Analysis Of Clinical Characteristics And Efficacy Of Patients With Chronic Myeloid Leukemia Complicated With T315I Mutation

Background and objectiveChronic myeloid leukemia(CML)is a malignant myeloproliferative disease(acquired hematopoietic stem cell malignant clonal disease)occurring in the early stage of pluripotential hematopoietic stem cells,characterized by abnormal Ph chromosome t(9:22)(q34)and the fusion gene of q11.2 and BCR-ABL was characterized.The course of the disease was slow,the peripheral blood granulocytes were significantly increased and immature,and the spleen was obviously enlarged.Chronic phase(CP),accelerated phase(AP),and blast crisis(BC)can be experienced as the natural course of disease,and most patients died in the blast crisis.As early as 1999,the commonly used therapies of CML include hydroxyurea,busulfan,interferon-a,etc.However,the best therapy is allogeneic hematopoietic stem cell sell transplantation(allo-HSCT).Nowadays,with the development of modern molecular biology technology,the pathogenesis of chronic myelogenous leukemia has been gradually uncovered,and CML is found to be a highly treatable disease,with a variety of small molecule oral BCR-ABL I kinase inhibitors available.The application of BCR-ABL1 tyrosine kinase inhibition(TKI)revolutionized CML treatment.The main purpose of modern CML therapy is no longer limited to the pursuit of hematological remission,but the pursuit of cytogenetic remission,namely the Ph+ cell extinction rate and the molecular biological remission,namely the BCR-ABL1 fusion gene conversion rate.TKI can specifically inhibit the expression of BCR-ABLI,significantly improve the overall survival(OS)and quality of life of patients with chronic myeloid leukemia(CML),and enable CML to enter the era of targeted therapy.However,drug resistance occurred in some patients during TKI treatment,and about 10%-25%of patients developed drug resistance,in which ABL kinase region point mutation was the main mechanism leading to TKIs drug resistance and treatment failure.Most ABL kinase mutation types can be covered by existing second-generation TKIs,such as nilotinib,dasatinib,and boshutinib,etc.However,it has little effect on T315I.T315I mutation is resistant to both the first and second generation of existing TKIs,which has become a difficult point in the diagnosis and treatment of patients with drug resistance to CML.T315I mutation is also known as T315I gatekeeper mutation,that is,315 threonine in ABL kinase domain is mutated to isoleucine.The detection rate of T315I mutation in the ABL kinase region is very high.Once CML patients are combined with T315I mutation,the prognosis is extremely poor,and currently the treatment options for CML patients with T315I mutation are limited.While there are few reports on the clinical characteristics,treatment response and survival differences of CML patients with T315I mutation.This study retrospectively analyzed the clinical data of 30 CML patients with T315I mutation and 36 CML patients without T315I mutation,and analyzed and compared the prognosis of CML-T315I+ patients with different treatment methods.The related literatures were reviewed in order to explore the clinical characteristics of CML-T315I+ patients and the response effect of T315I mutation patients to different treatments.In order to guide the clinical treatment of long-term TKI sequentially,the patients with relapsing refractory and universal drug resistance should be actively detected for BCR-ABL KD.T315I mutation was detected in time and effective TKI was screened for treatment to improve the prognosis of these patients as much as possible and accumulate clinical experience.Patients and methodsA retrospective analysis was performed on 66 patients with refractory recurrent CML who received long-term TKI sequential treatment in the department of hematology,department of hematology,north guangdong hospital,and department of hematology,affiliated hospital of guangdong medical university.30 CML patients was detected T315I mutation while 36 patients was not,at the initial diagnosis by ABL1 kinase region mutation.There were 25 cases in chronic phase,2 cases in acceleration phase and 3 cases in blast crisis.The median age of the patients was 36.5 yrs(16/73)yrs.There were 20 male patients and 10 female patients.The median time from initial diagnosis to detection of mutation was 43.5 m(5-108)m.T315I mutation was detected in 6 patients in the chronic phase,4 cases during the acceleration phase,20 patients in blast crisis.All patients were confirmed by cytogenetics and bone marrow morphology.The clinical characteristics of patients with CML-T315I+ were found by comparing the baseline data of the two groups.The data characteristics of 30 patients with CML-T315I+,mutations in the ABL kinase region,cytogenetic characteristics and