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OBJECTIVE To systematically evaluate the efficacy and safety of eltrombopag combined with immunosuppressive therapy （IST） for severe aplastic anemia （SAA）， and to provide evidence-based basis for clinical treatment of SAA. METHODS Retrieved from PubMed， Embase， Cochrane Library， ClinicalTrials.gov， VIP， CNKI and Wanfang data， randomized controlled trials （RCTs） and cohort studies about eltrombopag combined with IST （trial group） versus IST alone （control group） were collected from the inception to May 2023. After data extraction and quality evaluation （Cochrane manual 5.1.0） of included studies， meta-analysis， subgroup analysis， sensitivity analysis and publication bias analysis were performed by using RevMan 5.4 software. RESULTS A total of 12 studies were screened， including 1 344 patients. Compared with control group， objective remission rate （ORR） （RR＝1.34， 95%CI was 1.06-1.69， P＝0.01） and complete response rate （CRR） （RR＝1.88， 95%CI was 1.31-2.71， P＝ 0.000 6） at 3 months， ORR （RR＝1.33，95%CI was 1.23-1.43， P＜0.000 01） and CRR （RR＝1.88，95%CI was 1.57-2.25，P＜0.000 01） at 6 months were significantly increased in trial group. There was no statistically significant difference between the two groups in ORR （RR＝0.99， 95%CI was 0.82-1.18， P＝0.88） and CRR （RR＝1.02， 95%CI was 0.78-1.34， P＝0.87） at 12 months， two-year overall survival （OS） rate （HR＝0.61， 95%CI was 0.31-1.22， P＝0.17）， two-year event-free survival （EFS） rate （HR＝0.81， 95%CI was 0.61-1.07， P＝0.14）， clone evolution rate（RR＝1.01， 95%CI was 0.51-2.00， P＝ 0.98） or the incidence of adverse drug reactions such as liver/renal insufficiency， rash （P＞0.05）. Results of subgroup analysis showed that ORR and CRR of trial group at 6 months were higher than those of the control group in RCT and the cohort study subgroups （P＜0.05）. There was no statistically significant difference in the two-year OS rate， two-year EFS rate or clone evolution rate between trial group and control group in the two subgroups （P＞0.05）. The results of sensitivity analysis and publication bias analysis showed that the results of this study were robust and the possibility of publication bias was small. CONCLUSIONS The addition of eltrombopag in the IST regimen of SAA can improve the early hematological remission rate of patients， has no significant impact on short-term survival， and will not increase the occurrence of adverse drug reactions and clonal evolution.
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Severe aplastic anemia (SAA) is a severe bone marrow failure syndrome caused by multiple causes, which is clinically manifested with severe anemia, infection and bleeding. The complex pathogenesis of SAA has not been fully understood. SAA is characterized with acute onset, severe disease condition and rapid progression. At present, with the in-depth study of SAA and the improvement of diagnosis and treatment, the therapeutic strategy for SAA has been evolved from classical immunosuppressive therapy based on antithymocyte globulin and cyclosporine to the application of thrombopoietin receptor agonist and combined treatment based on allogeneic hematopoietic stem cell transplantation, which may promote the reconstruction of hematopoietic function of SAA patients to varying degree and significantly improve survival and clinical prognosis, becoming the research hotspot of SAA treatment. In this article, new advances in the treatment of SAA at home and abroad were reviewed.
