Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease.
ABSTRACT We prospectively evaluated the safety and efficacy of the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Seven patients were treated with 375 mg/m(2) rituximab weekly for 4 consecutive weeks. Rituximab was well tolerated with no severe toxicity observed during treatment. At 1 year, 3 patients showed a partial response to rituximab therapy, 3 had stable disease, and 1 had progressive disease. Rituximab allowed a reduction in the dose of steroids in 4 patients. Responsive manifestations included mild to moderate skin and oral lesions, and immune hemolytic anemia, and thrombocytopenia. Severe manifestations involving the skin, fascia, and eye did not respond to treatment. These observations suggest that rituximab therapy may be effective for select patients with corticosteroid-refractory chronic GVHD that is not advanced.
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ABSTRACT: The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the efficacy of B-cell-ablative therapy in lymphoproliferative disorders, autoimmune diseases and graft rejection. Anti-B-cell antibodies (Abs) directed against CD20 have therefore been generated, and of these, rituximab was the first anti-CD20 monoclonal Ab (mAb) to be applied. Rituximab-mediated apoptosis, complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity differ from one disease to another, and, for the same disease, from one patient to another. This knowledge has prompted the development of new anti-CD20 mAbs in the hope of improving B-cell depletion. The inclusion of CD20/anti-CD20 complexes in large lipid rafts (LRs) enhances the results of some, but not all, anti-CD20 mAbs, and it may be possible to include smaller LRs. Lipid contents of membrane may be abnormal in malignant B-cells, and could explain resistance to treatment. The function of these mAbs and the importance of LRs warrant further investigation. A detailed understanding of them will increase results for B-cell depletion in lymphoproliferative diseases.OncoTargets and Therapy 01/2010; 3:99-109. · 2.07 Impact Factor
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ABSTRACT: This article summarizes recent reports on the risks, pathogenesis and treatment of chronic graft-versus-host disease (GVHD). Chronic GVHD remains an elusive disorder to characterize and to treat. Recent evidence on tolerance induction by regulatory T-cells and on B-cell involvement shed some insights into the pathogenesis of chronic GVHD. In a recent large comparative study, the overall risk profiles for acute and for chronic GVHD were similar, but risk factors were not changed after adjustment for prior acute GVHD, supporting the concept that chronic GVHD is not an end stage of acute GVHD. Glucocorticoids remain the standard initial treatment of chronic GVHD, but the outcomes are not satisfactory, particularly for patients with high-risk features. Many treatments for chronic GVHD including extracorporeal photopheresis, rituximab, sirolimus, mycofenolate mofetil, imatinib, pentostatin and infusion of mesenchymal stem cells have been reported in several retrospective and relatively small phase I/II studies with a wide range of overall responses. No current therapies used for chronic GVHD have been approved by the US Food and Drug Administration. Large well designed prospective studies are warranted to establish better treatments. Targeted therapies based on the pathogenesis of chronic GVHD may lead to better outcomes.Current opinion in hematology 09/2011; 18(6):414-20. · 5.19 Impact Factor
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ABSTRACT: Steroid refractory chronic graft-versus-host disease (cGVHD) is associated with a significant morbidity and mortality. Although first-line treatment of cGVHD is based on controlled trials, second-line treatment is almost solely based on phase II trials or retrospective analyses. The consensus conference on clinical practice in cGVHD held in Regensburg aimed to achieve a consensus on the current evidence of treatment options as well as to provide guidelines for daily clinical practice. Treatment modalities are the use of steroids and calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalidomide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil, methotrexate, cyclophosphamide, pentostatin). Recent reports showed some efficacy of rituximab, alemtuzumab, and etanercept in selected patients. Moreover, tyrosine kinase inihibitors such as imatinib came into the field because of their ability to interfere with the platelet-derived growth factor (PDGF-R) pathway involved in fibrosis. An other treatment option is low-dose thoracoabdominal irradiation. Although different treatment options are available, the "trial-and-error system" remains the only way to identify the drug effective in the individual patient, and valid biomarkers are eagerly needed to identify the likelihood of response to a drug in advance. Moreover, the sparse evidence for most treatment entities indicates the urgent need for systematic evaluation of second-line treatment options in cGVHD.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):1-17. · 3.15 Impact Factor