| Background:Aplastic anemia (AA) is a bone marrow disorder that is characterized by pancytopenia with hypocellular bone marrow, and the most common symptoms are anemia, haemorrhage and fever or infections repeatedly. According to guidelines for the diagnosis and management of AA (British), AA is classified into severe AA (SAA), very SAA and non-SAA (NSAA). SAA and VSAA have the highest fatality if untreated, with the majority of deaths 1-2 years after diagnosis, from infections and/or hemorrhagic complications. Immunosuppressive therapy (1ST) and hematopoietic stem cell transplantation (HSCT) are the front-line treatment of AA.The standard immunosuppressive regimen is a combination of antithymocyte globulin (ATG) and cyclosphorine A.1ST is recommended for patients with NSAA who are transfusion dependent or patients with severe or very severe disease who are>40 years old or younger patients with severe or very severe disease who do not have an HLA-identical sibling donor. Its curative effect is mainly affected by low remission rate, long waiting time for efficacy, high recurrence rate, low remission rate, multiple clonal evolution et al.risk factors. While HSCT, which began in 1970s, is the only current treatments can be completely cured AA and its long-term remission rate was only 50%. The major causes of death are graft failure (GF) and graft-versus-host disease (GVHD) in allo-HSCT. With the development of transplantation technology progress, allogeneic HSCT (allo-HSCT) can acquire 75-90% chance of long-term cure for patients, who are young than 40 years, with SAA if an HLA-matched sibling donor (MSD) is available.Data from the European Group for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research suggest approximately 60% of HLA-MSD transplantations for SAA use PBSC grafts at present. Data from some centers have shown that PBSC transplantation (PBSCT) from MSDs have faster neutrophil and platelet engraftment compared to bone marrow transplantation (BMT) in patients with SAA. However, the Aplastic Anemia Working Party of the EBMT (WPSAA) has demonstrated that compared with BMT from MSDs for SAA, PBSCT is associated with higher risks of GVHD, in particularly chronic GVHD (cGVHD), which contribute to inferior OS. These findings demonstrate that BMT and PBSCT have their own advantage. In recent years, several centers have conducted allo-HSCT for SAA using PBSC combined with bone marrow (BM) as grafts, increasing stem cell dose, in an attempt to acquire faster hematological recovery and reduce acute GVHD (aGVHD) and cGVHD, and reducing death from infection and GVHD. So, what is the efficacy of PBSC combined BM transplant for patients with SAA. And compared with PBSCT, whether the quality of life will be improved by reducing rate of GVHD or improve OS after PBSC combined BM transplant. It is worthwhile to validate and discuss.According to statistics, currently only less than 30% of patients were able to find the HLA matched sibling donor. Along with the increasing of the one-child families, the numbers of patients who can accept sibling donor transplant si gradually reduce. However, with the conditioning regimen and relative technologies is improve for unrelated donor HSCT (UD-HSCT) and haploidentical HSCT (Haplo-HSCT), the long-term survival rate of UD-HSCT is up to 50%-80%, especially in the young patients undergoing HLA matched unrelated donor HSCT (MUD-HSCT) which the 5 year survival is as high as 95%, and the efficacy of Haplo-HSCT aslo has improved. These make the population of SAA patient for HSCT expanding.While SAA patients without matched related donor failing to 1ST, UD-HSCT is one choice of treatment, in particularly the MUD-HSCT. The WPSAA-EBMT have recently analyzed 1448 patients with acquired aplastic anemia, grafted between 2005 and 2009, and compared outcome of MSD (n=940) vs MUD (n=508) transplants (8/8 loci matched and 10/10 loci matched). This study suggests improved outcome of MUD-HSCT for acquired aplastic anemia in recent years. When compared with MSD-HSCT, MUD-HSCT had significantly more acute grade Ⅱ-Ⅳ (25% vs 13%) and significantly more chronic graft versus host disease (26% vs 14%),but not statistically inferior to MSD-HSCT. And In multivariate analysis, the strongest negative predictor of survival was the use of peripheral blood as a stem cell source. However, limited by the relevant policies of domestic, only allow to collect the unrelated donor PBSC as graft which it is undoubtedly constrained the efficacy of UD-HSCT for AA patients. In addition, graft rejection and GVHD are also restricted to the efficacy of UD-HSCT. So, these factors affect the efficacy of HSCT for patients with SAA, especially the unrelated donor derived PBSC as a graft. It there any strategies for improved?While SAA patients without MSD or MUD and failing to 1ST, Haplo-HSCT is one choice of treatment. The widespread existence of donors and fast process for seek a donors are the main advantages of the Haplo-HSCT, but GF, GVHD and immune reconstitution retardation are the main barrier to successful transplantation. At present, the strategies of the depletion T cell of graft for transplantation are being explored, but we hope there till has other strategies for improve the the efficacy of Haplo-HSCT.In recent years, with the study of the biological characteristics of the mesenchymal stem cells (MSCs) deepening, it makes MSCs more and more widely in clinical application. MSCs are essential components of the bone marrow microenvironment. MSCs is a Multipotent non hematopoietic precursor cells and mainly exists in bone marrow, there are also little in the adipose, placenta, fetal liver, umbilical cord blood and so on tissues