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OBJECTIVE@#To compare the efficacy of eltrombopag combined with cyclosporine A (CsA) and CsA alone in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).@*METHODS@#The clinical data of 76 patients with treatment-naive TD-NSAA in Ningde Municipal Hospital of Ningde Normal University and Affiliated Hospital of Nantong University from December 2017 to June 2021 were retrospectively analyzed. Among them, 45 cases were treated with eltrombopag combined with CsA, and 31 patients with compatible baseline characters were treated with CsA alone. The efficacy of patients between the two groups was compared, and the factors affecting the curative effects were also analyzed.@*RESULTS@#There were significant differences in hematological response (HR) and complete response(CR) rates between the two groups at 3, 6, 12 months, and follow-up endpoint of treatment (P<0.05). With the prolongation of eltrombopag treatment time, the curative effect increased gradually, and the patients achieved more CR and HR rates by the end of the follow-up period. Simultaneously, with the increase in the maximum stable dose of eltrombopag, the HR rate increased gradually. The megakaryocyte count in eltrombopag group was higher than that in control at 6 and 12 months (P<0.05). Compared with the control group, the median time of platelet transfusion independence in eltrombopag group was more shorter (P=0.018), and the median platelets transfusion volume was lower (P=0.009). At 3, 6, 12 months after eltrombopag, the change of platelet in eltrombopag group was higher than that in the control group (P<0.05). Analysis of related factors affecting the efficacy showed that sex, age, iron overload, platelet count before treatment had no effect on the efficacy, and the median maximum stable dosage and the administration period for eltrombopag were related to the curative effect. The patients of eltrombopag group experienced adverse events of varying degrees, but the reactions were mild and mostly tolerated.@*CONCLUSION@#Eltrombopag can effectively improve the hematopoietic response and promote platelet recovery for TD-NSAA patients with relatively more residual hematopoietic cells, and it is safe and well tolerated.
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Humans , Anemia, Aplastic/therapy , Retrospective Studies , Treatment Outcome , Cyclosporine/therapeutic use , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic useABSTRACT
OBJECTIVE@#To investigate the recovery characteristics of T cell subsets in patients with severe aplastic anemia (SAA) who received haploid hematopoietic stem cell transplantation(HSCT) and its relationship with acute graft-versus-host disease(aGVHD).@*METHODS@#The clinical data of 29 SAA patients who received haploid hematopoietic stem cell transplantation in the department of hematology, Shanxi Bethune Hospital from June 2018 to January 2022 were retrospectively analyzed. The absolute counts of CD3+T, CD4+T, CD8+T lymphocytes and the ratio of CD4+T/CD8+T lymphocytes in all patients before transplantation, 14, 21, 30, 60, 90 and 120 days after transplantation were analyzed. The proportion of T lymphocytes was compared in the non-aGVHD group, the grade Ⅰ-Ⅱ aGVHD group and the grade III-IV aGVHD group.@*RESULTS@#The counts of all T cells in 27 patients were far below the normal level at 14 and 21 days after transplantation, but there was obvious heterogeneity. There was a certain relationship between T cell immune reconstitution and conditioning regimen, age, and immunosuppressive treatment before transplantation. CD3+T cells showed a steady upward trend at 30, 60, 90, and 120 days after transplantation, and returned to the normal levels at 120 days after transplantation; faster recovery of CD4+T cells was closely related to aGVHD, which was at 30, 60, 90, 120 days after transplantation showed a slow upward trend, and which was still far below the normal level of 120 days after transplantation. CD8+T cell counts began to recover at 14 and 21 days after transplantation, and the recovery was earlier than the CD4+T cells, and its recovery speed was rapid 30 and 60 days after transptantation, which showed an upward trend and exceeded the normal levels 90 days after transplantation. Since CD8+ T cells reconstituted quickly, while the CD4+ T cells reconstitution was slowly, which made the long-term CD4+T/CD8+T cell ratio after transplantation was inverted . Compared with the non-aGVHD group, the absolute counts of CD3+T, CD4+T, and CD8+T cells in the aGVHD group were significantly higher than those in the non-aGVHD group at each time period after transplantation. In the aGVHD group, grade Ⅲ-Ⅳ aGVHD occurred more frequently in the early post-transplantation period (within 14-21 days), the grade Ⅰ-Ⅱ aGVHD group mostly occurred within 30-90 days after transplantation, and CD3+T, CD4+T, CD8+T cell counts in the grade Ⅲ-Ⅳ aGVHD group were significantly higher than those in the grade Ⅰ-Ⅱ aGVHD group; and the greater the proportion of CD4+T, the more severe the degree of aGVHD.@*CONCLUSION@#The speed of T cell immune reconstitution after SAA haploid transplantation is different, which is related to the conditioning regimen, age, and immunosuppressive therapy before transplantation. The rapid recovery of CD4+ T cells is closely related to the occurrence of aGVHD.
