单倍体移植治疗STIL-TAL1融合基因阳性的儿童急性T淋巴细胞白血病的疗效及预后分析

Effect and prognosis of haploidentical transplantation for STIL/TAL1-positive T-cell acute lymphoblastic leukemia in children

目的:探讨单倍体移植治疗儿童伴STIL-TAL1融合基因阳性的急性T淋巴细胞白血病(T-ALL)的疗效及预后。方法:回顾性分析我院2014年7月—2019年12月行单倍体移植术的21例伴STIL-TAL1融合基因阳性的儿童T-ALL患者,分析入组患儿移植后生存情况以及移植前疾病状态[包括完全缓解(CR)状态、骨髓微小残留病(MRD)、STIL-TAL1融合基因定量以及合并其他基因突变]对移植后无病生存(LFS)率和总生存(OS)率的影响。结果:21例患儿移植后+1个月评估,骨髓MRD均为阴性,STIL-TAL1融合基因定量均为0,20例患儿外周血CD3;细胞嵌合率及骨髓嵌合率为100%供者型,1例患儿外周血CD3;细胞嵌合率及骨髓嵌合率为混合嵌合状态,供者型为主。中位随访时间9.5(2~51)个月,3年OS率为55.1%,3年LFS率为67.1%,3年累计复发率及非复发死亡率分别为32.9%和27.1%。截至随访日期,共有9例患儿死亡,死亡原因为复发(5例,其中4例血液学复发、1例分子学复发)、感染(3例)及回输后肺泡出血(1例)。6例患儿移植后复发(其中5例血液学复发、1例分子学复发),复发中位时间为+90天(54~180天)。CR1组(13例)和CR2组(8例)移植后3年OS率分别为69.2%和31.3%(P=0.147),移植后3年LFS率分别为75.5%和48.6%(P=0.510)。移植前骨髓MRD阴性组(18例)和阳性组(3例)3年OS率分别为58.5%和33.3%(P=0.287),移植后3年LFS率分别为68.2%和66.7%(P=0.683)。移植前STIL-TAL1融合基因阴性组(18例)和阳性组(3例)3年OS率分别为64.3%和0(P=0.001)。单纯STIL-TAL1突变组(10例)和STIL-TAL1突变合并其他基因突变组(11例)3年OS率分别为60.0%和47.7%(P=0.697)。11例STIL-TAL1突变合并其他基因突变患儿中,移植前STIL-TAL1融合基因转阴组(9例)和未转阴组(2例)3年OS率分别为58.3%和0(P=0.027)。结论:伴STIL-TAL1融合基因阳性的儿童T-ALL患者,通过单倍体移植达到了较高的OS率及LFS率,同时避免髓外复发。移植前STIL-TAL1融合基因阳性能明显降低移植后OS率,即使采用加强预处理方案仍不能提高生存率,死亡率100%。初发病时合并其他基因突变,不影响疾病预后。故对于儿童伴STIL-TAL1融合基因阳性T-ALL患者,应采取强化疗方案,使骨髓MRD及STIL-TAL1基因转阴的情况下,尽快桥接异基因造血干细胞移植术,从而提高OS率及LFS率。

Objective:To investigate the efficacy and prognosis of haploidentical transplantation in the treatment of pediatric T-cell acute lymphoblastic leukemia(T-ALL)with positive STIL-TAL1 fusion gene.Methods:Twenty-one children with STIL/TAL1-positive T-ALL who underwent haploidentical transplantation in our hospital from July 2014 to December 2019 were retrospectively analyzed.The survival after transplantation and the effects of disease status before transplantation,including complete remission(CR)status,bone marrow minimal residual disease(MRD),quantification of STIL-TAL1 fusion gene and other gene mutations on leukemia-free survival(LFS)and overall survival(OS)were analyzed.Results:Evaluated at one month after transplantation,bone marrow MRD was negative and quantification of STIL-TAL1 fusion gene was 0 for all enrolled patients.The chimeric rate of CD3;cells in peripheral blood and bone marrow were 100%donor type in 20 cases.The chimeric rate of CD3;cells in peripheral blood and bone marrow were in mixed chimeric state in one case,which was mainly donor type.The median follow-up time was 9.5(2-51)months,the 3-year OS and LFS were 55.1%and 67.1%,respectively,otherwise the 3-year cumulative incidence of relapse and none-relapse mortality were 32.9%and 27.1%,respectively.By the follow-up date,9 patients died due to relapse(5 cases,hematological relapse in 4 cases,molecular relapse in 1 case),infection(3 cases)and alveolar hemorrhage after reinfusion(1 case),and the median time of relapse was+90 days(54-180 days).The 3-year OS and LFS in CR1 group(13 cases)and CR2 group(8 cases)were 69.2%vs 31.3%(P=0.147)and 75.5%vs 48.6%(P=0.510),respectively.The 3-year OS and LFS for bone marrow MRD negative group(18 cases)and positive group(3 cases)were 58.5%vs 33.3%(P=0.287)and 68.2%vs 66.7%(P=0.683),respectively.The 3-year OS of STIL-TAL1 fusion gene negative group(18 cases)and positive group(3 cases)before transplantation were 64.3%and 0(P=0.001).The 3-year OS of only STIL-TAL1 mutation group(10 cases)and STIL-TAL1 mutation combined with other gene mutations(11 cases)were 60.0%and 47.7%(P=0.697).Among 11 children with STIL-TAL1 mutation combined with other gene mutations,the 3-year OS of STIL-TAL1 fusion gene changed negative group(9 cases)and continuous positive group(2 cases)before transplantation were 58.3%and 0(P=0.027).Conclusion:For pediatric T-ALL patients with positive STIL-TAL1 fusion gene,haploidentical transplantation is an effective therapy with high OS and LFS achieved and avoiding extramedullary relapse.The positive STIL-TAL1 fusion gene before transplantation is a risk factor which significantly reduced the OS rate after transplantation,and even with intensive preconditioning regimens,the survival rate is still not improved.At initial stage of disease,other gene mutations did not affect the prognosis of STIL/TAL1-positive T-ALL.Therefore,to improve the OS for these patients,intensive chemotherapy should be adopted to make bone marrow MRD and STIL-TAL1 gene turn negative,then allogeneic hematopoietic stem cell transplantation should be conducted as soon as possible.