慢性髓系白血病的临床治疗研究
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摘要
第一部分伊马替尼治疗214例慢性髓性白血病疗效观察及发生耐药的多因素分析
目的
探讨伊马替尼治疗慢性髓性白血病（CML）的疗效及治疗过程中发生耐药的相关因素。
方法
回顾性分析2005年4月至2010年12月接受伊马替尼治疗的CML患者214例，随访患者治疗情况、疗效，分析影响耐药的各种因素。应用COX比例风险回归模型对影响耐药的各种因素进行单因素和多因素分析。
结果
截至随访终点，31例（14.5%）患者出现伊马替尼耐药，其中1例为加速期患者，2例为急变期患者；完全细胞遗传学缓解（CCyR）率为69.2%，主要分子生物学缓解（MMR）率为31.3%。以207例慢性期患者进行COX分析，单因素分析显示治疗前病程、HGB（血红蛋白计数）、WBC（白细胞计数）、是否获得完全细胞遗传学缓解、是否获得主要分子生物学缓解为伊马替尼耐药的影响因素。多因素COX回归分析表明：是否获得完全细胞遗传学缓解为伊马替尼耐药的独立影响因素。
结论
（1）伊马替尼治疗慢性粒细胞白血病214例，其中31例（14.5%）患者发生耐药。148例患者（69.2%）获得完全细胞遗传学缓解，67例患者（31.3%）获得主要分子生物学缓解。（2）是否获得完全细胞遗传学缓解是伊马替尼治疗慢性粒细胞白血病是否发生耐药的独立影响因素，且为保护因素。
第二部分伴T315I突变的13例BCR-ABL阳性白血病患者的治疗探讨
目的
对伴T315I突变的白血病患者的疗效进行分析，并初步探讨如何选择治疗方法。
方法
回顾性分析2010年1月至2013年1月13例伴T315I突变的白血病患者（慢性
髓系白血病急变期（CML-BC）4例、急性淋巴细胞白血病合并BCR-ABL阳性（ph+-ALL）9例），随访患者治疗情况、疗效及预后。
结果
（1）前11例伴T315I突变的白血病患者中6例行异基因造血干细胞移植，至随访时4例存活（包括1例移植后复发但尚存活的患者）,2例移植后复发者死亡；其余5例未移植患者均死亡。（2）病例12、13为移植后本病复发后检测到T315I突变，至随访时1例存活。
结论
针对伴T315I突变的白血病患者，异基因造血干细胞移植是唯一可以治愈的方法；高三尖杉酯碱可以成为一种新的治疗方式，为异基因造血干细胞移植提供契机，获得更好的疗效。
第三部分伊马替尼与异基因造血干细胞移植治疗慢性髓系白血病对比分析
目的
比较伊马替尼与异基因造血干细胞移植在慢性髓系白血病(CML)治疗的疗效。
方法
回顾性分析2001年3月至2012年10月接受伊马替尼或异基因造血干细胞移植的433例慢性髓系白血病患者，比较两组患者无事件生存率（EFS）、总体生存率（OS）。
结果
（1）伊马替尼（CML-CP）组EFS为88.5%，OS为93.2%，预期5年EFS84%、5年OS92%；而异基因造血干细胞移植组（CML-CP）组EFS为70%，OS为80%，预期5年EFS75%、5年OS79%。两组比较，伊马替尼组EFS及OS均明显高于异基因造血干细胞移植组（P值均<0.05）。（2）伊马替尼（AP+BC）组EFS为42.9%，OS为42.9%；而异基因造血干细胞移植组（AP+BC）组EFS为47.6%，OS为57.1%。两组比较，EFS及OS无明显统计学差异。
结论
对于CML-CP患者，伊马替尼组EFS及OS均明显高于异基因造血干细胞移植组；对于AP或BC期患者，两组无明显统计学差异，但本组AP+BC期患者病例数少，有待更多病例进一步研究。
Part one To evaluate the effect of Imatinib on treatment of214patientswith chronic myeloid leukemia and Multivariate Analysis ImatinibResistance factors For CML patients
Objective
To discuss curative effect of imatinib and imatinib resistance-related factors forchronic myeloid leukemia patients.
Methods
214patients of chronic myeloid leukemia received imatinib treatment in our hospitalfrom April2005to December2010. The therapy history and curative effect were regularfollowed up at outpatient ward in our hospital and influencing factors of drug resistancewere analyzed. Cox regression analysis was used to perform the single factor andmulti-factors analysis.
Results
To the deadline, thirty-one patients(14.49%) appeared drug resistance.One of themwas in accelerate phase, and two of them were in blastic phase.69.2%patients achievedcomplete cytogenetic response(CCyR).31.3%patients achieved major molecularresponse(MMR). We performed cox analysis with the207patients who were in chronicphase.Single factor cox regression analysis showed:the course before treatment、thehemoglobin count、the white blood cell count、whether achieved complete cytogeneticresponse or not and whether achieved major molecular response or not are the influencingfactors for imatinib resistance. The result of multi-factors cox regression analysis: whether achieved complete cytogenetic response or not is the independent factor which influencesdrug resistance.