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Humans , Anemia, Aplastic/therapy , CD8-Positive T-Lymphocytes , Retrospective Studies , Haploidy , Hematopoietic Stem Cell Transplantation , Graft vs Host DiseaseABSTRACT
The main purpose of our study was to evaluate the efficacy and safety of eltrombopag plus cyclosporine A (CsA) in transfusion-dependent non-severe aplastic anemia(TD-NSAA). The clinical characteristics of 13 TD-NSAA patients who received initial treatment of eltrombopag plus CsA from 2019 to 2021 were retrospectively analyzed. The 3-month overall hematological response (OR) rate was 12/13. Until the end of follow-up, 12 patients responded, among whom 2 patients reached complete response (CR) and 9 patients reached partial response (PR) and 1 with HR. Paroxysmal nocturnal hemoglobinuria (PNH) developed in one patient at 6 months after treatment. Five of thirteen patients reported mild adverse reactions, which were all manageable. Compared with historical data, the combination of eltrombopag with CsA is an effective regimen in patients with TD-NSAA.
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Objective:To explore the efficacy and clinical significance of Eltrombopag combined with immunosuppression therapy(IST) in the treatment of severe aplastic anemia (SAA) in children.Methods:Clinical data of 63 children with initially diagnosed SAA in the Department of Hematology of Xinxiang Central Hospital from May 2017 to June 2019 were retrospectively analyzed.All of them were all donors without siblings and they were classified into observation group (31 cases) and control group (32 cases). Patients in the observation group received IST combined with Eltrombopag treatment, and those in the control group received IST treatment.The Chi- square test was used to compare the overall remission (OR) rate and complete remission (CR) rate at 3 months, 6 months and 12 months, and incidence of infection and significant bleeding between groups.The t-test was used to compare the application of gra-nulocyte colony stimulating factor, the mean red blood cell transfusion, and the mean platelet infusion volume between groups.Kaplan-Meier method was adopted to analyze the 2-year overall survival (OS) rate and failure-free survival (FFS) rate, followed by the Log- rank test. Results:The 3-month and 6-month OR rate of the observation group were 61.29%(19/31 cases) and 80.64% (25/31 cases), respectively, which was significantly higher than that of the control group [37.50%(12/32 cases) and 59.38%(19/32 cases), χ2=45.27, 43.81, respectively, all P<0.05]. The 3-month and 6-month CR rate of the observation group were 32.26%(10/31 cases) and 45.16%(14 /31 cases), respectively, which was significantly higher than that of the control group [15.62%(5/32 cases) and 28.13%(9/32 cases), χ2=47.02, 48.35, respectively, all P<0.05]. The 12-month OR rate and CR rate in the observation group were 83.87%(26/31 cases), and 64.52%(20/31 cases), respectively, which were 81.25%(26/32 cases), and 59.38%(19/32 cases), respectively in the control group, and no significant differences in them were detected between the two groups (all P>0.05). The total amount of granulocyte colony stimulating factors [(13.58±4.28) doses vs.(23.24±6.68) doses, t=2.591], and the mean infusion volume of red blood cells [(5.48±1.67) U vs.(10.58±3.67) U, t=2.040] and platelets (4.15±2.47) bags vs.(9.15±3.87) bags, t=2.744) used in observation group within 6 months of treatment were significantly lower than those of the control group (all P<0.05). The rate of infection (16.13% vs.43.75%, χ2=47.12) and significant bleeding (16.13% vs.37.50%, χ2=44.52) in the observation group were significantly lower than those of the control group (all P<0.05). The 2-year OS rate of the observation group and control group were 93.55% (29/31 cases), and 87.50% (28/32 cases), respectively.No significant difference in the OS rate was found between groups ( P=0.407 3), nor as the 2-year FFS rate(87.10% vs.78.13%, P=0.326 6). Conclusions:IST combined with Eltrombopag can significantly improve the early treatment response rate of SAA children without a sibling identical donor, which can reduce red blood cell and platelet transfusion, and the incidence of infection and bleeding.
