N,Pedrosa F.Implementation of a simplified flow cytometric assays for minimal residual disease monitoring in childhood acute lymphoblastic leukemia[J].Cytometry.Part B,Clinical cytometry,2018,94(1):94-99
[11]朱明清,耿美菊,何海龙,等.186例儿童急性淋巴细胞白血病免疫表型特征[J].中国血液流变学杂志,2006,16(4):556-557
[12]Jalal SD,Al-Allawi NAS,Al Doski AAS.Immunophenotypic aberrancies in acute lymphoblastic leukemia from 282 Iraqi patients[J].International journal of laboratory hematology,2017,39(6):625-632
[13]Harris NL,Jaff ES,Diebold J,et a1.The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues:report of the Clinical Advisory Committee meeting--Airlie House,Virginia,November,1997[J].The hematology journal:the official journal of the European Haematology Association,2000,1(1):53-66
[14]Burnusuzov HA,Spasova MI,Murdjeva MA,et al.Immunophenotypic Modulation of the Blast Cells in Childhood Acute Lymphoblastic Leukemia Minimal Residual Disease Detection[J].Folia Med(Plovdiv),2016Mar,58(1):28-35
[15]Gaipa G,Basso G,Maglia O,et al.Drug-induced immunophenotypic modulation in childhood ALL:implications for minimal residual disease detection[J].Leukemia,2005,19(1):49-56
[16]Gaipa G,Basso G,Aliprandi S,et al.Prednisone induces immunophenotypic modulation of CD10 and CD34 in nonapoptotic B-cell precursor acute lymphoblastic leukemia cells[J].Cytometry B Clin Cytom,2008,74(3):150-155
[17]朱艳云.西妥昔单抗联合化疗前后肿瘤微环境中部分免疫指标变化的研究[D].解放军总医院,2011
[18]Koskenvuo M,Ekman I,Saha E,et al.Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment[J].Pediatric blood cancer,2016,63(9):1653-1656
[19]梁冠中,王艳峰,韩福才.化疗对非小细胞肺癌患者外周血中CD8+CD28-T细胞表达的影响[J].国际肿瘤学杂志,2016,43(5):335-339
[20]Birkebaek NH,Fisker S,Clausen N,et al.Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood[J].Med Pediatr Oncol,1998,30(6):35l-356
[21]Leung W,Rose SR,Zhou Y,et al.Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia[J].Clin Oncol,2002,20(13):2959-2964
[22]Manka P,Coombes JD,Boosman R,et al.Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment[J].Cancer letters,2018,419:175-186
[23]许艳丽,王顺清,杜庆华,等.造血B祖细胞与急性B淋巴细胞白血病细胞的流式细胞术免疫表型分析与鉴别[J].白血病·淋巴瘤2015,24(5):282-286
[24]Jalal SD,Al-Allawi NAS,Al Doski AAS.Immunophenotypic aberrancies in acute lymphoblastic leukemia from 282 Iraqi patients[J].International journal of laboratory hematology,2017,39(6):625-632
[25]Huang YJ,Coustan-Smith E,Kao HW,et al.Concordance of two approaches in monitoring of minimal residual disease in B-precursor acute lymphoblastic leukemia:Fusion transcripts and leukemia-associated immunophenotypes[J].Journal of the Formosan Medical Association=Taiwan,2017,116(10):774-781
[26]Eveillard M,Robillard N,Arnoux I,et al.Major impact of an early bone marrow checkpoint(day 21)for minimal residual disease in flow cytometry in childhood acute lymphoblastic leukemia[J].Hematol Oncol,2017,35(2):237-243
[27]T Chatterjee,R S Mallhi,S Venkatesan.Minimal residual disease detection using flow cytometry:Applications in acute leukemia[J].Medical journal,Armed Forces India,2013,26(3):279-284
[28]徐殿,何妙侠,郑建明.儿童急性淋巴细胞白血病微小残留病检测及其进展[J].检验医学,2013,28(4):342-346
[29]宋晓洁,冯伟平,韩雪娇,等.CD47在急性白血病干细胞中的表达及其对临床疗效及预后的影响[J].现代生物医学进展,2016,16(29):5760-5762,5796
[30]Tembhare PR,Ghogale S,Ghatwai N,et al.Evaluation of new markers for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia:CD73 and CD86 are the most relevant new markers to increase the efficacy of MRD[J].Cytometry B Clin Cytom,2018 Jan,94(1):100-111
[31]Zhang Yan,Tian Li-Ping,Zhang Ying,et al.Prospective study on comparing two methods:for dynamic monitoring of minimal residual disease in acute promyelocytic leukemia[J].Zhongguo shi yan xue ye xue za zhi,2014,22(1):50-53
[2]Borowitz MJ,Devidas M,Hunger SP,et al.Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors:a Children's Oncology Group study[J].Blood,2008,111(12):5477-5485
[3]赵旸.儿童难治复发急性淋巴细胞白血病的新治疗策略[J].临床儿科杂志,2018,36(8):639-642
[4]胡淑芬,谭冬梅,黎毓光.急性B淋巴细胞白血病微小残留病的监测[J].白血病·淋巴瘤,2013,22(4):248-250
[5]Setiadi A,Owen D,Tsang A,et al.The significance of peripheral blood minimal residual disease to predict early disease response in patients with B-cell acute lymphoblastic leukemia[J].International journal of laboratory hematology,2016,38(5):527-534
[6]王月芳,江咏梅,高举,等.原血细胞对于儿童急性B淋巴细胞白血病预后判断的价值[J].中国当代儿科杂志,2016,18(4):292-296
