Analysis Of ABL Kinase Domain Mutations In The Patients With Progressive Chronic Myeloid Leukemia

Objective:To analyze the incidence and mutation types of ABL kinase domain mutations in patients with chronic myeloid leukemia(CML)during accelerated phase and blast crisis,and explore factors that may influence ABL kinase domain mutation.Methods:The clinical data of 36 patients with CML during accelerated phase(AP)and blast crisis(BC)who were assessed for ABL kinase domain mutations and treated with tyrosine kinase inhibitor(TKI)in the Department of Hematology,the First Affiliated Hospital of Kunming Medical University from January 2015 to September 2017 were collected.According to the mutation of the ABL kinase area,the patients were divided into the mutation group and the non mutation group.The general situation and the clinical indexes of the 2 groups were compared,and the factors that might affect the mutation of the ABL kinase region were analyzed.Results:1.All the patients enrolled in the study were 36,among the 36 CML patients,age 40(16-75),male 23(63.89%),female 13(36.11%),12(33.33%)in the AP,24 cases(66.67%)in the BC,17(47.22%)in the mutation group,and 19(52.78%)in the non mutant group.The median time from progression to AP or BC was 37(0-146)months after diagnosis,44(0-146)months in the non mutation group,and 28(4-146)months in the mutant group.30 patients(83.33%)were treated with imatinib,of whom only 7 received imatinib as first-line treatment,22 received hydroxyurea therapy,and 6 received interferon therapy;6 patients(16.67%)were treated with nilotinib,of which one was treated with nilotinib for first line treatment,and 3 of 4 patients who had been treated with imatinib were changed to nilotinib because of the detection of mutation,1 case was only treated with hydroxyurea treatment;10(27.78%)patients were treated with dasatinib,of which 2 were treated with dasatinib for first line treatment,and 3 of the 6 patients who had received imatinib were changed to dadatinib,1 was treated for imatinib and nilotinib,and 1 among them was mutated in 2 patients who received only hydroxyurea treatment.2.Of the 17 patients with mutation,only 2 were detected in the CP,and the remaining 15 were detected during the ’AP or BC.The median time of mutation was 27(4-146)months after CML diagnosis,which was close to the time of the progression of the disease,that was 28(4-146)months.4 species of mutation were detected,respectively:Y253H(13.89%)、E255K/V(27.78%,)、T315I(11.11%)、F317V/I/C/L(2.78%).The highest proportion of E225K/V was detected in P-Loop region.Among the 17 cases of mutation,2 cases had assessed double mutations:Y253H+T315I,Y253H+E255K/V,1 case had assessed multiple mutations:Y253H+E255K/V+T315I,and 1 case’s mutation sites changed from T315I to Y253H.3.Sokal prognosis grouping,chromosome karyotype evolution,drug use,the time of beginning TKI treatment,leukocyte count,neutrophil ratio,neutrophil to lymphocyte(NLR),basophil ratio,proportion of infantile cells in peripheral blood,platelet count,and progression of bone marrow primitive cells,the OR value of these factors is greater than 1,suggesting that the above factors are risk factors for ABL kinase domain mutation;while the age,sex,progression time,optimal reaction,spleen size,lymphocyte proportion,monocyte proportion,eosinophil ratio,hemoglobin,and BCR-ABL P210 quantitative detection at first diagnosis were less than 1,suggesting that the factors mentioned above are protective factors for the mutation of ABL kinase region;as well as the OR value of BCR-ABL P210 was 1 at the time of progression,suggesting that this factor was not related to the occurrence of ABL kinase domain mutation.4.The P value of the evolution of chromosome karyotype(OR=15.954,95%CI:1.156-220.219)and the NLR of initial diagnosis(OR=1.06,95%CI:1.009-1.114)is less than 0.05,which is of statistical significance.It is suggested that the evolution of chromosome karyotype and the NLR of initial diagnosis may be an independent risk factor affecting the mutation of the ABL kinase domain. Conclusions:1.The mutation of ABL kinase area in the CML progressive patients receiving TKI treatment is easy to occur in the P-Loop region and(or)IM binding area,and the mutation time is close to the time of the progression of the disease.2.The P value of the evolution of chromosome karyotype(OR=15.954,95%CI:1.156-220.219)and the NLR of initial diagnosis(OR=1.06,95%CI:1.009-1.114)is less than 0.05,which is of statistical significance.It is suggested that the evolution of chromosome karyotype and the NLR of initial diagnosis may be an independent risk factor affecting the mutation of the ABL kinase domain.3.Starting TKI treatment time late(that is,not taking TKI as a first-line treatment for CML chronic patients)and irregular medication may lead to the mutation of the ABL kinase area.Therefore,once the CML diagnosis is clear,the TKI treatment should be started as soon as possible,and the drug should be standardized.4.Mutations in the ABL kinase region are still possible during the two generation of TKI treatment.Mutations in the ABL kinase domain should be monitored for patients using the two generation of TKI.