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OBJECTIVE@#To evaluate the clinical effect of haploid allogeneic hematopoietic stem cell transplantation(haplo-HSCT) in the treatment of severe aplastic anemia (SAA), and to explore the efficacy different between post-transplant cyclophosphamide (PT/Cy) and standard-dose ATG.@*METHODS@#The clinical data of 38 patients with SAA in our hospital from January 2012 to December 2019 were collected and retrospectively analyzed. The efficacy was evaluated. The patients with haplo-HSCT were divided into low-dose ATG combined with PT/Cy group and standard-dose ATG group, and the blood cell hematopoietic reconstruction time, GVHD incidence, mortality and survival time of the patients in the two groups was compared.@*RESULTS@#Among the 32 patients, hematopoietic reconstitution were detected in 9375%(30/32) recipients. The median time of neutrophil and platelet engraftment was 15(10-22) days and 13(7-30) days, respectively. The incidence of GVHD was 21.89%, the incidence of infection was 93.75%, and the 2-year overall survival rate was 84.38%. The hematopoietic reconstitution time, incidence of GVHD, mortality rate and survival time were no statistical differences between the patients in the two groups(all P>0.05).@*CONCLUSION@#Haplo-HSCT is an effective method for the treatment of SAA，low-dose ATG combined with PT/Cy can lighten the economic burden on patients, it would be a feasible treatment plan for SAA with light side effect.
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Humans , Anemia, Aplastic/therapy , Cyclophosphamide , Graft vs Host Disease , Haploidy , Hematopoietic Stem Cell Transplantation , Retrospective Studies , Transplantation ConditioningABSTRACT
Objective:To compare the clinical outcomes and safety of haploidentical donor (HID)and HLA-matched sibling donor(MSD)hematopoietic stem cell transplantation(HSCT)for severe aplastic anemia(SAA).Methods:From January 1, 2012 to December 31, 2019, retrospective review of clinical data was performed for 75 SAA patients undergoing HSCT at Department of Hematology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.Based upon donor sources, they were divided into two groups of MSD(49 cases)and HID (26 cases). And two groups were compared with regards to hematopoietic recovery, graft-versus-host disease(GVHD)infection and overall survival(OS).Results:Time of platelet and neutrophil engraftment of two groups was comparable(11 d vs.11 d, P=0.84; 11 d vs.12 d, P=0.08). Compared with HID group, MSD group had a lower incidence of acute GVHD(46.2% vs.18.4%, P=0.01)with a comparable incidence of grade Ⅱ-Ⅳ acute GVHD(26.9% vs.14.3%, P=0.24), grade Ⅲ-Ⅳ acute GVHD(15.4% vs.4.1%, P=0.09)and chronic GVHD(23.9% vs.23.1 %, P=0.71). A reactivation of CMV occurred in 27(55.1%)MSD and 22(84.6%)HID recipients( P=0.01). And the incidence of EB viremia was 69.4% and 61.5% respectively.After a median follow-up period of 54.0 and 18.5 months, the estimated 3-year OS rate of MSD and HID groups were 94.0% and 88.0% respectively ( P=0.35). Conclusions:HID HSCT is an effective and relatively safe option for SAA patients, especially for those in urgent need of treatment without MSD or refractory/relapse to immunosuppressive therapy.
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Haploidentical hematopoietic stem cell transplantation is a recommended alternative therapy for children with severe aplastic anemia who lack a human leukocyte antigen (HLA)-identical sibling donor and do not respond well to immunosuppressive therapy; however, due to non-identical HLA, the patients may have donor-specific anti-HLA antibody, which may lead to a relatively high incidence rate of poor graft function. Compared with HLA-identical transplantation, conditioning regimen for haploidentical transplantation still needs to be explored. This article reviews the detection and treatment of donor-specific anti-HLA antibody, the selection of conditioning regimen, and the mechanism and treatment of poor graft function in haploidentical hematopoietic stem cell transplantation.
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Child , Humans , Anemia, Aplastic/therapy , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Transplantation, HomologousABSTRACT
Severe aplastic anemia II (SAA-II) progresses from non-severe aplastic anemia (NSAA). The unavailability of efficacious treatment has prompted the need for haploidentical bone marrow transplantation (haplo-BMT) in patients lacking a human leukocyte antigen (HLA)-matched donor. This study aimed to investigate the efficacy of haplo-BMT for patients with SAA-II. Twenty-two patients were included and followed up, and FLU/BU/CY/ATG was used as conditioning regimen. Among these patients, 21 were successfully engrafted, 19 of whom survived after haplo-BMT. Four patients experienced grade II-IV aGvHD, including two with grade III-IV aGvHD. Six patients experienced chronic GvHD, among whom four were mild and two were moderate. Twelve patients experienced infections during BMT. One was diagnosed with post-transplant lymphoproliferative disorder and one with probable EBV disease, and both recovered after rituximab infusion. Haplo-BMT achieved 3-year overall survival and disease-free survival rate of 86.4% ± 0.73% after a median follow-up of 42 months, indicating its effectiveness as a salvage therapy. These promising outcomes may support haplo-BMT as an alternative treatment strategy for patients with SAA-II lacking HLA-matched donors.
