异基因造血干细胞移植后巨细胞病毒再活化对急性髓系白血病复发和生存的影响
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摘要
目的:探讨巨细胞病毒(CMV)再活化对于完全缓解期行异基因造血干细胞移植术(allo-HSCT)的急性髓系白血病(AML)患者复发和生存的影响。方法:对106例于完全缓解期行allo-HSCT的成人AML患者的资料进行回顾性分析,包括移植术后CMV再活化的发生情况和影响因素,以及CMV再活化对于复发和生存的影响。结果:67.0%(71/106)的患者在移植后12个月内出现了CMV再活化,中位时间为移植后46(1～117)d。HLA不全相合和预处理应用兔抗人胸腺细胞免疫球蛋白(ATG)是移植后CMV再活化的影响因素。106例患者移植后的中位随访时间为36(1～171)个月,19例患者移植后出现复发,中位复发时间为4.5(2～38)个月,3年累积复发率为17.8%。单因素分析显示,Ⅱ～Ⅳ度急性移植物抗宿主病和慢性移植物抗宿主病的发生可降低患者的复发率,而CMV再活化对于移植后的复发率无明显影响。106例患者的3年总生存率(OS)为77.2%,无病生存率(DFS)为76.0%。单因素分析显示,年龄>40岁和移植后CMV再活化影响患者的OS,但不影响DFS。Cox多因素回归分析显示,移植后CMV再活化是影响患者3年OS的独立危险因素。结论:HLA不全相合和预处理过程中应用ATG是导致移植后CMV再活化的危险因素,而CMV再活化对于完全缓解期AML移植后的复发并没有影响,但仍是影响此类患者生存的独立危险因素。
Objective:To investigate the impact of cytomegalovirus(CMV)reactivation on relapse and survival in acute myeloid leukemia(AML)patients undergoing allogeneic hematopoietic stem cell transplantation(alloHSCT)in complete remission(CR).Method:The clinical data from 106 adult AML patients undergoing alloHSCT in CR were retrospectively analyzed.The occurrence and risk factors of CMV reactivation after transplantation,as well as the impact of CMV reactivation on the relapse and survival of AML patients were statistically analyzed.Result:CMV reactivation occurred in 67.0%(71/106)patients within 1 year after transplantation.Median time to initial CMV reactivation was 46 days(range,1-117 days).HLA mismatch and administration of anti-thymoglobulin(ATG)in conditioning regimen were associated with CMV reactivation after transplantation.The median time of follow-up in 106 patients was 36 months(range,1-171 months)after transplantation.19 patients relapsed at a median time of 4.5 months(range,2-38 months).The 3-year cumulative recurrence rate of AML was17.8%.The onset ofⅡ-Ⅳ acute graft-versus-host disease and chronic graft-versus-host disease had preventive effect on AML relapse,while CMV reactivation had no such effect.The 3-year overall survival(OS)of 106 patients was 77.2%,and the disease-free survival(DFS)was 76.0%.Age>40 years old and CMV reactivation decreased OS but not DFS.Cox multivariate regression analysis showed that CMV reactivation after transplantation was an independent risk factor for 3-year OS.Conclusion:HLA mismatch and administration of ATG in conditioning regimen are the risk factors for CMV reactivation,and this reactivation remains a risk factor for poor posttransplantation outcomes and has no preventive effect on AML relapse for patients undergoing allo-HSCT in CR.
Objective:To investigate the impact of cytomegalovirus(CMV)reactivation on relapse and survival in acute myeloid leukemia(AML)patients undergoing allogeneic hematopoietic stem cell transplantation(alloHSCT)in complete remission(CR).Method:The clinical data from 106 adult AML patients undergoing alloHSCT in CR were retrospectively analyzed.The occurrence and risk factors of CMV reactivation after transplantation,as well as the impact of CMV reactivation on the relapse and survival of AML patients were statistically analyzed.Result:CMV reactivation occurred in 67.0%(71/106)patients within 1 year after transplantation.Median time to initial CMV reactivation was 46 days(range,1-117 days).HLA mismatch and administration of anti-thymoglobulin(ATG)in conditioning regimen were associated with CMV reactivation after transplantation.The median time of follow-up in 106 patients was 36 months(range,1-171 months)after transplantation.19 patients relapsed at a median time of 4.5 months(range,2-38 months).The 3-year cumulative recurrence rate of AML was17.8%.The onset ofⅡ-Ⅳ acute graft-versus-host disease and chronic graft-versus-host disease had preventive effect on AML relapse,while CMV reactivation had no such effect.The 3-year overall survival(OS)of 106 patients was 77.2%,and the disease-free survival(DFS)was 76.0%.Age>40 years old and CMV reactivation decreased OS but not DFS.Cox multivariate regression analysis showed that CMV reactivation after transplantation was an independent risk factor for 3-year OS.Conclusion:HLA mismatch and administration of ATG in conditioning regimen are the risk factors for CMV reactivation,and this reactivation remains a risk factor for poor posttransplantation outcomes and has no preventive effect on AML relapse for patients undergoing allo-HSCT in CR.
