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Hematology AND Aplastic anemia [keywords]
- Combined use of Chinese medicine with allogeneic hematopoietic stem cell transplantation for severe aplastic anemia patients. [Journal Article]
- Chin J Integr Med 2014 Dec; 20(12):903-9.
To determine the effect of combined treatment with Chinese medicine (CM) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) on patients with severe aplastic anemia (SAA).Eleven patients were treated with CM plus allo-HSCT. Nine patients received a conditioning regimen consisting of fludarabine (Flu), anti-thymocyte globulin (pig ALG), or anti-lymphocyte globulin (Rabbit ATG) and cyclophosphamide (CY), and two patients received pig ALG and CY. All patients were treated with Kidney (Shen)-reinforcing, blood-activating, and stasis-removing (KBS) herbal preparation beginning at 1 week before transplantation and ending at 8 weeks after transplantation. Chimerism status was assessed by analyzing short tandem repeat (STR) polymorphisms.All patients recovered hematopoietic function and none had graft failure. The median number of days required for the absolute neutrophil count (ANC) increased to >0.5×10(9)/L was 15 days (12-22 days) and for spontaneous platelet recovery to >20×10(9)/L without post-transplantation transfusion was 17 days (15-27 days). Nine patients were long-term survivors and achieved full donor chimerism. The overall cumulative incidence of acute graft versus host disease (GVHD) grades I-II and III-IV was 18.2% (2/11) and 9.1% (1/11), respectively. The overall accumulated incidence of chronic GVHD was 27.3% and all patients had limited chronic GVHD. At a median follow-up time of 32 months (range: 12-97 months), 9 patients were still alive. The estimated 5-year overall survival (OS) rate was 81.8%. The incidence of treatment-related mortality, 2-year post-transplantation, was 18.2%. Two patients died from GVHD after transplantation.Treatment with the KBS formulation may reduce the rate of graft failure and treatment-related mortality and improve the rate of OS in SAA patients with allo-HSCT.
- Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood. [JOURNAL ARTICLE]
- Haematologica 2014 Nov 25.
Refractory cytopenia of childhood is the most common type of childhood myelodysplastic syndrome. Because the majority of children with refractory cytopenia have a normal karyotype and a hypocellular bone marrow, differentiating refractory cytopenia from the immune-mediated bone marrow failure syndrome (very) severe aplastic anemia can be challenging. Flow cytometric immunophenotyping of bone marrow has been shown to be a valuable diagnostic tool in differentiating myelodysplastic syndrome from non-clonal cytopenias in adults. Here, we performed the first comprehensive flow cytometric analysis of immature myeloid, lymphoid cells and erythroid cells, and granulocytes, monocytes, and lymphoid cells in bone marrow obtained from a large prospective cohort of 81 children with refractory cytopenia. Children with refractory cyotopenia had a strongly reduced myeloid compartment, but not as severe as children with aplastic anemia. Furthermore, the number of flow cytometric abnormalities was significantly higher in children with refractory cytopenia than in healthy controls and in children with aplastic anemia, but lower than in advanced myelodysplastic syndrome. We conclude that flow cytometric immunophenotyping could be a relevant addition to histopathology in the diagnosis of refractory cytopenia of childhood. The multi-center studies EWOG-MDS RC06 and EWOG-MDS 2006 are registered with ClinicalTrial.gov identifiers NCT00499070 and NCT00662090.
- [Increasing peripheral blood neutrophils after G-CSF treatment is a predictor of early response to immunosuppressive therapy in severe aplastic anemia]. [English Abstract, Journal Article]
- Zhonghua Xue Ye Xue Za Zhi 2014 Nov; 35(11):974-9.
