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Hematology AND Aplastic anemia [keywords]
- Manifestations of Fulminant CD8 T-cell Post-transplant Lymphoproliferative Disorder Following the Administration of Rituximab for Lymphadenopathy with a High Level of Epstein-Barr Virus (EBV) Replication after Allogeneic Hematopoietic Stem Cell Transplantation. [Journal Article]
- Intern Med 2014; 53(18):2115-9.
We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.
- Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. [JOURNAL ARTICLE]
- Blood 2014 Sep 9.
Telomerase is a ribonucleoprotein enzyme that is necessary for overcoming telomere shortening in human germ and stem cells. Mutations in telomerase or other telomere-maintenance proteins can lead to diseases characterized by depletion of hematopoietic stem cells and bone marrow failure. Telomerase localization to telomeres requires an interaction with a region on the surface of the telomere-binding protein TPP1 known as the TEL patch. Here we identify a family with aplastic anemia and other related hematopoietic disorders, in which a one amino acid deletion in the TEL patch of TPP1 (ΔK170) segregates with disease. All family members carrying this mutation, but not those with wild-type TPP1, have short telomeres. When introduced into 293T cells, TPP1 with the ΔK170 mutation is able to localize to telomeres but fails to recruit telomerase to telomeres, supporting a causal relationship between this TPP1 mutation and bone marrow disorders. ACD/TPP1 is thus a newly-identified telomere-related gene in which mutations cause aplastic anemia and related bone marrow failure disorders.
- Allogeneic hematopoietic stem cell transplantation as the first-line treatment option in a patient with severe aplastic anemia without a matched related donor: A case report. [JOURNAL ARTICLE]
- Oncol Lett 2014 Oct; 8(4):1831-1833.
The outcomes of matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) in patients with severe aplastic anemia (SAA) remain controversial. The clinical outcome in patients that undergo transplantation following failed IST is typically poorer when compared with patients that initially underwent transplantation. Clinical treatment algorithms have been proposed to determine the management of such patients, and account for individual conditions, personal preferences and prognostic risk factors. The present study reports the promising outcome of a 22-year-old patient exhibiting SAA. The patient underwent peripheral blood stem cell transplantation (PBSCT) from an MUD using a fludarabine-based conditioning regimen and low-dose total body irradiation as an alternative method to first-line IST. The patient achieved rapid bone marrow reconstitution and has been in complete remission for 32 months. The aim of the fludarabine-based conditioning regimen with PBSCT was to improve the patient's therapeutic outcome and provide a convenient treatment strategy. Furthermore, this regimen extends the application of HSCT to patients who are older or those that are without a matched related donor.
- Recurrent life-threatening reactions to platelet transfusion in an aplastic anaemia patient with a paroxysmal nocturnal haemoglobinuria clone. [Journal Article]
- Intern Med J 2014 Sep; 44(9):925-7.
A 60-year-old woman was diagnosed with non-severe aplastic anaemia when she presented with anaemia and thrombocytopenia. She developed recurrent life-threatening hypotensive reactions during transfusion of leukodepleted platelet concentrates, and washed platelet concentrates prevented the development of such reactions subsequently. A paroxysmal nocturnal haemoglobinuria clone was detected on investigating for aplastic anaemia, which has been speculated to play a role in the recurrent hypotensive reactions.
- Arsenic trioxide and microRNA-204 display contrary effects on regulating adipogenic and osteogenic differentiation of mesenchymal stem cells in aplastic anemia. [JOURNAL ARTICLE]
- Acta Biochim Biophys Sin (Shanghai) 2014 Sep 3.
Our previous studies have demonstrated that arsenic trioxide (ATO) had the clinical efficacy in treating patients with aplastic anemia (AA). However, the mechanisms remain to be elucidated. The important components of the bone marrow hematopoietic microenvironment, bone marrow mesenchymal stem cells (BMSCs), are often altered in AA patients. In this study, it was found that AA BMSCs were prone to be induced into adipocytes rather than osteoblasts. ATO treatment can at least partially restore the differentiation imbalance of AA BMSCs. We further identified miR-204 as a key regulator in AA BMSC differentiation. Luciferase reporter assay showed that miR-204 could directly bind to the 3'-untranslated region of Runx2 mRNA, a key transcription factor regulating osteogenesis. Moreover, adipogenic differentiation was promoted and osteogenic differentiation was inhibited in miR-204 over-expressed cells, whereas osteogenesis was enhanced and adipocyte formation was inhibited in cells that lost miR-204 function, which suggested its endogenous function. Together we showed that ATO could inhibit adipogenic differentiation, but promote osteogenic differentiation in AA BMSCs, providing a possible explanation for ATO clinical efficacy in AA patients. MiR-204 plays a key role in regulating BMSCs differentiation, and down-regulating miR-204 expression might be a novel strategy to treat AA.
- "Moderate" dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution. [JOURNAL ARTICLE]
- Blood 2014 Sep 3.
