The Research On TKIs-related Adverse Events And Efficacy In Chronic Myeloid Leukemia

1.The analysis of Tyrosine Kinase Inhibitors(TKIs)-related adverse events of 836 patients with chronic myeloid leukemia(CML)in a single centerObjective 1.To retrospectively analyze the clinical data of patients with CML and summarize the clinical features of CML patients in this center from 2010 to 2016.2.To analyze the treatment-related adverse events of TKIs in patients with CML in this center.Method 1.We collected the clinical informations of 836 CML patients from 2010 to 2016,and analyzed the clinical characteristics,chromosome abnormalities and the types of BCR-ABL fusion among these patients.2.We followed up the patients by telephone and understood the use of various types of TKIs and TKIs-related adverse events.And specifically analyzed the incidence and distribution of hematological(shown as a decline in various blood cell counts)and non-hematological adverse events(gastrointestinal discomfort,abnormal liver function,edema,rash and pruritus)in various TKIs.Result 1.From 2010 to 2016,of 836 CML patients in the center,the median age was 44.5 years old,males more than females(the ratio was 1.67:1).The chromosome karyotype was dominated by simple t(9;22)(q34;q11).The majority of BCR-ABL1 fusion were P210,the minority were P190 and other rare fusion types(about 1.1%).2.Of 836 CML patients,776 patients(92.8%)started TKIs within 1 month after diagnosis,only 3.6% of patients started taking the drugs after 6 months.The first-line TKIs were mainly imatinib,with a total of 654 cases(78.2%),and 122 cases(14.6%)of the second-generation TKIs,of which 103 cases(12.3%)with nilotinib and 19 cases(2.3%)with dasatinib.3.Of the 836 patients with CML,231(27.6%)patients had no adverse events during the entire course of TKIs,and 579(69.3%)patients had clear adverse events,and 26(3.1%)patients could not be sure of any adverse events.4.Of the 810 patients with CML who could determine the incidence of adverse events,697 had received imatinib treatment,294 had received nilotinib treatment,and 107 had received dasatinib treatment,respectively.The most common adverse events of imatinib were edema(21.7%),followed by gastrointestinal discomfort(17.2%),leucopenia(13.9%),thrombocytopenia(13.1%),rash,pruritus(9.7%)and anemia(4.9%),muscle and joint pain(4.9%),and the most common adverse events of nilotinib were rash,pruritus(31.0%),followed by abnormal liver function(16.3%),thrombocytopenia(16.0%),muscle and joint pain(9.5%),leucopenia(8.5%),and gastrointestinal discomfort(6.8%),and the most common adverse events of dasatinib were thrombocytopenia(29.9%),followed by leucopenia(14.0%),anemia(12.1%),serous effusion(10.3%),gastrointestinal discomfort(8.4%)and edema(7.5%).Conclusion 1.Data from 836 patients with CML in the Center from 2011 to 2016 showed that CML patients were more common in males and the age of onset was mainly 31-60 years old.2.The distribution of chromosomal karyotype and the type of BCR-ABL1 fusion transcript were basically consistent with those reported in the literature.The chromosome karyotype was mainly t(9;22)(q34;q11).The BCR-ABL1 fusion transcript type was mainly P210.3.In patients with CML,more than 90% of patients started TKIs within 1 month after diagnosis.The first-line TKIs were mainly imatinib mesylate(Gleevec),followed by domestic Imatinib and nilotinib.4.During the treatment of TKIs,about 70% patients with CML had adverse events,and only less than 30% patients had no adverse events.The most common adverse events of imatinib,nilotinib,and dasatinib were edema,skin rash,pruritus,and thrombocytopenia,respectively.Serous effusions were only more common in dasatinib,and all other adverse events occurred in all three types of TKIs.2.Analysis of the influencing factors of treatment response in CML-CP patients with TKIs-related adverse eventsObjective To investigate the relationship between TKIs treatment-related adverse events and treatment response(main molecular response MMR and complete cytogenetic response CCy R)median time in patients with CML-CP.Method We analyzed the correlations between the six most common adverse events(gastrointestinal discomfort,leukopenia,thrombocytopenia,rash,pruritus,anemia,muscle and joint pain)in first-line imatinib-treated CML-CP patients,the six most common adverse events(rash,pruritus,abnormal liver function,thrombocytopenia,muscle and joint pain,leukopenia,gastrointestinal discomfort)in first-line nilotinib-treated CML-CP patients,and factors such as age,sex,karyotype,whether the drug was changed,whether the adverse events can be tolerated(no adverse events,adverse events but can be tolerated,and not tolerated),and the classification of adverse events(no adverse events,non-hematological adverse events,hematological adverse events,both had)and the median time to reach CCy R/MMR during the follow-up observation period(from the time that the disease was diagnosed to the follow-up deadline)or during the imatinib/nilotinib treatment period(from the diagnosis of the disease to the end of imatinib/nilotinib treatment).SPSS20.0 software was used for statistical analysis,Kaplan-Meier method and Cox regression model were used for univariate and multivariate analysis,respectively,and various meaningful values(P< 0.05)during the treatment period of imatinib/nilotinibrelated adverse events were included in multi-factor model a for analysis,and all single factor(P<0.05)were included in multi-factor model b for analysis.We took P<0.05 as the difference was statistically significant.Result 1.During the follow-up period,528 patients in first-line imatinib-treated CML-CP could analyze the association between adverse events during imatinib treatment and the time to reach