异基因造血干细胞移植治疗染色体核型预后中等急性髓系白血病
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摘要
背景:以往研究显示完全缓解期染色体核型预后中等的急性髓系白血病患者行亲缘全相合异基因外周血造血干细胞移植有较高的无病生存率和总体生存率,但影响移植预后的相关因素并未完全明确。目的:评价HLA相合异基因外周血造血干细胞移植治疗完全缓解期染色体核型预后中等急性髓系白血病的疗效,并对预后相关因素进行分析。方法:对2009年1月至2015年1月进行HLA全相合异基因外周血造血干细胞移植的50例完全缓解期染色体核型预后中等的急性髓系白血病患者进行回顾性分析,计算总体生存率,并对影响预后的各因素进行统计学分析。结果与结论:(1)4年总体生存率为64%,累积复发率及移植相关非复发死亡率分别为18%及20%。急性移植物抗宿主病的总体发生率为26%;(2)女性供者男性受者配对移植患者4年总体生存率低于非女性供者男性受者移植患者(P=0.041);移植前大于1个疗程才能达完全缓解的患者4年总体生存率低于移植前1个疗程能达完全缓解的患者(P=0.038);年龄≥40岁的患者4年总体生存率低于年龄<40岁的患者(P=0.056);亲缘供者移植和非亲缘移植患者的4年总体生存率差异无显著性意义(P=0.427)。女性供者男性受者移植及年龄≥40岁患者移植相关非复发死亡率明显增高(P值分别为0.024和0.043);(3)多因素分析确认,与移植预后相关的因素有:女性供者男性受者配对移植(P=0.031,RR=1.38,95%CI 1.03-1.95)、移植前大于1个疗程才能达完全缓解(P=0.016,RR=1.46,95%CI 1.10-1.98)、年龄≥40岁(P=0.024,RR=1.63,95%CI 1.32-2.12);(4)结果表明,HLA全相合异基因外周血造血干细胞移植是染色体核型预后中等急性髓系白血病缓解后治疗的有效方法。女性供者男性受者配对移植、移植前大于1个疗程才能达完全缓解、年龄≥40岁是影响这类患者预后的主要危险因素。这类患者行异基因外周血造血干细胞移植时,供者受者的性别组合比是否为亲缘供者更为重要。
BACKGROUND: Previous studies have shown that HLA-identical sibling allogeneic peripheral blood hematopoietic stem celltransplantation(allo-HSCT) provides higher disease-free and overall survival rates for patients with intermediate cytogenetic risk acute myeloid leukemia(AML) in complete remission(CR). But prognosis factors have not been fully defined.OBJECTIVE:To evaluate the outcome of patients with intermediate cytogenetic risk AML undergoing HLA-matched allo-HSCT in CR,and to analyze the prognostic factors.METHODS:Fifty cases of intermediate cytogenetic risk AML in CR receiving HLA-matched allo-HSCT from January2009 to January 2015 were retrospectively analyzed.Primary outcome measures of the study included overall survival(OS),relapse rate and non-relapse mortality.RESULTS AND CONCLUSION:The 4-year OS of the study population reached to 64%,and the relapse rate and NRM reached to 18%and 20%respectively.Incidence of acute graft-versus-host disease was 26%.Different prognosis was observed between female donor/male recipient(FDMR)combination transplant and control(4-year OS:50%vs.71.9%,P=0.041),between patients requiring more than one course of induction chemotherapy to achieve CR and control(4-year OS:40%vs.70%,P=0.038),between older age(≥40 years)and control(4-year OS:44.4%vs.68.3%,P=0.056).The 4-year OS for matched sibling donor and matched unrelated donor was 63.2%and 66.7%(P=0.427),respectively.Further analysis revealed significantly high non-relapse mortality in FDMR combination transplant(P=0.024)and older age(≥40 years;P=0.043).Multivariate analysis revealed three negative prognostic factors:FDMR combination(P=0.031,RR=1.38,95%CI:1.03-1.95),requiring more than one course of induction chemotherapy to achieve CR(P=0.016,RR=1.46,95%CI:1.10-1.98)and older age(≥40 years;P=0.024,RR=1.63,95%CI:1.32-2.12).To conclude,HLA-matched allo-HSCT is a choice for the intermediate cytogenetic risk AML case in CR.FDMR combination,requiring more than one course of induction chemotherapy to achieve CR and older age(≥40 years)are confirmed as risk factors of poor prognosis for HLA-matched allo-HSCT patients with intermediate cytogenetic risk AML in CR.To these cases,the donor-recipient sex combination is more important than the donor type in donor selection.