First line therapy of aplastic anemia with high dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower "moderate" dose, in combination with aggressive supportive care, to determine if severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine, antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pre-therapy blood counts and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5, confirmed fungal infections documented in 6, and 9 patients died. Nine (41%) patients responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 and cytogenetic abnormalities were observed in 4 patients, including monosomy 7. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283.
- Congenital amegakaryocytic thrombocytopenia: three case reports from patients with different clinical diagnoses and somatic abnormalities. [JOURNAL ARTICLE]
- Blood Coagul Fibrinolysis 2014 Sep 3.
The congenital amegakaryocytic thrombocytopenia (CAMT) is a syndrome characterized by preservation of granulocytic and erythroid cells during genesis, with a gradual or progressive decrease in the number of megakaryocytic series of cells in the bone marrow. At later times, most patients develop aplastic anemia. It is important to rule out specific causes of thrombocytopenia that develop in the early stages of CAMT. Typically, there are no specific somatic abnormalities that accompany this deadly disease. Here we present three CAMT cases that presented with different clinical diagnoses, with various physical anomalies in two of those cases. The first patient was examined because of a cytomegalovirus infection. The second patient had been referred with a suspected neonatal alloimmune thrombocytopenia, whereas the third patient presented with chronic immune thrombocytopenic purpura. Subsequently, all three patients were diagnosed with CAMT. Two of the patients had physical anomalies. In particular, the first patient had a duplex urinary system. To our knowledge, this is the first patient with CAMT to have a duplicated collecting sysem. The second patient had a secundum atrial septal defect, an atypical facial appearance, and growth retardation. Since CAMT could also be observed outside the neonatal period, the differential diagnosis for thrombocytopenia should be considered for all age groups. Moreover, it should be considered that CAMT may also be accompanied with somatic abnormalities.
- Recent Developments in Drug Therapy for Aplastic Anemia. [REVIEW]
- Ann Pharmacother 2014 Sep 2.
This article reviews recent developments in immunosuppressive therapy (IST) for aplastic anemia (AA) patients who are not candidates for stem cell transplant (SCT); including, front-line, salvage, and novel treatment options with a focus on response rates (RRs) and overall survival (OS).A PubMed literature search was performed from 1977 to June 2014 using the search terms aplastic anemia, horse antithymocyte globulin (hATG), rabbit ATG (rATG), thymoglobulin, and cyclosporine (CSA). Additional references were identified from a review of literature citations.All English-language studies investigating IST for treatment of AA in non-SCT candidates were evaluated.Studies indicate addition of CSA and corticosteroids to hATG for treatment of AA improves RRs, decreases relapse rates, and improves 5-year OS. hATG improved RRs, relapse rates, and OS compared to rATG in the front-line setting. Studies support the use of rATG when front-line IST with hATG fails or when hATG is unavailable. Front-line daclizumab can be considered for nonsevere AA (NAA); however, data is limited. Alemtuzumab or eltrombopag are options for relapsed AA in select patients.hATG with methylprednisolone and CSA is recommended for front-line treatment of AA, whereas rATG is reserved for salvage therapy. Front-line use of daclizumab has been studied in NAA patients, but additional prospective trials are needed before this is adopted into clinical practice. Alemtuzumab and eltrombopag have been studied for treatment of AA; recruiting is ongoing in clinical trials to assess the appropriate dosing strategy and place in therapy.
- Outcomes of immunosuppressant therapy with lower dose of antithymocyte globulin and cyclosporine in aplastic anemia. [JOURNAL ARTICLE]
- Hematology 2014 Sep 2.
Objective Immunosuppressant therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is an established treatment option for patients with aplastic anemia (AA), who are not eligible for allogeneic stem cell transplantation. However, data on the dose of ATG and its efficacy from the developing countries is minimal. Methods We performed a retrospective analysis of all AA patients (age >12 years), treated with equine ATG and cyclosporine from a single center in India. Patients who received or were eligible for stem cell transplantation were excluded. The overall response rate (ORR) to IST was calculated at 3 and 6 months. We also determined the influence of using a lower dose of Atgam ATG (25 mg/kg/day × 4 days) and compared its efficacy against the standard dose of locally manufactured Thymogam ATG (40 mg/kg/day × 4 days). Factors influencing the ORR were analyzed using Fisher's exact test with a significant P < 0.05. Results Thirty-nine patients with AA treated with ATG and cyclosporine were studied. Median age was 31 years with a male:female ratio of 0.85:1. The ORR was 58% at 3 months, 77% at 6 months and was similar with lower dose Atgam and standard dose Thymogam. On multivariate analysis of ORR at 6 months, the interval between the onset of symptoms to the initiation of therapy was close to attaining statistical significance (odds ratio 23.53, P value 0.053) while the other variables did not attain significance. Conclusions IST with equine ATG in a lower dose (25 mg/kg/day × 4 days) and cyclosporine is a feasible and effective treatment option for AA in resource-constrained settings.
- New Directions for Rabbit Antithymocyte Globulin (Thymoglobulin(®)) in Solid Organ Transplants, Stem Cell Transplants and Autoimmunity. [JOURNAL ARTICLE]
- Drugs 2014 Aug 28.
In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn's disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.