青少年急性淋巴细胞白血病临床特征及预后分析
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摘要
目的探讨经中国儿童白血病协作组(CCLG)-2008方案治疗的青少年急性淋巴细胞白血病患者的临床特征及预后。方法对2008年2月至2012年12月就诊于首都医科大学附属北京儿童医院血液肿瘤中心的青少年组(10~18岁)与儿童组(<10岁)患者临床表现、免疫分型、遗传学特征及预后情况等进行对比分析。结果共有723例患儿接受CCLG-2008方案治疗。其中青少年102例(14.11%)。相比儿童患者,青少年患者骨髓免疫分型具有更高T-系表达比例(14.71%vs.5.80%),且细胞遗传学特征分析提示,青少年患者中存在明确的预后不良基因表现型t(9;22)(8.82%vs.4.99%)以及t(1;19)(8.82%vs.5.15%)表达比例增高的趋势,而提示预后良好的t(12;21)(21.74%vs.8.82%)发生比例则显著减低。但在相同危险分组情况下,中危组青少年组与儿童组5年整体生存率(overall survival,OS)与无事件生存率(event-free survival,EFS)差异无统计学意义,分别为(92.88%vs.90.86%)与(77.09%vs.82.90%)。值得注意的是,在高危组中,青少年组患者5年EFS明显低于儿童组(42.78%vs.54.12%)。结论尽管存在预后不良因素,青少年白血病患者在接受儿童急性淋巴细胞白血病CCLG-2008化疗方案后仍可得到较满意的OS。但如何改善高危组青少年患者的预后则仍是当前治疗难点。
Objective To summarize the clinical characteristics and outcome of adolescent patients with acute lymphoblastic leukemia(ALL)treated with Chinese Children's Leukemia Group(CCLG)-2008 protocol over a 5-year period from 2008 to 2013. Methods Clinical features,immunophenotypes,cytogenetic abnormalities and prognosis of adolescent patients aged 10 to 18 were compared with younger patients under 10 years old. Results During 2008—2012,723 patients with ALL were enrolled in our study. About 14.11% of them were 10-to 18-year old patients.Compared to younger ones,adolescent patients demonstrated a higher incidence of T-cell lineage phenotype(14.71% vs5.8%),t(9;22)(8.82% vs. 4.99%),t(1;19)(8.82% vs. 5.15%),and significantly lower frequency of t(12;21)(21.74% vs. 8.82%). In intermediate group,the 5-year overall survival rate(OS)and event-free survival rate(EFS)of adolescent patients was compatible with paediatric patients,(92.88% vs. 90.86%) and(77.09% vs. 82.9%),respectively. However,the EFS of adolescent patients with high-risk ALL was worse than paediatric patients(42.78% vs. 54.12%). Conclusion Despite the increased incidence of adverse prognostic factors,the survival rate of adolescent patients has been improved when treated with paediatric ALL protocol. However,the poor prognosis of adolescent patients in the high-risk group remains to be the current challenge.
Objective To summarize the clinical characteristics and outcome of adolescent patients with acute lymphoblastic leukemia(ALL)treated with Chinese Children's Leukemia Group(CCLG)-2008 protocol over a 5-year period from 2008 to 2013. Methods Clinical features,immunophenotypes,cytogenetic abnormalities and prognosis of adolescent patients aged 10 to 18 were compared with younger patients under 10 years old. Results During 2008—2012,723 patients with ALL were enrolled in our study. About 14.11% of them were 10-to 18-year old patients.Compared to younger ones,adolescent patients demonstrated a higher incidence of T-cell lineage phenotype(14.71% vs5.8%),t(9;22)(8.82% vs. 4.99%),t(1;19)(8.82% vs. 5.15%),and significantly lower frequency of t(12;21)(21.74% vs. 8.82%). In intermediate group,the 5-year overall survival rate(OS)and event-free survival rate(EFS)of adolescent patients was compatible with paediatric patients,(92.88% vs. 90.86%) and(77.09% vs. 82.9%),respectively. However,the EFS of adolescent patients with high-risk ALL was worse than paediatric patients(42.78% vs. 54.12%). Conclusion Despite the increased incidence of adverse prognostic factors,the survival rate of adolescent patients has been improved when treated with paediatric ALL protocol. However,the poor prognosis of adolescent patients in the high-risk group remains to be the current challenge.
引文
[1]中华医学会儿科学分会血液学组.儿童急性淋巴细胞白血病诊疗建议[J].中华儿科杂志,2014,52(9):641-644.
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[12]Roberts KG,Morin RD,Zhang J,et al.Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia[J].Cancer Cell,2012,22(2):153-166.
[13]Roberts KG,Li Y,Payne-Turner,et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia[J].New Engl Med,2014,371(11):1005-1015.
[14]Den B,van Slegtenhorst RX,Menezes De,et al.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome:a genome-wide classification study[J].Lancet Oncol,2009,10(2):125-134.
[15]Roberts KG,Pei D,Campana D,et al.Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease[J].J Clin Oncol,2014,32(27):3012-3020.
[16]Jia M,Wang ZJ,Li JY,et al.The impact of IKZF1 deletion on the prognosis of acute lymphoblastic leukemia:an updated metaanalysis[J].Cancer Biomarkers,2014,14(6):493-503.
[17]Harewood LH,Robinson R,Harris,et al.Amplification of AML1on a duplicated chromosome 21 in acute lymphoblastic leukemia:a study of 20 cases[J].Leukemia,2003,17(3):547-553.