Conclusions
We summarized from214chronic myeloid leukemia patients receiving imatinib andthirty-one patients(14.5%) appeared drug resistance.One hundread and forty-eightpatients achieved complete cytogenetic response(CCyR) with a proportion of69.2%.Sixty-seven patients achieved major molecular response(MMR) with a proportionof31.3%.（2）Whether achieved complete cytogenetic response or not is the independentfactor which influences imatinib resistance for chronic myeloid leukemia patients, and it’sa protective factor.
Part two To discuss the treatment for the thirteen BCR-ABL positiveleukemia patients with the T315I mutation
Objective
To discuss the curative effect for the leukemia patients with the T315I mutation,and todiscuss on how to choose the treatment preliminarily.
Methods
We assessed thirteen leukemia patients with the T315I mutation from January2010toJanuary2013through retrospective analysis(four CML cases in blastic phase, nine ALLcases with Ph chromosome positive); The therapy history,curative effect and prognosiswere followed up.
Results
6cases of the first11leukemia patients with T315I mutation underwent allogeneichematopoietic stem cell transplantation, and4cases were alive to the time offollow-up(including1case of recurrence after transplantation but was still alive),the left2cases who recurred after transplantation were dead; The other5cases who don’t underwenttransplant died.(2)The cases of12and13both underwent allogeneic hematopoietic stem cell transplantation and the T315I mutation was detected after the recurrence ofdisease,and1case was alive to the time of follow-up.
Conclusions
To the leukemia patients with T315I mutation,allogeneic hematopoietic stem celltransplantation is the only way to cure; Homoharringtonine may be a new treatment;It canprovides an opportunity for allogeneic hematopoietic stem cell transplantation,and then geta better curative effect.
Part three To contrast the effect of Imatinib and Allogeneichematopoietic stem cell transplantation in the treatment of chronicmyeloid leukemia
Objective
To compare the curative effect of imatinib and allogeneic hematopoietic stem celltransplantation in the treatment of chronic myeloid leukemia.
Methods
433patients of chronic myeloid leukemia received imatinib or allogeneichematopoietic stem cell transplantation from March2001to October2012.Compared theevent free survival (EFS) and overall survival (OS) between the two groups.
Results
(1)The EFS of the group of imatinib(CML in the chronic phase) was88.5%, and theOS was93.2%,while the expected5-year EFS was84%and the expected5-year OS was92%. The EFS of the group of allogeneic hematopoietic stem cell transplantation (CML inthe chronic phase) was70%, and the OS was80%,while the expected5-year EFS was75%and the expected5-year OS was79%.To compare between the two groups,the EFS and OSof the group of imatinib were significantly higher than that of the group of allogeneichematopoietic stem cell transplantation(P value were both <0.05).(2) The EFS of the group of imatinib(CML in the accelerate and blast phase) was42.9%, and the OS was42.9%. The EFS of the group of allogeneic hematopoietic stem cell transplantation (CMLin the accelerate and blast phase) was47.6%, and the OS was57.1%. To compare the EFSand OS,there were no significant difference between the two groups.
Conclusions
The EFS and OS of the group of imatinib were significantly higher than that of thegroup of allogeneic hematopoietic stem cell transplantation for the patients of CML in thechronic phase. While there was no significant difference between the two groups for thepatients of CML in the accelerate and blast phase;but as with little cases,we need morepatients for further research for these two progress stage.
目的
探讨伊马替尼治疗慢性髓性白血病（CML）的疗效及治疗过程中发生耐药的相关因素。
方法
回顾性分析2005年4月至2010年12月接受伊马替尼治疗的CML患者214例，随访患者治疗情况、疗效，分析影响耐药的各种因素。应用COX比例风险回归模型对影响耐药的各种因素进行单因素和多因素分析。
结果
截至随访终点，31例（14.5%）患者出现伊马替尼耐药，其中1例为加速期患者，2例为急变期患者；完全细胞遗传学缓解（CCyR）率为69.2%，主要分子生物学缓解（MMR）率为31.3%。以207例慢性期患者进行COX分析，单因素分析显示治疗前病程、HGB（血红蛋白计数）、WBC（白细胞计数）、是否获得完全细胞遗传学缓解、是否获得主要分子生物学缓解为伊马替尼耐药的影响因素。多因素COX回归分析表明：是否获得完全细胞遗传学缓解为伊马替尼耐药的独立影响因素。
结论
（1）伊马替尼治疗慢性粒细胞白血病214例，其中31例（14.5%）患者发生耐药。148例患者（69.2%）获得完全细胞遗传学缓解，67例患者（31.3%）获得主要分子生物学缓解。（2）是否获得完全细胞遗传学缓解是伊马替尼治疗慢性粒细胞白血病是否发生耐药的独立影响因素，且为保护因素。
第二部分伴T315I突变的13例BCR-ABL阳性白血病患者的治疗探讨
目的
对伴T315I突变的白血病患者的疗效进行分析，并初步探讨如何选择治疗方法。
方法
回顾性分析2010年1月至2013年1月13例伴T315I突变的白血病患者（慢性
髓系白血病急变期（CML-BC）4例、急性淋巴细胞白血病合并BCR-ABL阳性（ph+-ALL）9例），随访患者治疗情况、疗效及预后。
结果
