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Neal S Young - One of the best experts on this subject based on the ideXlab platform.
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eltrombopag mobilizes iron in patients with Aplastic Anemia
Blood, 2018Co-Authors: Neal S Young, Danielle M Townsley, Zhen Zhao, Qian Sun, Lori J Sokoll, Michael B Streiff, Zhe Cheng, Sophie Grasmeder, Cynthia E DunbarAbstract:TO THE EDITOR: The thrombopoietin receptor agonist eltrombopag (EPAG) has been shown to restore hematopoiesis in patients with severe Aplastic Anemia (SAA) refractory to immunosuppressive therapy and to significantly improve response rates when used in combination with immunosuppressive therapy in
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a plasma microrna signature as a biomarker for acquired Aplastic Anemia
Haematologica, 2017Co-Authors: Kohei Hosokawa, Sachiko Kajigaya, Phillip Scheinberg, Xingmin Feng, Marie J Desierto, Maria Del Pilar Fernandez Ibanez, Olga Rios, Barbara Weinstein, Danielle M Townsley, Neal S YoungAbstract:Aplastic Anemia is an acquired bone marrow failure characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the bone marrow. In Aplastic Anemia, a major challenge is to develop immune biomarkers to monitor the disease. We measured circulating microRNAs in plasma samples of Aplastic Anemia patients in order to identify disease-specific microRNAs. A total of 179 microRNAs were analyzed in 35 plasma samples from 13 Aplastic Anemia patients, 11 myelodysplastic syndrome patients, and 11 healthy controls using the Serum/Plasma Focus microRNA Polymerase Chain Reaction Panel. Subsequently, 19 microRNAs from the discovery set were investigated in the 108 plasma samples from 41 Aplastic Anemia patients, 24 myelodysplastic syndrome patients, and 43 healthy controls for validation, confirming that 3 microRNAs could be validated as dysregulated (>1.5-fold change) in Aplastic Anemia, compared to healthy controls. MiR-150-5p (induction of T-cell differentiation) and miR-146b-5p (involvement in the feedback regulation of innate immune response) were elevated in Aplastic Anemia plasma, whereas miR-1 was decreased in Aplastic Anemia. By receiver operating characteristic curve analysis, we developed a logistic model with these 3 microRNAs that enabled us to predict the probability of a diagnosis of Aplastic Anemia with an area under the curve of 0.86. Dysregulated expression levels of the microRNAs became normal after immunosuppressive therapy at 6 months. Specifically, miR-150-5p expression was significantly reduced after successful immunosuppressive therapy, but did not change in non-responders. We propose 3 novel plasma biomarkers in Aplastic Anemia, in which miR-150-5p, miR-146b-5p, and miR-1 can serve for diagnosis and miR-150-5p for disease monitoring. Clinicaltrials.gov identifiers:00260689, 00217594, 00961064.
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current concepts in the pathophysiology and treatment of Aplastic Anemia
Hematology, 2013Co-Authors: Neal S YoungAbstract:Historically viewed in isolation as an odd, rare, and invariably fatal blood disease, Aplastic Anemia is now of substantial interest for its immune pathophysiology, its relationship to constitutional BM failure syndromes and leukemia, and the success of both stem cell transplantation and immunosuppressive therapies in dramatically improving survival of patients. Once relegated to a few presentations in the red cell and Anemia sessions of the ASH, the Society now sponsors multiple simultaneous sessions and plenary and scientific committee presentations on these topics. This update emphasizes developments in our understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system.
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how i treat acquired Aplastic Anemia
Blood, 2012Co-Authors: Phillip Scheinberg, Neal S YoungAbstract:Survival in severe Aplastic Anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute.
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cytokine signature profiles in acquired Aplastic Anemia and myelodysplastic syndromes
Haematologica, 2011Co-Authors: Xingmin Feng, Phillip Scheinberg, Jaroslaw P Maciejewski, Leigh Samsel, Olga Nunez, Courtney Prince, Rebecca D Ganetzky, Philip J Mccoy, Neal S YoungAbstract:Although Aplastic Anemia and myelodysplasia have been extensively investigated, little is known about their circulating cytokine patterns. We compared plasma soluble cytokines in 33 Aplastic Anemia, 57 myelodysplasia patients, and 48 healthy controls. High levels of thrombopoietin and granulocyte colony-stimulating factor, with low levels of CD40 ligand, chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 11, epidermal growth factor, vascular endothelial growth factor, and chemokine (C-C motif) ligand 11 were a signature profile for Aplastic Anemia. High levels of tumor necrosis factor-α, interleukin-6, chemokine (C-C motif) ligand 3, interleukin-1 receptor antagonist, and hepatocyte growth factor were a cytokine signature for myelodysplasia. Despite similar clinical presentations, distinct cytokine profiles were observed between Aplastic Anemia and hypocellular myelodysplasia. Future studies focusing on cytokines that better discriminate these two entities such as thrombopoietin and chemokine (C-C motif) ligand 3 may be useful tools in clinical practice.
