Basic And Clinical Study Of Efficacy And Adverse Effects Of Flumatinib In Ph+ ALL

Research background and purpose:Philadelphia chromosome-positive acute lymphoblastic leukemia is characterized by aggressive progression,poor response to standard chemotherapy and high risk of recurrence.TKI combined with chemotherapy increased the 5-year overall survival rate of Ph+ALL from 10% to 40%～50%,significantly improving the long-term survival of patients.Flumatinib,a derivative of imatinib,has a good antitumor effect on BCR-ABL mutations of different phenotypes.In chronic myeloid leukemia,flumatinib is superior to imatinib in the treatment of CML,and its efficacy is comparable to that of other second-generation TKI.Moreover,flumatinib has fewer adverse reactions and better safety for patients.However,there are few reports of flumatinib in Ph+ ALL,especially whether flumatinib can prevent central leukemia.Therefore,by observing the clinical efficacy and safety of patients with Ph+ALL treated with flumatinib as the main regimen,this study clarified the status of flumatinib in ph+ALL.This study also innovatively explored the relationship between the blood concentration of flumatinib in different parts(peripheral blood,bone marrow,cerebrospinal fluid)and the clinical efficacy and adverse reactions of the disease,and conducted SUP-B15 cell line experiment to provide clinical practice basis for the selection of reasonable TKI in Ph+ALL patients.Materials and Methods:Chapter 1: The clinical data of 29 patients with Ph+ALL who received flumatinib in Sichuan Provincial People’s Hospital from January 2020 to January 2023 were retrospectively analyzed.Complete remission rate and Minimal residual disease rate,Major molecular response,Complete molecular response,Overall Survival and Progression-free surviva were statistically analyzed to evaluate the efficacy and adverse reactions.Meanwhile,the differences between the two groups of patients receiving flumatinib at the first diagnosis and changing to flumatinib for other reasons were analyzed.The effects of age stratification,risk stratification and initial white blood cell count on the efficacy and survival of Ph+ALL were explored.Chapter 2: The concentration of flumatinib in different parts of the patient(peripheral blood,bone marrow,cerebrospinal fluid)was detected.The concentration of TKI in 16 patients at different time was analyzed,and its relationship with remission of disease and adverse reactions was analyzed.Chapter 3: The inhibitory effects of imatinib,dasatinib and flumatinib on SUP-B15 cell lines were evaluated on the cytopharmacodynamic level.Result:1.A total of 29 patients with Ph+ ALL were included.After flumatinib combined with VP induction therapy,the induced CR,3-month CR and 6-month CR rates were96.3%,87.5% and 86.7%.The negative conversion rate of MRD was 82.6%,91.3% and95.6% in 1,2 and 3 months after treatment,respectively.The rates of MMR were 73.9%,87.5% and 93.3% in 1,3 and 6 months after treatment,and the rates of CMR were52.2%,62.5% and 73.3%,respectively.The 37.9% of patients were transplanted and continued to use flumatinib for 1 year after transplantation.All patients maintained deep remission up to the time of follow-up.Median follow-up was 12 months(1-33 months),progression-free survival(PFS)was 11 months(1-33 months),and median overall survival(OS)was 12 months(1-33 months).The comparison of first-line flumatinib patients with flumatinib change from other TKI patients showed no significant statistical difference between the two groups.The analysis of efficacy and prognosis suggested that age significantly affected the efficacy of molecular remission of disease.In terms of prognosis,age ≥ 60 years old,presence of IKZF1,failure to achieve induced remission,failure to achieve MMR after 3 months of treatment,and failure to undergo hematopoietic stem cell transplantation in high-risk patients all had adverse effects on prognosis.During treatment,the adverse reactions of patients were mainly myelosuppression liver insufficiency and infection,which were generally tolerable.2.TKI concentrations in peripheral blood,bone marrow and cerebrospinal fluid of 11 patients receiving flumatinib,3 patients receiving dasatinib and 2 patients receiving imatinib were collected and analyzed.The concentration of flumatinib in Ph+ ALL bone marrow was the highest,that is,bone marrow > serum > cerebrospinal fluid.Flumatinib is widely distributed in tissues and has the ability to penetrate the blood-brain barrier.In this study,the concentration of drugs in cerebrospinal fluid of the patients using Dasatinib was lower than the lower limit of detection.3.Pharmacodynamic analysis of Ph+ ALL cell line(SUP-B15)showed that flumatinib could promote the apoptosis of SUP-B15 cells,inhibit the proliferation of cells,and block the cells in G1 phase,and the IC50 value of flumatinib in CCK-8method was the smallest compared with Imatinib and Dasatinib.Conclusion:1.In Ph+ ALL patients,flumatinib combined with chemotherapy can achieve good efficacy in early response rate,MRD negative transformation and molecular genetic remission.Patients with Ph+ ALL who switched from other TKI to flumatinib achieved sustained remission.Advanced age affects the outcome of the disease.In terms of prognosis,age ≥60 years old,presence of IKZF1,failure to achieve induced remission,failure to achieve MMR in 3 months after treatment,and failure to undergo hematopoietic stem cell transplantation in high-risk patients ALL have adverse effects on the prognosis of Ph+ ALL.The adverse reactions were mainly myelosuppression and liver function impairment,which were generally tolerable.2.Flumatinib had the highest concentration in Ph+ ALL bone marrow,that is,bone marrow > serum > cerebrospinal fluid.It is suggested that flumatinib has the strongest effect on the clearance of intramedullary and extramedullary infiltrated leukemia cells.Flumatinib can be detected in the cerebrospinal fluid,and it is speculated that flumatinib may have the ability to cross the blood-brain barrier.3.Cell experiments showed that flumatinib could induce the differentiation of Ph+ALL cell line--SUP-B15,promote cell apoptosis,inhibit cell proliferation,and block cells in G1 phase.Meanwhile,CCK-8 method suggested that flumatinib had a stronger inhibitory effect on SUP-B15 cell proliferation than Imatinib and Dasatinib.