Analysis Of Childhood Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Treated With Imatinib Or Dasatinib

Background and purposePhiladelphia chromosome positive(Ph+)children acute lymphoblastic leukemia(ALL)is considered as an inferior prognosis group,with 3%-5% incidence.Fusion genes resulting from chromosomal rearrangements of the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9,is the leukemogenesis-driven event.Low response rate and high relapsed rate is the major bottle-neck prior to the advent of BCR-ABL1 targeted tyrosine kinase inhibitors.The milestone of clinical application of FDA-approved Imatinib has significantly improved the Ph+ALL outcome.Imatinib,the first generation of TKI,specifically targets BCR-ABL1 kinase and exerts inhibitory function via blocking the ATP binding site of BCR-ABL1.Major clinical research institutions have successively confirmed that the combination of chemotherapy with imatinib significantly improves the prognosis of Ph+ALL.The clinical application of imatinib significantly improves the children Ph+ALL outcome.However,problems remain s uc h a s drug resistance,developmental retardation,myelo-suppression.ABL1 mutation-induced relapse is the major cause of treatment failure.Except for the above issues,mounting evidences show that the incapability of blood brain barrier penetrance makes imatinib doesn’t benefit those Ph+ALL with CNS involvement.New generation TKI,e.g.Dasatinib are thus created to overcome such short-comings.Dasatinib can target both BCR-ABL1 and SCR family kinases.In vitro experiments showed that dasatinib had an affinity for ABL1 that was 325 times higher than imatinib and 16 times higher thanNilotinib.At the same time,dasatinib was effective against most imatinib-resistant BCR-ABL1 mutants except T315 I.Dasatinib has better central nervous system(CNS)penetrating and active than imatinib,In theory.Dasatinib is more effective than imatinib in the treatment of central nervous system leukemia.However,Past clinical trials have shown that there was no significant difference in prognosis between Ph+ALL patients treated with dasatinib and those treated with imatinib.Therefore,It is unclear whether dasatinib is more effective on prognosis and Side effects than imatinib.Based on the above background,we intend to study the clinical characteristics and efficacy of imatinib and dasatinib in this center for Philadelphia patients with chromosomal positive acute lymphoblastic leukemia.In addition,we will conduct a retrospective analysis of the efficacy differences between imatinib and dasatinib through a meta-analysis.Method Ph+ALL Patients diagnosed in Guangzhou women and children’s medical center from May 2015 to February 2020 were included,receiving CCCG-ALL-2015 chemotherapy regimens combined with imatinib or dasatinib.All patients were diagnosed by clinical,pathological,genetic testing and other methods.None of the patients received any other treatment prior to diagnosis and had other malignancies.We retrived the clinical characteristics and biological characteristics of the patients in our hospital,and retrospectivly collected follow-up information.We summarized and compared the clinical characteristics and response of imatinib group and dasatinib group.Furthermore,we conducted a meta-analysis on efficacy of imatinib and dasatinib in the treatment of childhood Ph+ALL using published studies.Results In this study inclueded 13 children diagnosed with Ph+ALL in guangzhou women and children’s medical center.ALL the patients were treated with CCCG-ALL-2015 protocol combined with imatinib or dasatinib.The initial diagnosis age of Ph+ALL patients was older,and Ph+ALL was more common in males with high number of white blood cells and B linerage immune type.In imatinib group,2/3 patients experienced poor early response,and 1/3 patient enrolled into high risk group due to incomplete remission.In dasatinib group,1 patient received imatinib therapy for 30 days and was excluded from subsequent analysis.4/8 patietns experienced poor early response,and all patients got complete remission at day46.In terms of toxic and side effects,the two groups were similar,mainly including systemic damage to the respiratory system,digestive system,nervous system,etc.Patients enrolled in dasatinib group were more likely burden with blung infection,abdominal pain,diarrhea,headache,bone pain,muscle pain,skin rash,and fluid storage of digestive tract bleeding(such as hydrops in the chest and abdomen).There was no significant difference of adverse events in cardiovascular and urinary,but there was a significant difference of adverse events in neurological and others.Through the one-arm meta-analysis of the included literature,we compared of the prognosis of Ph+ALL patients treated with imatinib and dasatinib,we found that patients treated with dasatinib had better prognosis than imatinib in 3 years EFS,3 years OS and 5 years OS but 5 years OS of dasatinib group was inferior than imatinib group.Conclusions Ph+ALL children diagnosised with older age and higher total number of white blood cells.Male and B lineage immune type were more common in Ph+ALL.Patients treated with dasatinib may have a better early treatment response and remission rate than imatinib.Neurotoxicity was more common in matinib group,and the incidence of severe gastrointestinal hemorrhage with daxatinib was more common in dasatinib group.There was no significant difference in the adverse events of cardiovascular,urinary,respiratory and digestive system between the two groups.Meta-analysis found that dasatinib was significantly better than imatinib in 3-year EFS,OS and 5-year OS,but imatinib was slightly higher in 5-year EFS than dasatinib.