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The New England Journal of Medicine Aug 2011In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem-cell transplantation and improves blood counts and survival. Although horse ATG is the standard therapy, rabbit ATG is more potent in depleting peripheral-blood lymphocytes and is preferred in other clinical circumstances.
METHODS
From December 2005 through July 2010, we performed a randomized trial comparing these two ATG formulations in conventional regimens. Patients were treated at a single facility. The primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to enroll 60 patients each for the rabbit-ATG and horse-ATG groups and was powered to detect a difference of 25 percentage points in the response rate.
RESULTS
A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse-ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit-ATG group (P=0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P=0.008) in the respective groups when stem-cell-transplantation events were not censored.
CONCLUSIONS
In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.).
Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Animals; Antilymphocyte Serum; Blood Cell Count; Child; Child, Preschool; Female; Horses; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Rabbits; Stem Cell Transplantation; Survival Rate; Young Adult
PubMed: 21812672
DOI: 10.1056/NEJMoa1103975 -
Current Opinion in Hematology May 2008Most acquired aplastic anemia is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and an empty bone marrow, which can be... (Review)
Review
PURPOSE OF REVIEW
Most acquired aplastic anemia is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and an empty bone marrow, which can be successfully treated with either immunosuppressive therapy or hematopoietic stem-cell transplantation.
RECENT FINDINGS
In aplastic anemia, oligoclonally expanded cytotoxic T cells induce apoptosis of hematopoietic progenitors. T-bet, a transcription factor that binds to the interferon-gamma promoter region, is upregulated in aplastic anemia T cells. Regulatory T cells are significantly reduced in patients' peripheral blood and in an aplastic anemia murine model, infusion of regulatory T cells ameliorates disease progression. In a minority of cases, loss-of-function mutations in telomerase complex genes may underlie disease development. Long-term survival, once strongly linked to response to immunosuppressive therapy, can now be achieved even among nonresponders due to significant advances in supportive care and better salvage treatments.
SUMMARY
Evidence has accumulated in the recent years further corroborating an immune-mediated process underlying aplastic anemia pathogenesis. Hematopoietic stem-cell transplantation from a matched sibling donor is preferred for children and young adults with severe aplastic anemia, and immunosuppressive therapy is employed when hematopoietic stem-cell transplantation is not feasible due to age, lack of a histocompatible sibling, co-morbidities, or by patient choice.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents
PubMed: 18391779
DOI: 10.1097/MOH.0b013e3282fa7470 -
American Journal of Transplantation :... Aug 2017
Topics: Antilymphocyte Serum; CD4-Positive T-Lymphocytes; Cross Reactions; Humans; Lymphopenia
PubMed: 28544604
DOI: 10.1111/ajt.14370 -
Haematologica Jun 2019
Topics: Antilymphocyte Serum; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Neoplasms; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 31152088
DOI: 10.3324/haematol.2019.216952 -
F1000Research 2020Aplastic anemia (AA) in its severe form has historically been associated with high mortality. With limited supportive care and no effective strategy to reverse marrow... (Review)
Review
Aplastic anemia (AA) in its severe form has historically been associated with high mortality. With limited supportive care and no effective strategy to reverse marrow failure, most patients diagnosed with severe AA (SAA) died of pancytopenia complications. Since the 1970s, hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have changed SAA's natural history by improving marrow function and pancytopenia. Standard IST with horse anti-thymocyte globulin plus cyclosporine produces a hematologic response rate of 60 to 70%. In the long term, about one-third of patients relapse, and 10 to 15% can develop cytogenetic abnormalities. Outcomes with either HSCT or IST are similar, and choosing between these modalities relies on age, availability of a histocompatible donor, comorbidities, and patient preference. The introduction of eltrombopag, a thrombopoietin receptor agonist, improved SAA outcomes as both salvage (second-line) and upfront therapy combined with IST. As a single agent, eltrombopag in doses up to 150 mg daily improved cytopenias in 40 to 50% in those who failed initial IST, which associated with higher marrow cellularity, suggesting a pan-stimulatory marrow effect. When eltrombopag was combined with IST as upfront therapy, overall (about 90%) and complete responses (about 50%) were higher than observed extensively with IST alone of 65% and 10%, respectively. Not surprisingly, given the strong correlation between hematologic response rates and survival in SAA, most (>90%) were alive after a median follow-up of 18 months. Longer follow-up and real-word data continue to confirm the activity of this agent in AA. The use of eltrombopag in different combinations and doses are currently being explored. The activity of another thrombopoietin receptor agonist in AA, romiplostim, suggests a class effect. In the coming years, the mechanisms of their activity and the most optimal regimen are likely to be elucidated.