[18]Diouf B,Crews KR,Lew G,et al.Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia[J].JAMA,2015,313(8):815-823.
[19]Kawedia JD,Kaste SC,Pei D,et al.Pharmacokinetic,pharmacodynamic,and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia[J].Blood,2011,117(8):2340-2347.
[20]Hayakawa FT,Sakura T,Yujiri,et al.Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol:a phase II study by the Japan Adult Leukemia Study Group[J].Blood Cancer,2014,4(2):252.
[21]Yang J,Landier W,Yang W,et al.Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia[J].J Clin Oncol,2015,33(11):1235-1242.
[22]Zgheib NK,Akika R,Mahfouz R,et al.NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon[J].Pediatr Blood Cancer,2017,64(1):146-150.
[23]Goldstone AH,Richards SM,Lazarus HM,et al.In adults with standard-risk acute lymphoblastic leukemia,the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission,and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients:final results of the International ALL Trial(MRC UKALL XII/ECOG E2993)[J].Blood,2008,111(4):1827-1833.
[24]Thomas X,Boiron JM,Huguet F,et al.Outcome of treatment in adults with acute lymphoblastic leukemia:analysis of the LALA-94 trial[J].J Clin Oncol,2004,22(20):4075-4086.
[25]Seftel MD,Neuberg D,Zhang MJ,et al.Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission[J].Am J Hematol,2016,91(3):322-329.
[2]Ward EC,De Santis A,Robbins,et al.Childhood and adolescent cancer statistics[J].CA J Clin,2014,64(2):83-103.
[3]Harrison CJ.Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia[J].Br J Haematol,2009,144(2):147-156.
[4]Tricoli JV,Blair DG,Anders CK,et al.Biologic and clinical characteristics of adolescent and young adult cancers:acute lymphoblastic leukemia,colorectal cancer,breast cancer,melanoma,and sarcoma[J].Cancer,2016,122(7):1017-1028.
[5]刘凯奇,赵邢力,魏威,等.青少年急性淋巴细胞白血病单中心临床研究[J].中华内科杂志,2016,55(2):102-106.
[6]Ramanujachar RS,Richards IH.Adolescents with acute lymphoblastic leukaemia:outcome on UK national paediatric(ALL97)and adult(UKALLXII/E2993)trials[J].Pediatr Blood Cancer,2007,48(3):254-261.
[7]de Bont JM,Holt B,Dekker AW,et al.Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands[J].Leukemia,2004,18(12):2032-2035.
[8]Boissel N,Auclerc MF,Lheritier V,et al.Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults?Comparison of the French FRALLE-93 and LALA-94 trials[J].J Clin Oncol,2003,21(5):774-780.
[9]Barry E,De Angelo DJ,Neuberg D,et al.Favorable outcome for adolescents with acute lymphoblastic leukemia treated on DanaFarber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols[J].J Clin Oncol,2007,25(7):813-819.
[10]Curran E,Stock W.How I treat acute lymphoblastic leukemia in older adolescents and young adults[J].Blood,2015,125(24):3702-3710.
[11]Mullighan CG,Su X,Zhang J,et al.Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia[J].New Engl Med,2009,360(5):470-480.
[12]Roberts KG,Morin RD,Zhang J,et al.Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia[J].Cancer Cell,2012,22(2):153-166.
[13]Roberts KG,Li Y,Payne-Turner,et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia[J].New Engl Med,2014,371(11):1005-1015.
[14]Den B,van Slegtenhorst RX,Menezes De,et al.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome:a genome-wide classification study[J].Lancet Oncol,2009,10(2):125-134.
[15]Roberts KG,Pei D,Campana D,et al.Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease[J].J Clin Oncol,2014,32(27):3012-3020.
[16]Jia M,Wang ZJ,Li JY,et al.The impact of IKZF1 deletion on the prognosis of acute lymphoblastic leukemia:an updated metaanalysis[J].Cancer Biomarkers,2014,14(6):493-503.
[17]Harewood LH,Robinson R,Harris,et al.Amplification of AML1on a duplicated chromosome 21 in acute lymphoblastic leukemia:a study of 20 cases[J].Leukemia,2003,17(3):547-553.
[18]Diouf B,Crews KR,Lew G,et al.Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia[J].JAMA,2015,313(8):815-823.
[19]Kawedia JD,Kaste SC,Pei D,et al.Pharmacokinetic,pharmacodynamic,and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia[J].Blood,2011,117(8):2340-2347.
[20]Hayakawa FT,Sakura T,Yujiri,et al.Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol:a phase II study by the Japan Adult Leukemia Study Group[J].Blood Cancer,2014,4(2):252.
[21]Yang J,Landier W,Yang W,et al.Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia[J].J Clin Oncol,2015,33(11):1235-1242.
[22]Zgheib NK,Akika R,Mahfouz R,et al.NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon[J].Pediatr Blood Cancer,2017,64(1):146-150.
[23]Goldstone AH,Richards SM,Lazarus HM,et al.In adults with standard-risk acute lymphoblastic leukemia,the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission,and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients:final results of the International ALL Trial(MRC UKALL XII/ECOG E2993)[J].Blood,2008,111(4):1827-1833.
[24]Thomas X,Boiron JM,Huguet F,et al.Outcome of treatment in adults with acute lymphoblastic leukemia:analysis of the LALA-94 trial[J].J Clin Oncol,2004,22(20):4075-4086.
[25]Seftel MD,Neuberg D,Zhang MJ,et al.Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission[J].Am J Hematol,2016,91(3):322-329.