- Suspected Pulmonary Infection with Trichoderma longibrachiatum after Allogeneic Stem Cell Transplantation. [Journal Article]
- IMIntern Med 2017; 56(2):215-219
- Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serio...
Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B.
- Gene mutations in bone marrow failure syndromes. [Journal Article]
- RKRinsho Ketsueki 2016; 57(12):2519-2525
- Acquired bone marrow failure syndromes consist of aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS). Clonal hematopoiesis is frequently observed in non-n...
Acquired bone marrow failure syndromes consist of aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS). Clonal hematopoiesis is frequently observed in non-neoplastic disorders, aplastic anemia and PNH as well as a neoplastic phenotype, MDS. However, the significance of such clonal hematopoiesis, particularly in aplastic anemia, remains to be elucidated. Recent advancements in next generation sequencing technology have revealed a diverse clonal structure in these bone marrow failure syndromes, as well as in age-related clonal hematopoiesis in healthy people. In this review article, we describe gene mutations in bone marrow failure syndromes, together with those detected in healthy people.
- Simultaneous occurrence of autoimmune hemolytic anemia and pure red cell aplasia. [Journal Article]
- RKRinsho Ketsueki 2016; 57(12):2512-2516
- Simultaneous onset of autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) is rare and any possible association between these two disorders remains obscure. A 46-year-old previously he...
Simultaneous onset of autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) is rare and any possible association between these two disorders remains obscure. A 46-year-old previously healthy woman was diagnosed as having AIHA based on severe anemia, positive direct and indirect Coomb's tests, decreased serum haptoglobin, elevated serum LDH, and indirect bilirubin-dominant hyperbilirubinemia. Oral steroid administration (1 mg/kg) and subsequent half-pulse steroid therapy ameliorated the AIHA, but the anemia was unexpectedly prolonged with the low peripheral blood reticulocyte count further decreasing to 0.11%. Bone marrow aspiration revealed a marked decrease in erythroblasts with an M/E ratio of 69.5. Anti-parvovirus B19 IgM antibody and serum B19 viral DNA (10(9) copy/ml) were detected but no other distinct abnormalities which might have caused acquired PRCA were detected. Therefore, she was considered likely to have idiopathic AIHA and acquired PRCA simultaneously. AIHA-mediated erythroblastosis probably raised the parvovirus B19 DNA level to an extraordinary degree and thereby led to severe aplastic crisis, subsequently causing prolonged anemia. Parvovirus B19 infection should be considered in AIHA patients showing unexpectedly low reticulocyte counts.
- [Eltrombopag for refractory thrombocytopenia in patients with allogeneic hematopoietic stem cell transplantation]. [Journal Article]
- ZXZhonghua Xue Ye Xue Za Zhi 2016 Dec 14; 37(12):1065-1069
- Objective: To evaluate the efficacy and safety of eltrombopag in post-HSCT thrombocytopenia. Methods: A total of 10 patients who underwent post-HSCT thrombocytopenia at Peking University center, who ...
Objective: To evaluate the efficacy and safety of eltrombopag in post-HSCT thrombocytopenia. Methods: A total of 10 patients who underwent post-HSCT thrombocytopenia at Peking University center, who had been treated with eltrombopag, were retrospectively evaluated. Results: Of the 10 cases, 5 males and 5 females with a median of 34 years old (range, 17-54 years), 5 patients were acute myeloid leukemia, 3 with acute lymphoid leukemia and 2 with severe aplastic anemia. Nine patients had undergone haplo-identical donor transplantation, and one patient was a matched related recipient. All patients had failed prior treatment for thrombocytopenia before eltrombopag started. The median time when eltrombopag started was 221 days (range, 73-917 days) after transplantation. Five patients (50%) had achieved CR. The cumulative incidence of 30-day CR was 35.7%. The median time to platelet recovery ≥ 50 × 10(9)/L without transfusion support was 16 days (range, 10-56 days). At the last follow-up, three of the patients with CR had withdrawal eltrombopag and remained normal platelet counts. No patients experienced drug-related adverse events. Conclusion: Eltrombopag is effective and well tolerated in patients with refractory post-HSCT thrombocytopenia.
