| BackgroundChronic myeloid leukemia is a malignant tumor of clonal proliferation of bone marrow hematopoietic stem cells.The natural course of the disease includes chronic phase(CP),accelerated phase(AP)and blastic crisis(BC),and the latter two are referred to as advanced stage.The Ph chromosome is the key chromosome abnormality in CML,The c-Abl proto-oncogene on 9q34 combines with the Bcr gene on 22q11,thereby forms the Bcr-Abl fusion gene,its transcriptional product P210 protein is an abnormal protein tyrosine kinase(PTK)with high activity,and is considered to be the cause of CML.The long-term efficacy and safety of TKIs in the treatment of CML have been confirmed by numerous clinical data,and TKIs have become the first-line treatment of CML.However,there will be TKIS drug-resistance that lead to BC during the using of TKIs in CML treatment.CML may keep in CP in years,however,it will finally accelerat and eventually progress to BC,where the patients show resistance to TKIS and response badly to the chemotherapy.The worsen of disease can happen at any time.The clinical manifestation of BC is similar to that of acute leukemia,but its treatment is refractory.At present,the treatment of BC has not been greatly improved,and the biological mechanism of BC still remains unknown,therefore the research of the mechanism of advanced stage has been the focus of the basic research of CML in recent years.Analyzing the abnormalities of chromosome,gene and clinical data of CML patients at advanced stage,will not only provide data to support the individual therapy,but also provide clue for basic research,which may help accelerate the development of new drugs and bring hope to the radical cure of CML.ObjectiveAnalyze the basic clinical information,chromosome characteristics and genetic alterations of CML-BC patients.Analysing the correlation between different regimens and prognosis of advanced stage patients to reveal related laboratory and clinical prognostic factors during the evolution of CML patients in BC.It provide research clues and theoretical data for the clinical individualization treatment.MethodsInvestigate the clinical data of 66 patients with advanced stage CML in the Affiliated Cancer Hospital of Zhengzhou University from January 2009 to March2018;collect 133 cases of bone marrow samples from different periods,and record chromosome characteristics;39 patients were detected by resistance gene,and record the patients’gene mutation status;analyze the characteristics of patients’history,treatment course,chromosome and gene mutation.Use SPSS19.0 software,and adoptχ~2test,Kaplan-Meier plots and Cox regression analysis.Results1.The 66 patients inciuded in the study had a median age at 46 years,with a ratio of 1.54 to 1 for men and women.In the advanced stage,there were 57 cases of BC,accounting for 86.4%,of which 7 cases were accompanied by extramedullary infiltration,accounting for 12.3%.Among CML-BC,there were 30 patient in megakaryoblastic crisis,accounting for 52.7%.The proportion of additional chromosomes in chromosome examination in advanced stage was 31.7%.The most common abnormal chromosome types were+der(22)Ph,+21,+8.In the results of typical Ph+chromosome examination,45 cases of simple Ph+chromosome group were in CP,51 cases of which were in advanced stage.There was 1 case of typical Ph chromosome combined with chromosome abnormalities,which belonged to CP,and 82 cases belonged to advanced stage.There was a statistical difference between simple Ph chromosome and typical Ph chromosome with additional abnormalities in the distribution of chronic phase and advanced stages of the disease(χ~2=16.776,p<0.01).There were no significant differences between the simple translocation and complex translocation,between typical Ph chromosome and variant Ph chromosome(p>0.05).2.The chromosomal results of 62 patients were observed dynamically,and 21patients(33.9%)had chromosomal evolution,of which 17 patients(27.4%)developed into advancd phase,1 patient(1.6%)developed from AP to BC,and 3patients(4.8%)continued to be in BC.3.Among the 62 cases of survival analysis,apart from 3 patients which were treated with Ponatinib combined with chemotherapy regimen,the remaining 59 cases divided into 5 groups according to the treatment scheme and underwent survival analysis.The OS in the chemotherapy group was significantly lower than that in the other 4 groups,and the differences were statistically significant(p<0.01).The OS in the Imatinib combined with chemotherapy group was significantly lower than that in the other 4 groups,and the differences were statistically significant(p<0.01).There were not significant differences between the Dasatinib combined with chemotherapy group,the Nilotinib combined with chemotherapy group and the allo-HSCT group in OS(p>0.05).Of 24 patients who adopted the Dasatinib combined with chemotherapy,the OS in the Dasatinib 140mg group was better than that in the Dasatinib 100mg group,the difference was statistically significant(p=0.041).4.Of all the patients with advaced stage CML,39 patieents were detected by drug-resistance gene.Mutations in ABL kinase domain were detected in 20 cases(51.3%),and T315I mutation rate was the highest,which occured in 11 cases(28.2%).There was no significant difference of the OS between patients with and without mutation,with T315I mutation and without T315I mutation(p>0.05).Conclusions1.Additional chromosomal abnormalities often occur in advaced phase CML,evolution of chromosomes and additional chromosomes suggests continuous progression of the disease.2.The degree of disease progression is an independent prognostic factor.Patients can benefit from Dasatinib or Nillotinib combined with the chemotherapy and allo-HSCT.In Dasatinib combined with chemotherapy group,the OS with Dasatinib 140mg is superior to that with Dasatinib 100mg.3.The T315I mutation is the most common mutation found in ABL tyrosine kinase point mutations in advaced phase.There was no significant difference of the OS between patients with and without mutation,with T315I mutation and without T315I mutation. |
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