Study On Safety And Efficacy Of Donor Lymphocyte Infusion To Prevent Relapse After Allogeneic Hematopoietic Stem Cell Transplantation In High-risk Leukaemia/MDS Patients

Part Ⅰ Donor lymphocyte infusion to prevent relapse of high-risk acute leukaemia after matched sibling donor peripheral blood stem cell transplantationObjective Relapse is the main reason for the failure of allogeneic hematopoietic stem cell transplantation（allo-HSCT）in patients with acute myeloid leukaemia（AML）.Donor lymphocyte infusion（DLI）can be used to prevent relapse after allogeneic hematopoietic stem cell transplantation.The purpose of this study was to analyse the safety and efficacy of prophylactic DLI after matched sibling donor hematopoietic stem cell transplantation（MSD-HSCT）in high-risk AML patients.Objects and Methods A prospective,single-arm study was conducted among AML patients with continuous high-risk characteristics who were hospitalised in our centre and received MSD-HSCT treatment from June 2016 to April 2019.The definition of AML for high-risk features meets at least one of the following:1)in the non-remission（NR）state before transplantation,including primary induction failure,relapse untreated,or refractory to reinduction chemotherapy;2)achieving first complete remission（CR1）with≥three cycles of induction of chemotherapy;3)AML remission/MDS-EB patients carrying at least one of TP53,DNMT3A,TET2,or FLT3-ITD^highgene mutations.Selected patients were implanted successfully and more than 30 days after transplantation.Patients were planed to receive prophylactic DLI from+30 to+60 days after MSD-HSCT.All patients who received prophylactic DLI before day+60（MSD-HSCT）,their Cyclosporine A（CSA）for routine prevention of acute graft-versus-host disease（a GVHD）from day-9,still maintained a trough concentration 150–250 ng/ml.CSA was maintained at 150-250 ng/ml for four weeks.The evaluation indicators were the relapse rate,relapse-free survival（RFS）,and overall survival（OS）.Safety indicators included hemocytopenia,infection,the incidence of acute and chronic GVHD associated with infusion,and non-relapse mortality.Results There were no patients who received prophylactic DLI after MSD-HSCT to have DLI-related pancytopenia.The cumulative incidences of grade II-IV and grade III-IV of a GVHD after DLI were 24.5%（95%CI,12.2%-36.8%）and 18.2%（95%CI,6.6%-29.8%）,and the incidence of chronic graft-versus-host disease（c GVHD）was 20.0%（95%CI,7.4%-32.6%）.The 3-year cumulative incidences of non-relapse mortality（NRM）was 8.3%（95%CI,0.3%～16.3%）,and the relapse rate was 33.9%（95%CI,20%-47.8%）.The 3-year relapse-free survival was 59.3%（95%CI,45%-73.6%）,and overall survival（OS）was60.6%（95%CI,46.8%-74.4%）.Conclusions It was preliminarily confirmed that the preventive DLI of our centre was feasible.In MSD-HSCT with peripheral blood grafts,prophylactic DLI after transplantation is safe and effective.Part Ⅱ Donor lymphocyte infusion to prevent relapse of high-risk acute leukaemia after haploidentical peripheral blood stem cell transplantationObjective To explore the safety and efficacy of DLI to prevent relapse of high-risk acute leukaemia after haploidentical allogeneic peripheral blood stem cell transplantation.Objects and Methods We conducted a prospective,single-arm study for leukaemia patients with high-risk characteristics.They underwent haploidentical donor hematopoietic stem cell transplantation（HID-HSCT）in our centre between October 2014 and May 2019.The following criteria defined the very high-risk features:1)AML,the disease in NR status including primary induction failure or relapsed,2)AML achieving CR1 with≥three cycles of induction of chemotherapy,3)AML remission,MDS-EB or acute lymphoblastic leukaemia（ALL）remission with TET2,DNMT3A,FLT3-ITD^high,ASXL1,or TP53 mutation,4)chronic myelogenous leukaemia（CML）with BCR-ABL T315I mutation（due to unavailability of targeted therapy）.Selected patients were implanted successfully and