Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia

Study Overview
=================
Brief Summary
-----------------
Severe aplastic anemia, characterized by pancytopenia and a hypocellular bone marrow, is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of patients will not show blood count improvement after ATG/CsA. General experience and small pilot studies have suggested that such patients may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor blood count responses to a single course of ATG, even when transfusion-independence is achieved, have a markedly worse prognosis than patients with robust hematologic improvement. The management of such cases is uncertain. This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive a further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin, r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H ). Primary endpoint will be response rate at 3 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 3 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

Detailed Description
-----------------
Severe aplastic anemia, characterized by pancytopenia and a hypocellular bone marrow, is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of patients will not show blood count improvement after ATG/CsA. General experience and small pilot studies have suggested that such patients may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor blood count responses to a single course of ATG, even when transfusion-independence is achieved, have a markedly worse prognosis than patients with robust hematologic improvement. The management of such cases is uncertain. This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin , r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H ). Primary endpoint will be response rate at 6 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 6 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

Official Title
-----------------
A Randomized Trial of Immunosuppression in Aplastic Anemia Patients With Refractory Pancytopenia or Suboptimal Hematologic Response After h-ATG/CsA Treatment

Conditions
-----------------
Aplastic Anemia

Intervention / Treatment
-----------------
* Drug: Campath-1H
* Drug: r-ATG
* Drug: CsA


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Severe aplastic anemia confirmed at NIH by: Bone marrow cellularity less than 30% (excluding lymphocytes) At least two of the following: Absolute neutrophil count less than 500/microL; Platelet count less than 20,000/ microL; Reticulocyte count less than 60,000/ microL. Severe aplastic anemia refractory to prior course(s) of h-ATG/CsA defined after 3 months from treatment with less or equal to 4 years from receiving h-ATG. OR Suboptimal response to initial immunosuppression with h-ATG/CsA as defined by platelet and reticulocyte count less than 50,000 /microL at 3 months. Age greater than or equal to 2 years of age EXCLUSION CRITERIA: Diagnosis of Fanconi anemia. Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microL) will not be excluded initially if results of cytogenetics are not available or pending. If evidence of a clonal disorder is later identified, the subject will go off study. Prior treatment courses with rabbit ATG or high dose cyclophosphamide (200 mg/kg or equivalent). Infection not adequately responding to appropriate therapy. Underlying immunodeficiency state including seropositivity for HIV. Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within two weeks of enrollment. Previous hypersensitivity to Campath-1H or its components. 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. Serum creatinine greater than 2.5 mg/dL. Current pregnancy or lactation or unwillingness to take contraceptives. Inability to understand the investigational nature of the study or give informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: r-ATG /cyclosporine<br>A randomized trial of rabbit anti-thymocyte globulin (r-ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day). | Drug: r-ATG<br>* Rabbit ATG 3.5mg/kg/day for consecutive 5 days<br>* Other names: Rabbit Anti-Thymoglobulin;Drug: CsA<br>* CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs.<br>* Other names: Cyclosporine;|
| Experimental: Alemtuzumab (Campath-1H)<br>A randomized trial of rabbit anti-thymocyte globulin (ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day). | Drug: Campath-1H<br>* Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day).<br>* Other names: Alemtuzumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Number of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment at 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count | Number of participants with robust hematologic recovery with reticulocyte or platelet count ≥ 50,000/uL | 6 months | 
| Percentage of Cumulative Incidence of Relapse in Participants | Percentage of cumulative incidence of relapse of disease in participants | 3 year | 
| Percentage of Cumulative Incidence of Clonal Evolution in Participants | Percent of cumulative incidence of clonal evolution in participants to either paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia or acute leukemia. | 3 years | 
| Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Percentage of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment | 3 months and 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Alemtuzumab (Campath-1H), Rabbit ATG, Severe Aplastic Anemia, Cyclosporine, Thrombocytopenia, Leukopenia, Neutropenia, Autoimmunity, Relapse, Anemia