Adverse Events Of Second-generation TKI In Newly Diagnosedchronic-phase Chronic Myeloid Leukemia(CML-CP):A Meta-analysis

Objective:Chronic myeloid leukemia(CML) is an acquired disease of the malignant clone,it is mainly originated from abnormal pluripotent hematopoietic stem cells in bone marrow and involved the myeloid cells.It have three phases,they are chronic phase(CP),accelerated phase(AP) and blastic phase or blast crisis(BP/BC).Half of the patients of CP enter into the AP or BP after 3-4 years.Now,the important treatment is tyrosine kinase inhibitor(TKI) of CML,imatinib(IM) is the first antineoplastic drug of molecular targeted therapy,it is the first-generation TKI and the first-line treatment drug.In2010,dasatinib and nilotinib are allowed to treatment the patient with CML for the first-line by FDA.Therefore,the clinicians are confused to choose the TKI which is the appropriate initial therapy,they not only consider the curative effect of drugs,but also need to take into account other factors(such as:drug adverse events).The purpose of this study is to evaluate the adverse events of the second-generation TKI in patients with CML-CP.Methods:We searched Pubmed(1966 to 2014), Ovid(1966 to 2014), The Cochrane library,CNKI(1979 to 2014),VIP(1989 to 2014) and Wan fang(1999 to 2014),we also scanned references of all included studies and pertinent reviews.We used the Rev Man 5.2software for data analysis,and review the related articles of case series to know the adverse events of the second-generation tyrosine kinase inhibitors in patients with CML-CP.Results:Total 2344 articles have been checked out,including 869 articles of dasatinib and1475 articles of nilotinib.After sifting, 13 articles had being taken into consideration,10 randomized controlled trials(including 6 articles of dasatinib and 4 articles of nilotinib)and 3 case series articles(including 1 articles of dasatinib and 2 articles of nilotinib).1.The meta analysis of dasatinib showed that(1)Compared with imatinib,there were statistical significance:dasatinib was higher than imatinib of leading to anemia[RR=1.48,95%CI(1.10,1.99),P=0.009],Thrombocytopenia[RR=1.81,95%CI(1.43,2.28),P<0.00001],pulmonary arterial hypertension [RR=12.00, 95%CI(1.57,91.95),P=0.02],and pleural effusion[RR=28.69,95%CI(11.82,69.63),P<0.00001].(2)Compared with imatinib,there were statistical significance:dasatinib was lower than imatinib of leading to rash[RR=0.76,95%CI(0.62,0.92),P=0.005],bone pain[RR=0.71,95%CI(0.55,0.92),P=0.009].(3)Compared with imatinib,there were no statistical significance:dasatinib was similar with imatinib of leading to neutropenia [RR=1.10,95%CI(0.93,1.32),P=0.27],bleeding [RR=1.15,95%CI(0.74,1.79),P=0.54],and between QTc duration [RR=0.71,95%CI(0.39,1.29),P=0.26].2.The meta analysis of nilotinib showed that:(1)Compared with imatinib,there were statistical significance:nilotinib was higher than imatinib of leading to blooding[RR=3.34,95%CI(1.59,6.98),P=0.001,]pancreatitis[RR=2.52,95%CI(1.05,6.03),P=0.04],increased blood sugar[RR=23.59,95%CI(5.84,95.24),P<0.00001],rash[RR=2.16,95%CI(1.86,2.51),P<0.00001], ischemic heart disease[RR=3.36,95%CI(1.43,7.88),P=0.005] and peripheral arterial occlusive disease[RR=8.07,95%CI(1.07,60.71),P=0.04].(2)Compared with imatinib, there were statistical significance: nilotinib was lower than imatinib of leading to Center granulocytopenia caused[RR=0.52,95%CI(0.43,0.62),P<0.00001](3)Compared with imatinib,there were no statistical significance:nilotinib was similar with imatinib of leading to anemia [RR=0.70,95%CI(0.48,1.01),P=0.06], thrombocytopenia[RR=1.26,95%CI(0.98,1.63),P=0.07] and between QTc duration[RR=0.50,95%CI(0.11,2.21),P=0.36].3.The case series showed that:the appear rates of dasatinib that lead to anemia、thrombocytopenia and neutropenia in patients with CML-CP are 6.5%,9.7%,21.0%.And the appear rates of nilotinib that lead to anemia,thrombocytopenia and neutropenia in patients with CML-CP are 0%,2.7%,4.1% and 4.5%,10.4%,11.9%.4.The deficiency of this study:(1)The purpose of this study was that to explore the difference of adverse reactions in patients with dasatinib and nilotinib,not to analyze its effect.And dasatinib and nilotinib were expensive,this study did not collect economic data.(2)The study were Ⅱ or Ⅲ phase of clinical trial,the results still need test ofⅣclinical trial.(3)There was no direct comparison of randomized controlled trials between nilotinib and dasatinib,so this research adopted the comparison with imatinib for control group.(4)The literature was limited to language of Chinese and English,there may be language bias.(5)Because the literature was less,the unused funnel graph method to evaluate publication bias,therefore may produce publication bias.Conclusions:1.Dasatinib was higher of leading to anemia,thrombocytopenia,pulmonary hypertension,and the incidence of pleural effusion than imatinib,was lower of leading to rash and bone pain than imatinib,was similar with imatinib of leading to bleeding,the incidence of neutropenia and QTc duration.2.Nilotinib was higher of leading to increased blood sugar,rash,bleeding,pancreatitis,ischemic heart disease and peripheral arterial occlusive disease incidence than imatinib,was lower of leading to incidence of granulocytopenia than imatinib,was similar with imatinib of leading to anemia,thrombocytopenia,and the incidence of QTc duration.3.Special adverse reactions were showed:nilotinib was higher of leading to pancreatitis,high blood sugar, the incidence of ischemic heart disease and peripheral arterial occlusive disease than imatinib;dasatinib was higher of leading to pleural effusion and the incidence of pulmonary hypertension than imatinib,but the incidence of bone pain was lower than imatinib.4.The case literature reports:dasatinib was higher than nilotinib of leading to anemia,thrombocytopenia and neutropenia.