骨髓单个核细胞端粒长度与急性髓系白血病异基因造血干细胞移植后复发的关系

Correlation of telomere length of bone marrow mononuclear cells with relapse after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

目的探讨接受异基因造血干细胞移植(allo-HSCT)的急性髓系白血病(AML)骨髓单个核细胞端粒长度与患者预后的关系。方法回顾性分析2020年6月至2021年6月在贵州医科大学附属医院接受allo-HSCT的33例AML患者移植前、移植后和供者动员前骨髓单个核细胞端粒长度以及随访相关资料。采用端粒限制性片段法测定端粒长度, 比较不同预后患者间端粒长度。以实际1年内复发为金标准, 采用受试者工作特征(ROC)曲线分析患者移植前或供者动员前端粒长度判断患者移植后1年复发的效果, 依据患者或供者端粒长度最佳临界值将患者进行分层, 采用Kaplan-Meier法比较各分层患者无进展生存情况, 并行log-rank检验。结果 33例患者中位年龄34岁(14~61岁), 男性17例, 女性16例;初诊为AML 31例, 骨髓增生异常综合征(MDS)转为AML 1例, 慢性粒细胞白血病(CML)转为AML 1例;同胞全相合移植14例, 同胞半相合移植19例。供者中位年龄30岁(20~65岁), 男性24名, 女性9名。供者(33名)动员前骨髓单个核细胞端粒长度均长于患者移植前(33例)、移植+30天(31例)[分别为(6.67±0.31)kb、(6.40±0.33)kb、(6.48±0.33)kb, 均P<0.05], 患者移植前、移植+30天差异无统计学意义(t=0.89, P=0.378), 患者移植+180天(11例)骨髓单个核细胞端粒长度为(6.66±0.18)kb。移植后急性移植物抗宿主病(aGVHD)发生率45.5%(15/33), 有明确影像学及病原学依据的感染发生率为39.4%(13/33), 移植后1年内死亡率为3.0%(1/33), 移植后1年内复发率为15.2%(5/33)。发生aGVHD组与未发生aGVHD组间、感染组与非感染组间供者动员前骨髓单个核细胞端粒长度差异均无统计学意义(均P>0.05)。与移植后1年内未复发患者比较, 移植后1年内复发患者的供者动员前骨髓单个核细胞端粒长度更短[(6.39±0.19)kb比(6.72±0.30)kb, t=-3.23, P=0.011], 患者移植前端粒长度更长[(6.75±0.16)kb比(6.35±0.36)kb, t=4.17, P=0.001]。ROC曲线分析显示, 判断患者移植后1年内复发的患者移植前及供者动员前骨髓单个核细胞端粒长度最佳临界值分别为6.48、6.42 kb。患者移植前骨髓单个核细胞端粒<6.48 kb组PFS优于端粒长度≥6.48 kb组(P=0.003), 供者动员前骨髓单个核细胞端粒长度>6.42 kb组PFS优于端粒长度≤6.42 kb组(P<0.001)。结论 AML allo-HSCT治疗中, 患者移植前骨髓单个核细胞端粒长度长、供者骨髓单个核细胞端粒长度短时, 患者移植后1年内复发风险增加。

Objective To investigate the relationship between telomere length of bone marrow mononuclear cells and prognosis of patients with acute myeloid leukemia(AML)who received allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods Telomere length of bone marrow mononuclear cells before transplantation,after transplantation and before donor mobilization as well as information related to follow-up of 33 AML patients who received allo-HSCT in the Affiliated Hospital of Guizhou Medical University between June 2020 and June 2021 were retrospectively analyzed.Telomere length was detected by using telomeric terminal restriction fragment(TRF)method.Telomere length was compared among patients with different prognoses.The recurrence within 1 year was treated as the gold standard and receiver operating characteristic(ROC)curve was used to analyze the effect of telomere length before transplantation or before donor mobilization in the judgement of the recurrence within 1 year after transplantation.The patients were stratified according to the optimal threshold value of telomere length for patients or donors,and Kaplan-Meier method was used to compare the progression-free survival(PFS)of patients with different stratification,and log-rank test was performed.Results The median age of 33 patients was 34 years(14-61 years),and there were 17 males and 16 females;31 patients were initially diagnosed with AML,1 patient transferred from myelodysplastic syndrome(MDS)to AML,and 1 patient transferred from chronic granulocytic leukemia(CML)to AML;14 received identical sibling transplantation and 19 received haploidentical sibling transplantation.The median age of the donors was 30 years(20-65 years),including 24 males and 9 females.Telomere length of bone marrow mononuclear cells before mobilization in 33 donors was longer than that in patients before transplantation(33 cases)and at+30 d after transplantation(31 cases)[(6.67±0.31)kb,(6.40±0.33)kb,(6.48±0.33)kb,respectively;all P<0.05],and the difference between patients before and at+30 d after transplantation was not statistically significant(t=0.89,P=0.378),and the telomere length of bone marrow mononuclear cells in 11 patients+180 d after transplantation was(6.66±0.18)kb.The incidence of acute graft-versus-host disease(aGVHD)after transplantation was 45.5%(15/33),the incidence of infection with clear imaging and pathogenic basis was 39.4%(13/33),the mortality rate within 1 year after transplantation was 3.0%(1/33),and the recurrence rate within 1 year after transplantation was 15.2%(5/33).There were no statistically significant differences in telomere length of donor pre-mobilization bone marrow mononuclear cells between the groups with and without aGVHD and between the infected and non-infected groups(all P>0.05).Compared with patients who had not relapsed within 1 year after transplantation,telomere length of donor pre-mobilization bone marrow mononuclear cells was shorter in patients who relapsed within 1 year after transplantation[(6.39±0.19)kb vs.(6.72±0.30)kb,t=-3.23,P=0.011],telomere length was longer in patients before transplantation[(6.75±0.16)kb vs.(6.35±0.36)kb,t=4.17,P=0.001].ROC curve analysis showed that the optimal threshold values for telomere length of pre-transplantation and donor pre-mobilization bone marrow mononuclear cells were 6.48 and 6.42 kb,respectively for patients who relapsed within 1 year after transplantation.PFS in patients with pre-transplantation bone marrow mononuclear cells telomere length<6.48 kb was better than that in patients with telomere length≥6.48 kb(P=0.003);PFS in patients with pre-mobilization bone marrow mononuclear cells telomere length>6.42 kb was better than that in patients with telomere length≤6.42 kb(P<0.001).Conclusions In allo-HSCT for AML,patients have an increased risk of relapse within 1 year after transplantation when their pre-transplantation bone marrow mononuclear cells telomere length is long and the donor bone marrow mononuclear cells telomere length is short.