and organs. The present study shows that MSCs has low immunogenicity, hematopoietic support and immunoregulation properties and has already begun tentatively applied to HSCT in order to improve transplant recipients of bone marrow microenvironment, promote engraftment, prevention or treatment of GVHD. In recent years, several research centers reported study of UD or haploid donor HSCT in combination with MSCs infusion for SAA. Their results show that the combination of MSCs infusion with HSCT is feasible, effective. However, current research reports were the case report or small sample. Therefore, the feasibility and efficacy the strategy of alternative donor (matched or less loci mismatched unrelated donor, sibling donor multilocus mismatched donor or haploid donor) HSCT combined with MSCs infusion for SAA are needed prospective, multi center, large-scale clinical studies to confirme.Objective:To compare matched sibling HSCT using peripheral blood stem cells (PBSC) alone or with bone marrow (BM) for SAA. To investigate the feasibility and efficacy the strategy of alternative donor HSCT combined with MSCs infusion for SAAin order to provide reference for selecting sources of stem cells and improving alternative donor transplantation strategy for SAA.Methods:(1) we performed a retrospective multicenter (Guangzhou General Hospital of Guangzhou Military Command, The First Affiliated Hospital, Sun Yat-sen University, the Third Affiliated Hospital of Sun Yat-sen Universit, Sun Yat-Sen Memorial Hospital, Nanfang Hospital and Zhujiang Hospital) analysis of 65 SAA patients who received allogeneic HSCT (allo-HSCT) from 2003 October to 2014 January.33 patients received PBSC and BM, and 32 received PBSC. The conditioning regimen was cyclophosphamide+antithymocyte globulin±fludarabine±busulfan, and graft-versus-host disease (GVHD) prophylaxis was cyclosphorine A+short time methotrexate±mycophenolate mofetil (MMF). Median infusion dose of CD34+was 5.70×106/kg in the PBSC+BM cohort and 4.80×106/kg in the PBSC cohort. (2) Performing a prospective multicenter in 22 evaluable patients with SAA or VSAA who received HSCT from 2013 May to 2015 March in Guangzhou General Hospital of Guangzhou Military Command and Guangzhou First People’s Hospital. Diagnostic criteria is or similar to the standard of Camitta. Twenty-two patients received related donors HSCT (≥ 8/8 loci matched related donor but not MSD) or UD-HSCT(≥8/8 loci matched unrelated donor).All patients gave informed consent and signed informed consent. Eighteen of 22 patients are SAA,4 are VSAA. The median age of 22 patients was 29(8-58). Nineteen of 22 patients received related donors HSCT and 3 received UD-HSCT. In related donors HSCT, the conditioning regimen is BU+CTX+ATG, GVHD prophylaxis is cyclosphorine A +shor time methotrexate+MMF and using PBSC combined with BM or PBSC as grafts. In UD-HSCT, the conditioning regimen is Flu+CTX+ATG, GVHD prophylaxis is cyclosphorine A+shor time methotrexate and using PBSC as grafts. Median infusion dose of CD34+was 4.28 (0.47～11.15)×10^6/kg, and intravenous infusion of the third party donor BMSCs on the day of transplantation and 14 days after transplantation with a median infusion dose 1～10÷10^6/kg, respectively. (3) Analyses were done with SPSS version 13.0 (Chicago, IL, USA). The χ2 test or Fischer’s exact test was used for categorical variables and the nonparametric Mann-Whitney U test for continuous variables. Kaplan-Meier method and log-rank test were used to determine OS from transplant to death and EFS from transplant to severe events. All statistical tests were two-sided, with P<0.05 indicating statistical significance.Results:(1) The median time of neutrophil and platelet engraftment were 14 and 12 days,18 and 19 days in the PBSC+BM and PBSC cohorts (P=0.123, P=0.818, respectively). Graft failure was not significantly affected by stem cell sources:3.0%in the PBSC+BM and 9.1% in the PBSC cohort. Compared with using PBSC alone, allo-HSCT using PBSC+BM contributed to lower incidences of acute GVHD (aGVHD) (21.9 vs 3.0%, p=0.027) and poor graft function (PGF) (28.1 vs 6.1%, p=0.023). Although allo-HSCT using PBSC+BM or using PBSC alone yielded similar overall survival (90.9 vs 84.4%, p=0.493), a superior event-free survival (EFS) was observed in PBSC+BM cohort (81.8 vs50.0%, p=0.026). (2) In 22 evaluable patients, no vital signs abnormal and liver, kidney and heart damage related adverse reaction after BMSCs infusion. All patients acquired hematopoietic engraftment. The median time of neutrophil and platelet engraftment was 12 (8-17)and 15.6 (9～37)days, respectively. Of the 22 patients,12 (54.5%) cases had no aGVHD,5 (22.7%) cases had grade 1,3 (13.6%) cases had grade Ⅱ,2 (9.1%) cases had grade III, no case have grade FV aGVHD. And 18 patients survival more than 100 days after transplantation,4 (22.2%) cases had cGVHD and 1 of 4 had the extensive cGVHD. CMV and EB virus infection rate increased after transplantation. Seventeen (77.3%) cases had cytomegalovirus infection, EB virus infection in 12 (54.5%) cases. The transplantation related mortality (TRM) at+100 day,+6 months and+1 years was 18.2%,22.8% and 27.3%, respectively. A total of 16 patients have survived at a median follow-up of 278 days (range30-605) with an OS rate of 72.7%.Conclusion:Our results suggested that SAA patients may benefit from allo-HSCT using PBSC+BM from matched sibling donors by rapid hematological engraftment, superior EFS, and reduced incidence of aGVHD and PGF. The strategy of alternative donor HSCT combined with MSCs infusion is feasibility and qcuired acceptable results, but need to be wary of virus infection after transplantation. |
PDF Full Text Request