（1）前11例伴T315I突变的白血病患者中6例行异基因造血干细胞移植，至随访时4例存活（包括1例移植后复发但尚存活的患者）,2例移植后复发者死亡；其余5例未移植患者均死亡。（2）病例12、13为移植后本病复发后检测到T315I突变，至随访时1例存活。
结论
针对伴T315I突变的白血病患者，异基因造血干细胞移植是唯一可以治愈的方法；高三尖杉酯碱可以成为一种新的治疗方式，为异基因造血干细胞移植提供契机，获得更好的疗效。
第三部分伊马替尼与异基因造血干细胞移植治疗慢性髓系白血病对比分析
目的
比较伊马替尼与异基因造血干细胞移植在慢性髓系白血病(CML)治疗的疗效。
方法
回顾性分析2001年3月至2012年10月接受伊马替尼或异基因造血干细胞移植的433例慢性髓系白血病患者，比较两组患者无事件生存率（EFS）、总体生存率（OS）。
结果
（1）伊马替尼（CML-CP）组EFS为88.5%，OS为93.2%，预期5年EFS84%、5年OS92%；而异基因造血干细胞移植组（CML-CP）组EFS为70%，OS为80%，预期5年EFS75%、5年OS79%。两组比较，伊马替尼组EFS及OS均明显高于异基因造血干细胞移植组（P值均<0.05）。（2）伊马替尼（AP+BC）组EFS为42.9%，OS为42.9%；而异基因造血干细胞移植组（AP+BC）组EFS为47.6%，OS为57.1%。两组比较，EFS及OS无明显统计学差异。
结论
对于CML-CP患者，伊马替尼组EFS及OS均明显高于异基因造血干细胞移植组；对于AP或BC期患者，两组无明显统计学差异，但本组AP+BC期患者病例数少，有待更多病例进一步研究。
Part one To evaluate the effect of Imatinib on treatment of214patientswith chronic myeloid leukemia and Multivariate Analysis ImatinibResistance factors For CML patients
Objective
To discuss curative effect of imatinib and imatinib resistance-related factors forchronic myeloid leukemia patients.
Methods
214patients of chronic myeloid leukemia received imatinib treatment in our hospitalfrom April2005to December2010. The therapy history and curative effect were regularfollowed up at outpatient ward in our hospital and influencing factors of drug resistancewere analyzed. Cox regression analysis was used to perform the single factor andmulti-factors analysis.
Results
To the deadline, thirty-one patients(14.49%) appeared drug resistance.One of themwas in accelerate phase, and two of them were in blastic phase.69.2%patients achievedcomplete cytogenetic response(CCyR).31.3%patients achieved major molecularresponse(MMR). We performed cox analysis with the207patients who were in chronicphase.Single factor cox regression analysis showed:the course before treatment、thehemoglobin count、the white blood cell count、whether achieved complete cytogeneticresponse or not and whether achieved major molecular response or not are the influencingfactors for imatinib resistance. The result of multi-factors cox regression analysis: whether achieved complete cytogenetic response or not is the independent factor which influencesdrug resistance.
Conclusions
We summarized from214chronic myeloid leukemia patients receiving imatinib andthirty-one patients(14.5%) appeared drug resistance.One hundread and forty-eightpatients achieved complete cytogenetic response(CCyR) with a proportion of69.2%.Sixty-seven patients achieved major molecular response(MMR) with a proportionof31.3%.（2）Whether achieved complete cytogenetic response or not is the independentfactor which influences imatinib resistance for chronic myeloid leukemia patients, and it’sa protective factor.
Part two To discuss the treatment for the thirteen BCR-ABL positiveleukemia patients with the T315I mutation
Objective
To discuss the curative effect for the leukemia patients with the T315I mutation,and todiscuss on how to choose the treatment preliminarily.
Methods
We assessed thirteen leukemia patients with the T315I mutation from January2010toJanuary2013through retrospective analysis(four CML cases in blastic phase, nine ALLcases with Ph chromosome positive); The therapy history,curative effect and prognosiswere followed up.
Results
6cases of the first11leukemia patients with T315I mutation underwent allogeneichematopoietic stem cell transplantation, and4cases were alive to the time offollow-up(including1case of recurrence after transplantation but was still alive),the left2cases who recurred after transplantation were dead; The other5cases who don’t underwenttransplant died.(2)The cases of12and13both underwent allogeneic hematopoietic stem cell transplantation and the T315I mutation was detected after the recurrence ofdisease,and1case was alive to the time of follow-up.
Conclusions
To the leukemia patients with T315I mutation,allogeneic hematopoietic stem celltransplantation is the only way to cure; Homoharringtonine may be a new treatment;It canprovides an opportunity for allogeneic hematopoietic stem cell transplantation,and then geta better curative effect.
Part three To contrast the effect of Imatinib and Allogeneichematopoietic stem cell transplantation in the treatment of chronicmyeloid leukemia
Objective
To compare the curative effect of imatinib and allogeneic hematopoietic stem celltransplantation in the treatment of chronic myeloid leukemia.
Methods
433patients of chronic myeloid leukemia received imatinib or allogeneichematopoietic stem cell transplantation from March2001to October2012.Compared theevent free survival (EFS) and overall survival (OS) between the two groups.