引文
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[9]Green ML,Leisenring WM,Xie H,et al.CMV reactivation after allogeneic HCT and relapse risk:evidence for early protection in acute myeloid leukemia[J].Blood,2013,122:1316-1324.
[10]Foley B,Cooley S,Vermeris MR,et al.Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+natural killer cells with potent function[J].Blood,2012,119:2665-2674.
[11]Cooley S,Weisdorf DJ,Guethlein LA,et al.Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogeneous leukemia[J].Blood,2010,116:2411-2419.
[12]Scheper W,van Dorp S,Kersting S,et al.γδ-T cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia[J].Leukemia,2013,27:1328-1338.
[13]Bao X,Zhu Q,Xue S,et al.Cytomegalovirus induces strong antileukemic effect in acute myeloid leukemia patients following sibling HSCT without ATG-containing regimen[J].Am J Transl Res,2016,8:653-661.
[14]Chang YJ,Wang Y,Liu YR,et al.Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry:a retrospective and prospective analysis[J].J Hematol Oncol,2017,10:134.
[15]Schmidt-Hieber M,Labopin M,Beelen D,et al.CMVserostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation:a report from the Acute Leukemia Working Party of EBMT[J].Blood,2013,122:3359-3364.
[16]Teira P,Battiwalla M,Ramanathan M,et al.Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era:a CIBMTR analysis[J].Blood,2016,127:2427-2438.
[17]Nichols WG,Corey L,Gooley T,et al.High risk if death due to bacterial and fungal infection among cytomegalovirus(CMV)-seronegative recipients of stem cell transplants from seropositive donors:evidence for indirect effects of primary CMV infection[J].J Infect Dis,2002,185:273-282.
[18]Cantoni N,Hirsch HH,Khanna N,et al.Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease[J].Biol Blood Marrow Transplant,2010,16:1309-1314.
[2]Elmaagacli AH,Steckel NK,Koldehoff M,et al.Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk:evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients[J].Blood,2011,118:1402-1412.
[3]Green ML,Leisenring WM,Xie H,et al.CMV reactivation after allogeneic HCT and relapse risk:evidence for early protection in acute myeloid leukemia[J].Blood,2013,122:1316-1324.
[4]Mullier F,Kabamba-Mukadi B,Bodéus M,et al.Definition of clinical threshold for CMV real-time PCR after comparison with PP65antigenaemia and clinical data[J].Acta Clin Belg,2009,64:477-482.
[5]Stelljes M,Krug U,Beelen DW,et al.Allogeneic transplantation versus chemotherapy as postremission therapy for acute myeloid leukemia:a prospective matched pairs analysis[J].J Clin Oncol,2014,32:288-296.
[6]Manjappa S,Bhamidipati PK,Stokerl-Goldstein KE,et al.Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen[J].Biol Blood Marrow Transplant,2014,20:46-52.
[7]卢岳,吴彤,曹星玉,等.抢先治疗减少异基因造血干细胞移植后早期巨细胞病毒疾病的临床研究[J].临床血液学杂志,2011,24(11):655-658,661.
[8]Ljungman P,Hakki M,Boeckh M.Cytomegalovirus in hematopoietic stem cell transplant recipients[J].Hematol Oncol Clin North Am,2011,25:151-169.
[9]Green ML,Leisenring WM,Xie H,et al.CMV reactivation after allogeneic HCT and relapse risk:evidence for early protection in acute myeloid leukemia[J].Blood,2013,122:1316-1324.
[10]Foley B,Cooley S,Vermeris MR,et al.Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+natural killer cells with potent function[J].Blood,2012,119:2665-2674.
[11]Cooley S,Weisdorf DJ,Guethlein LA,et al.Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogeneous leukemia[J].Blood,2010,116:2411-2419.
[12]Scheper W,van Dorp S,Kersting S,et al.γδ-T cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia[J].Leukemia,2013,27:1328-1338.
[13]Bao X,Zhu Q,Xue S,et al.Cytomegalovirus induces strong antileukemic effect in acute myeloid leukemia patients following sibling HSCT without ATG-containing regimen[J].Am J Transl Res,2016,8:653-661.
[14]Chang YJ,Wang Y,Liu YR,et al.Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry:a retrospective and prospective analysis[J].J Hematol Oncol,2017,10:134.
[15]Schmidt-Hieber M,Labopin M,Beelen D,et al.CMVserostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation:a report from the Acute Leukemia Working Party of EBMT[J].Blood,2013,122:3359-3364.
[16]Teira P,Battiwalla M,Ramanathan M,et al.Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era:a CIBMTR analysis[J].Blood,2016,127:2427-2438.
[17]Nichols WG,Corey L,Gooley T,et al.High risk if death due to bacterial and fungal infection among cytomegalovirus(CMV)-seronegative recipients of stem cell transplants from seropositive donors:evidence for indirect effects of primary CMV infection[J].J Infect Dis,2002,185:273-282.
[18]Cantoni N,Hirsch HH,Khanna N,et al.Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease[J].Biol Blood Marrow Transplant,2010,16:1309-1314.