A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure

Many bone marrow failure syndromes in humans are now recognized to result from immunological mechanisms. These diseases include aplastic anemia; single hematopoietic lineage failures such as pure red cell aplasia, Diamond Blackfan Anemia, agranulocytosis, and amegakaryocytic thrombocytopenic purpura; and some types of myelodysplasia. Patients with these conditions, who may suffer variable degrees of anemia, leukocytopenia, and thrombocytopenia, alone or combination, have been shown to respond to a wide variety of immunosuppressive agents, ranging from corticosteroids to cyclosporine (CSA) and antithymocyte globulin (ATG). However, except for severe aplastic anemia, which has been shown to be appropriately treated with either bone marrow transplantation or a combination of ATG and CSA, single agents or regimens have usually not been applied systematically to other immune-mediated hematologic diseases. In an effort to discover other and especially less toxic treatments for immunologically-mediated bone marrow diseases, we seek to apply a new therapy, a humanized anti-interleukin-2 receptor (lL-2R) monoclonal antibody (mAb ), to a subset of patients with bone marrow failure. Anti-IL-2R mAb acts against activated lymphocytes, thus sharing an important mechanism of action with ATG. However, the mAb is much less toxic than ATG and may be administered to outpatients at relatively infrequent intervals (every 2 weeks). The primary objective is to test the efficacy of anti-IL-2R mAb (daclizumab), we propose to treat four groups of patients: 1) moderate aplastic anemia, 2) single lineage failure states including pure red cell aplasia or Diamond Blackfan anemia, 3) relapse of severe aplastic anemia and 4) refractory severe aplastic anemia not responding to both horse and rabbit ATG/CsA. Subjects will receive daclizumab once every other week for a total of 5 doses. Patients relapsing after response to initial treatment may be treated with 2 additional courses of daclizumab. In November 2005, the relapsed and refractory severe aplastic anemia arms were closed by the Data and Safety Monitoring Board (DSMB) for lack of efficacy. In October 2008, the moderate aplastic anemia arm was closed by the DSMB when the data was determined sufficient for making statistical inferences regarding the original hypotheses. In October 2008, accrual to the Diamond Blackfan anemia arm was closed by the DSMB for lack of accrual. The Primary endpoint is hematologic response at 3 months. Secondary endpoints include transfusion dependence, overall survival, life threatening toxicity, transformation-free survival, and response duration.