Results
(1)The EFS of the group of imatinib(CML in the chronic phase) was88.5%, and theOS was93.2%,while the expected5-year EFS was84%and the expected5-year OS was92%. The EFS of the group of allogeneic hematopoietic stem cell transplantation (CML inthe chronic phase) was70%, and the OS was80%,while the expected5-year EFS was75%and the expected5-year OS was79%.To compare between the two groups,the EFS and OSof the group of imatinib were significantly higher than that of the group of allogeneichematopoietic stem cell transplantation(P value were both <0.05).(2) The EFS of the group of imatinib(CML in the accelerate and blast phase) was42.9%, and the OS was42.9%. The EFS of the group of allogeneic hematopoietic stem cell transplantation (CMLin the accelerate and blast phase) was47.6%, and the OS was57.1%. To compare the EFSand OS,there were no significant difference between the two groups.
Conclusions
The EFS and OS of the group of imatinib were significantly higher than that of thegroup of allogeneic hematopoietic stem cell transplantation for the patients of CML in thechronic phase. While there was no significant difference between the two groups for thepatients of CML in the accelerate and blast phase;but as with little cases,we need morepatients for further research for these two progress stage.
引文
[1] Druker BJ,Guilhot F,O'Brien SG,et al.Five-year follow-up of patients receivingimatinib for chronic myeloid leukemia.N Engl J Med,2006,355:2408-2417.
[2]周可树,王翠翠,赵耀中,等.伊马替尼治疗慢性粒细胞白血病135例远期疗效观察.白血病·淋巴瘤,2010,19:646-650.
[3] Soverini S,Gnani A,De Benedittis C, et al. Validation of the New EuropeanLeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysisin chronic myeloid leukemia: An analysis of the GIMEMA CML working partystudies. Blood2011;118:112.
[4] Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[5] Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[6] O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[7] Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patientswith refractory chronic myeloid leukemia and other hematologic malignancies: Firstresults of safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[1]Druker BJ,Guilhot F,O'Brien SG,et al.Five-year follow-up of patients receiving imatinibfor chronic myeloid leukemia.N Engl J Med,2006,355:2408-2417.
[2]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[3]周可树,王翠翠,赵耀中,等.伊马替尼治疗慢性粒细胞白血病135例远期疗效观察.白血病·淋巴瘤,2010,19:646-650.
[4]Timothy P,Andreas H,Susan B,et al.Long-term prognostic significance of earlymolecular response to imatinib in newly diagnosed chronic myeloid leukemia:ananalysis from the International Randomized Study of Interferon andSTI571(IRIS).Blood,2010,116(19):3758-3765.
[5] Jorge Cortes,Moshe Talpaz,Susan O'Brien,et al.Molecular Responses in Patients withChronic Myelogenous Leukemia in Chronic Phase Treated with ImatinibMesylate.Clin Cancer Res,2005,11:3425-3432.
[6] Richard D. Press, Chad Galderisi, Rui Yang, et al.A Half-Log Increase in BCR-ABLRNA Predicts a Higher Risk of Relapse in Patients with Chronic Myeloid Leukemiawith an Imatinib-Induced Complete Cytogenetic Response.Clin CancerRes,2007,13:6136-6143.
[7]Hochhaus A,O'Brien SG,Guilhot F,et al.Six-year follow-up of patients receivingimatinib for the first-line treatment of chronic myeloid leukemia. Leukemia,2009,23:1054-1061.
[8]Guiloht F,Larson RA,Ohrien SG.Time to CCyR does not affect long-term outcomes forpatients on imatinib therapy.Blood,2007,110:Abstract27.
[9]Breccia M,Daverio D,Pane F,et al.Discontinuation of imatinib therapy after achievementof complete molecular responsein a Ph+CML patient treated while in long lastingcomplete cytogenetic remission(CCR) induced by interferon.Leuk Res,2006,30:1577-9.
[10]Merante S,Orlandi E,Bernasconi P,et al.Outcome of four patients with chronicmyeyloid leukemia after imatinib mesylate discontinuation. Haematologica,2005,90:979-81.
[11]Goh HG,Kim YJ,Kim DW,et al.Previous best responses can be re-achieved byresumption after imatinib discontinuation in patients with chronic myeloid leukemia:implication for intermittent imatinib therapy.Leuk Lymphoma,2009,50:944-51.
[1] O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[2] Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patientswith refractory chronic myeloid leukemia and other hematologic malignancies: Firstresults of safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[3] Cortes JE,Kim D,Pinilla-Ibarz J, et al. Initial findings from the PACE trial: A pivotalphase2study of ponatinib in patients with CML and Ph+ALL resistant or intolerantto dasatinib or nilotinib, or with the T315I mutation. Blood2011;118:109.
[4] Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[5]李小丰，李景贺，王春红，等.三氧化二砷对T315I突变细胞株KBM5R有诱导凋亡作用.中华实验血液学杂志，2011,19:643-647.
[6] Alfonso Q,Hagop K,Jorge C.Homoharringtonine,Omacetaxine Mepesuccinate,ANDChronic Myeloid Leukemia Circa2009.Cancer,2009Dec1;115(23):5382-5393.
[7] Meir Wetzler,David Segal.Omacetaxine as an Anticancer Therapeutic:What is Old isNew Again.Curr Pharm Des,2011,17(1):59-64.
[8] Quintas-Cardama A,Cortes J.Homoharringtonine for the treatment of chronicmyelogenousleukemia.Expert Opin Pharmacother,2008,9:1029-1037.
