Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia

Study Overview
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Brief Summary
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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%.

Detailed Description
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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.

Official Title
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A Randomized Study of Three Immunosuppressive Regimens in Treatment Naive Patients With Severe Aplastic Anemia: Horse ATG/CsA Taper vs Rabbit-ATG/CsA vs Alemtuzumab

Conditions
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Immunosuppresion, Thrombocytopenia, Pancytopenia, Neutropenia

Intervention / Treatment
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* Biological: Anti-thymocyte globulin (rabbit)
* Biological: Anti-thymocyte globulin (horse)
* Drug: Cyclosporine
* Drug: Alemtuzumab


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Severe aplastic anemia characterized by bone marrow cellularity less than 30% (excluding lymphocytes) and at least two of the following: Absolute neutrophil count less than 500/microliter Platelet count less than 20,000/microliter Absolute reticulocyte count less than 60,000/microliter Age greater than or equal to 2 years old Weight greater than 12 kg EXCLUSION CRITERIA: Diagnosis of Fanconi's anemia Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microliter) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder is later identified, the patient will go off study. Prior immunosuppressive therapy with ATG, ALG, alemtuzumab, or high dose cyclophosphamide. Infection not adequately responding to appropriate therapy. Serologic evidence of HIV infection. Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within 2 weeks of enrollment. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy, or that death within 7-10 days is likely. Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible. Current pregnancy, or unwillingness to take oral contraceptives or refrain from pregnancy if of childbearing potential. Not able to understand the investigational nature of the study or give informed consent.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Horse ATG/CsA taper<br>h-ATG (Anti-thymocyte globulin (horse)) + 6 months CsA (Cyclosporine) followed by an 18 month CsA taper | Biological: Anti-thymocyte globulin (horse)<br> <br> Drug: Cyclosporine<br> <br> |
| Experimental: Rabbit ATG/CsA<br>r-ATG (Anti-thymocyte globulin (rabbit)) + 6 months CsA (Cyclosporine) | Biological: Anti-thymocyte globulin (rabbit)<br> <br> Drug: Cyclosporine<br> <br> |
| Experimental: Alemtuzumab<br>Alemtuzumab administered for 10 days | Drug: Alemtuzumab<br> <br> * Other names: Campath;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response | Hematologic response is defined as subjects having blood counts no longer meeting the standard (Camitta) criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) Absolute neutrophil count > 500/ μL Platelet count > 20,000/ μL Reticulocyte count > 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria. | 3 months | 
| Hematologic Response | Hematologic response is defined as subjects having blood counts no longer meeting the standard (Camitta) criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) Absolute neutrophil count > 500/ μL Platelet count > 20,000/ μL Reticulocyte count > 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria. | 6 months | 
| Hematologic Response | Hematologic response is defined as subjects having blood counts no longer meeting the standard (Camitta) criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) Absolute neutrophil count > 500/ μL Platelet count > 20,000/ μL Reticulocyte count > 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, T-cells, Hematopoiesis, Autoimmunity, Thrombocytopenia, Severe Aplastic Anemia, SAA