- [Delayed hematologic response to immunosuppressive therapy in severe aplastic anemia]. [Journal Article]
- ZXZhonghua Xue Ye Xue Za Zhi 2016 Dec 14; 37(12):1038-1043
- Objective: To explore the characteristics of delayed hematologic response in very/severe aplastic anemia (V/SAA) patients who were treated with immunosuppressive treatment (IST) as first-line approac...
Objective: To explore the characteristics of delayed hematologic response in very/severe aplastic anemia (V/SAA) patients who were treated with immunosuppressive treatment (IST) as first-line approach, and investigate the rationality of early salvage treatment in refractory patients. Methods: The data of V/SAA patients front-line treated with IST were retrospectively analyzed. Delayed response was defined as acquiring hematologic response between 6 and 12 months after 1 course of IST. The clinical as well as hematologic characteristics of the delayed responded patients were investigated. Results: Of the 533 patients, 45 (8.44%, 45/533) were delayed hematologic responders, which accounted for 29.03% (45/155) of the whole non-responders at 6 months. The quality of response in delayed responders analyzed at 12 months (χ(2)=62.616, P <0.001) and at the end of follow-up (χ(2)=6.299, P=0.043) was significantly worse than that of robust response group. There were more VSAA patients in delayed response group compared with robust response group (57.8% vs 38.3%, P=0.013), and all the baseline absolute reticulocyte (ARC) count, ARC proportion and absolute neutrophil count (ANC) were much lower than that in delayed response group. Multivariate analysis about the above 2 groups showed that the baseline ARC count <10×10(9)/L significanty reduced the chance of hematologic response within 6 months [OR=3.641(95% CI 1.718-7.719) , P=0.001], and not any factor was found to predict delayed hematologic response in non-responders at 6 months. The 5-year overall survival of 76.50% (95% CI 71.6%-81.4%) and event free survival of 29.10%(95% CI 25.2%-33.0% ) in non-responders at 6 months, both were worse than 97.6% (95% CI 96.6%-98.6% ) and 84.0% (95% CI 81.1%-86.9% ) (P <0.001) of robust response group. Conclusion: The incidence of delayed hematologic response in V/SAA patients by IST is low. The quality of delayed response is not satisfactory and there is no effective means to predict the delayed response. It is reasonable to carry out salvage treatment as early as possible.
- Outcome of anti-thymocyte immunoglobulin plus cyclosporine A for severe aplastic anaemia with chronic hepatitis B virus infection. [Journal Article]
- AHAnn Hematol 2017 Jan 13
- The influence of chronic hepatitis B virus (HBV) infection on the efficacy of intensive immunosuppressive treatment (IST) of severe aplastic anaemia (SAA) patients remains unclear. Previous reports o...
The influence of chronic hepatitis B virus (HBV) infection on the efficacy of intensive immunosuppressive treatment (IST) of severe aplastic anaemia (SAA) patients remains unclear. Previous reports on this topic have been mostly case reports or have had a relatively short follow-up. Eight SAA patients carrying chronic HBV infection and 24 matched patients without HBV at a ratio of 1:3 were included in this retrospective analysis. The patients were treated with anti-thymocyte globulin (ATG) and cyclosporine A. Entecavir was or was not administered throughout the IST course to patients with positive or negative HBV-DNA results, respectively. No evident HBV reactivation developed. The overall response was 87.5% by 12 months, and the recurrence rate was 12.5%. There were no significant differences in overall response, overall survival and event-free survival between groups. Entecavir can effectively prevent reactivation of HBV in SAA patients with positive HBV-DNA who received intensive IST. Regular surveillance may be sufficient for HBV-DNA negative patients who should receive antiviral drugs immediately when their HBV-DNA status changes from negative to positive. The prognosis of SAA patients with chronic HBV infection after intensive IST treatment is not worse than those without HBV infection.
- Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. [Journal Article]
- IJInt J Hematol 2017 Jan 11
- Aplastic anemia patients who received rabbit antithymocyte globulin exhibited response and survival rates inferior to those who received horse antithymocyte globulin in several studies. Therefore, we...