BACKGROUND: Previous studies have shown that HLA-identical sibling allogeneic peripheral blood hematopoietic stem celltransplantation(allo-HSCT) provides higher disease-free and overall survival rates for patients with intermediate cytogenetic risk acute myeloid leukemia(AML) in complete remission(CR). But prognosis factors have not been fully defined.OBJECTIVE:To evaluate the outcome of patients with intermediate cytogenetic risk AML undergoing HLA-matched allo-HSCT in CR,and to analyze the prognostic factors.METHODS:Fifty cases of intermediate cytogenetic risk AML in CR receiving HLA-matched allo-HSCT from January2009 to January 2015 were retrospectively analyzed.Primary outcome measures of the study included overall survival(OS),relapse rate and non-relapse mortality.RESULTS AND CONCLUSION:The 4-year OS of the study population reached to 64%,and the relapse rate and NRM reached to 18%and 20%respectively.Incidence of acute graft-versus-host disease was 26%.Different prognosis was observed between female donor/male recipient(FDMR)combination transplant and control(4-year OS:50%vs.71.9%,P=0.041),between patients requiring more than one course of induction chemotherapy to achieve CR and control(4-year OS:40%vs.70%,P=0.038),between older age(≥40 years)and control(4-year OS:44.4%vs.68.3%,P=0.056).The 4-year OS for matched sibling donor and matched unrelated donor was 63.2%and 66.7%(P=0.427),respectively.Further analysis revealed significantly high non-relapse mortality in FDMR combination transplant(P=0.024)and older age(≥40 years;P=0.043).Multivariate analysis revealed three negative prognostic factors:FDMR combination(P=0.031,RR=1.38,95%CI:1.03-1.95),requiring more than one course of induction chemotherapy to achieve CR(P=0.016,RR=1.46,95%CI:1.10-1.98)and older age(≥40 years;P=0.024,RR=1.63,95%CI:1.32-2.12).To conclude,HLA-matched allo-HSCT is a choice for the intermediate cytogenetic risk AML case in CR.FDMR combination,requiring more than one course of induction chemotherapy to achieve CR and older age(≥40 years)are confirmed as risk factors of poor prognosis for HLA-matched allo-HSCT patients with intermediate cytogenetic risk AML in CR.To these cases,the donor-recipient sex combination is more important than the donor type in donor selection.
引文
[1]Cornelissen JJ,van Putten WL,Verdonck LF,et al.Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults:benefits for whom.Blood.2007;109(9):3658-3666.
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[3]Gupta T,Kannan S,Dantkale V,et al.Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia:a systematic review and meta-analysis.Hematol Oncol Stem Cell Ther.2011;4(1):17-29.
[4]Glucksberg H,Storb R,Fefer A,et al.Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.Transplantation.1974;18(4):295-304.
[5]Lanino E,Rondelli R,Locatelli F,et al.Early(day-7)versus conventional(day-1)inception of cyclosporine-A for graft-versus-host disease prophylaxis after unrelated donor hematopoietic stem cell transplantation in children.Long-term results of an AIEOP prospective,randomized study.Biol Blood Marrow Transplant.2009;15(6):741-748.
[6]Bautista F,Moreno L,Fernández-Navarro JM,et al.Evaluation of chimerism by quantitative PCR analysis of DNApolymorphism after allogeneic hematopoietic stem cell transplantation in a pediatric population with malignancies.Pediatr Transplant.2011;15(1):81-87.
[7]Grimwade D,Walker H,Oliver F,et al.The importance of diagnostic cytogenetics on outcome in AML:analysis of 1,612patients entered into the MRC AML 10 trial.The Medical Research Council Adult and Children's Leukaemia Working Parties.Blood.1998;92(7):2322-2333.
[8]Ringdén O,Pavletic SZ,Anasetti C,et al.The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation.Blood.2009;113(13):3110-3118.
[9]D?hner H,Estey EH,Amadori S,et al.Diagnosis and management of acute myeloid leukemia in adults:recommendations from an international expert panel,on behalf of the European LeukemiaN et.Blood.2010;115(3):453-474.
[10]Suciu S,Mandelli F,de Witte T,et al.Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia(AML)in first complete remission(CR1):an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial.Blood.2003;102(4):1232-1240.
[11]Imahashi N,Suzuki R,Fukuda T,et al.Allogeneic hematopoietic stem cell transplantation for intermediate cytogenetic risk AML in first CR.Bone Marrow Transplant.2013n;48(1):56-62.
