Treatment Status Of Chronic Myeloid Leukemia In The Era Of Tyrosine Kinase Inhibitors

Background and objective:Chronic myeloid leukemia(CML)is a common myeloproliferative tumor originating from hematopoietic stem cells.It is characterized by abnormal Philadelphia chromosome t(9;22)(q34;q11)and BCR-ABL fusion gene.Tyrosine kinase inhibitor(TKI)imatinib,a targeted drug developed for the mechanism of tumorigenesis,has greatly improved the outcome and quality of life of patients.However,the problem of imatinib resistance has become increasingly prominent,and ABL kinase region mutation is considered to be the main mechanism.With the exception of T3151,most of the ABL kinase region mutations that lead to imatinib resistance can be overcome by the second generation TKI,and the patients can still achieve good therapeutic effects.The life expectancy of chronic patients treated with standardized TKI is equal to that of healthy people,the quality of life during treatment has become the focus of patients,drug withdrawal and Treatment free remission(TFR)has become a new treatment goal for patients.The results of many drug withdrawal studies have shown that 40%-50%of the patients who received long-term effective TKI treatment and achieved stable deep molecular remission((DMR)reached TFR after drug withdrawal.Based on the above research background,according to the clinical data of Nanfang Hospital of Southern Medical University in the past 10 years to understand the treatment status of CML patients in our center in the era of TKIMethods:1.Collect the medical records of newly diagnosed CML patients in Nanfang Hospital from January 2008 to November 2019 and analyze the clinical characteristics,TKI medication and treatment response,chromosome karyotype and prognosis of newly diagnosed patients and ABL kinase region mutation and prognosis retrospectively to explore the treatment of CML patients in our center.2.The efficacy and safety of domestic dasatinib in 76 patients with chronic CML who had not reached the best response after 3 months of imatinib treatment in Southern Hospital were retrospectively analyzed to explore the best time for drug conversion.3.To observe the molecular recurrence,immunological changes and plasma steady-state valley concentration changes of 28 chronic CML patients who received long-term effective TKI treatment for more than 42 months and maintained stable DMR for at least 18 months,and to explore the feasibility of maintaining major molecular remission for DMR patients.Results:1.The median age of the 892 newly diagnosed CML patients in our center was 36 years old,with more males than females(63.9%vs 36.1%).92.0%of the patients were in chronic stage.The Sokal scores of low,moderate and high risk groups were 40.5%,35.4%and 24.2%,respectively.TKI treatment began about 9 days after diagnosis,and the median follow-up time was 33 months.The cumulative OS and PFS of 5 years were 92.4%and 87.4%,respectively.2.The best response rates of first-line imatinib treatment for 3,6 and 12 months were 65.7%,65.9%and 61.2%,respectively,and those of second-line TKI treatment for 3,6 and 12 months were 47.1%,42.4%and 44.7%,respectively.3.Among the newly diagnosed patients,Ph+CML accounted for 97.2%,of which standard translocation accounted for 85.2%.In AC A,the "major path" exception accounts for 40.8%,and the "minor path" exception accounts for 59.2%.The 5-year OS of ACA group and non-ACA group was 90.7%and 96.7%(P=0.005),and the 5-year PFS was 72.2%and 96.0%(P<0.001).4.The detection rate of point mutations in ABL kinase region in patients with poor curative effect was 20.2%,and the detection rate of T315I was the highest.From August 2018 to October 2019,the positive rate of ASXL1 in 62 patients with TKI resistance detected by NGS in the ABL kinase region positive group was higher than that in the ABL enzyme region negative group(P=0.047).The 5-year OS of the ABL kinase region positive group and the negative group were 79.4%and 90.4%(P=0.359),and the 5-year PFS were 60.4%and 85.4%(P=0.122).There was no significant difference between the two groups.5.The proportion of BCR-ABLIS≤10%in early conversion group,late conversion group and non-conversion group at the third month of follow-up was 77.2%,61.5%and 57.1%,respectively,and there was no difference among the three groups(Purge 0.312).The proportion of BCR-ABLIS≤1%in the sixth month was 59.1%,53.8%and 46.4%,respectively,and there was no difference among the three groups.The proportion of BCR-ABLIS≤0.1%at the 12th month was 50.0%,26.9%and 17.9%,respectively.The early conversion group was better than the non-conversion group(P=0.031),but there was no difference between the late conversion group and the non-conversion group(P>0.05).At this time,the CCyR rates were 81.8%,65.4%and 46.4%respectively(P=0.035).The early conversion group was better than the non-conversion group(P=0.018),but there was no difference between the late conversion group and the non-conversion group(P>0.05)6.During the follow-up period of TKI reduction therapy,3 patients had molecular recurrence,and MMR could be reached again 3 months after the original dose treatment.There was no specific immunological change in patients before and after dose reduction treatment,but the proportion of NK cells in patients with molecular recurrence was lower than that in patients without recurrence after reduction treatment(P=0.013),and there were no specific changes in the rest.The plasma steady-state valley concentration of imatinib decreased with the decrease of dose in patients(P=0.001),but there was no significant difference between MMR group and non-MMR group(P=0.274).Conclusion:1.The patients with CML in China tend to be younger,the molecular response of TKI treatment is good,and the long-term effect and prognosis are good.2.The patients with additional chromosome abnormalities are more likely to develop the disease and have a poor prognosis than those with standard translocation.3.There was no significant difference in OS and PFS between ABL kinase region mutation positive and negative patients.There is other gene mutations in ABL kinase region affected the efficacy and prognosis of TKI patients4.Early conversion of domestic dasatinib to imatinib in patients with chronic CML who did not reach the best response for 3 months is beneficial for patients to obtain better molecular response earlier and may be helpful for more patients to achieve TFR.5.DMR patients can be treated with TKI reduction therapy before trying to help screen patients who are prone to recurrence.