[9] Verma D，Fava C，Kantarjian H，et al．Complexity of BCR-ABL kinase domainmutationsduring the course of therapy with tyrosine kinase inhibitors in chronicmyeloid1eukemia．Am JHematol,2009,84:256-257．
[10] Jorge C,Jeff H,Delphine R,et al.Phase2study subcutaneous omacetaxinemepesuccinate after TKI failure in patients with chronic-phase CML with T315Imutation.Blood,2012,120:2573-2580.
[1]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[2] Gratwohl A,Brand R,Apperley J,et al.Allogeneic hematopoietic stem celltransplantation for chronic myeloid leukemia in Europe2006:transplantactivity,long-term data and current results.An analysis by the Chronic LeukemiaWorking Party of the European Group for Blood and Marrow Transplantation(EBMT).Haematologica.2006;91(4):513-521.
[3] Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[4] Jabbour E,Kantarjian H,Jones D, et al. Characteristics and outcomes of patients withchronic myeloid leukemia and T315I mutation following failure of imatinib mesylatetherapy. Blood2008;112:53–55.
[5] Allogeneic hematopoietic stem cell transplantation(allo SCT) for chronic myeloidleukemia the imatinib era:evaluation of its imapact within a subgroup of therandomized German CML Study IV.Blood.2010;115:1880-1885.
[6] Schiffer CA.BCR-ABL tyrosine kinase inhibitors for chronic myelogenousleukemia.N Engl J Med,2007,357:258-265.
[7] Pavlovsky C,Kantarjian H,Cortes JE.First-line therapy for chronic myeloidleukemia:past,present,and future.Am J Hematol,2009,84:287-293.
[8] Kantarjian HM,Cortes J,La Rosee P,et al.Optimizing therapy for patients with chronicmyelogenous leukemia in chronic phase.Cancer,2010,116:1419-1430.
[9] Baccarani M,Saglio G,Goldman J,et al.Evolving concepts in the management ofchronic myeloid leukemia:recommendations from an expert panel on behalf of theEuropean LeukemiaNet.Blood.2006;108(6):1809-1820.
[10] Baccarani M,Cortes J,Pane F,et al.Chronic myeloid leukemia:an update of conceptsand management recommendations of European LeukemiaNet.J Clin Oncol.2009;27(35):6041-6051.
[11] Gratwohl A,Heim D.Current role of stem cell transplantation in chronic myeloidleukemia.Best Pract Res Clin Haematol.2009;22(3):431-443.
[12] Goldman JM.Treatment strategies for CML.Best Pract Res Clin Haematol.2009;22(3):303-313.
[13] Qian Jiang，Lan-Ping Xu，Dai-Hong Liu，et al.Imatinib mesylate versus allogeneichematopoietic stem cell transplantation for patients with chronic myelogenousleukemia in the accelerated phase.Blood,2011,117:3032-3040.
[1]O’Brien S,Berman E,Borghaei H,et al.NCCN clinical practice guidelines inoncology:chronic myelogenous leukemia.J Natl Canc Netw,2009,7:982-1023.
[2]Gishizky ML,Johnson-White J,Witte ON.Efficient transplantation of BCR-ABL inducedchronic myelogenous leukemia-like syndrome in mice.Proc Natl Acad SciUSA.1993,90:3755-3759.
[3]Silver RT,Woolf SH,Hehlmann R,et al.An evidence-based analysis of the effect ofbusulfan,hydroxyurea,interferon and allogeneic bone marrow transplantation in thechronic phase of chronic myeloid leukemia:developed for the American Society ofHematology.Blood,1999,94:1517-1536.
[4]NCCN Clinical Practice Guidelines in Oncology(NCCN GuidelinesTM)-FREE:ChronicMyelogenous Leukemia.Version2.2011[2011-03-29]. http//www.nccn.org/professionals/physician_gls/f_guidelines.asp.
[5]Baccarani M,Saglio G,Goldman J,et al.Evolving concepts in the management of chronicmyeloid leukemia:recommendations from an expert panel on behalf of the EuropeanLeukemiaNet.Blood,2006,108:1809-1820.
[6]Baccarani M,Cortes J,Pane F,et al.Chronic myeloid leukemia.an update of concepts andmanagement Recommendations of the EuropeanLeukemiaNet.J Clin Oncol,2009,27:6041-6051.
[7]World Health Organization Classification of Tumors.Pathology and Genetic of Tumorsof Haematopoietic and Lymphoid Tissue.2008.
[8]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[9]张之南.血液病诊断及疗效标准[M].北京：科学出版社，2007:134-136.
[10]Schiffer CA.BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia.NEngl J Med,2007,357:258-265.
[11]Pavlovsky C,Kantarjian H,Cortes JE.First-line therapy for chronic myeloidleukemia:past,present,and future.Am J Hematol,2009,84:287-293.
[12]Kantarjian HM,Cortes J,La Rosee P,et al.Optimizing therapy for patients with chronicmyelogenous leukemia in chronic phase.Cancer,2010,116:1419-1430.
[13]Druker BJ,Lydon NB. Lessons learned from the development of an abl tyrosine kinaseinhibitor for chronic myelogenous leukemia. J Clin Invest2000;105:3–7.