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Humans , Anemia, Aplastic/therapy , Bone Marrow Transplantation , Graft vs Host Disease , HLA Antigens , Hematopoietic Stem Cell Transplantation , Transplantation ConditioningABSTRACT
Objective To evaluate the safety and efficacy of an further optimized pretreatment protocol for the treatment of severe aplastic anemia (SAA) by haploidentical peripheral hematopoietic stem cell transplantation. Methods From July 2009 to July 2019, 26 SAA patients in the Affiliated Hospital of North China University of Technology were treated with haploidentical peripheral blood stem cell transplantation. The "Beijing protocol" of haploid transplantation for treating SAA is modified busulfan (BU)/cyclophosphamide (CY) + rabbit anti thymocyte globulin (ATG) regimen. We based on it and further refined it. Here's how it works: (1) According to the different volumes of hematopoietic tissue in bone marrow biopsy before transplantation, different methods for clearance of residual hematopoietic cells were established in SAA patients. If bone marrow hematopoietic tissue volume<10%, the bone marrow was pretreated with Beijing protocol of BU/CY+ATG. If 10% ≤ bone marrow hematopoietic tissue volume ≤25%, the dose of BU for 1 day was added on the basis of the original protocol: Increase the dose of BU to 9.6 mg/kg (intravenous drip in 3 days), which became a modified BU/CY+ATG transplantation preconditioning protocol. (2) According to the diagnosis of the disease, the transplantation pretreatment was designed: Patients with SAA-PNH syndrome or with PNH alone were treated with further modified BU/CY+ATG transplantation preconditioning protocol, and the BU dose was set as 9.6 mg/kg (intravenous drip in 3 days). Transplantation way: The "Beijing protocol" is use of bone marrow plus peripheral blood hematopoietic stem cell. Based on it, the protocol was modified to simple peripheral blood hematopoietic stem cell transplantation. Results 22 of 26 SAA patients underwent hematopoietic reconstruction. The patients were followed up until December 2019, and the results were as follows: During a median follow-up period of 48 (5-122) months, 5 patients died, 4 of whom suffered transplant-related deaths (15.4%, 4/26), and 1 of whom was due to central nervous system infection (3.8%, 1/26). The 3-year overall survival rate (OSR) was 84.2%, the 3-year progression-free survival (PFS) was 72.6% (SAA I: 100.0%, SAA-PNH: 100.0%, SAA II: 72.2%). Conclusions The further improved BU/CY+ATG transplantation preconditioning scheme is safe and effective in SAA with haploid peripheral blood stem cell transplantation. It is suitable not only for SAA I, SAA II, but also for patients with PNH clone, thus being worth wider clinical aplplication.
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BACKGROUND: Allogeneic hematopoietic stem cell transplantation is still the only cure method for acquired severe aplastic anemia. How to select patients for treatment has become a research hotspot in recent years. OBJECTIVE: To review the progress of allogeneic hematopoietic stem cell transplantation from three aspects: HLA full-phase matched unrelated donor hematopoietic stem cell transplantation (MUD-HSCT), unrelated cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (HID-HSCT). METHODS: Literatures on allogeneic hematopoietic stem cell transplantation for severe aplastic anemia collected in PubMed, CNKI full-text database and WanFang database from 2000 to 2018 were retrieved with the keywords “unrelated donor; haploidentical; unrelated cord blood; severe aplastic anemia” in Chinese and English. RESULTS AND CONCLUSION: MSD-HSCT is the first-line treatment for severe aplastic anemia, but in view of China’s special national conditions, HLA matched donor is not easy to find. As an important alternative treatment, MUD-HSCT is close to MSD-HSCT. However, the incidence of graft versus host disease and severe infection after MUD-HSCT is still higher than that after MSD-HSCT. It is still necessary to consider multiple factors when choosing MUD-HSCT treatment. Umbilical cord blood hematopoietic stem cells are widely used because of their abundant sources and high match success rate. The probability of UCBT is very high when the amount of pre-frozen total nucleated cells is more than 3.9×107/kg. However, in view of the delay of UCBT and immune function reconstruction, unless other transplantation methods are not feasible in clinical treatment of severe aplastic anemia and immunosuppressive therapy fails in the first course of treatment, UCBT should not be considered. HID-HSCT has the advantages of easy access and good compliance of donors and is close to full-matched transplantation. It has become an important alternative to transplantation. The use of baliximab and/or antithymocyte globulin is expected to reduce the incidence of graft versus host disease and expand the clinical application of HID-HSCT.
