Tyrosine Kinase Inhibitors And Allogeneic Hematopoietic Stem Cell Transplantation For Chronic Myeloid Leukemia

Objective:In imatinib era, the aim of the treatment for CML is to reach cytogenetic remission and molecurlar remission by TKIs. Although imatinib is currently the most effective drug for treating patients with CML, but it can not eliminate the leukemia stem cells. The further limitation of imatinib is that it does not actually cure CML. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still regarded as the only curative treatment. But allo-HSCT has been limited by high rates of transplant-related mortality (TRM), graft versus host disease (GVHD).Based on the social-economic characteristic of our country, and distinctive features of the disease phase of CML and the patient age at disease onset, we utilize TKIs combined with different condition regimen allo-HSCT to treat CML. The present study observed the safety and efficacy of these different treatment plans. The aim of the study is to provide a stratified and optimized strategy for CML treatment and to improve the cure rate of CML. Part1:Efficacy and Prognosis of Chronic Myeloid Leukemia Treated With Imatinib MesylateMethods:We analyzed116CML recipients treated with imatinib at our hospital between the years2003and2008. We summarized the epidemiology and on the current status of imatinib treatment of Chinese patients. Univariate and multivariable analyses were used to evaluate the treatment efficacy.Results:A total of116cases of CML patients were included in this study. The patients included82males and34females with a median age of40years (age range,8-74years). For102patients in chronic phase, the cumulative incidences of response to imatinib in12months were:MCyR,71.1%; CCyR,61.9%; and CMR,47.9%. For14patients in accelerated phase, the respective response rates were CCyR35.7%, CMR28.6%.The3-year progression-free survival and5-year overall survival was73.3%and74.8%. Four factors emerged as predictors of disease progression:molecular response, cytogenetic response, disease phase, and disease duration prior to imatinib treatment, but the only CCyR (OR=0.068), accelerate phase (OR=8.471), disease duration prior to imatinib (OR=4.086) were significant after multivariate analysis.Conclusion:The results indicate that the suboptimal outcome in patients is associated with delayed imatinib therapy, so the importance of the optimal treatment opportunity for CML should be emphasized.Part2:Reduced intensity conditioning allogeneic hematopoietic stem cell transplantation combined with imatinib for chronic myeloid leukemia in first chronic phaseMethods:We analyzed40CML in first chronic phase recipients treated with RIC allo-HSCT combined with pre-and post-transplantation imatinib at our hospital between the years June2005and July2011. Condition regimen consisted of fludarabine, busulfan and ATG. Transplant related mortality, overall survival and disease free survival were evaluated with Kaplan-Meier curves. Univariate and multivariable analysis were used to evaluate the treatment efficacy.Results:A total of40cases of CML in first chronic phase patients were included in this study. The patients included22males and18females with a median age of26years (age range,12-49years). HLA-matched siblings (n=17) and unrelated donors (n=23). Engraftment of neutrophils and platelets was achieved in38out of40(95%) patients within a median of12days (range,8-23days) and16days (range,0-36days), respectively. Acute GVHD was observed in27.5%patients, Ⅲ-Ⅳ aGVHD was2.5%,43.2%patients developed chronic GVHD, while extensive cGVHD was8.1%.100d TRM was2.6±2.5%. After a median follow-up of53months (range2-82months),1-year and6-year TRM was10.5±5.0%,13.3±5.5%;1-year cumulative incidence relapse rate, overall survival and disease-free survival were17.4±6.5%,87.3±5.3%,83.2±6.3%respectively.6-year cumulative incidence relapse rate, overall survival and disease-free survival were17.4±6.5%,84.5±5.8%,83.2±6.3%. Univariate analysis showed disease duration prior to transplant, EBMT risk and major cytogenetic response before transplant were associated with survival, disease duration prior to transplant was significant after multivariate analysis.Conclusion:Imatinib combined with RIC allo-HSCT could provide a safe, well-tolerated therapeutic option for patients with CML in the first chronic phase. Imatinib changed the kinetics of disease relapse after RIC allo-SCT and the anti-leukemic immunologic function of RIC could provide a definite cure for CML.Part3:Tyrosine Kinase Inhibitors combined myeloablative allogenetic haematopoietic stem cell transplantation for advanced phases of chronic myeloid leukemiaMethods:We analyzed22advanced chronic myeloid leukemia recipients treated with myeloablative allo-HSCT combined with pre-and post-transplantation tyrosine kinase inhibitors at our hospital between the years Feb2005and July2011. To evaluate the efficacy and saftety of myeloablative allogeneic hematopoietic cell transplantation (allo-HSCT) combined with pre-and post-transplant TKIs for CML in advanced stage. Transplant related mortality, relapse rate, overall survival and disease free survival were evaluated with Kaplan-Meier curves.Results:A total of22cases of CML in advanced phase patients, with accelerated phase (n=8) or blast crisis (n=14) were enrolled in this study. The median age at transplant was31.5years (range:12-50). Of these22patients,9patients treated with the second TKIs failed to imatinib. HLA-matched siblings (n=10), unrelated donors (n=9) and haploidentical(n=3). Engraftment of neutrophils and platelets was achieved in all patients within a median of15days (range,8-21days) and20days (range,13-32days), respectively. Acute GVHD occurred in54.5%of patients,18.1%patients suffered from III to IV aGVHD. Chronic GVHD was observed in55%of patients, while15%patients suffered from extensive cGVHD. After a median follow-up of29months (range2-85months), The3-year estimated rates of relapse, transplant-related mortality, overall survival and diease-free survival were22.3±10.5%,15.2±8.1%,65.2±11%,65.2±11%, respectively. The6-year estimated rates of relapse, transplant-related mortality, overall survival and diease-free survival were22.3±10.5%,25.8±12.2%,57±12.3%,57±12.3%, respectively.Conclusion:CML in advanced phases may have a satisfactory outcome after myeloablative allo-HSCT combined with TKIs, which could provide a good quality of remission prior to transplant and reduce relapse risk with low toxicities.