Aplastic Anemia
Conditions
Keywords
Alemtuzumab (Campath-1H), Rabbit ATG, Severe Aplastic Anemia, Cyclosporine, Thrombocytopenia, Leukopenia, Neutropenia, Autoimmunity, Relapse, Anemia
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.
Interventions
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 6 months | Number of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count | 6 months | Number of participants with robust hematologic recovery with reticulocyte or platelet count ≥ 50,000/uL |
| Percentage of Cumulative Incidence of Relapse in Participants | 3 year | Percentage of cumulative incidence of relapse of disease in participants |
| Percentage of Cumulative Incidence of Clonal Evolution in Participants | 3 years | Percent of cumulative incidence of clonal evolution in participants to either paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia or acute leukemia. |
| Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 3 months and 6 months | Percentage of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| r-ATG /Cyclosporine 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).
r-ATG: Rabbit ATG 3.5mg/kg/day for consecutive 5 days
CsA: CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. | 27 |
| Alemtuzumab (Campath-1H) 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).
Campath-1H: Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
Baseline characteristics
| Characteristic | r-ATG /Cyclosporine | Alemtuzumab (Campath-1H) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 9 Participants | 12 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 14 Participants | 36 Participants |
| Region of Enrollment United States | 27 participants | 27 participants | 54 participants |
| Sex: Female, Male Female | 11 Participants | 13 Participants | 24 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 27 | 4 / 27 |
| other Total, other adverse events | 7 / 27 | 12 / 27 |
| serious Total, serious adverse events | 7 / 27 | 12 / 27 |
Outcome results
Primary
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
Time frame: 6 months
Population: 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| r-ATG /Cyclosporine | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | No Response | 18 participants |
| r-ATG /Cyclosporine | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Partial Response | 9 participants |
| r-ATG /Cyclosporine | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Complete Response | 0 participants |
| Alemtuzumab (Campath-1H) | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | No Response | 17 participants |
| Alemtuzumab (Campath-1H) | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Partial Response | 9 participants |
| Alemtuzumab (Campath-1H) | Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | Complete Response | 0 participants |
Secondary
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
Time frame: 6 months
Population: 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| r-ATG /Cyclosporine | Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count | 9 Participants |
| Alemtuzumab (Campath-1H) | Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count | 9 Participants |
Secondary
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.
Time frame: 3 years
Population: 1 participant was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-ATG /Cyclosporine | Percentage of Cumulative Incidence of Clonal Evolution in Participants | 16 Percentage of Cumulative Incidence |
| Alemtuzumab (Campath-1H) | Percentage of Cumulative Incidence of Clonal Evolution in Participants | 5 Percentage of Cumulative Incidence |
Secondary
Percentage of Cumulative Incidence of Relapse in Participants
Percentage of cumulative incidence of relapse of disease in participants
Time frame: 3 year
Population: 1 participants was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-ATG /Cyclosporine | Percentage of Cumulative Incidence of Relapse in Participants | 19 percentage of cumulative incidence |
| Alemtuzumab (Campath-1H) | Percentage of Cumulative Incidence of Relapse in Participants | 9 percentage of cumulative incidence |
Secondary
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
Time frame: 3 months and 6 months
Population: 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| r-ATG /Cyclosporine | Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 6 Months | 33 percentage of participants |
| r-ATG /Cyclosporine | Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 3 Months | 19 percentage of participants |
| Alemtuzumab (Campath-1H) | Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 3 Months | 19 percentage of participants |
| Alemtuzumab (Campath-1H) | Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. | 6 Months | 37 percentage of participants |