[14]Deininger M,O'Brien SG,Guilhot F, et al. International randomized study of interferonvs. STI571(IRIS)8-year follow up: Sustained survival and low risk for progression ofevents in patients with newly diagnosed chronic myeloid leukemia in chronic phase(CML-CP) treated with imatinib. Blood2009;114.
[15]Timothy P,Andreas H,Susan B,et al.Long-term prognostic significance of earlymolecular response to imatinib in newly diagnosed chronic myeloid leukemia:ananalysis from the International Randomized Study of Interferon andSTI571(IRIS).Blood,2010,116(19):3758-3765.
[16]Soverini S,Gnani A,De Benedittis C, et al. Validation of the New EuropeanLeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysisin chronic myeloid leukemia: An analysis of the GIMEMA CML working partystudies. Blood2011;118:112.
[17]Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[18]Jabbour E,Kantarjian H,Jones D, et al. Characteristics and outcomes of patients withchronic myeloid leukemia and T315I mutation following failure of imatinib mesylatetherapy. Blood2008;112:53–55.
[19]Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[20]O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[21]Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patients withrefractory chronic myeloid leukemia and other hematologic malignancies: First resultsof safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[22]Cortes JE,Kim D,Pinilla-Ibarz J, et al. Initial findings from the PACE trial: A pivotalphase2study of ponatinib in patients with CML and Ph+ALL resistant or intolerantto dasatinib or nilotinib, or with the T315I mutation. Blood2011;118:109.
[23]Alfonso Q,Hagop K,Jorge C.Homoharringtonine,Omacetaxine Mepesuccinate,ANDChronic Myeloid Leukemia Circa2009.Cancer,2009Dec1;115(23):5382-5393.
[24]Meir Wetzler,David Segal.Omacetaxine as an Anticancer Therapeutic:What is Old isNew Again.Curr Pharm Des,2011,17(1):59-64.
[25]Quintas-Cardama A,Cortes J.Homoharringtonine for the treatment of chronicmyelogenousleukemia.Expert Opin Pharmacother,2008,9:1029-1037.
[26] Verma D，Fava C，Kantarjian H，et al．Complexity of BCR-ABL kinase domainmutationsduring the course of therapy with tyrosine kinase inhibitors in chronicmyeloid1eukemia．Am JHematol,2009,84:256-257．
[27]Jorge C,Jeff H,Delphine R,et al.Phase2study subcutaneous omacetaxinemepesuccinate after TKI failure in patients with chronic-phase CML with T315Imutation.Blood,2012,120:2573-2580.
[28]Qian Jiang，Lan-Ping Xu，Dai-Hong Liu，et al.Imatinib mesylate versus allogeneichematopoietic stem cell transplantation for patients with chronic myelogenousleukemia in the accelerated phase.Blood,2011,117:3032-3040.
[2]周可树,王翠翠,赵耀中,等.伊马替尼治疗慢性粒细胞白血病135例远期疗效观察.白血病·淋巴瘤,2010,19:646-650.
[3] Soverini S,Gnani A,De Benedittis C, et al. Validation of the New EuropeanLeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysisin chronic myeloid leukemia: An analysis of the GIMEMA CML working partystudies. Blood2011;118:112.
[4] Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[5] Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[6] O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[7] Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patientswith refractory chronic myeloid leukemia and other hematologic malignancies: Firstresults of safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[1]Druker BJ,Guilhot F,O'Brien SG,et al.Five-year follow-up of patients receiving imatinibfor chronic myeloid leukemia.N Engl J Med,2006,355:2408-2417.
[2]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[3]周可树,王翠翠,赵耀中,等.伊马替尼治疗慢性粒细胞白血病135例远期疗效观察.白血病·淋巴瘤,2010,19:646-650.
[4]Timothy P,Andreas H,Susan B,et al.Long-term prognostic significance of earlymolecular response to imatinib in newly diagnosed chronic myeloid leukemia:ananalysis from the International Randomized Study of Interferon andSTI571(IRIS).Blood,2010,116(19):3758-3765.
[5] Jorge Cortes,Moshe Talpaz,Susan O'Brien,et al.Molecular Responses in Patients withChronic Myelogenous Leukemia in Chronic Phase Treated with ImatinibMesylate.Clin Cancer Res,2005,11:3425-3432.
[6] Richard D. Press, Chad Galderisi, Rui Yang, et al.A Half-Log Increase in BCR-ABLRNA Predicts a Higher Risk of Relapse in Patients with Chronic Myeloid Leukemiawith an Imatinib-Induced Complete Cytogenetic Response.Clin CancerRes,2007,13:6136-6143.
[7]Hochhaus A,O'Brien SG,Guilhot F,et al.Six-year follow-up of patients receivingimatinib for the first-line treatment of chronic myeloid leukemia. Leukemia,2009,23:1054-1061.
[8]Guiloht F,Larson RA,Ohrien SG.Time to CCyR does not affect long-term outcomes forpatients on imatinib therapy.Blood,2007,110:Abstract27.
[9]Breccia M,Daverio D,Pane F,et al.Discontinuation of imatinib therapy after achievementof complete molecular responsein a Ph+CML patient treated while in long lastingcomplete cytogenetic remission(CCR) induced by interferon.Leuk Res,2006,30:1577-9.