[12]Lee SJ,Klein J,Haagenson M,et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood.2007;110(13):4576-4583.
[13]Randolph SS,Gooley TA,Warren EH,et al.Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched,related hematopoietic stem cell transplants.Blood.2004;103(1):347-352.
[14]Moore J,Nivison-Smith I,Goh K,et al.Equivalent survival for sibling and unrelated donor allogeneic stem cell transplantation for acute myelogenous leukemia.Biol Blood Marrow Transplant.2007;13(5):601-607.
[15]Cho BS,Kim JH,Yoon JH,et al.Superior transplantation outcomes of 8/8-matched unrelated donors as well as matched siblings to autologous transplantation for acute myeloid leukemia with intermediate cytogenetics in first remission.Eur J Haematol.2013;90(5):365-374.
[16]Hsieh YY,Hong YC,Hsiao LT,et al.Effect of allogeneic hematopoietic stem cell transplantation from matched siblings or unrelated donors during the first complete remission in patients with cytogenetically normal acute myeloid leukemia.Eur J Haematol.2011;86(3):237-245.
[17]Koreth J,Schlenk R,Kopecky KJ,et al.Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission:systematic review and meta-analysis of prospective clinical trials.JAMA.2009;301(22):2349-2361.
[18]Spierings E,Kim YH,Hendriks M,et al.Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvH D and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation.Biol Blood Marrow Transplant.2013;19(8):1244-1253.
[19]Li S,Kawata H,Katsuyama Y,et al.Association of polymorphic MHC microsatellites with GVHD,survival,and leukemia relapse in unrelated hematopoietic stem cell transplant donor/recipient pairs matched at five HLA loci.Tissue Antigens.2004;63(4):362-368.
[20]Ayuk F,Diyachenko G,Zabelina T,et al.Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors.Exp Hematol.2008;36(8):1047-1054.
[21]Gahrton G.Risk assessment in haematopoietic stem cell transplantation:impact of donor-recipient sex combination in allogeneic transplantation.Best Pract Res Clin Haematol.2007;20(2):219-229.
[22]Martin PJ.Increased disparity for minor histocompatibility antigens as a potential cause of increased GVHD risk in marrow transplantation from unrelated donors compared with related donors.Bone Marrow Transplant.1991;8(3):217-223.
[23]Kollman C,Spellman SR,Zhang MJ,et al.The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy.Blood.2016;127(2):260-267.
[24]Kongtim P,Di Stasi A,Rondon G,et al.Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant.2015;21(4):713-719.
[25]Gao L,Wen Q,Chen X,et al.Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation:a multicenter randomized controlled study in southwest China.Biol Blood Marrow Transplant.2014;20(12):1932-1939.
[26]Bejanyan N,Weisdorf DJ,Logan BR,et al.Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation:a center for international blood and marrow transplant research study.Biol Blood Marrow Transplant.2015;21(3):454-459.
[27]Stern M,Brand R,de Witte T,et al.Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation.Am J Transplant.2008;8(10):2149-2157.
[28]Nannya Y,Kataoka K,Hangaishi A,et al.The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk.Transpl Int.2011;24(5):469-476.
[29]Kurosawa S,Yamaguchi T,Uchida N,et al.Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission.Biol Blood Marrow Transplant.2011;17(3):401-411.
[30]de Lima M,Couriel D,Thall PF,et al.Once-daily intravenous busulfan and fludarabine:clinical and pharmacokinetic results of a myeloablative,reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.Blood.2004;104(3):857-864.
[2]Koreth J,Schlenk R,Kopecky KJ,et al.Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission:systematic review and meta-analysis of prospective clinical trials.JAMA.2009;301(22):2349-2361.
[3]Gupta T,Kannan S,Dantkale V,et al.Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia:a systematic review and meta-analysis.Hematol Oncol Stem Cell Ther.2011;4(1):17-29.
[4]Glucksberg H,Storb R,Fefer A,et al.Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.Transplantation.1974;18(4):295-304.
[5]Lanino E,Rondelli R,Locatelli F,et al.Early(day-7)versus conventional(day-1)inception of cyclosporine-A for graft-versus-host disease prophylaxis after unrelated donor hematopoietic stem cell transplantation in children.Long-term results of an AIEOP prospective,randomized study.Biol Blood Marrow Transplant.2009;15(6):741-748.
[6]Bautista F,Moreno L,Fernández-Navarro JM,et al.Evaluation of chimerism by quantitative PCR analysis of DNApolymorphism after allogeneic hematopoietic stem cell transplantation in a pediatric population with malignancies.Pediatr Transplant.2011;15(1):81-87.
