The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures.Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively.There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years).The median follow-up time was 7 months (1-116 months).Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34 + cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease.Data were analyzed by univariate and multivariate conditional logistic regression analyses.Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%).Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF.Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF.Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years.The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625,95% confidence interval: 1.411-5.347)for each increment in age level.Patients with mismatched blood type (OR=4.051)or CMV infection (OR=9.146)had an increased risk of PGF.We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.
The aim of the present study was to investigate the effect of persistent low-dose iridium-192 (Ir192) exposure on immunological function, chromosome aberration and the telomerase activity of bone marrow mononuclear cells (BMNCs), in order to increase clinical knowledge of the late effects of persistent low-dose Ir192 gamma-ray exposure. Patients (n=54) accidentally exposed to persistent low-dose Ir192 were included in this 10-year follow-up study. Clinical symptoms, peripheral blood, bone marrow, cellular and humoral immune status, chromosome aberrations and the telomerase activity of BMNCs were analyzed in this study. Exposure to low-dose Ir192 resulted in different degrees of clinical symptoms and significantly lowered complement C3 and C4 levels, CD3+, CD4+ and CD8+ T cell levels, the lymphocyte transformation rate and the percentage of natural killer (NK) cells. It also led to increases in peripheral blood and bone marrow abnormality rates, chromosome aberration rate and BMNC telomerase activity. Exposure to persistent low-dose Ir192 radiation resulted in different degrees of immune dysfunction, and abnormalities of blood cells and bone marrow, which recovered within 1-3 years. Chromosome aberrations were observed to take 5-10 years to recover. However, it would take >10 years for the telomerase activity of BMNCs to be reduced to normal levels. A prolonged follow-up time is required in order to monitor clonal proliferative diseases such as leukemia.
For patients with advanced leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), a major obstacle to success, especially in those with a high leukemia cell burden, is relapse of the underlying disease. To improve the outcome of allo-HSCT for refractory leukemia, we investigated the strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosuppressants therapy for graft-versus-host disease (GVHD) during the early stage after transplantation. A total of 51 patients with refractory leukemia (median age, 30.0 years; unfavorable karyotypes, 49%) received fludarabine (Flu) 30 mg/m(2)/day and cytarabine 2 g/m(2)/day (on days -10 to -6), 4.5 Gy total body irradiation (TBI)/day (on days -5 and -4), and cyclophosphamide (Cy) 60 mg/kg/day and etoposide 600 mg/day (on days -3 and -2) for conditioning. Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion to avoid overwhelming GVHD reactions if acute GVHD (aGVHD) did not develop at day +30. All 51 patients developed regimen-related toxicities (13 with grade III-IV); 93.9% of them achieved complete remission by day +30. Median follow-up was 41 months (range, 6.6 to 92.2 months); 5-year overall survival (OS) and disease-free survival (DFS) were 44.6% +/- 8.1% and 38.2% +/- 7.7%, respectively. Thirteen patients relapsed; the 3-year cumulative incidence of leukemia relapse was 33.3%. On multivariate analysis, cytogenetic status was the only significant pretransplantation factor. Survival was better in patients with grade I or II aGVHD than in those without aGVHD. Our data indicate that the sequential strategy of cytoreductive chemotherapy followed immediately by intensified myeloablative (MA) conditioning for allo-HSCT and rapid tapering of prophylactic immunosuppressants for GVHD in the early stage after transplantation has an acceptable toxicity profile and may be a better approach to treating refractory leukemia.
Acute myeloid leukemia (AML) is the most common childhood cancer and is a major cause of morbidity among adults with hematologic malignancies. Several novel genetic alterations, which target critical cellular pathways, including alterations in lymphoid development-regulating genes, tumor suppressors and oncogenes that contribute to leukemogenesis, have been identified. The present study aimed to identify molecular markers associated with the occurrence and poor prognosis of AML. Information on these molecular markers may facilitate prediction of clinical outcomes. Clinical data and RNA expression profiles of AML specimens from The Cancer Genome Atlas database were assessed. Mutation data were analyzed and mapped using the maftools package in R software. Kyoto Encyclopedia of Genes and Genomes, Reactome and Gene Ontology analyses were performed using the clusterProfiler package in R software. Furthermore, Kaplan-Meier survival analysis was performed using the survminer package in R software. The expression data of RNAs were subjected to univariate Cox regression analysis, which demonstrated that the mutation loads varied considerably among patients with AML. Subsequently, the expression data of mRNAs, microRNAs (miRNAs/miR) and long non-coding RNAs (lncRNAs) were subjected to univariate Cox regression analysis to determine the the 100 genes most associated with the survival of patients with AML, which revealed 48 mRNAs and 52 miRNAs. The top 1,900 mRNAs (P<0.05) were selected through enrichment analysis to determine their functional role in AML prognosis. The results demonstrated that these molecules were involved in the transforming growth factor-β, SMAD and fibroblast growth factor receptor-1 fusion mutant signaling pathways. Survival analysis indicated that patients with AML, with high MYH15, TREML2, ATP13A2, MMP7, hsa-let-7a-2-3p, hsa-miR-362-3p, hsa-miR-500a-5p, hsa-miR-500b-5p, hsa-miR-362-5p, LINC00987, LACAT143, THCAT393, THCAT531 and KHCAT230 expression levels had a shorter survival time compared with those without these factors. Conversely, a high KANSL1L expression level in patients was associated with a longer survival time. The present study determined genetic mutations, mRNAs, miRNAs, lncRNAs and signaling pathways involved in AML, in order to elucidate the underlying molecular mechanisms of the development and recurrence of this disease.
