Clinical And Molecular Genetic Study On Chronic Myeloid Leukemia Thrated By Second Generation Tyrosine Kinase Inhibitors

Objectives1.To explore the clinical,moleculargenetic characteristics and factors affecting effects of Philadelphia-positive chronic myeloid leukemia(Ph+CML)treated by second generation tyrosine kinase inhibitors(TKIs).2.To explore factors affecting the PFS and OS of CML patients and its prognostic value.Comparing the rate of patients achieving best effects before and after they received new drug of second generation TKIs.Analyzing the OS and PFS of patients accepted different second generation TKIs as first-line or second-line treatment separately,and studying the prognostic value of early molecular reactions(EMR)of CML.Methods1.A database review was undertaken of the diagnostic characteristics of 316 Ph+CML patients treated by second generation TKIs over 12 months in our center up to March 2017.Effects of second generation TKIs and the role of clinical and moleculargenetic characteristics in outcome were evaluated.2.A database review was undertaken of the BCR-ABL IS transcripts and disease progresses of 342 CML patients without special restrictions of course.TO analyze the difference of OS,PFS,CCyR and MMR among each groups.Studying the prognostic value of EMR in patients accepted the second generation TKIs as first-line treatment.Results1.The basic characteristics of Ph+CML patients treated by second generation TKIs over 12 months included:1)Gender:male 194,female 122(male vs female=1.59:1);2)Median age:46(18-85)-year-old,Median age at diagnosis:41(13-78)-year-old;3)Median course of the disease:44(12-312)months;4)Median PLT count in 65 patients:293(73-893)×109/L;Bone marrow blast cells in 171 patients:1.5(0-16.5)%;Median size of spleen in 78 patients:3.5(0-12)centimeters;Median Sokal score in 51 patients:0.87(0.57-3.7),including low risk of 19,middle risk of 28 and high risk of 4;5)Cytogenetic analysis:t(9;22)172/234(72.3%);t(v;22)18/234(8.93%),in which 15 patients occurred at diagnosis,with alternations in 1,17 chromosome more frequently observed which were found in three patients;-Y 1/234(0.4%),which was observerd during the course of treatment;Minor-route additional chromosomal abnormality(ACA)22/234(9.4%),in which only 10 patients occured at diagnosis and 12 during the course;Major-route ACA22/234(9.4%),with+8(14/21,66.7%)ranking the top followed by+Ph(6/21,28.6%),+19(3/21,14.35%)and i(17q)(1/21,4.8%),18 patients observed major-route ACAs during treatment and only 4 at diagnosis.6)Moleculargenetic characteristics analysis:185/231(80.1%)without mutation,25/231(10.8%)with one mutation,21/231 with two or more than two mutations.Among all of those mutations observed,T315I(13/46,28.26%)mutated ranking the top followed by E255K/V(11/46,23.9%),Y253H(18/46,7.4%),M244V(7/46,15.2%),E459K/G(6/46,13%)and G250E(3/46,6.5%).Among 316 patients treated by second generation TKIs over 12 months,206(female/male:89/117)patients acquired MMR vs 110(female/male:33/77)without MMR.Therate of MMR in patients with ACAs(P<0.001,?~2=21.037),mutations(P=0.019,?~2=7.879),gender of male(P=0.022,?~2=5.275)and(or)longer course(P=0.013,?~2=3.112)was lower than the others.To study the correlation between efficacy and course,gender,ACAs,mutations by logistic regression analyse.Then we find that the efficacy has relations with gender(P=0.006),ACAs(P<0.001)and mutations(P=0.02).Further analysis of the results showed that minor-route ACA and major-route ACA groups featured significant difference in MMR rate in contrast to other groups(P=0.001respectively),and the frequencies of mutations was meaningless(P=0.685,?~2=0.164).2.Among 342 patients without special restrictions of course:1)Gender:male 206,female 136(male vs female=3:2);2)Median age:46(18-85)-year-old.A total of 3 cases died in follow-up stage,in which one case died of cerebral infarction,81/342 patients progressed during the process of treatment,median OS:40(2-240)months,median PFS:35(1-172)months.107 patients(31.3%)received drug of nilotinib as first-line treatment vs169(49.4%)as second-line,while 11 patients(3.2%)received drug of generic dasatinib as first-line treatment vs 35(10.2%)as second-line,and there are 20 patients(5.8%)accepted nilotinib and generic dasatinib one after another.215/322 patients(66.8%)acquired MMR after 12 months while 107/322 patients(33.2%)without MMR.The rate of PFS in patients without mutations(196/243)78.06%is higher than the others(47/243)36.17%(P<0.001,?~2=13.921);According to the chromosomal abnormalities,patients were divided into three groups,major-route ACA(24/251)(PFS rate=25%),minor-route ACA(23/251)(PFS rate=60.87%)and the others(169/251)(PFS rate=82.84%),the PFS rate of these three groups made statistical differences(P=0.02,?~2=7.79).Among 110 patients with PCR assessment,30 patients with BCR-ABL1 transcripts>10%in 3 months has a inferior PFS(76.67%)to the rest of patients(PFS:97.5%)with BCR-ABL1 transcripts<10%at 3months(P<0.001,?~2=16.583).The rate of acquiring best effect of patients accepted second-generation TKIs as second-line treatment is higher than received treatment of second-generation TKIs before(P<0.001,?~2=55.833).There's no obvious statistical significance difference in groups divided by Sokal score,choice of TKIs drugs(P>0.05).Conclusions1.Analysis of the clinical and genetic features of Ph+CML patients prove that patients with additional chromosomal abnormalities,mutations and longer course will lead to poor effect,the men often poorly responds to the treatment of TKIs,the number of mutations in someone makes no significance to effect.2.Analysis the EFS of patients show that patients with major-route ACAs,mutation and(or)without EMR have a relatively poor prognosis in contrast to the others.There's no significant statistical differences in PFS of patients treated by nilotinib or dasatinib.Patients who changed drugs for resistance or intolerance with first-line treatment have a improved rate of achieving best effects after accepting new treatment of second generation TKIs.