Aplastic anemia patients who received rabbit antithymocyte globulin exhibited response and survival rates inferior to those who received horse antithymocyte globulin in several studies. Therefore, we conducted a meta-analysis to compare rabbit and horse antithymocyte globulin as immunosuppressive therapy for aplastic anemia. We searched online databases for studies that compared antithymocyte globulin regimens as first-line treatment for aplastic anemia, including both randomized and non-randomized controlled trials. The early mortality rate at 3 months and overall response rate at 6 months were evaluated. Thirteen studies were included in the analysis. The risk ratio (RR) of early mortality for rabbit vs. horse antithymocyte globulin was 1.33 [95% confidence interval (CI) 0.69-2.57; P = 0.39], with significant heterogeneity. A sensitivity analysis suggested higher early mortality rate in patients who received rabbit antithymocyte globulin. The overall response rate was significantly higher in patients who received horse antithymocyte globulin (RR 1.27; 95% CI 1.05-1.54; P = 0.015). In conclusion, in aplastic anemia patients treated with ATG, early mortality rate was not significantly different in patients receiving horse or rabbit ATG, although a sensitivity analysis showed higher early mortality in the rabbit ATG group. Horse ATG was associated with significantly higher response rate than rabbit ATG.
- dUTPase (DUT) is Mutated in a Novel Monogenic Syndrome with Diabetes and Bone Marrow Failure. [Journal Article]
- DDiabetes 2017 Jan 10
- We describe a new syndrome characterized by early onset diabetes mellitus, associated with bone marrow failure affecting mostly the erythrocytic lineage. Using whole exome sequencing in a remotely co...
We describe a new syndrome characterized by early onset diabetes mellitus, associated with bone marrow failure affecting mostly the erythrocytic lineage. Using whole exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (NCBI Gene ID: 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, while none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β cell integrity, and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.
- Cotransplantation of bone marrow-derived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia: an interim summary for a multicenter phase II trial results. [Journal Article]
- BMBone Marrow Transplant 2017 Jan 09
- Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for severe aplastic anemia (SAA) is mainly limited by the high incidence of graft failure and GvHD. Mesenchymal stem cells (MSCs) h...
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for severe aplastic anemia (SAA) is mainly limited by the high incidence of graft failure and GvHD. Mesenchymal stem cells (MSCs) have been shown to support hematopoiesis in vivo and to display potent immunosuppressive effects to prevent or treat GvHD after HSCT. In a multicenter phase II trial, we developed an approach with co-transplantation of MSCs in patients undergoing haplo-HSCT. Forty-four patients with SAA were included. The conditioning regimen included busulfan, cyclophosphamide and thymoglobulin (ATG). The recipients received cyclosporin A (CsA), mycophenolate mofetil and short-term methotrexate for GvHD prophylaxis. Three out of 44 patients, who died early before hematopoietic engraftment, were not assessed. Evaluable patients (97.6%; 40/41) achieved hematopoietic reconstitution and sustained full donor chimerism. The median time for myeloid engraftment was 12 days (range 8-21 days) and for platelet engraftment was 19 days (range 8-154 days). The incidence was 29.3% for grade II-IV acute GvHD and 14.6% for chronic GvHD. The overall survival was 77.3% with a median 12-month (range 0.9-30.8) follow-up for surviving patients. These data suggest that co-transplantation of MSCs could reduce the risk of graft failure and severe GvHD in haplo-HSCT for SAA.Bone Marrow Transplantation advance online publication, 9 January 2017; doi:10.1038/bmt.2016.347.
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- Induced Pluripotent Stem Cell Technology: A Window for Studying the Pathogenesis of Acquired Aplastic Anemia and Possible Applications. [Review]
- EHExp Hematol 2017 Jan 03
- Recent progress in human induced pluripotent stem cells (iPSCs) has opened the door to better understand the biology of human diseases, especially in rare disorders, such as acquired aplastic anemia ...
Recent progress in human induced pluripotent stem cells (iPSCs) has opened the door to better understand the biology of human diseases, especially in rare disorders, such as acquired aplastic anemia (AA), in which the target hematopoietic tissues are depleted. The advent of somatic cell reprogramming has presented new routes for generating hematopoietic stem cells (HSCs) from patient-derived iPSCs and their differentiation into hematopoietic lineages. The purpose of this review is to discuss the recent advances in iPSC research technology and its potential applications in disease modeling for understanding the pathogenesis of bone marrow failure syndrome (BMFS) and the potential clinical utility of iPSC-derived cells.