Abstract Objectives In patients with very severe aplastic anemia ( VSAA ), neutropenia is prolonged and persistent, resulting in refractory overwhelming infections. Hematopoiesis recovery is urgently needed. Methods Six patients with de novo VSAA lacking HLA ‐identical sibling donors and those who experienced refractory infections underwent haploidentical related donor ( HRD ) hematopoietic stem cell transplantation ( HSCT ) as a first‐line therapy. The conditioning regimen consisted of busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Culture‐expanded allogeneic bone marrow‐derived mesenchymal stromal cells were infused on day 0 and day +14. Results From diagnosis to HSCT , 6 patients experienced a total of 28 episodes of persistent fever, and the median number was 4 (range, 3‐7). All cases developed major bacterial infections and invasive pulmonary fungal infection pre‐ HSCT . The median time from diagnosis to HSCT was 2 months (range, 1‐3.5 months). All patients achieved sustained, full donor chimerism, and the median time of myeloid recovery and platelet engraftment was 13 days (range, 9‐19 days) and 15.5 days (range, 10‐23 days), respectively. One patient died of aGVHD , and 5 patients are alive after a median follow‐up of 21 months (range 17‐40.5). Conclusions Upfront HRD ‐ HSCT may be a safe and promising choice for patients with VSAA in critical situations without suitably matched donors.
Highlights•MSCs ameliorate the thymic function of aGVHD patients.•MSCs repaire damaged thymus, thus the incidence of cGVHD decreases.•MSCs have similar efficacy to aGVHD, but our strategy differs with other literature.AbstractRefractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. Forty-seven patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were given at a median dose of 1 × 106 cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD in the MSC group were lower than those in the non-MSC group (P = .045 and P = .005). The ratio of CD3+CD4+/CD3+CD8+ T cells, the frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs), and the levels of signal joint T cell–receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pretreatment. MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse.
To observe the changes of telomere length and telomerase activity in patients with aplastic anemia (AA), and relationship with immunosuppressive therapy (IST) efficacy, to explore the pathogenesis of AA and the role of telomere length in evaluating immunosuppressive therapy efficacy.71 cases of AA patients between September 2010 and March 2013 were enrolled into this study. 3 ml peripheral blood specimens from this cohort of patients were collected to test the telomere length in peripheral blood mononuclear cell (PBMNC) with flow-FISH and detect telomerase activity with TRAP-PCR-ELISA method.Telomere length and age showed negative correlation (b=-0.387, P=0.001) in normal control, NSAA and SAA + VSAA groups, telomere length became shorter with the growth of age, and normal control group telomere length decreased along with the age growth slightly greater than the other two groups (NSAA, SAA+VSAA). Besides the effect of age on telomere length, no significant difference was observed between NSAA and SAA+VSAA groups (P=0.573), and NSAA, SAA+VSAA (30.957 ± 4.502,29.510 ± 5.911)groups were significantly shorter than normal control group (51.086±10.844) (P<0.01). Telomere length in NR group (25.357±4.848)was significantly lower than normal control group (51.086 ± 10.844) (P=0.005), telomere length in CR(32.808 ± 4.685)/PR groups (30.334±4.464) compared with normal control group had no significant difference (P=0.517, P=0.254). Telomere length below 29.21% obviously decreased outcomes of IST. Telomerase activity had significant difference (χ²=20.385, P<0.01). The telomerase activity had no significant difference in terms of age and gender in three groups, multiple comparison found that telomerase activities in SAA + VSAA (0.324±0.178) (P<0.01), and NSAA (0.234±0.175) groups (P=0.002) were significantly higher than normal control group (0.107±0.083).Telomere length of PBMNC in AA patients was significantly shortened than normal control group with telomerase activity increased, and telomere shorted more apparently in NR group, these patients should adjust the treatment as early as possible. Telomeres could predict the curative effect of IST.
Objective:To observe the level of reticulated platelets(RP) in patients with different hematopathy with the same level of platelet and discuss the significance of RP in recognizing different causes of thrombocytopenic disorders.Method:RP of 15 healthy volunteers,11 new diagnosed patients with idiopathic thrombocytopenic purpura(ITP),10 patients with aplastic anemia(AA),10 thrombocytopenic patients with non-acquired hematopoietic reconstitution after hematopoietic stem cell transplantation and 5 thrombocytopenic patients with acquired hematopoietic reconstitution after hematopoietic stem cell transplantation were measured by flow cytometry.Result:The RP% was significantly higher in patients with ITP and acquired hematopoietic reconstitution after transplantation(P0.01),while RP% had no difference among AA group,non-acquired hematopoietic reconstitution after transplantation group and normal controls(P0.05).Conclusion:Measurement of RP reflects the etiology of thrombocytopenic disorders,especially thrombocytopenia caused by immune factors,and guides for immunosuppressant therapy.
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