[10]Merante S,Orlandi E,Bernasconi P,et al.Outcome of four patients with chronicmyeyloid leukemia after imatinib mesylate discontinuation. Haematologica,2005,90:979-81.
[11]Goh HG,Kim YJ,Kim DW,et al.Previous best responses can be re-achieved byresumption after imatinib discontinuation in patients with chronic myeloid leukemia:implication for intermittent imatinib therapy.Leuk Lymphoma,2009,50:944-51.
[1] O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[2] Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patientswith refractory chronic myeloid leukemia and other hematologic malignancies: Firstresults of safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[3] Cortes JE,Kim D,Pinilla-Ibarz J, et al. Initial findings from the PACE trial: A pivotalphase2study of ponatinib in patients with CML and Ph+ALL resistant or intolerantto dasatinib or nilotinib, or with the T315I mutation. Blood2011;118:109.
[4] Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[5]李小丰，李景贺，王春红，等.三氧化二砷对T315I突变细胞株KBM5R有诱导凋亡作用.中华实验血液学杂志，2011,19:643-647.
[6] Alfonso Q,Hagop K,Jorge C.Homoharringtonine,Omacetaxine Mepesuccinate,ANDChronic Myeloid Leukemia Circa2009.Cancer,2009Dec1;115(23):5382-5393.
[7] Meir Wetzler,David Segal.Omacetaxine as an Anticancer Therapeutic:What is Old isNew Again.Curr Pharm Des,2011,17(1):59-64.
[8] Quintas-Cardama A,Cortes J.Homoharringtonine for the treatment of chronicmyelogenousleukemia.Expert Opin Pharmacother,2008,9:1029-1037.
[9] Verma D，Fava C，Kantarjian H，et al．Complexity of BCR-ABL kinase domainmutationsduring the course of therapy with tyrosine kinase inhibitors in chronicmyeloid1eukemia．Am JHematol,2009,84:256-257．
[10] Jorge C,Jeff H,Delphine R,et al.Phase2study subcutaneous omacetaxinemepesuccinate after TKI failure in patients with chronic-phase CML with T315Imutation.Blood,2012,120:2573-2580.
[1]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[2] Gratwohl A,Brand R,Apperley J,et al.Allogeneic hematopoietic stem celltransplantation for chronic myeloid leukemia in Europe2006:transplantactivity,long-term data and current results.An analysis by the Chronic LeukemiaWorking Party of the European Group for Blood and Marrow Transplantation(EBMT).Haematologica.2006;91(4):513-521.
[3] Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[4] Jabbour E,Kantarjian H,Jones D, et al. Characteristics and outcomes of patients withchronic myeloid leukemia and T315I mutation following failure of imatinib mesylatetherapy. Blood2008;112:53–55.
[5] Allogeneic hematopoietic stem cell transplantation(allo SCT) for chronic myeloidleukemia the imatinib era:evaluation of its imapact within a subgroup of therandomized German CML Study IV.Blood.2010;115:1880-1885.
[6] Schiffer CA.BCR-ABL tyrosine kinase inhibitors for chronic myelogenousleukemia.N Engl J Med,2007,357:258-265.
[7] Pavlovsky C,Kantarjian H,Cortes JE.First-line therapy for chronic myeloidleukemia:past,present,and future.Am J Hematol,2009,84:287-293.
[8] Kantarjian HM,Cortes J,La Rosee P,et al.Optimizing therapy for patients with chronicmyelogenous leukemia in chronic phase.Cancer,2010,116:1419-1430.
[9] Baccarani M,Saglio G,Goldman J,et al.Evolving concepts in the management ofchronic myeloid leukemia:recommendations from an expert panel on behalf of theEuropean LeukemiaNet.Blood.2006;108(6):1809-1820.
[10] Baccarani M,Cortes J,Pane F,et al.Chronic myeloid leukemia:an update of conceptsand management recommendations of European LeukemiaNet.J Clin Oncol.2009;27(35):6041-6051.
[11] Gratwohl A,Heim D.Current role of stem cell transplantation in chronic myeloidleukemia.Best Pract Res Clin Haematol.2009;22(3):431-443.
[12] Goldman JM.Treatment strategies for CML.Best Pract Res Clin Haematol.2009;22(3):303-313.
[13] Qian Jiang，Lan-Ping Xu，Dai-Hong Liu，et al.Imatinib mesylate versus allogeneichematopoietic stem cell transplantation for patients with chronic myelogenousleukemia in the accelerated phase.Blood,2011,117:3032-3040.
[1]O’Brien S,Berman E,Borghaei H,et al.NCCN clinical practice guidelines inoncology:chronic myelogenous leukemia.J Natl Canc Netw,2009,7:982-1023.
[2]Gishizky ML,Johnson-White J,Witte ON.Efficient transplantation of BCR-ABL inducedchronic myelogenous leukemia-like syndrome in mice.Proc Natl Acad SciUSA.1993,90:3755-3759.
[3]Silver RT,Woolf SH,Hehlmann R,et al.An evidence-based analysis of the effect ofbusulfan,hydroxyurea,interferon and allogeneic bone marrow transplantation in thechronic phase of chronic myeloid leukemia:developed for the American Society ofHematology.Blood,1999,94:1517-1536.
[4]NCCN Clinical Practice Guidelines in Oncology(NCCN GuidelinesTM)-FREE:ChronicMyelogenous Leukemia.Version2.2011[2011-03-29]. http//www.nccn.org/professionals/physician_gls/f_guidelines.asp.
