| Objective:To investigate the epidemiological and clinical-biological characteristics of patients in China diagnosed with high hyperdiploidy B-cell acute lymphoblastic leukemia(ALL).Additionally,the study seeks to identify potential risk factors associated with prognosis.Another objective is to analyze the clinical features of high hyperdiploidy patients with poor response to induction therapy,and to identify the factors that may affect their prognosis.By achieving these objectives,this study can provide a basis for further risk stratification of high hyperdiploidy patients.Furthermore,the study explores the value of transcriptome sequencing in the application of high hyperdiploidy ALL in children.Methods:This study is a retrospective clinical study in which the first two parts of the study were from pediatric B-ALL patients initially diagnosed from January 2015 to December 2019 in20 hospitals across China.All patients were diagnosed and treated with the CCCG-ALL-2015 protocol with long-term follow-up until July 31,2022.The third part of the study was from Wuhan Tongji Hospital and covered pediatric patients with B-ALL diagnosed for the first time from October,2020,to December,2022,and treated with the CCCG-ALL-2020protocol,with follow-up until February 28,2023.Chromosome numbers between 51-67were determined to be high hyperdiploidy based on the karyotype culture of chromosome G/R bands.Transcriptome sequencing was performed using the Illumina Hiseq X platform to sequence RNA from patient samples at the whole-transcriptome level,using t-SNE clustering and scikit-learn classification algorithms to detect high hyperdiploidy subtypes,and Mu Tect2 software to detect variant genes.The study was statistically processed using the Kaplan-Meier method,Fine-Gray test,multifactorial Cox proportional risk model,binomial classification logistic regression,chi-square test,and Mann-Whitney U test.Results:(1)The prevalence of high hyperdiploidy was approximately 18.51%of the 5717 patients with B-ALL enrolled.The median age at presentation was 3.83 years,only 1.61%of patients presented with extramedullary leukemia.Flow immunophenotyping revealed high expression of CD123(median expression 88.70%).3.50%(37/1058)of the patients also had common fusion gene alterations.The 5-year overall survival(OS)rate for high hyperdiploidy ALL patients was found to be 94.0%,while the 5-year event-free survival(EFS)rate was 81.9%.Several independent risk factors associated with EFS in high hyperdiploidy ALL patients were identified,including age≥5 years(HR=1.95),hemoglobin level≥90 g/L(HR=0.61),CNS2/CNS3(HR=3.92),day 19 minimal residual disease(MRD)level≥1%(HR=1.68),MRD level≥0.01%at day 46(HR=2.09),and with MLL rearrangement leukemia(MLLr)(HR=9.88).The 5-year cumulative incidence of relapse(CIR)rate in high hyperdiploidy ALL patients was 14.4%.Independent risk factors associated with relapse in high hyperdiploidy patients included age≥5 years,CNS2 or CNS3,day 19 MRD level≥1%,and day 46 MRD level≥0.01%.Day 19 MRD and day 46MRD levels were strongly associated with the prognosis of patients with high hyperdiploidy ALL:the day 19 MRD≥1%group had the lower 5-year EFS rate of 69.3%and the higher5-year CIR rate of 23.5%;the day 46 MRD≥0.01%group had a 5-year EFS rate of only65.7%and a high 5-year CIR rate of 28.7%.(2)Of the 930 patients in the high hyperdiploidy primary low-risk group,195(20.97%)were identified as having a poor response to induction therapy.Day 19 minimal residual disease(MRD)levels were found to be more than 1%in 159(81.5%)patients in the poor induction response group.The prognosis was poor in the poor induction therapy response group with a 5-year EFS rate of 71.5%and a 5-year CIR rate of 22.1%.Positive MRD at day 46 and haemoglobin level were independent risk factors for EFS in patients in the poor induction response group.Chromosome trisomy pattern(+4,+10),(+4,+10,+18)and chromosome modality number(58 to 67)were protective factors for poor induction response with odds ratios of 0.69,0.67 and 0.38,respectively.(3)In 102 patients with B-ALL from a single centre,the detection rate of hyperdiploidy by transcriptome sequencing methods was significantly higher than that by karyotype culture(35.0%vs 17.07%,P=0.029).The expression of CD123 was significantly higher in the high hyperdiploidy group detected by karyotype culture than in the non-high hyperdiploidy group,and the difference was statistically significant(98.4%vs 45.7%,P<0.001);The expression of CD123 was significantly higher in the high hyperdiploidy group detected by transcriptome sequencing than in the non-high hyperdiploidy group,and the difference was statistically significant(97.6%vs 41.6%,P<0.001);Among the high hyperdiploidy patients detected by transcriptome sequencing,there was no significant difference in the expression of CD123 between the high hyperdiploidy group detected by karyotype culture and the non-high hyperdiploidy group detected by karyotype culture(98.4%vs 71.9%,P=0.498).Conclusion:(1)The prevalence of high hyperdiploidy ALL in B-ALL is about 18.51%,the age of onset is mostly below 5 years,the white blood cell count at initial diagnosis is mostly less than10×10~9/L,and it is less often accompanied by extramedullary leukemia and fusion gene alterations.Leukemia immunophenotyping shows the specific expression of CD123.(2)The overall prognosis of high hyperdiploidy ALL is good,but some patients with poor outcome,and the prognosis is highly heterogeneous.Age≥5 years,CNS2/CNS3,MRD≥1%at day 19 and MRD≥0.01%at day 46 were independent risk factors for EFS and recurrence in high hyperdiploidy patients.(3)The prognosis of high hyperdiploidy patients in the poor induction response group was poor,and independent risk factors affecting their event-free survival included MRD at day46(≥0.01%)and hemoglobin level(<90g/L).The presence of three forms(+4,+10),(+4,+10,+18),and higher modal chromosome numbers(58-67)may reduce the risk of treatment failure induced in patients with high hyperdiploidy,and can be considered as indicators for further risk stratification in high hyperdiploidy ALL.(4)Compared to karyotype culture techniques,transcriptome sequencing has significantly higher detection rates and higher specificity for high hyperdiploidy ALL.The application of transcriptome sequencing technology can effectively reduce the false negative rate in patients with high hyperdiploidy ALL. |
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