To testify whether absolute neutrophil count (ANC) response to preimmunosuppressive-therapy (pre-IST) granulocyte-stimulating factor (G-CSF) treatment could predict early response to IST in severe aplastic anemia (SAA).Clinical data and hematologic response of 125 SAA patients treated with antithymocyte globulin (r-ATG) combined with cyclosporine were retrospectively analyzed. Correlation of ANC response to pre-IST G-CSF treatment and early response to IST were statistically analyzed, and receiver operating characteristic (ROC) curve was used to estimate the value of increased ANC (∆ANC) in predicting early IST response.The hematologic response (HR) rate to IST in ANC reponded patients was significantly higher than non-responded group (3-month HR 49.0% vs 28.9%, P=0.023; 6-month HR 61.2% vs 40.8%, P=0.026). With ∆ANC≥0.5×10⁹/L as cutoff level, the best point to predict early IST response was 10 days after G-CSF (d 10). Response of ANC to pre-IST G-CSF treatment at d 10 was among the independent factors of predicting 3-month (P=0.004), but not for 6-month response to IST. The overall 5-year survival rate was 92.8% and 69.5% in ANC responded and non-responed groups, respectively (P=0.025).Responding to pre-IST G-CSF treatment reflected the residual bone marrow hematopoiesis, and could act as a convenient and practical predictor to early IST response as well as long-term survival in SAA.
- Cotransplantation of human umbilical cord mesenchymal and haplo-hematopoietic stem cells in patients with severe aplastic anemia. [JOURNAL ARTICLE]
- Cytotechnology 2014 Nov 19.
To evaluate the efficacy and safety of cotransplantation of human umbilical cord mesenchymal stem cells (UC-MSCs) and haploidentical hematopoietic stem cells (HSCs) and to determine the correlation factors affecting incidence of graft versus host disease (GVHD) in patients with severe aplastic anemia (SAA), twenty-four SAA patients received haploidentical HSCs and UC-MSCs co-transplantation. Grafts came from a combination of granulocyte colony stimulating factor (G-CSF)-primed bone marrow and G-CSF mobilized peripheral blood stem cell of haploidentical donors, and in vitro expanded third-party donor derived UC-MSCs were employed as the cell graft. The conditioning regimens consisted of rabbit anti-human T-lymphocyte immunoglobulin (ATG), cyclophosphamide and fludarabine with or without busulfan. GVHD was prevented by using cyclosporine A (CSA), ATG, anti-CD25 monoclonal antibody and mycophenolate mofetil. All 24 patients achieved hematopoietic reconstitution. Median time to absolute neutrophil count >2 × 10(9)/L and platelet count >20 × 10(9)/L were 11 and 13 days, respectively. An incidence of 25 % on grade I-II acute GVHD was found while an incidence of 25 % of grade III-IV acute GVHD was seen. Blood type (r = 0.152, P = 0.043) and patient/donor pair (r = 0.541, P = 0.022) were significantly correlated with incidence of cGVHD. Transplantation related mortality was observed in 20.8 % of the cases. Co-transplantation of haploidentical HSCs and hUC-MSCs on SAA was an effective and safe approach in reducing GVHD and transplantation related mortality. The adequate conditioning regimen and early treatment for infection also played a critical role in the success of HSCT.
- Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. [JOURNAL ARTICLE]
- Blood 2014 Nov 18.
The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPC). Most patients respond to immunosuppressive therapies (IST), but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of clonal evolution to -7. All patients had a dominant HSPC clone bearing specific acquired mutations detected in 50 to 90 percent of circulating granulocytes. However, mutations in candidate genes associated with MDS/AML were present in only four cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition prior to the emergence of -7. Single telomere length analysis (STELA) confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML following SAA, and provides a possible mechanism for development of aneuploidy.
- Hematopoietic stem cell transplantation in infants. [JOURNAL ARTICLE]
- Pediatr Blood Cancer 2014 Nov 12.
