American journal of hematology
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Multicenter Study Clinical Trial
Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.
The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. ⋯ The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).
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Impact of a venous thromboembolism prophylaxis "smart order set": Improved compliance, fewer events.
Venous thromboembolism (VTE) affects over 700,000 Americans annually. Prophylaxis reduces the risk of VTE by 60% but many patients still do not receive risk-appropriate VTE prophylaxis. To improve our institution's VTE prophylaxis performance, we developed mandatory computerized clinical decision support-enabled "smart order sets" that required providers to assess VTE risk factors and contraindications to pharmacologic prophylaxis. ⋯ Radiographically documented symptomatic VTE within 90 days of hospital discharge declined from 2.5% to 0.7% (P = 0.002). Preventable harm was completely eliminated (1.1% to 0%, P = 0.001) with no difference in major bleeding or all-cause mortality. A VTE prophylaxis computerized clinical decision support-enabled "smart order set" improved prescription of risk-appropriate VTE prophylaxis, reduced symptomatic VTE and eliminated preventable harm from VTE without increasing major bleeding.
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Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus and a small risk of disease progression into acute myeloid leukemia or myelofibrosis. ⋯ Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications. In low risk patients, this is effectively and safely accomplished by the use of low-dose aspirin in both PV and ET and phlebotomy (hematocrit target of <45%) in PV. In high risk patients, treatment with hydroxyurea is additionally recommended, although not mandated in older patients without JAK2V617F or CV risk factors. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. Screening for clinically significant AvWS is recommended before administrating aspirin in the presence of extreme thrombocytosis.
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Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. ⋯ Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.