Hideki Muramatsu - One of the best experts on this subject based on the ideXlab platform.
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paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric Aplastic Anemia
Haematologica, 2015Co-Authors: Atsushi Narita, Yusuke Okuno, Xinan Wang, Yinyan Xu, Hirotoshi Sakaguchi, Nao Yoshida, Nobuhiro Nishio, Hideki Muramatsu, Yuko Sekiya, Nozomu KawashimaAbstract:Acquired Aplastic Anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in Aplastic Anemia. We enrolled 113 Aplastic Anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of Aplastic Anemia patients was −0.99 standard deviation (SD) (range −4.01–+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.
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comparison of long term outcomes between children with Aplastic Anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine
Haematologica, 2015Co-Authors: Asahito Hama, Masahiro Tsuchida, Yoshiyuki Kosaka, Shouichi Ohga, Atsushi Narita, Hiromasa Yabe, Hideki Muramatsu, Yoshiyuki Takahashi, Ryoji Kobayashi, Akira OharaAbstract:The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1–16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1–146 months). Out of 186 patients, 62 (33%) were classified with Aplastic Anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic Anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients ( P <0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with Aplastic Anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in Aplastic Anemia than in the other groups ( P =0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development ( P =0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with Aplastic Anemia.
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first line treatment for severe Aplastic Anemia in children bone marrow transplantation from a matched family donor versus immunosuppressive therapy
Haematologica, 2014Co-Authors: Nao Yoshida, Yoshiyuki Kosaka, Shouichi Ohga, Hiromasa Yabe, Ryoji Kobayashi, Hiroshi Yagasaki, Kenichiro Watanabe, Kazuko Kudo, Akira Morimoto, Hideki MuramatsuAbstract:The current treatment approach for severe Aplastic Anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe Aplastic Anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe Aplastic Anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86–90) versus 92% (90–94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54–59) versus 87% (85–90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992–1999 versus 2000–2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe Aplastic Anemia.
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peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood Aplastic Anemia
Haematologica, 2014Co-Authors: Hirotoshi Sakaguchi, Xinan Wang, Atsushi Narita, Sayoko Doisaki, Yinyan Xu, Nobuhiro Nishio, Asahito Hama, Hideki Muramatsu, Nozomu Kawashima, Nao YoshidaAbstract:Predicting the response to immunosuppressive therapy could provide useful information for clinician to make the strategies for treating patients with Aplastic Anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with Aplastic Anemia, using flow-fluorescence in situ hybridization. The median age of patients was 10 years (range, 1.5 to 16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies with antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at 6 months was 52% (33/64). The probability of 5-years failure free survival and overall survival were 56% (95% confidence interval, 41- 69%) and 97% (87-99%). The median of telomere length in responders was -0.4 standard deviation (-2.7 to +3.0 standard deviation), whereas -1.5 standard deviation (-4.0 to +1.6 standard deviation) in non-responders (P<0.001). Mulitivariate analysis revealed that telomere length shorter than -1.0standard deviation (hazard ratio, 22.0; 95% confidence interval, 4.19-115; P<0.001), platelet count at diagnosis less than 25x109/L (13.9; 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (4.81; 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what have been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is promising assay in predicting the response to immunosuppressive therapy in children with Aplastic Anemia.
Phillip Scheinberg - One of the best experts on this subject based on the ideXlab platform.
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eltrombopag added to standard immunosuppression for Aplastic Anemia
The New England Journal of Medicine, 2017Co-Authors: Danielle M Townsley, Phillip Scheinberg, Olga Rios, Barbara Weinstein, Thomas Winkler, Ronan Desmond, Bogdan Dumitriu, Janet Valdez, Jennifer Lotter, Xingmin FengAbstract:BackgroundAcquired Aplastic Anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with Aplastic Anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe Aplastic Anemia. MethodsWe enrolled 92 consecutive patients in a prospective phase 1–2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic resp...
