Efficacy,safety And Pharmacokinetics Of Dasatinib In Children With Core-binding Factor-acute Myeloid Leukemia

Background:The prognosis of childhood acute myeloid leukemia(AML)has improved significantly over the past few decades,with an overall long-term survival rate of approximately 60%.However,relapse remains the leading cause of treatment failure.The core binding factor acute myeloid leukemia(CBF-AML)is one of the most common cytogenetic subtypes of acute myeloid leukemia,and about 20%of children with CBF-AML relapse after drug withdrawal under the current treatment regimen.In recent years,dasatinib has been tried in the treatment of CBF-AML,but the clinical data is limited and systematic clinical studies are lacking.The therapeutic window of dasatinib is not clear,because pharmacokinetic process in children has not been a complete research.In this study,we regarded solving dasatinib combined chemotherapy regimens treating with CBF-AML in children patients as the breakthrough point.On the basis of evaluating the efficacy and safety to explore the factors influencing process for dasatinib,and further establish individualized drug delivery system based on these factors.There have been several preclinical and clinical studies of dasatinib in CBF-AML.The in vitro experiments showed that dasatinib combined with daunorubicin could significantly prolong the survival of AML stem cells and make the chemotherapy drugs have better targeting.In addition,in vivo efficacy studies of AML mouse models have shown that a single dose of dasatinib can prolong the survival of diseased mice,and can also have a synergistic effect with cytarabine.A clinical study has been conductde in adult patients who received dasatinib in combination with conventional chemotherapy to treat the CBF-AML,and compared with the historical control group.The results proved that the use of dasatinib could achieve a higher tumor remission rate without serious adverse events.More and more evidence that dasatinib is a promising targeted antitumor drug for the treatment of children with CBF-AML.Objective:There is limited clinical evidence for the use of dasatinib in the treatment of CBF-AML.Based on clinical experience and mechanism of action,dasatinib may be a drug that can be used to treat the CBF-AML.The purpose of this study was to evaluate the efficacy,safety pharmacokinetic of dasatinib in the application of CBF-AML.Methods and Results:Twenty diagnosed pediatric patient(3.32-14.4 years of age)were included.A total of 40 DAS concentrations ranged from<LOQ to 286.1 ng/mL were used for population pharmacokinetic analysis.The mean(standard deviation)of estimated AUC 0-inf.Cmax,Tmax and CL/F were 405(156)ng·h/mL,52.91(16.03)ng·h/mL,2.64(0.69)h and 3281(1113)mL/min/m2,respectively.All CBF-AML patients were alive from December 2019.Both the estimated cumulative incidence of CR and CMR were 95%and 70%,respectively.During DAS treatment,one patient developed grade 3-4 hematologic adverse reactions.Other adverse reactions were mild,such as nausea,vomiting,limb pain and rash,and none of the patients stopped taking dasatinib because of the adverse reactions.Conclusions:The results of this pilot study indicate that drug disposition and tolerability of DAS were similar to those observed in adult patients.Oral DAS(60-80 mg/m2 once daily)is effective and safe in pediatric CBF-AML patients.