Clinical And Biological Characteristics And Prognosis Analysis Of Childhood T-cell Acute Lymphoblastic Leukemia

Part 1.Prediction of outcomes by clinical characteristics and early treatment esponses in childhood T-cell acute lymphoblastic leukemia.Objectives:To explore the predictive values of clinical characteristics and early treatment responses in childhood T-cell acute lymphoblastic leukemia in single center.Methods:From 2008 to 2016,97 consecutive patients aged?15 years with newly diagnosed T-ALL were treated with CCLG2008 in Soochow children's hospital.Predictive value of clinical characteristics and early treatment responses which include prednisone response,bone marrow morphology at day 15 and day 33 during induction chemotherapy and week 12 before consolidation therapy were analyzed.Results:The 3-year overall survival rate(OS)and event free survival rate(EFS)for these patients were 68.1%±5.3%and 59.3%±5.5%,respectively.Patients with initial white blood cell count more than100×10~9/L have a lower 3-year OS than those with less WBC count.Prednisone poor responder was strongly associated with decreased survival rates.And patients who got M3 bone marrow morphology at D15 tend to have a lower 3-year EFS than those who achieved M1/M2.Conclusion:Our study demonstrated that prednisone response was still one of the most powerful predictor of treatment outcome in childhood T-ALL patients and conventional morphological assessments of treatment response still played important roles in predicting treatment outcomes and tailoring treatment intensity especially in countries with inadequate skills or financial resources for MRD monitoring.Part 2.Whole genome analysis of pediatric T-cell acute lymphoblastic leukemia.Objectives:To explore the genomic landscape and identify prognostic biomarkers in childhood T-ALL through the next-generation sequencing technology.Methods: Whole genome sequencing(WGS)was performed in matched germline and tumor samples from 31 Chinese children with T-ALL,30 of whom were also profiled by transcriptome sequencing(RNA-seq).Results: On average,we observed 6.4 coding mutations per patient with 9.9 and 3.2 copy number losses and gains,respectively.Consistent with previous reports,NOTCH1 was most frequently targeted by somatic genomic alterations(primarily as activating sequencing mutations),followed by FBXW7,USP7,PTEN,WT1,and BCL11 B.Intrachromosomal rearrangement proximal to the TAL1 gene was also frequent(11 of 31 patients),leading to robust expression of the STIL-TAL1 fusion,as described previously.The other fusion genes identified were TCF7/SPI1,TCRA/TLX1,SET/NUP214,NUP214/ABL1,TCRB/LMO2,KMT2A/NUTM2 D,KMT2A/MLLT1,TLX3/CDK6.And four patients with insertion in the noncoding elements of TAL1 were also recognized.Conclusion: We need to validate our findings in more clinical patients' sample.Part 3.Noncoding mutation in TAL1 predicts a poor clinical outcome in pediatric T-cell acute lymphoblastic leukemiaObjective : The present study was designed to investigate the incidence and clinical significance of TAL1 noncoding mutation in childhood T-cell acute lymphoblastic leukemia(T-ALL).Methods: The incidence of TAL1 noncoding mutation was analyzed by polymerase chain reaction(PCR)and Sanger sequencing in 89 children with T-ALL.Results : We have eight patients(9%)presented with heterozygous somatic mutation,three types of insertion,in noncoding elements of TAL1.All eight patients showed resistance to prednisone treatment.These cases with TAL1 mutation had a higher white blood cell(WBC)count than the cases without the type of mutation.Survival analysis showed patients with the mutation had lower overall survival rate(OS)and event free survival rate(EFS)than those without the abnormality.Cox analysis for 2-year OS identified TAL1 mutation and prednisone response as independent prognostic factors.Conclusions: It is concluded that TAL1 noncoding mutation is not rare in pediatric T-ALL patients.And patients with such type of mutation tend to have a poor clinical outcome.Part 4.A Clinical features and outcomes of pediatric T-cell acute lymphoblastic leukemia with a few recurrent chromosome rearrangements.Objective: To investigate predictive value of some chromosome alterations including STIL/TAL1,translocations involving T cell receptor(TCR)genes and TCF/SPI1.Methods: STIL/TAL1,translocations involving T cell receptor(TCR)genes were identified through karyotype,q RT-PCR and WGS/WTS.The incidence of TCF/SPI1 was analyzed by polymerase chain reaction(PCR)and Sanger sequencing in 76 children with T-ALL.Results: 22 out of 96 patients have STIL/TAL1 deletion.Patients with STIL/TAL1 tend to have a good early treatment response.The 3-year OS was lower in this fusion gene group,but it didn't reach significant importance.We have 9 patients out of 89 presented with genetic alterations involving TCR genes,which are LMO2/TCR??(n=4),LMO1/TCR??(n=1),MLLT3/TCR??(n=1),TLX1/TCR??(n=1),MYC/TCR??(n=1),LMO2/TCR?.4 out of 76 patients have TCF7/SPI1 fusion.All these four patients respond well to the chemotherapy and are alive.No adverse events happen to them.Conclusion: The prognostic significance of these alterations remain unclear.We still need to collect more samples for validation.But all these alterations make perfect candidates for minimal residual disease monitoring.