It is rare for infants, who are less than 365 days old, to receive hematopoietic stem cell transplantation (HSCT). Our objective was to review the indications, survival, and late effects of infants who received HSCT.Between April 1992 and March 2010, a total of 1,363 children underwent HSCT (775 allogeneic [allo]; 588 autologous [auto]) in the Hospital for Sick Children, Toronto. Of these, 51 (3.7%) were infants.Seventeen infants received allo HSCT for a genetic metabolic disorder. The median age at HSCT was 211 days (29-334 days). After median follow-up of 8.9 years (2.9-20.2 years), 12 patients remained alive, representing an overall survival rate of 70%. Infants with non-metabolic disorders (n = 34); 10 (three neuroblastoma [NBL], three brain tumor, two acute meylogenous leukemia [AML], one rhabdomyosarcoma, and one retinoblastoma) received auto HSCT, and 24 (eight hemophagocytic lymphohistiocytosis [HLH], four juvenile meylomonocytic leukemia [JMML], four Wiscott-Aldrych Syndrome [WAS], three acute lymphoblastic leukemia [ALL], two AML, one severe aplastic anemia [SAA], one chronic granulomatous disease [CGD], and one amegakaryocytic thrombocytopenia) received allo HSCT. Their median age at HSCT was 255 days (142-365 days). At median follow-up of 8.7 years (2.5-17.6 years), 26 infants remained alive, representing an overall survival rate of 76%. In the auto HSCT category, eight of 10 infants are long-term survivors. Late effects such as organ dysfunction, endocrinopathy, and secondary tumors were within accepted range.The survival rate of infants who receive HSCT is encouraging. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. [Journal Article]
- Rambam Maimonides Med J 2014 Oct; 5(4):e0028.
Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.
- Increased Bone Marrow (BM) Plasma Level of Soluble CD30 and Correlations with BM Plasma Level of Interferon (IFN)-γ, CD4/CD8 T-Cell Ratio and Disease Severity in Aplastic Anemia. [Journal Article]
- PLoS One 2014; 9(11):e110787.
Idiopathic aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. Immune abnormalities such as decreased lymphocyte counts, inverted CD4/CD8 T-cell ratio and increased IFN-γ-producing T cells have been found in AA. CD30, a surface protein belonging to the tumor necrosis factor receptor family and releasing from cell surface as a soluble form (sCD30) after activation, marks a subset of activated T cells secreting IFN-γ when exposed to allogeneic antigens. Our study found elevated BM plasma levels of sCD30 in patients with SAA, which were closely correlated with disease severity, including absolute lymphocyte count (ALC) and absolute netrophil count (ANC). We also noted that sCD30 levels were positively correlated with plasma IFN-γ levels and CD4/CD8 T-cell ratio in patients with SAA. In order to explain these phenomena, we stimulated T cells with alloantigen in vitro and found that CD30+ T cells were the major source of IFN-γ, and induced CD30+ T cells from patients with SAA produced significantly more IFN-γ than that from healthy individuals. In addition, increased proportion of CD8+ T cells in AA showed enhanced allogeneic response by the fact that they expressed more CD30 during allogeneic stimulation. sCD30 levels decreased in patients responded to immunosuppressive therapy. In conclusion, elevated BM plasma levels of sCD30 reflected the enhanced CD30+ T cell-mediated immune response in SAA. CD30 as a molecular marker that transiently expresses on IFN-γ-producing T cells, may participate in mediating bone marrow failure in AA, which also can facilitate our understanding of AA pathogenesis to identify new therapeutic targets.
- Recent advances in treatment of aplastic anemia. [REVIEW]
- Korean J Intern Med 2014 Nov; 29(6):713-726.
Recent advances in the treatment of aplastic anemia (AA) made most of patients to expect to achieve a long-term survival. Allogeneic stem cell transplantation (SCT) from HLA-matched sibling donor (MSD-SCT) is a preferred first-line treatment option for younger patients with severe or very severe AA, whereas immunosuppressive treatment (IST) is an alternative option for others. Horse anti-thymocyte globuline (ATG) with cyclosporin A (CsA) had been a standard IST regimen with acceptable response rate. Recently, horse ATG had been not available and replaced with rabbit ATG in most countries. Subsequently, recent comparative studies showed that the outcomes of patients who received rabbit ATG/CsA were similar or inferior compared to those who received horse ATG/CsA. Therefore, further studies to improve the outcomes of IST, including additional eltrombopag, are necessary. On the other hand, the upper age limit of patients who are able to receive MSD-SCT as first-line treatment is a current issue because of favorable outcomes of MSD-SCT of older patients using fludarabine-based conditioning. In addition, further studies to improve the outcomes of patients who receive allogeneic SCT from alternative donors are needed. In this review, current issues and the newly emerging trends that may improve their outcomes in near futures will be discussed focusing the management of patients with AA.