PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4, CD8 T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
Bone marrow (BM) is a source of various stem and progenitor cells in the adult, and it is able to regenerate a variety of tissues following transplantation. In the 1970s the first BM stem cells identified were hematopoietic stem cells (HSCs). HSCs have the potential to differentiate into all myeloid (including erythroid) and lymphoid cell lineages in vitro and reconstitute the entire hematopoietic and immune systems following transplantation in vivo. More recently, nonhematopoietic stem and progenitor cells have been identified that can differentiate into other cell types such as endothelial progenitor cells (EPCs), contributing to the neovascularization of tumors as well as ischemic tissues, and mesenchymal stem cells (MSCs), which are able to differentiate into many cells of ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, stem and progenitor cells can be forced out of the BM to circulate into the peripheral blood, a phenomenon called "mobilization." This chapter reviews the molecular mechanisms behind mobilization and how these have led to the various strategies employed to mobilize BM-derived stem and progenitor cells in experimental and clinical settings. Mobilization of HSCs will be reviewed first, as it has been best-explored--being used extensively in clinics to transplant large numbers of HSCs to rescue cancer patients requiring hematopoietic reconstitution--and provides a paradigm that can be generalized to the mobilization of other types of BM-derived stem and progenitor cells in order to repair other tissues.
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