[7]Baraka A,Sherief LM,Kamal NM,et al.Detection of minimal residual disease in childhood B-acute lymphoblastic leukemia by 4-color flowcytometry[J].International journal of hematology,2017,105(6):784-791
[8]Fossat C,Roussel M,Arnoux I,et al.Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia:A French multicenter study[J].Cytometry B Clin Cytom,2014:1
[9]Fossat C,Roussel M,Arnoux I,et al.Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia:A French multicenter study[J].Cytometry B Clin Cytom,2015,88(1):21-29
[10]Vinhas E,Lucena-Silva N,Pedrosa F.Implementation of a simplified flow cytometric assays for minimal residual disease monitoring in childhood acute lymphoblastic leukemia[J].Cytometry.Part B,Clinical cytometry,2018,94(1):94-99
[11]朱明清,耿美菊,何海龙,等.186例儿童急性淋巴细胞白血病免疫表型特征[J].中国血液流变学杂志,2006,16(4):556-557
[12]Jalal SD,Al-Allawi NAS,Al Doski AAS.Immunophenotypic aberrancies in acute lymphoblastic leukemia from 282 Iraqi patients[J].International journal of laboratory hematology,2017,39(6):625-632
[13]Harris NL,Jaff ES,Diebold J,et a1.The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues:report of the Clinical Advisory Committee meeting--Airlie House,Virginia,November,1997[J].The hematology journal:the official journal of the European Haematology Association,2000,1(1):53-66
[14]Burnusuzov HA,Spasova MI,Murdjeva MA,et al.Immunophenotypic Modulation of the Blast Cells in Childhood Acute Lymphoblastic Leukemia Minimal Residual Disease Detection[J].Folia Med(Plovdiv),2016Mar,58(1):28-35
[15]Gaipa G,Basso G,Maglia O,et al.Drug-induced immunophenotypic modulation in childhood ALL:implications for minimal residual disease detection[J].Leukemia,2005,19(1):49-56
[16]Gaipa G,Basso G,Aliprandi S,et al.Prednisone induces immunophenotypic modulation of CD10 and CD34 in nonapoptotic B-cell precursor acute lymphoblastic leukemia cells[J].Cytometry B Clin Cytom,2008,74(3):150-155
[17]朱艳云.西妥昔单抗联合化疗前后肿瘤微环境中部分免疫指标变化的研究[D].解放军总医院,2011
[18]Koskenvuo M,Ekman I,Saha E,et al.Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment[J].Pediatric blood cancer,2016,63(9):1653-1656
[19]梁冠中,王艳峰,韩福才.化疗对非小细胞肺癌患者外周血中CD8+CD28-T细胞表达的影响[J].国际肿瘤学杂志,2016,43(5):335-339
[20]Birkebaek NH,Fisker S,Clausen N,et al.Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood[J].Med Pediatr Oncol,1998,30(6):35l-356
[21]Leung W,Rose SR,Zhou Y,et al.Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia[J].Clin Oncol,2002,20(13):2959-2964
[22]Manka P,Coombes JD,Boosman R,et al.Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment[J].Cancer letters,2018,419:175-186
[23]许艳丽,王顺清,杜庆华,等.造血B祖细胞与急性B淋巴细胞白血病细胞的流式细胞术免疫表型分析与鉴别[J].白血病·淋巴瘤2015,24(5):282-286
[24]Jalal SD,Al-Allawi NAS,Al Doski AAS.Immunophenotypic aberrancies in acute lymphoblastic leukemia from 282 Iraqi patients[J].International journal of laboratory hematology,2017,39(6):625-632
[25]Huang YJ,Coustan-Smith E,Kao HW,et al.Concordance of two approaches in monitoring of minimal residual disease in B-precursor acute lymphoblastic leukemia:Fusion transcripts and leukemia-associated immunophenotypes[J].Journal of the Formosan Medical Association=Taiwan,2017,116(10):774-781
[26]Eveillard M,Robillard N,Arnoux I,et al.Major impact of an early bone marrow checkpoint(day 21)for minimal residual disease in flow cytometry in childhood acute lymphoblastic leukemia[J].Hematol Oncol,2017,35(2):237-243
[27]T Chatterjee,R S Mallhi,S Venkatesan.Minimal residual disease detection using flow cytometry:Applications in acute leukemia[J].Medical journal,Armed Forces India,2013,26(3):279-284
[28]徐殿,何妙侠,郑建明.儿童急性淋巴细胞白血病微小残留病检测及其进展[J].检验医学,2013,28(4):342-346
[29]宋晓洁,冯伟平,韩雪娇,等.CD47在急性白血病干细胞中的表达及其对临床疗效及预后的影响[J].现代生物医学进展,2016,16(29):5760-5762,5796
[30]Tembhare PR,Ghogale S,Ghatwai N,et al.Evaluation of new markers for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia:CD73 and CD86 are the most relevant new markers to increase the efficacy of MRD[J].Cytometry B Clin Cytom,2018 Jan,94(1):100-111
[31]Zhang Yan,Tian Li-Ping,Zhang Ying,et al.Prospective study on comparing two methods:for dynamic monitoring of minimal residual disease in acute promyelocytic leukemia[J].Zhongguo shi yan xue ye xue za zhi,2014,22(1):50-53