Topics: Anemia, Aplastic; Animals; Antilymphocyte Serum; Cyclosporine; Hematopoietic Stem Cell Transplantation; Horses; Humans; Immunosuppressive Agents; Salvage Therapy
PubMed: 32953089
DOI: 10.12688/f1000research.22214.1 -
Haematologica Jul 2017
Topics: Anemia, Aplastic; Antilymphocyte Serum; Humans; Immunosuppressive Agents
PubMed: 28655810
DOI: 10.3324/haematol.2017.171538 -
International Journal of Hematology Dec 2005
Topics: Antilymphocyte Serum; Cyclosporine; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Myelodysplastic Syndromes; Radiotherapy; Stem Cells
PubMed: 16533744
DOI: 10.1532/IJH97.05139 -
Frontiers in Immunology 2022Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial...
INTRODUCTION
Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial pad allotransplantation tolerance.
METHOD
In this study, 19 VBM, nine mystacial pad, and six sequential VBM and mystacial pad allografts were transplanted from Brown Norway (BN) rats to Lewis (LEW) rats to test our hypothesis. The VBM recipients were divided into antilymphocyte serum (ALS) monotherapy group (two doses of ALS on day 3 pretransplantation and day 1 posttransplantation), immunosuppressant group [a week of 2 mg/kg/day tacrolimus (Tac) and 3 weeks of 3 mg/kg/day rapamycin (RPM)], and combined therapy group. The mystacial pad recipients were divided into VBM and non-VBM transplantation groups, and both groups were treated with an immunosuppression regimen that consists of ALS, Tac, and RPM. For the recipients of sequential VBM and mystacial pad allotransplantations, additional Tac was given 1 week after mystacial pad transplantation. Allograft survival, donor-specific tolerance, and chimerism level were evaluated.
RESULTS
With the administration of ALS and short-term Tac and RPM treatments, VBM recipients demonstrated long-term graft survival (>120 days) with persistent chimerism for 30 days. CD3 T cells from tolerant rats showed donor-specific hyporesponsiveness and tolerance to donor skin grafts but not to third-party counterparts. Furthermore, mystacial pad graft recipients with VBM transplantation exhibited a higher allograft survival rate than those without VBM transplantation [median survival time (MST) >90 days vs. 70 days, < 0.05].
CONCLUSION
This study demonstrated that VBM transplantation is an efficient strategy to induce and maintain donor-specific tolerance for an osseous-free allograft.
Topics: Animals; Rats; Antilymphocyte Serum; Bone Marrow; Graft Rejection; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus; Tacrolimus; Transplantation Tolerance
PubMed: 36578498
DOI: 10.3389/fimmu.2022.1059271 -
Drug Design, Development and Therapy 2016Aplastic anemia (AA) is a potential life-threatening hematopoietic stem cell (HSC) disorder resulting in cytopenia. The mainstays of treatment for AA are definitive... (Review)
Review
Aplastic anemia (AA) is a potential life-threatening hematopoietic stem cell (HSC) disorder resulting in cytopenia. The mainstays of treatment for AA are definitive therapy to restore HSCs and supportive measures to ameliorate cytopenia-related complications. The standard definitive therapy is HSC transplantation for young and medically fit patients with suitable donors and immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine for the remaining patients. A significant proportion of patients are refractory to IST or relapse after IST. Various strategies have been explored in these patients, including second course of antithymocyte globulin, high-dose cyclophosphamide, and alemtuzumab. Eltrombopag, a thrombopoietin mimetic, has recently emerged as an encouraging and promising agent for patients with refractory AA. It has demonstrated efficacy in restoring trilineage hematopoiesis, and this positive effect continues after discontinuation of the drug. There are ongoing clinical trials exploring the role of eltrombopag as a first-line therapy in moderate to severe AA and a combination of eltrombopag with IST in severe AA.
Topics: Alemtuzumab; Anemia, Aplastic; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Benzoates; Cyclophosphamide; Cyclosporine; Hematopoietic Stem Cells; Humans; Hydrazines; Immunosuppressive Agents; Pyrazoles
PubMed: 27695288
DOI: 10.2147/DDDT.S95715 -
Jornal Brasileiro de Nefrologia 2015
Topics: Antilymphocyte Serum; Humans; Immunosuppressive Agents; Kidney Transplantation
PubMed: 26154633
DOI: 10.5935/0101-2800.20150025