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Severe aplastic anemia (SAA) is a rare type of bone marrow hematopoietic failure, which is associated with toxic T lymphocyte-based immune dysfunction, abnormal hematopoietic microenvironment and damage of hematopoietic stem cells in patients. SAA characterized by acute onset, rapid progression and high mortality rate, which requires rapid and stable recovery of the patients' hematopoietic function. In this article, the therapeutic progresses on immunosuppressive therapy (IST), sibling human leukocyte antigen (HLA)-matched allogenetic hematopoietic stem cell transplantation (allo-HSCT), replacement of donor hematopoietic stem cell transplantation and unrelated umbilical cord blood hematopoietic stem cell transplantation (UCBT) for SAA were reviewed.
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Objective To evaluate the effect of pretransplant iron overload on the clinical efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). Methods Clinical data of 80 SAA recipients who underwent allo-HSCT for the first time were retrospectively analyzed. According to the incidence of iron overload, all recipients were divided into the iron overload group (n=20) and non-iron overload group (n=60). The engraftment rate, incidence of postoperative complications and clinical prognosis of the recipients afterallo-HSCT were statistically compared between two groups. The influencing factors of 2-year overall survival (OS) and 180 d transplantation related mortality (TRM) were analyzed by Cox proportional hazards regression model. Results The engraftment rate of neutrophils in the non-iron overload group was 98% (59/60), significantly higher than 75% (15/20) in the iron overload group (P < 0.05). The engraftment rate of platelet in the non-iron overload group was 90% (54/60), significantly higher than 65% (13/20) in the iron overload group (P < 0.05). The incidence rate of bloodstream infection in the non-iron overload group was 23% (14/60), remarkably lower than 40% (8/20) in the iron overload group (P < 0.05). The 180 d TRM of the recipients in the non-iron overload group was 17%, significantly lower than 45% in the iron overload group (P < 0.05). The 1- and 2-year OS of the recipients in the non-iron overload group were 82% and 80%, significantly higher than 50% and 44% in the iron overload group (both P < 0.05). Iron overload or not was an independent risk factor of the OS and TRM of the recipients (both P < 0.05). Conclusions Iron overload can affect the OS and TRM of SAA patients after allo-HSCT.
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OBJECTIVE@#To observe the therapeutic effect of tetramethylpyrazine on immune-mediated bone marrow failure (BMF) induced by different doses of X-ray exposure in C57 mice.@*METHODS@#C57BL6 mice were randomized into 4 groups, including a blank control group and 3 X-ray exposure groups with X-ray exposure at low (5.0 Gy), moderate (5.75 Gy), and high (6.5 Gy) doses. After total body irradiation with 0.98 Gy/min X-ray. The mice as recipient received injections of 4×10 lymphocytes from DBA/2 mice via the tail vein within 4 h. The survival rate of the recipient mice, peripheral blood cell counts, bone marrow nucleated cell count, and bone marrow pathology were examined at 14 days after the exposure. In the subsequent experiment, C57 mice were exposed to 5.0 Gy X-ray and treated with intraperitoneal injection of tetramethylpyrazine at the low (5 mg/mL), moderate (10 mg/mL), or high (20 mg/mL) doses (12 mice in each group) for 14 consecutive days, and the changes in BMF were observed.@*RESULTS@#X-ray exposure, especially at the high dose, resulted in significantly lowered survival rate in the mouse models of BMF at 14 days. As the X-ray dose increased, the mice showed significantly reduced peripheral blood counts of red blood cells, white blood cells, platelets and lowered bone marrow nucleated cell counts with obvious bone marrow congestion and reduction of nucleated cells ( < 0.05 or 0.001). In the mice exposed to 5.0 Gy X-ray, tetramethylpyrazine at the high dose most obviously increased bone marrow nucleated cells ( < 0.01) and red blood cells ( < 0.001), and even at the low dose, tetramethylpyrazine significantly increased the counts of white blood cells ( < 0.05) and platelets ( < 0.01) following the exposure. Tetramethylpyrazine dose-dependently alleviated bone marrow hyperemia, increased bone marrow nucleated cell counts, and lowered Fas protein expression in the bone marrow.@*CONCLUSIONS@#X-ray irradiation at 5.0 Gy is suitable for establish mouse models of immune-mediated BMF. Tetramethylpyrazine promotes bone marrow repair by regulating Fas cell apoptosis signals, which further expands the traditional Chinese medicine theory of "removing blood stasis to create new."