[7]Grimwade D,Walker H,Oliver F,et al.The importance of diagnostic cytogenetics on outcome in AML:analysis of 1,612patients entered into the MRC AML 10 trial.The Medical Research Council Adult and Children's Leukaemia Working Parties.Blood.1998;92(7):2322-2333.
[8]Ringdén O,Pavletic SZ,Anasetti C,et al.The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation.Blood.2009;113(13):3110-3118.
[9]D?hner H,Estey EH,Amadori S,et al.Diagnosis and management of acute myeloid leukemia in adults:recommendations from an international expert panel,on behalf of the European LeukemiaN et.Blood.2010;115(3):453-474.
[10]Suciu S,Mandelli F,de Witte T,et al.Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia(AML)in first complete remission(CR1):an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial.Blood.2003;102(4):1232-1240.
[11]Imahashi N,Suzuki R,Fukuda T,et al.Allogeneic hematopoietic stem cell transplantation for intermediate cytogenetic risk AML in first CR.Bone Marrow Transplant.2013n;48(1):56-62.
[12]Lee SJ,Klein J,Haagenson M,et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood.2007;110(13):4576-4583.
[13]Randolph SS,Gooley TA,Warren EH,et al.Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched,related hematopoietic stem cell transplants.Blood.2004;103(1):347-352.
[14]Moore J,Nivison-Smith I,Goh K,et al.Equivalent survival for sibling and unrelated donor allogeneic stem cell transplantation for acute myelogenous leukemia.Biol Blood Marrow Transplant.2007;13(5):601-607.
[15]Cho BS,Kim JH,Yoon JH,et al.Superior transplantation outcomes of 8/8-matched unrelated donors as well as matched siblings to autologous transplantation for acute myeloid leukemia with intermediate cytogenetics in first remission.Eur J Haematol.2013;90(5):365-374.
[16]Hsieh YY,Hong YC,Hsiao LT,et al.Effect of allogeneic hematopoietic stem cell transplantation from matched siblings or unrelated donors during the first complete remission in patients with cytogenetically normal acute myeloid leukemia.Eur J Haematol.2011;86(3):237-245.
[17]Koreth J,Schlenk R,Kopecky KJ,et al.Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission:systematic review and meta-analysis of prospective clinical trials.JAMA.2009;301(22):2349-2361.
[18]Spierings E,Kim YH,Hendriks M,et al.Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvH D and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation.Biol Blood Marrow Transplant.2013;19(8):1244-1253.
[19]Li S,Kawata H,Katsuyama Y,et al.Association of polymorphic MHC microsatellites with GVHD,survival,and leukemia relapse in unrelated hematopoietic stem cell transplant donor/recipient pairs matched at five HLA loci.Tissue Antigens.2004;63(4):362-368.
[20]Ayuk F,Diyachenko G,Zabelina T,et al.Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors.Exp Hematol.2008;36(8):1047-1054.
[21]Gahrton G.Risk assessment in haematopoietic stem cell transplantation:impact of donor-recipient sex combination in allogeneic transplantation.Best Pract Res Clin Haematol.2007;20(2):219-229.
[22]Martin PJ.Increased disparity for minor histocompatibility antigens as a potential cause of increased GVHD risk in marrow transplantation from unrelated donors compared with related donors.Bone Marrow Transplant.1991;8(3):217-223.
[23]Kollman C,Spellman SR,Zhang MJ,et al.The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy.Blood.2016;127(2):260-267.
[24]Kongtim P,Di Stasi A,Rondon G,et al.Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant.2015;21(4):713-719.
[25]Gao L,Wen Q,Chen X,et al.Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation:a multicenter randomized controlled study in southwest China.Biol Blood Marrow Transplant.2014;20(12):1932-1939.
[26]Bejanyan N,Weisdorf DJ,Logan BR,et al.Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation:a center for international blood and marrow transplant research study.Biol Blood Marrow Transplant.2015;21(3):454-459.
[27]Stern M,Brand R,de Witte T,et al.Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation.Am J Transplant.2008;8(10):2149-2157.
[28]Nannya Y,Kataoka K,Hangaishi A,et al.The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk.Transpl Int.2011;24(5):469-476.
[29]Kurosawa S,Yamaguchi T,Uchida N,et al.Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission.Biol Blood Marrow Transplant.2011;17(3):401-411.
[30]de Lima M,Couriel D,Thall PF,et al.Once-daily intravenous busulfan and fludarabine:clinical and pharmacokinetic results of a myeloablative,reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.Blood.2004;104(3):857-864.