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a plasma microrna signature as a biomarker for acquired Aplastic Anemia
Haematologica, 2017Co-Authors: Kohei Hosokawa, Sachiko Kajigaya, Phillip Scheinberg, Xingmin Feng, Marie J Desierto, Maria Del Pilar Fernandez Ibanez, Olga Rios, Barbara Weinstein, Danielle M Townsley, Neal S YoungAbstract:Aplastic Anemia is an acquired bone marrow failure characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the bone marrow. In Aplastic Anemia, a major challenge is to develop immune biomarkers to monitor the disease. We measured circulating microRNAs in plasma samples of Aplastic Anemia patients in order to identify disease-specific microRNAs. A total of 179 microRNAs were analyzed in 35 plasma samples from 13 Aplastic Anemia patients, 11 myelodysplastic syndrome patients, and 11 healthy controls using the Serum/Plasma Focus microRNA Polymerase Chain Reaction Panel. Subsequently, 19 microRNAs from the discovery set were investigated in the 108 plasma samples from 41 Aplastic Anemia patients, 24 myelodysplastic syndrome patients, and 43 healthy controls for validation, confirming that 3 microRNAs could be validated as dysregulated (>1.5-fold change) in Aplastic Anemia, compared to healthy controls. MiR-150-5p (induction of T-cell differentiation) and miR-146b-5p (involvement in the feedback regulation of innate immune response) were elevated in Aplastic Anemia plasma, whereas miR-1 was decreased in Aplastic Anemia. By receiver operating characteristic curve analysis, we developed a logistic model with these 3 microRNAs that enabled us to predict the probability of a diagnosis of Aplastic Anemia with an area under the curve of 0.86. Dysregulated expression levels of the microRNAs became normal after immunosuppressive therapy at 6 months. Specifically, miR-150-5p expression was significantly reduced after successful immunosuppressive therapy, but did not change in non-responders. We propose 3 novel plasma biomarkers in Aplastic Anemia, in which miR-150-5p, miR-146b-5p, and miR-1 can serve for diagnosis and miR-150-5p for disease monitoring. Clinicaltrials.gov identifiers:00260689, 00217594, 00961064.
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how i treat acquired Aplastic Anemia
Blood, 2012Co-Authors: Phillip Scheinberg, Neal S YoungAbstract:Survival in severe Aplastic Anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute.
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eltrombopag and improved hematopoiesis in refractory Aplastic Anemia
The New England Journal of Medicine, 2012Co-Authors: Matthew J Olnes, Phillip Scheinberg, Ronan Desmond, Bogdan Dumitriu, Katherine R Calvo, Yong Tang, Ankur R Parikh, Susan Soto, Angelique Biancotto, Xingmin FengAbstract:BACKGROUND Severe Aplastic Anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. METHODS We conducted a phase 2 study involving patients with Aplastic Anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. RESULTS Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. CONCLUSIONS Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe Aplastic Anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.).
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cytokine signature profiles in acquired Aplastic Anemia and myelodysplastic syndromes
Haematologica, 2011Co-Authors: Xingmin Feng, Phillip Scheinberg, Jaroslaw P Maciejewski, Leigh Samsel, Olga Nunez, Courtney Prince, Rebecca D Ganetzky, Philip J Mccoy, Neal S YoungAbstract:Although Aplastic Anemia and myelodysplasia have been extensively investigated, little is known about their circulating cytokine patterns. We compared plasma soluble cytokines in 33 Aplastic Anemia, 57 myelodysplasia patients, and 48 healthy controls. High levels of thrombopoietin and granulocyte colony-stimulating factor, with low levels of CD40 ligand, chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 11, epidermal growth factor, vascular endothelial growth factor, and chemokine (C-C motif) ligand 11 were a signature profile for Aplastic Anemia. High levels of tumor necrosis factor-α, interleukin-6, chemokine (C-C motif) ligand 3, interleukin-1 receptor antagonist, and hepatocyte growth factor were a cytokine signature for myelodysplasia. Despite similar clinical presentations, distinct cytokine profiles were observed between Aplastic Anemia and hypocellular myelodysplasia. Future studies focusing on cytokines that better discriminate these two entities such as thrombopoietin and chemokine (C-C motif) ligand 3 may be useful tools in clinical practice.
Matt Kalaycio - One of the best experts on this subject based on the ideXlab platform.
