| Background:The prognosis of adolescent and adult acute lymphoblastic leukemia(acute lymphoblastic leukemia,ALL)is poor,and recurrence is an important cause of death.The change of genetic information plays an important role in the pathogenesis and recurrence of ALL,and the level of minimal residual disease(MRD)has also been proved to be closely related to the recurrence of ALL patients.However,there is no consistent conclusion about the impact of molecular genetic changes on disease diagnosis and prognosis,and the guiding significance of MRD level for the treatment of ALL patients is not clear.The purpose of this study was to explore the frequency spectrum of gene mutation and its prognostic significance when combined with MRD and hematopoietic stem cell transplantation(HSCT)in adolescents and adult patients aged≥15 years old,so as to further improve the risk stratification of ALL patients and guide treatment decision-making.Methods:The basic characteristics,cytogenetics,molecular genetics,MRD level,treatment regimen and survival outcome of 404 patients with ALL diagnosed for the first time in Shandong Provincial Hospital,Yantai Yuhuangding Hospital and the Affiliated Hospital of Qingdao University from January 1,2014 to December 20,2021 were collected,and the correlation and survival analysis were carried out by SPSS25 and R software.Results:Part 1.A total of 147 ALL patients with second-generation sequencing results were included,of which 91.2%had at least one mutation and 67.35%had polygenic(≥2)mutations.The most common mutations in T-ALL are NOTCH1(8/21,38.10%),PHF6(7/21,33.33%),RUNX1(4/21,19.05%),PTEN(4/21,19.05%),JAK3(3/21,14.29%),TET2(3/21,14.29%),JAK1(3/21,14.29%),SPEN(2/21,9.52%),while in B-ALL,FAT1(19/123,15.45%),TET2(18/123,14.63%),NARS(17/123,13.82%),KMT2D(17/123,13.82%),FLT3(16/123,13.01%),RELN(13/123,10.57%),ASXL1(9/123,7.31%)are most common mutations.Correlation analysis revealed a common mutation pattern,which was significantly different between T-ALL and B-ALL.Then the prognostic factors of 107 patients with B-ALL were analyzed,including sex,age,white blood cell count,Ph chromosome status,HSCT,hepatitis B virus infection status,MRD level,bone marrow remission status after induction chemotherapy and genes with mutation frequency≥ 6.Univariate analysis showed that FLT3 mutation(P=0.033),RELN mutation(P=0.055),TP53 mutation(P=0.075)and relapse(P=0.033)were adverse factors affecting the overall survival(OS)of B-ALL patients.Patients with negative MRD after induction therapy(P=0.004)and receive HSCT(P=0.001)had better OS.Multivariate analysis revealed that minimal residual disease after one course of chemotherapy(MRD1),≥1%(P=0.004),TP53 mutation(P=0.010)and RELN mutation(P=0.045)were independent risk factors for OS.Patients who undergo HSCT tended to have better OS,but there was no statistical significance in multivariate analysis(P=0.079).NOTCH 1 mutation(P=0.015)and recurrence(P=0.000)were independent adverse prognostic factors of event-free survival.Part 2.We studied the effect of MRD levels on the prognosis of patients with B-ALL after chemotherapy,and the guiding significance of different MRD1 levels for(post-remission therapy,PRT)selection.A total of 195 ALL patients with MRD data were included in this part,and the prognosis of B-ALL patients was analyzed.The results of univariate analysis showed that complete remission was achieved after one induction chemotherapy,MRD1<0.01%,minimal residual disease after two courses of chemotherapy(MRD2)<0.01%,minimal residual disease after three courses of chemotherapy(MRD3)<0.01%,patient with standard risk of non-genetic risk stratification and patients in stem cell transplantation(SCT)group had better OS and disease-free survival(DFS),while those older than 35 years old had worse OS(P=0.024).In the multivariate analysis,only whether MRD3<0.01%and the way of PRT(CMT or HSCT)were independent prognostic factors for OS and DFS.What’s more,MRD2≥0.01%(P=0.036)and patients grouped into the chemotherapy(CMT)group(P=0.000)was significantly associated with a high risk of recurrence.Patients were divided into four groups according to the time they reached negative MRD,subgroup A(MRD1-/MRD2±/MRD3±);subgroup B(MRD1+/MRD2-/MRD3±);subgroup C(MRD1+/MRD2+/MRD3-);subgroup D(MRD1+/MRD2+/MRD3+);The results showed that the 5-year OS of subgroup A,B,C and D were 64.75%,52.15%,43.85%and 24.32%(P=0.000),and the 5-year DFS were 50.17%,57.27%,17.38%and 7.35%(P=0.000),respectively.Achieving negative MRD before transplantation was significantly associated with better OS and DFS.In addition,among the patients with negative MRD1,there was no significant difference in OS between the SCT group and the CMT group.The 5-year OS was 71.9%and 60.9%(P=0.176),respectively.The 5-year DFS was 68.6%and 27.1%,respectively(P=0.004).The recurrence rate in the CMT group was significantly higher than that in the SCT group(45.95%vs 21.43%,P=0.041),but the response rate(64.71%)and survival rate(52.94%)to retreatment after recurrence were high.The prognosis of patients with positive MRD1 was poor.The 5-year OS of patients in CMT group and SCT group were 23.0%and 62.6%(P=0.000),respectively.Conclusion:The distribution and co-occurrence of gene mutations in patients with ALL are closely related to the immunophenotype of patients.RELN and TP53 mutations are significantly associated with poor prognosis in patients with ALL.In addition,the earlier the patients were MRD negative after chemotherapy,the better prognosis would achieve.For the patients achieve negative MRD early after chemotherapy,although there was no significant difference in OS between the chemotherapy group and the transplantation group,allo-HSCT could significantly reduce the recurrence rate and obtain better DFS.Of course,this needs to be further verified in prospective randomized controlled trials. |
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