伴TP53基因突变急性B淋巴细胞白血病的临床特征及预后分析 Translated title: Clinical and prognostic values ofTP53 mutation in patients with B-lineage acute lymphoblastic leukemia

Abstract

目的

研究TP53基因突变阳性急性B淋巴细胞白血病（B-ALL）患者的临床特征及预后。

方法

回顾性分析2016年1月至2019年12月在苏州大学附属第一医院治疗的479例初诊B-ALL患者的临床资料。

结果

479例B-ALL患者中，34例（7.1％）TP53基因突变阳性，共检测到36个TP53突变，其中移码基因突变10个（27.8％），错义突变23个（63.9％），无义突变3个（8.3％）。共有34个（94.4％）突变位于DNA结合结构域（第5～8号外显子）。伴TP53基因突变组患者平均突变基因数目（2.3个）与无TP53基因突变组（1.1个）差异有统计学意义（ P<0.001）。Ph阳性和Ph-like阳性患者在TP53基因突变阴性组中的比例显著高于TP53突变阳性组，差异有统计学意义（ P<0.001）。TP53基因突变阴性组3年总生存（OS）率、无事件生存（EFS）率显著高于TP53基因突变阳性组（ χ ²＝4.694， P＝0.030； χ ²＝5.080， P＝0.024）。多因素分析中，1个疗程诱导化疗未完全缓解（CR）是影响患者OS的独立预后不良因素。34例伴TP53基因突变患者中16例在第1次CR（CR ₁）状态行异基因造血干细胞移植（allo-HSCT），2例移植后复发输注供者来源的抗CD19嵌合抗原受体T（CAR-T）细胞后获CR ₂。11例巩固化疗过程中复发的TP53基因突变患者中6例行抗CD19 CAR-T细胞治疗，4例获得缓解且微小残留病（MRD）转阴，缓解后桥接allo-HSCT，其中2例持续CR。

结论

伴TP53基因突变B-ALL患者中错义突变最常见，突变位点主要分布于DNA结合结构域。伴TP53基因突变的B-ALL患者复发后CAR-T细胞治疗清除MRD后应尽早行allo-HSCT。伴TP53基因突变的B-ALL患者在allo-HSCT后仍有较高的复发率，输注供者来源的CAR-T细胞能获得较好的持续缓解。

Translated abstract

Objective

To investigate the survival and prognosis of B-lineage acute lymphoblastic leukemia（B-ALL）patients with TP53 mutation.

Methods

The clinical data of 479 newly diagnosed BALL patients treated in the First Affiliated Hospital of Soochow University from January 2016 to December 2019 were retrospectively analyzed.

Results

Among 479 B-ALL patients, 34 cases（7.1％） were positive for TP53 gene mutation, and a total of 36 TP53 mutations were detected, including 10 frameshift gene mutations（27.8％）, 23 missense mutations（63.9％）and 3 nonsense mutations（8.3％）. A total of 34（94.4％）mutations were located in the DNA binding domain（exons 5–8）.The average number of mutated genes in patients with TP53 gene mutation（2.3）and the group without TP53 gene mutation （1.1）were statistically different（ P<0.001）. The proportion of Ph positive and Ph-like positive patients in the TP53 gene mutation negative group was significantly higher than that of the TP53 mutation positive group, and the difference was statistically significant（ P<0.001）. The 3-year OS and EFS rates of the TP53 gene mutation negative group were significantly higher than those of the TP53 gene mutation positive group. The differences in OS and EFS rates between the two groups were statistically significant（ χ ²=4.694, P=0.030; χ ²=5.080, P=0.024）. In the multivariate analysis, failure to achieve remission（CR）after one course of induction chemotherapy was an independent adverse prognostic factor affecting OS.Of the 34 patients with TP53 mutation, 16 underwent allogeneic hematopoietic stem cell transplantation（allo-HSCT） in the CR ₁ state, and 2 patients with recurrence after transplantation obtained CR ₂ after infusion of donorderived anti-CD19 chimeric antigen receptor T（CAR-T）cells. Among the 11 patients with TP53 gene mutation who relapsed during consolidation chemotherapy, 6 received anti-CD19 CAR T cell therapy, 4 patients achieved remission and minimal residual disease（MRD）turned negative, followed by bridging allo-HSCT, and 2 of them sustained CR.

Conclusion

Missense mutations are the most common in B-ALL patients with TP53 gene mutation, and the majority of mutations were located in the DNA binding domain. B-ALL patients with TP53 gene mutation should undergo allo-HSCT as soon as possible after CAR-T cell therapy has cleared the MRD after recurrence. B-ALL patients with TP53 gene mutation still have a higher recurrence rate after allo-HSCT, and the infusion of donor-derived CAR-T cells can achieve better sustained remission.