A Single-Group Meta-Analysis:Efficacy And Long-term Outcomes Of Second-generation Tyrosine Kinase Inhibitors Integrated Into Chemotherapy Followed By Allogeneic Hematopoietic Stem Cell Transplantation Of Ph+ALL

Background:Philadelphia chromosome positive acute lymphoblastic leukemia(Ph+ALL)has long been regarded as the most acute leukemia with the worst prognosis due to the poor effect of conventional chemotherapy.With the development of targeted drugs,researchers found that Tyrosine kinase inhibitors(TKIs)could inhibit the proliferation of cancer cells.First-generation TKI Imatinib provides patients with more sustained molecular remission and enables longer survival in patients undergoing Allogeneic hematopoietic stem cell transplantation(allo-HSCT).In recent years,due to reports of imatinib resistance,second-generation TKIs are playing an increasingly important role in the treatment of Ph+ALL.However,current studies have been characterized by a small number of subjects and an insufficiently comprehensive approach,and some scholars have asked whether allo-HSCT is still necessary given that more and more patients are able to achieve sustained deep molecular remission.Therefore,we ask whether sample sizes can be pooled from real world studies to study the efficacy and long-term outcome of second generation TKIs integrated into Ph+ALL chemotherapy sequenced allo-HSCT,and discuss the necessity of allo-HSCT.Objective:Based on 17 effective event indexes including hematological and molecular responses after induction therapy,risk of recurrence and death,long-term survival,etc.,the efficacy and long-term outcome of second generation TKIs integrated into Ph+ALL chemotherapy sequentially allo-HSCT were systematically evaluated,and the difference in survival outcome between the transplant group and the chemotherapy group was compared,in order to provide reference for clinical drug use.Method:China National Knowledge Network,VIP database,Wanfang Database,PubMed,Embase,Cochrane Library,Clinical trials.gov database were searched for studies published before November 2022.ROBINS-I,a non-randomized intervention study bias risk assessment tool,was used to assess bias in the included studies.STATA 14.0 software was used to perform effect index merging,bias analysis and sensitivity analysis.The random effects model was used in the process of effect index merging.Results:A total of 20 literature with 1171 patients were included.Meta-analysis showed that:In the period of second generation of TKIs in Ph+ALL chemotherapy followed by allo-HSCT treatment course,The rates of Complete remission(CR),Major molecular remission(MMR)and Complete molecular remission(CMR)after 4 weeks of induction therapy were 97.3%(94.5%～99.3%),31.1(20.8%-42.4%)and 35.5%(23.1%-48.9%).The rates of MMR and CMR after 3 months of induction therapy respectively were 61.8%(32.8%-86.9%)and 52.6%(35.6%-69.4%).The cumulative CMR rate was 74.0%(54.3%-89.8%).The mortality rate during induction therapy was 3.4%(1.7%～5.5%).The recurrence rate was 18.7%(13.4%-24.5%)and the mortality rate was 18.9%(10.7%-28.4%)in the transplant group.The recurrence rate is 50.0%(35.7%-64.3%)and the mortality rate was 36.9%(18.1%-57.7%)in the chemotherapy group.The incidence of Acute graft versus host disease(a-GVHD)was 50.5%(43.5%to 57.4%).The incidence of Chronic graft versus host disease(c-GVHD)was 41.6%(29.8%-53.8%).The 3-year Overall survival(OS)rate of the transplant group was 78.8%(66.3%-89.0%),and the 3-year Event-free survival(EFS)rate was 69.3%(61.9%-76.2%).The 3-year OS rate of the whole cohort was 67.5%(55.0%～79.0%),and the 3-year EFS rate was 59.7%(46.3%～72.4%).Conclusion:1.This study described the true benefit of second-generation TKIs in combination with chemotherapy for Ph+ALL from diagnosis to long-term outcome.This combination therapy showed higher rates of first-time CR and cumulative CMR(97.3%;74.0%),regardless of whether allo-HSCT was received,the overall 3-year OS rate was 67.50(55.0%～79.0%).The analysis results of this study provide more accurate data support for clinical practice.2.The recurrence rate and mortality of patients in the transplant group were significantly lower than those in the chemotherapy group(18.7%vs 50%;18.9%vs 36.9%),the 3-year OS rate and 3-year EFS rate of the transplant group were better than those of the whole cohort(78.8%vs 67.5%;69.3%vs 59.7%),allo-HSCT still has a significant advantage in first-line use of second-generation TKIs.This conclusion supports the necessity of allo-HSCT in the era of TKI.