curative effect observation of different treatment methods were analyzed,so as to help identify patients with suspected T315I+ at early clinical stage and select the best treatment method in time.Results1.Sex,age,spleen size,leukocyte,hemoglobin,platelet,percentage of basophil,percentage of eosinophil,percentage of bone marrow primordial cells,proportion of bone marrow primordial cells in the first diagnosis of CML in both groups.There was no statistical difference in BCR-ABL(IS),but there was significant difference in Sokal score(P<0.024).2.Among the CML patients with T315I mutation,26 cases had Sokal score,11.5%(3/26)cases had low risk,19.2%(5/26)cases were moderate risk,69.2%(18/26)cases had high risk,the difference was statistically significant(P<0.05)3.The median stage from initial diagnosis to detection of T315I mutation in 30 CML patients with T315I mutation was 43.5m.76.6%(23/30 cases)of patients had additional chromosome aberrations,in which +8 were the most common chromosome aberrations.53.3%(16/30 patients)had multiple genetic mutations.There were 3 mutations in 3 patients and 2 mutations in 13 patients,including CYP3A5 mutation in 1 patient.4.Among the CML patients with T315I mutation,there were 25 cases in the chronic stage,2 cases in the accelerated stage and 3 cases in the acute stage at the initial diagnosis.The detection rate of T315I after CML disease progression(acceleration phase and blast crisis)was significantly higher than that of chronic phase.When T315I mutation was detected,there were 6 cases(20%)in chronic phase,4 cases(13.3%)in acceleration phase and 20 cases(66.7%)in acute phase,and the difference was statistically significant(P=.001)5.There were 20 males(66.7%)and 10 females(33.3%)in CML patients with T315I.The difference was not statistically significant(P=.068).6.In the treatment choice,30 patients with T315I mutation were treated with TKI.86%of the patients were treated with TKI for the second generation or the third generation because of drug resistance or intolerance.Among them,48%of the patients were treated with the second generation of TKI,7%of the patients with the second generation of TKI and the third generation of TKI,31%of the patients were replaced by the second generation of TKI and the third generation of TKI.7.30 CML patients with T315I mutation were detected for T315I mutation,29 patients were treated with TKI:6 patients(20.7%)received Imatinib treatment,and 5 patients(20.7%)received Nilotinib,18 cases(62.3%)treated with Dasatinib.The difference was statistically significant(P=.004)8.Among the 30 CML patients with T315I mutation,20%(6/30)patients received Ponatinib(PO)treatment after T315I mutation,and the 5-year survival rate was 83.3%.23.3%(7/30 patients)were treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT),with a 5-year recurrence rate of 100%and a 5-year survival rate of 71.4%.23.3%(7/30 patients)received Ponatinib(PO)bridged allogeneic hematopoietic stem cell transplantation(allo-HSCT),with a 5-year recurrence rate of 85.7%.The remaining 33.3%(10/30 patients)were treated with other therapies(dasatinib + interferon,hydroxyl urea,high-tricuspidine,and other traditional therapies),with a 5-year survival rate of 30%.There was no statistically significant difference in efficacy between the Ponatinib treatment group and the Ponatinib bridging allo-HSCT treatment group(P=.857).The efficacy of allo-HSCT treatment group bridged with Panatinib was statistically different from that of other treatment groups(P=.016).There was a statistically significant difference in efficacy between the treatment group and other treatment groups(P=.032),and no statistically significant difference in the survival function between the patients treated with Panatinib alone and those in the transplant group(P=.557).Contusions1.Patients with relapse and refractory CML were more likely to develop T315I mutation in high risk of Sokal score.2.T315I mutation is easy to be detected in patients with refractory CML recurrence who have received long-term sequential treatment,and the detection rate after disease progression is significantly higher than that of chronic disease3.CML patients with T315I mutation often have additional chromosomal nuclear aberrations and multiple genetic mutations,and have poor prognosis.Even after hematopoietic stem cell transplantation,the recurrence rate is still high.4.Long-term maintenance therapy of Ponatinib or allogeneic hematopoietic stem cell transplantation(HSCT)may improve the prognosis and prolong the survival of patients with CML-T3151.5.For well-tolerated CML-CP patients with T315I mutation,the maintenance of single drug of ponatinib is equivalent to the survival rate of patients with allogeneic hematopoietic stem cell transplantation,which can replace allogeneic hematopoietic stem cell transplantation in a sense.