Study On The Treatment And Prognostic Factors Of Adult Acute Lymphoblastic Leukemi

Objective:To analyze the efficacy and safety of pediatric-inspired regimen(IH-2014A regimen)in the treatment of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia(Ph-ALL),and to explore the prognostic significance of minimal residual disease(MRD)combined with traditional risk factors.Methods:The medical records and survival of 338 newly diagnosed adult Ph-ALL patients from 1st April 2014 to 31st December 2020 were analyzed.The cohort was a single arm,prospective clinical study cohort(ChiCTR-OOC-15006328).Results:From 1st April 2014 to 31st December 2020,338 consecutive cases of newly diagnosed adult Ph’ALL patients in our center were included and treated for at least one cycle.There were 200 males(59.2%)and 138 females(40.8%),with a median age of 27(14～69)years.Of these patients,253(74.9%)were B-ALL,85(25.1%)were T-ALL.The surviving patients were followed up until 30th June 20.1.The median follow-up time was 39(0.33～87.46)months.338 patients received induction therapy,12 patients died during induction therapy and 4 patients died during consolidation chemotherapy.The overall chemotherapy-related mortality was 4.7%.321 patients were evaluated by bone marrow puncture after induction.288 patients achieved complete remission(CR)after induction.The CR rate after induction was 85.2%.The median overall survival(OS)time of all patients has not been reached,and the median event free(EFS)time is 24.71 months.The median disease-free survival(DFS)time of 311 patients with CR(including patients who achieved CR after salvage treatment)was 50.43 months.It is estimated that the 5-year OS rate,EFS rate and DFS rate are 52.6%,44.2%and 49.9%,respectively.The 1-year,3-year and 5-year cumulative incidence of recurrence(CIR)of patients with CR were 24.6±7.5%,35.3±3.0%and 38.8±3.4%,respectively.There were 312 patients with bone marrow MRD data by flow cytometry available for analysis after induction treatment.Combined with the traditional risk factors at diagnosis,56 patients(17.9%)in the standard-risk group were MRD negative(SR-MRD neg),46 patients(14.7%)in the standard-risk group were MRD positive(SR-MRD pos),99 patients(31.7%)in the highrisk group were MRD negative(HR-MRD neg),and 111 patients(35.6%)in the highrisk group were MRD positive(HR-MRD pos).The estimated 5-year OS rates of the above four groups were 86.7%,48.0%,62.1%and 36.6%,respectively(P<0.001).The CIR of the four groups also had significant statistical difference(P<0.001).For patients receiving allogeneic hematopoietic stem cell transplantation(allo-HSCT),the estimated 5-year OS rates of SR-MRD neg,SR-MRD pos,HR-MRD neg and HR-MRD pos were 84.4%,63.0%,64.7%and 60.6%,respectively(P=0.626).For patients who did not receive allo-HSCT,the estimated 5-year OS rates of SR-MRD neg,SR-MRD pos,HRMRD neg and HR-MRD pos were 88,1%,33.2%,57.6%and 10.5%respectively(P<0.001).Multivariate analysis showed that age>40 years old,positive MRD level after induction and central nervous system leukemia were independent adverse prognostic factors of OS and DFS.Conclusion:IH-2014A regimen is effective and well tolerated in adult Ph’ALL patients.MRD after induction combined with traditional risk factors has good predictive significance for long-term survival and recurrence.SR-MRD neg patients do not need to undergo HSCT in CR1.Whether patients with HR-MRD neg received allo-HSCT has no significant effect on survival.Allo-HSCT can significantly improve the survival and reduce recurrence of patients who are still positive for MRD after induction,whether in the standard-risk group or in the high-risk group.This new risk stratification method is easy to operate,has low requirements for detection technology,and has obvious significance in predicting patient survival.It is convenient for wide clinical promotion.Objective:To investigate the relationship of dasatinib between plasma concentration and cerebrospinal fluid(CSF)concentration in the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph+ALL).Methods:We used liquid chromatography-tandem mass spectroscopy(LC-MS/MS)to measure the plasma and CSF concentrations of dasatinib in a prospective,single-arm study in the treatment of adult Ph+ALL patients.Results:The maximum plasma drug concentration after oral administration of dasatinib occurred 2 hours after administration,and the plasma concentration varied greatly among different individuals.The paired samples of plasma and CSF revealed the median plasma concentration before administration of dasatinib was 2.1±2.08 ng/ml and detectable but below the limit of quantification(LQ)(0.194 ng/ml)of dasatinib in CSF was found in only 1 of the 27 patients.As for the paired samples 2 h after administration,the median plasma concentration was 87.14±63.01 ng/ml and detectable level(0.231,0.297,0.410,0.679 ng/ml)of dasatinib in CSF was found in 4 of the 25 patients,but only one above the LQ.Five patients with an escalation of dasatinib to 70mg twice daily(140mg/d),detectable levels of dasatinib in CSF were found in all patients,2 of them above the LQ(1.010 and 0.845 ng/ml),one approached the LQ(0.489ng/ml),and the remaining 2 below the LQ(0.104 and 0.274 ng/ml).Conclusion:Dasatinib orally administered 100mg once daily was well absorbed by the patient but penetrated poorly into the CSF.The use of a higher drug dosage(140mg/d)may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF.