| Background and Purpose:Which with complex,Aplastic anemia(AA)is a life-threatening hematologic disease causing by multiple pathogenic mechanism.According to the symptoms,AA can be divided into non-severe aplastic anemia(NSAA),severe aplastic anemia(SAA)and very severe aplastic anemia(VSAA).Many complications,such as infection,hemorrhage,and severe anemia,are common factors leading to death,espcically in SAA and VSAA patients.Immunosupressive therapy(IST)and allogeneic hematological stem cell transplantation(Allo-HSCT)are the main treatments for SAA at present.Allo-HSCT is an effective and curative treatment option for patients with severe aplastic anemia(SAA).Sucessful and stable engraftment of donor’s hematopoietic stem cells is a major challenge in patients with SAA after transplantation for the low toxicity and the low mortality of transplantation.Non-myeloablative contioning regimen is usually used in aplastic anemia transplantation.But patients using non-myeloablative regimen is always accompany with mixed hematopoietic chimerism(MC)of donor and recipient and MC has been shown to be associated with both primary and secondary graft failure.In this study,we retrospectively analyzed 287 severe aplatic aneamia patients undergoing allogeneic hematopoietic stem cell transplantation to analyze the risk factors of mixed chimerism(MC)and secondary graft failure(SGF).Meanwhile,we also investigated the treatments for MC and SGF.Methods: Research object:A retrospective study reviewed the data from October 2012 through January2020 complied at the Guangzhou First People’s Hospital.A total of 287 patients who were diagnosed with SAA and received allo-HSCT were analyzed.Among the 287 patients,167 were males(58.2%)and 120 were females.Mean age was 28±12 years,and the median time from diagnosis to treatment was 4 months(1-35 months).201 cases of SAA and 86 cases of VSAA were diagnosed.In patients who underwent matched related or haplo-identical transplantation,mobilized bone marrow and peripheral blood stem cells(PBSCs)were the stem cell source,whereas patients who underwent matched unrelated transplantation received only PBSCs.Twenty-eight cases were conditioned with CTX+ATG regimen,111 cases were conditioned with FCA regimen,67 cases with matched donor using busulfan(BU)+CTX+ATG as the conditioning regimen,and 81 cases with Haplo-HSCT were conditioned with Bu Cy+ATG regimen.The changes of hematopoietic chimerism after transplantation were observed.The chimerism analysis was performed monthly in the first 3 months after transplantation,and every 3 months from 3 months to 1 year after transplantation,and every 6 months after 1 year.If changes in peripheral blood cell counts were found during the follow-up,chimerism analysis was performed at the same time.Bone marrow specimens of different genders between paients and donors were examined by FISH and microsatellite DNA fingerprinting,while peripheral blood microsatellite DNA fingerprinting was only performed for the same gender.According to the degree of chimerism and peripheral blood level,patients were divided into four groups: Group 1: patients who remained in a completely donor chimerism(DC)after transplantation and never experienced MC or GF.Group 2: MC without cytopenia.Group 3: MC(not SGF)with cytopenia that required G-CSF and/or transfusion support.Group 4: SGF with MC or almost recipient-type chimerismhe or the severe cytopenia especially neutropenia for more than 1 month,or the extremely neutropenia over 2 weeks.Results:Among the 287 patients,229(79.8%)were continuous completely donor chimerism and 58(20.2%)were decreased chimerism after transplantation.The median time of decreased chimerism was 3 months(1-23 months).Group 2 had 28 cases,accounting for 9.7%.Group 3 had a total of 20 cases,accounting for 7.0%.There were 10 cases in group 4,accounting for 3.5%.The 2-year overall survival rate between group 1 and group 2 and group 3 had on difference.The 2-year overall survival rate in group 4 was only 20% and lower than group 1,2 and 3(p<0.05).Different contioning regimen might affect the chimerism.The low-intensity contioning regimen was a risk factor for the formation of mixed chimerism after transplantation.Furthermore,the rate of mixed chimerism was high in CTX+ATG contioning regimen after transplantation with an incidence of 53.57%..Different donor transplantation methods also had an effect on the occurrence of mixed chimerism of donor and recipient after transplantation.The incidence of MC after matched related transplantation was significantly higher than Matched unrelated and haploid transplantation(33.0%),and 2 patients died after SGF.Haploid transplantation had a lower incidence of mixed chimerism than MSD and MUD,but a higher incidence of SGF.SAA patients after allo-HSCT with mixed chimerism could return to complete donor chimerism throug adjustment of immunosuppressive agen timely.Infusing donor stem cell,mesenchymal stem cells(MSC),or umbilical cord blood(UCB)stem cells were used for the treatment of progressive mixed chimerism or secondary graft failure.Among 11 patients underwent DSI or MSC infusion with or without UCB,6 patients had hematological recovery with an effective rate of54.5%.Conclusions:SGF was associated with early(+3 months)presence of MC,and the increasing levels of recipient chimerism.Some patients with stable mixed chimerism after SAA transplantation could maintain effective hematopoiesis.The donor/recipient sex-mismatching was a high risk factor for MC.The aplastic aneamia patients who received reduced intensity conditioning regimen were more likely to achieve MC.SAA patients after allo-HSCT with mixed chimerism could return to complete donor chimerism throug adjustment of immunosuppressive agen timely.DSC,MSC with or without UCB infusion may effective for some patients with progressive mixed chimerism.Secondary transplantation was the only effective way for the treatment of secondary graft failure patients. 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