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efficacy of rabbit anti thymocyte globulin in severe Aplastic Anemia
Haematologica, 2011Co-Authors: Manuel G Afable, Mohammed Shaik, Yuka Sugimoto, Anjali S Advani, Michael J Clemente, Hideki Makishima, Alan E. Lichtin, Mikkael A Sekeres, Paul Elson, Matt KalaycioAbstract:Background A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60–70% of patients with severe Aplastic Anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe Aplastic Anemia. Design and Methods Twenty patients with severe Aplastic Anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin. Results Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% ( P =0.43), 45% versus 58% ( P =0.44) and 50% versus 58% ( P =0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone ( P =0.01) and a pretreatment absolute reticulocyte count greater than 30×109/L ( P =0.007) as independent predictors of response and younger age ( P =0.003), higher pretreatment absolute neutrophil ( P =0.02) and absolute lymphocyte counts ( P =0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy. Conclusions Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe Aplastic Anemia. [Clinicaltrial.gov][1]: [NCT01231841][2]) [1]: http://Clinicaltrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01231841&atom=%2Fhaematol%2F96%2F9%2F1269.atom
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efficacy of rabbit anti thymocyte globulin in severe Aplastic Anemia
Haematologica, 2011Co-Authors: Manuel G Afable, Mohammed Shaik, Yuka Sugimoto, Anjali S Advani, Michael J Clemente, Hideki Makishima, Alan E. Lichtin, Mikkael A Sekeres, Paul Elson, Matt KalaycioAbstract:Background A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60–70% of patients with severe Aplastic Anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe Aplastic Anemia.Design and Methods Twenty patients with severe Aplastic Anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin.Results Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30×109/L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy.Conclusions Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe Aplastic Anemia. Clinicaltrial.gov: NCT01231841)
Nao Yoshida - One of the best experts on this subject based on the ideXlab platform.
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paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric Aplastic Anemia
Haematologica, 2015Co-Authors: Atsushi Narita, Yusuke Okuno, Xinan Wang, Yinyan Xu, Hirotoshi Sakaguchi, Nao Yoshida, Nobuhiro Nishio, Hideki Muramatsu, Yuko Sekiya, Nozomu KawashimaAbstract:Acquired Aplastic Anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in Aplastic Anemia. We enrolled 113 Aplastic Anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of Aplastic Anemia patients was −0.99 standard deviation (SD) (range −4.01–+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.
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first line treatment for severe Aplastic Anemia in children bone marrow transplantation from a matched family donor versus immunosuppressive therapy
Haematologica, 2014Co-Authors: Nao Yoshida, Yoshiyuki Kosaka, Shouichi Ohga, Hiromasa Yabe, Ryoji Kobayashi, Hiroshi Yagasaki, Kenichiro Watanabe, Kazuko Kudo, Akira Morimoto, Hideki MuramatsuAbstract:The current treatment approach for severe Aplastic Anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe Aplastic Anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe Aplastic Anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86–90) versus 92% (90–94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54–59) versus 87% (85–90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992–1999 versus 2000–2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe Aplastic Anemia.
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peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood Aplastic Anemia
Haematologica, 2014Co-Authors: Hirotoshi Sakaguchi, Xinan Wang, Atsushi Narita, Sayoko Doisaki, Yinyan Xu, Nobuhiro Nishio, Asahito Hama, Hideki Muramatsu, Nozomu Kawashima, Nao YoshidaAbstract:Predicting the response to immunosuppressive therapy could provide useful information for clinician to make the strategies for treating patients with Aplastic Anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with Aplastic Anemia, using flow-fluorescence in situ hybridization. The median age of patients was 10 years (range, 1.5 to 16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies with antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at 6 months was 52% (33/64). The probability of 5-years failure free survival and overall survival were 56% (95% confidence interval, 41- 69%) and 97% (87-99%). The median of telomere length in responders was -0.4 standard deviation (-2.7 to +3.0 standard deviation), whereas -1.5 standard deviation (-4.0 to +1.6 standard deviation) in non-responders (P<0.001). Mulitivariate analysis revealed that telomere length shorter than -1.0standard deviation (hazard ratio, 22.0; 95% confidence interval, 4.19-115; P<0.001), platelet count at diagnosis less than 25x109/L (13.9; 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (4.81; 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what have been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is promising assay in predicting the response to immunosuppressive therapy in children with Aplastic Anemia.