Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in 70% of patients, but most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For these patients, comparable long term survival is attainable with immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA). However, of those patients treated with horse ATG(h-ATG)/CsA, one quarter to one third will not respond, and about 50% of responders relapse. Auto-reactive T cells may be resistant to the effect of ATG/CsA (non-responders), while in others residual auto-reactive T cells expand post-treatment, leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). As long term survival is correlated to response rates and robustness of hematopoietic recovery, novel immunosuppressive regimens that can achieve hematologic response and decrease relapse rates are needed.~This trial will compare the effectiveness of three immunosuppressive regimens as first line therapies in patients with SAA with early hematologic response as the primary endpoint, as well as assess the role of extended CsA treatment after h-ATG in reducing numbers of late events of relapse and clonal evolution. Randomization is employed to obtain an equal distribution of subject to each arm; comparisons of early hematologic responses will be made among the rates observed among the three concurrent arms (rabbit-ATG [r-ATG] versus standard h-ATG; alemtuzumab vs standard h-ATG). For long course CSA, comparison of primary end points will be to well established historic relapse rate of 38% at 2-3 years and a cumulative rate of clonal evolution of 15%.~In the original design subjects were randomized to one of three different regimens: h-ATG + 6 months CsA followed by an 18 month CsA taper; r-ATG + 6 months CsA; or alemtuzumab (Campath). Subjects failing to respond to r-ATG will be crossed over to alemtuzumab (Campath), and subjects failing alemtuzumab (Campath) will be crossed over to r-ATG. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath) as salvage therapy.~The Campath arm was closed to new accrual for lack of efficacy on 4/10/2008. Subsequently, new accruals will be randomized to h-ATG + 6 months CsA followed by an 18 month CsA taper or r-ATG + 6 months CsA. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath ) as salvage therapy. Subjects who fail to respond to r-ATG + 6 months CsA will be offered treatment with h-ATG as salvage therapy or will go off-study to alternative treatments or stem cell transplant (from sibling or unrelated donor).~The primary endpoint will be hematologic response, defined as no longer meeting criteria for SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at 6 months, response at 3 and 12 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia. Long-course CSA will be assessed separately for its efficacy in reducing late events of relapse and evolution by comparison to historical control data.
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in 70% of patients, but most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For these patients, comparable long term survival is attainable with immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA). However, of those patients treated with horse ATG(h-ATG)/CsA, one quarter to one third will not respond, and about 50% of responders relapse. Auto-reactive T cells may be resistant to the effect of ATG/CsA (non-responders), while in others residual auto-reactive T cells expand post-treatment, leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). As long term survival is correlated to response rates and robustness of hematopoietic recovery, novel immunosuppressive regimens that can achieve hematologic response and decrease relapse rates are needed.~This trial will compare the effectiveness of three immunosuppressive regimens as first line therapies in patients with SAA with early hematologic response as the primary endpoint, as well as assess the role of extended CsA treatment after h-ATG in reducing numbers of late events of relapse and clonal evolution. Randomization is employed to obtain an equal distribution of subject to each arm; comparisons of early hematologic responses will be made among the rates observed among the three concurrent arms (rabbit-ATG [r-ATG] versus standard h-ATG; alemtuzumab vs standard h-ATG). For long course CSA, comparison of primary end points will be to well established historic relapse rate of 38% at 2-3 years and a cumulative rate of clonal evolution of 15%.