more than 60 days after transplantation.All patients who were planed to receive prophylactic DLI between+60 and+90 days after HID-HSCT,their CSA for routine prevention of a GVHD from day-9,still maintained a trough concentration 150–250 ng/ml.CSA was maintained at 150-250 ng/ml for six weeks.The evaluation indicator was focused on the relapse rate,RFS,and OS.Safety indicators included hemocytopenia,infection,the incidence of acute and chronic GVHD associated with infusion,and non-relapse mortality.Results A total of 39 patients with high-risk leukaemia were treated with HID-HSCT,of which25 patients received prophylactic DLI after transplantation.Fourteen patients did not receive prophylactic DLI because they met the exclusion criteria.On the 100th day after prophylactic DLI,the cumulative incidences of II～IV and III～IV acute GVHD were 28.0%（95%CI,8.06%-43.61%）and 12.2%（95%CI,0-24.2%）,respectively.The cumulative incidences of chronic GVHD in 1-year and 2-year after prophylactic DLI were 15.7%（95%CI,8.1%-21.8%）and 23.6%（95%CI,10.7%-36.7%）,respectively.The cumulative incidence of NRM were 29.4%（95%CI,17.9%-40%）and 36.2%（95%CI,27.5%-48.9%）,respectively.In Kaplan-Meier estimates,1-year,and 2-year for OS were 45.3%（95%CI,30.9%-55.7%）and34.0%（95%CI,21.5%-46.5%）,and for RFS were 44.6%（95%CI,34.1%-55.1%）and 33.5%（95%CI,21.0%-46.0%）,respectively.Conclusions Prophylactic DLI can reduce the risk of relapse in cases of acceptable toxicity for patients who received HID-HSCT.Part Ⅲ Donor lymphocyte infusion combined with decitabine to prevent relapse ofAML after allogeneic peripheral blood stem cell transplantationObjective The purpose of this study was to reduce the risk of relapse after allo-HSCT of acute myeloid leukaemia carrying the poor gene through the prophylactic DLI combined with decitabine.Another purpose of this study was to explore the safety and efficacy of this method.Objects and Methods This study is a prospective clinical study.Patients with AML/MDS with mutations in the undesirable genes TP53,DNMT3A,FLT3-ITD^high,TET2,ASXL1 were the study subjects.Patients were planned to be prophylactically used of decitabine combined with DLI,or only DLI after allo-HSCT.Prophylactic G-CSF-primed DLI after transplantation was planned for all patients at+30～+60 days for MSD-HSCT and+60～+90 days for HID-HSCT,respectively.Short-term CSA drugs were used to prevent DLI-related GVHD.Decitabine sequential DLI regimen:5 days of decitabine treatment（10mg/m²/d from day 1 to day 5）followed by DLI on day 7.The evaluation indicator was focused on the relapse rate,RFS,and OS.Safety indicators included hemocytopenia,infection,the incidence of acute and chronic GVHD associated with infusion,and non-relapse mortality.Results 41 AML/MDS patients with adverse prognostic gene mutations received allogeneic hematopoietic stem cell transplantation.Six patients with molecular relapse or haematological relapse who received preemptive or therapeutic DLI were not enrolled.Thirty-five patients with negative MRD before prophylactic DLI were included in the study.The median age was 37 years（17-64 years）.Ten patients did not receive the planned prophylactic DLI due to contraindications.Twenty-five patients received prophylactic DLI for the median of 90 days（46-236 days）after transplantation,of which eight patients were delayed DLI because of GVHD（6 cases）and hemocytopenia（2 cases）.The cumulative incidences of acute GVHD grade II-IV and III-IV at 100 days post-DLI in 25 patients were29.3%and 15.1%,respectively.Those of chronic GVHD,NRM,and relapse at 3-year post-DLI were 21.5%,24.0%,and 31.2%,respectively.The 3-year of RFS and OS were51.1%and 50.5%.Conclusions Prophylactic DLI showed good tolerance and efficacy in reducing relapse in AML patients with unfavourable gene mutations after allo-HSCT.It showed good patience and efficacy in AML patients with damaging gene mutations for the prophylactic use of decitabine combined with DLI.