CCy R.Univariate analysis showed that patients taking Indian imatinib,dressing,adverse event and intolerance,thrombocytopenia and anemia had a longer median time to CCy R(all P<0.05),patients with non-hematological adverse event,gastrointestinal discomfort,and edema had a shorter median time to CCy R(all P < 0.05).The results of multivariate analysis model a showed that patients with edema(P = 0.003)had a shorter median time to CCy R.The results of multivariate analysis model b showed that patients with dressing(P=0.014)and thrombocytopenia(P=0.020)had a longer median time to CCy R,whereas patients with non-hematological adverse events(P=0.031)and edema(P)= 0.020)had a shorter median time to CCy R.618 patients in first-line imatinib-treated CML-CP could analyze the correlation between adverse events during imatinib treatment and the time to achieve MMR.Univariate analysis showed that male patients,those taking Indian imatinib,those who had undergone dressing changes,who had adverse event and intolerance,who had thrombocytopenia,and anemia had a longer median time to MMR(all P<0.05);Patients with non-hematological adverse events,gastrointestinal discomfort,edema,and rash,pruritus had a shorter median time to MMR(all P < 0.05).The results of multivariate analysis model a showed that patients with gastrointestinal discomfort(P=0.005),edema(P=0.006),and rash,pruritus(P=0.004)had a shorter median time to MMR and patients with thrombocytopenia(P=0.041)had a longer median time to MMR.The results of the multivariate analysis model b showed that Male patients(P=0.005),Indian imatinib(P=0.012),and patients who had undergone drug exchange(P<0.001)had a longer median time to achieve MMR,patients with edema(P=0.021)and rash,pruritus(P<0.001)had a shorter median time to MMR.2.During the treatment period of imatinib,528 patients in first-line imatinib-treated CML-CP could analyze the correlation between adverse events during imatinib treatment and the time to reach CCy R.Univariate analysis showed that patients with Indian imatinib,adverse event and intolerance,thrombocytopenia had a longer median time to CCy R(P < 0.05);patients with gastrointestinal discomfort and edema had a shorter median time to CCy R(P < 0.05).The multivariate analysis model a showed that patients with edema(P=0.003)had a shorter median time to achieve CCy R,whereas patients with thrombocytopenia(P=0.025)had a longer median time to reach CCy R.Multivariate analysis model b showed that patients with non-hematological adverse events(P=0.016)and edema(P=0.007)had a shorter median time to achieve CCy R,whereas patients with thrombocytopenia(P=0.009)had a longer median time to reach CCy R.618 patients in first-line imatinib-treated CML-CP could analyze the correlation between adverse events during imatinib treatment and the time to achieve MMR.Univariate results showed that male patients,those taking Indian Imatinib,those with adverse event and intolerance,and thrombocytopenia had a longer median time to MMR(P < 0.05);those with gastrointestinal discomfort and edema had a shorter median time to MMR(P < 0.05).In multivariate analysis model a,the results showed that patients with gastrointestinal discomfort(P=0.008)and edema(P=0.006)had a shorter median time to MMR;patients with thrombocytopenia(P=0.025)had a longer median time to MMR.In multivariate analysis model b,the results showed that: male patients(P = 0.004)had a longer median time to MMR;patients with gastrointestinal discomfort(P = 0.005)and edema(P = 0.001)had a shorter median time to MMR.3.During nilotinib treatment,76 patients in first-line nilotinib-treated CML-CP could analyze the correlation between adverse events during nilotinib treatment and the time to reach CCy R.Univariate analysis results were not significant.103 patients in first-line nilotinib-treated CML-CP could analyze the correlation between adverse events during nilotinib treatment and the time to achieve MMR.Univariate analysis showed that patients with non-hematologic adverse events and abnormal liver function had a shorter median time to MMR(P<0.05),whereas patients with thrombocytopenia had a longer median time to MMR(P<0.05).Multivariate analysis showed that patients with abnormal liver function(P=0.016)had a shorter median time to MMR.Conclusion 1.During the follow-up period,the analysis of the correlation between adverse events during imatinib treatment and the time to reach CCy R/MMR in first-line imatinib-treated CML-CP patients showed that: patients with dressing and thrombocytopenia had a longer median time to achieve CCy R,whereas those with non-hematologic adverse events and edema had a shorter median time to achieve CCy R;male patients and dressing patients had a longer median time to achieve MMR,while patients with edema and rash,pruritus had a shorter median time to MMR.2.During the imatinib treatment period,the analysis of the correlation between adverse events during imatinib treatment and the time to reach CCy R/MMR in first-line imatinib-treated CML-CP patients showed that: patients with non-hematologic adverse event and edema had a shorter median time to achieve CCy R,whereas patients with thrombocytopenia had a longer median time to achieve CCy R;the median time for male patients to achieve MMR was longer,while patients with gastrointestinal discomfort and edema had a shorter median time to achieve MMR.3.During the nilotinib treatment period,the analysis of the correlation between adverse events during nilotinib treatment and the time to reach CCy R/MMR in first-line nilotinib-treated CML-CP patients showed that: all factors were not related to the median time for patients to achieve CCy R.Patients with abnormal liver function had a shorter median time to achieve MMR.