[5]Baccarani M,Saglio G,Goldman J,et al.Evolving concepts in the management of chronicmyeloid leukemia:recommendations from an expert panel on behalf of the EuropeanLeukemiaNet.Blood,2006,108:1809-1820.
[6]Baccarani M,Cortes J,Pane F,et al.Chronic myeloid leukemia.an update of concepts andmanagement Recommendations of the EuropeanLeukemiaNet.J Clin Oncol,2009,27:6041-6051.
[7]World Health Organization Classification of Tumors.Pathology and Genetic of Tumorsof Haematopoietic and Lymphoid Tissue.2008.
[8]中华医学会血液学分会.中国慢性髓系白血病诊断与治疗指南（2011年版）.中华血液学杂志,2011,32:426-432.
[9]张之南.血液病诊断及疗效标准[M].北京：科学出版社，2007:134-136.
[10]Schiffer CA.BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia.NEngl J Med,2007,357:258-265.
[11]Pavlovsky C,Kantarjian H,Cortes JE.First-line therapy for chronic myeloidleukemia:past,present,and future.Am J Hematol,2009,84:287-293.
[12]Kantarjian HM,Cortes J,La Rosee P,et al.Optimizing therapy for patients with chronicmyelogenous leukemia in chronic phase.Cancer,2010,116:1419-1430.
[13]Druker BJ,Lydon NB. Lessons learned from the development of an abl tyrosine kinaseinhibitor for chronic myelogenous leukemia. J Clin Invest2000;105:3–7.
[14]Deininger M,O'Brien SG,Guilhot F, et al. International randomized study of interferonvs. STI571(IRIS)8-year follow up: Sustained survival and low risk for progression ofevents in patients with newly diagnosed chronic myeloid leukemia in chronic phase(CML-CP) treated with imatinib. Blood2009;114.
[15]Timothy P,Andreas H,Susan B,et al.Long-term prognostic significance of earlymolecular response to imatinib in newly diagnosed chronic myeloid leukemia:ananalysis from the International Randomized Study of Interferon andSTI571(IRIS).Blood,2010,116(19):3758-3765.
[16]Soverini S,Gnani A,De Benedittis C, et al. Validation of the New EuropeanLeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysisin chronic myeloid leukemia: An analysis of the GIMEMA CML working partystudies. Blood2011;118:112.
[17]Cortes J,Jabbour E,Kantarjian H, et al. Dynamics of BCR-ABL kinase domainmutations in chronic myeloid leukemia after sequential treatment with multipletyrosine kinase inhibitors. Blood2007;110:4005–4011.
[18]Jabbour E,Kantarjian H,Jones D, et al. Characteristics and outcomes of patients withchronic myeloid leukemia and T315I mutation following failure of imatinib mesylatetherapy. Blood2008;112:53–55.
[19]Nikolai V,Jorge C,Richard C,et al.Stem Cell Transplantation for Patients With ChronicMyeloid Leukemia Resistant to Tyrosine Kinase Inhibitors With BCR-ABL KinaseDomain Mutation T315I.Cancer,2010Aug1;116(15):3631-3637.
[20]O'Hare T,Shakespeare WC,Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor forchronic myeloid leukemia, potently inhibits the T315I mutant and overcomesmutation-based resistance. Cancer cell2009;16:401–412.
[21]Cortes J,Talpaz M,Deininger M, et al. A phase1trial of oral AP24534in patients withrefractory chronic myeloid leukemia and other hematologic malignancies: First resultsof safety and clinical activity against T315I and resistant mutations. Blood2009;114:643.
[22]Cortes JE,Kim D,Pinilla-Ibarz J, et al. Initial findings from the PACE trial: A pivotalphase2study of ponatinib in patients with CML and Ph+ALL resistant or intolerantto dasatinib or nilotinib, or with the T315I mutation. Blood2011;118:109.
[23]Alfonso Q,Hagop K,Jorge C.Homoharringtonine,Omacetaxine Mepesuccinate,ANDChronic Myeloid Leukemia Circa2009.Cancer,2009Dec1;115(23):5382-5393.
[24]Meir Wetzler,David Segal.Omacetaxine as an Anticancer Therapeutic:What is Old isNew Again.Curr Pharm Des,2011,17(1):59-64.
[25]Quintas-Cardama A,Cortes J.Homoharringtonine for the treatment of chronicmyelogenousleukemia.Expert Opin Pharmacother,2008,9:1029-1037.
[26] Verma D，Fava C，Kantarjian H，et al．Complexity of BCR-ABL kinase domainmutationsduring the course of therapy with tyrosine kinase inhibitors in chronicmyeloid1eukemia．Am JHematol,2009,84:256-257．
[27]Jorge C,Jeff H,Delphine R,et al.Phase2study subcutaneous omacetaxinemepesuccinate after TKI failure in patients with chronic-phase CML with T315Imutation.Blood,2012,120:2573-2580.
[28]Qian Jiang，Lan-Ping Xu，Dai-Hong Liu，et al.Imatinib mesylate versus allogeneichematopoietic stem cell transplantation for patients with chronic myelogenousleukemia in the accelerated phase.Blood,2011,117:3032-3040.