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Animals , Mice , Bone Marrow , Mice, Inbred C57BL , Mice, Inbred DBA , Pyrazines , Whole-Body IrradiationABSTRACT
Objective@#To investigate the efficacy of haplotype hematopoietic stem cell transplantation in the treatment of acquired severe aplastic anemia (SAA) in children.@*Methods@#The clinical characteristics of 59 pediatric patients with SAA, including 26 cases VSAA, 37males and 22 females, 47 cases typeⅠ and 12 cases typeⅡ, undrerwent haplo-HSCT in our hospital between December 1st, 2011 and December 1st, 2017 were retrospectively analyzed. Among 59 patients, 56 patients with a median age of 4.5 (1.2-14.8) years and median weight of 43 (12-80) kg underwent their first HSCT and 3 patients underwent their second HSCT. All patients received the following conditioning regimen: busulfan, cyclophosphamide, and rabbit ATG or Bu (–, CTX) , fludarabineand rabbit ATG. The prophylaxis of acute graft versus host disease (aGVHD) was cyclosporine (CsA) , MMF and methotrexate. All patients received bone marrow transfusion on day 01 and peripheral stem cell transfusion on day 02 from haploid donor. The median dose of donor mononuclear cell counts was 15.60 (7.74-21.04) ×108/kg of recipient weight and CD34+ cell counts was 4.86 (3.74-7.14) ×106/kg of recipient weight.@*Results@#Neutrophils and platelets of all 59 children were implanted. The median implantation time of granulocytes and platelets were 13 (10-19) d, 19 (9-62) d, respectively. The incidence of grade Ⅰ-Ⅱ aGVHD was 45.76% (27 cases) and grade Ⅲ/Ⅳ 13.56% (8 cases) , The incidence of chronic GVHD was 8.47% (5 cases) , The incidences of CMV and EBV viremia were 59.32% (35 cases) and 28.81% (17 cases) , respectively. The median follow-up was 30 (8-80) months, 57 patients survived with disease free, 2 patients died of GVHD. Both of the estimated 5-year OS and DFS rates were (96.4±2.5) %.@*Conclusion@#Haplo-HSCT could improve the outcomes of SAA children.
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The efficacy and safety of co-transplantation of unrelated donor peripheral blood stem cells (UD-PBSCs) combined with umbilical cord mesenchymal stem cells (UC-MSCs) in refractory severe aplastic anemia-Ⅱ(RSAA-Ⅱ) were analyzed retrospectively. Fifteen patients with RSAA-Ⅱ underwent UD-PBSCs and UC-MSCs co-transplantation, among whom 14 cases had hematopoietic reconstitution without severe graft versus-host disease (GVHD). The 5-year overall survival rate was 78.57%. Combination of UD-PBSCs and UC-MSCs transplantation could be a safe and effective option for RSAA-Ⅱ.
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Objective@#To evaluate the efficacy and safety of mesenchymal stem cells in allogeneic hematopoietic stem cell transplantation for patients with refractory severe aplastic anemia (R-SAA) .@*Method@#The clinical data of 25 R-SAA patients receiving co-transplantation of mesenchymal stem cells combined with peripheral blood stem cells from sibling donors (10 cases) and unrelated donors (15 cases) from March 2010 to July 2018 in Zhengzhou University Affiliated Tumor Hospital were retrospectively analyzed. Antithymocyte globulin (ATG) treatment was ineffective/relapsed in 11 cases, and cyclosporine (CsA) treatment ineffective/relapsed in 14 cases.@*Results@#There were 13 male and 12 female among these patients. One patient had a primary graft failure, one patient had a poorly engraftment of platelets, and the remaining 23 patients achieved hematopoietic engraftment. The median time of granulocyte engraftment was 12.5 (10-23) days and 15 (11-25) days for megakaryocyte. Incidences of grade Ⅰ/Ⅱ acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) were 37.5% (9/24) and 21.7% (5/23) , respectively. There was no severe GVHD and no severe complications that related to transplantation. 21 of 25 (84%) patients were alive with a median follow-up of 22.9 (1.6-107.8) months. The 5-year overall survival rate after transplantation was (83.6±7.5) %.@*Conclusion@#The combination of mesenchymal stem cells is reliable and safe in the treatment of R-SAA in peripheral blood stem cell transplantation of unrelated donors and sibling donors, which could significantly reduce the incidence of GVHD and severe transplantation-related complications.
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; A i m To explore the effects of tetramethylpyrazine (T M P) on renal oxidative stress in immune-mediated bone marrow failure (B M F) C57 mice. Methods C57 mice were randomly divided into normal control group, total body irradiation group (T B I), model group, TMP low dose group (5 g • L " 1), T M P medium dose group (10 g • L " 1), and T M P high dose group (2 0 g • L " 1) . The B M F model was established by total body irradiation with 5. 0 Gy X-ray and l y m - phocyte infusion. The peripheral blood triline cells, bone marrow nucleated cells, bone marrow pathology, kidney pathology and oxidative stress indexes were observed 14 days later. Results Bone marrow pathology of the model group showed that the bone marrow nucleated cells decreased and the peripheral blood triline cells decreased significantly, indicating that the i m - mune-mediated B M F model was successfully established. Renal pathology of model group showed tubular edema, and the oxidative stress index M DA increased, and the antioxidant stress indicators GSH, SOD, GSHPx decreased, indicating that there was renal oxidative stress damage in BMF mice. After treatment with TMP, there was no obvious abnormality in renal pathology, the oxidative stress index MDA of the kidney decreased and the antioxidant stress index GSH, SOD increased. Immunohistochemistry showed that the expression of HIF-1 a decreased and VEGF existence was observed. Conclusions TMP can alleviate renal oxidative stress injury in immune-mediated BMF mice, which may be related to the regulation of HIF-1 oc/ VEGF expression.
ABSTRACT
ABSTRACT Background: This study investigated the influence of two conditioning regimens on the chimerical status of 104 patients with acquired severe aplastic anemia. Methods: Patients were monitored for at least 18 months after related bone marrow transplantation and reaching partial or complete hematologic recovery. Group I patients (n = 55) received 200 mg/kg cyclophosphamide alone and Group II (n = 49) received 120 mg/kg cyclophosphamide associated with 12 mg/kg busulfan. Patients were classified in three chimerism levels according to the percentage of donor cells in the peripheral blood. Results: Chimerism ≤50% occurred in 36.4% of Group I and none of Group II; chimerism 51-90% was found in 20.0% of Group I and 10.2% of Group II; and chimerism >90% was found in 43.6% of Group I versus 89.8% of Group II. A significant association (p-value < 0.001) was found between conditioning type and chimerism levels. A higher number of infused cells was associated with higher levels of chimerism only in Group I (p-value = 0.013). Multivariate analysis showed that chimerism >90% is associated with the cyclophosphamide plus busulfan conditioning (p-value < 0.001) and higher number of infused cells (p-value = 0.009), suggesting that these factors are predictive of graft outcome. Regarding hematological recovery, higher chimerism levels were associated with higher neutrophil (p-value = 0.003) and platelet counts (p-value < 0.001) in Group I only. These results show that myeloablative conditioning favors full donor chimerism and non-myeloablative conditioning predisposes to mixed chimerism or autologous recovery of hematopoiesis. Conclusion: These data show that autologous recovery depends on the intensity of immunosuppression and that the immunosuppressive function of cyclophosphamide alone can induce this type of hematopoietic recovery.