Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia
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Purpose
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(Registered Trademark)). 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.
| Condition | Intervention | Phase |
|---|---|---|
|
Aplastic Anemia |
Drug: Alemtuzumab (Campath-1H) Drug: Thymoglobulin (r-ATG) Drug: Cyclosporine (CsA) |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Randomized Trial of Immunosupression in Aplastic Anemia Patients With Refractory Pancytopenia or Suboptimal Hematologic Response After h-ATG/CsA Treatment |
- No longer meeting criteria for severe aplastic anemia. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Secondary endpoints will include: a) relapse; b) robustness of hematologic recovery w/ANC or platelet count greater than or equal to 50000/microL at 3 months; c) 6-month response rate; d) clonal evoluation to MDS, PNH or acute leukemia; and e) s... [ Time Frame: months/years ] [ Designated as safety issue: No ]
| Enrollment: | 54 |
| Study Start Date: | July 2003 |
| Estimated Study Completion Date: | July 2013 |
| Estimated Primary Completion Date: | July 2013 (Final data collection date for primary outcome measure) |
-
Drug: Alemtuzumab (Campath-1H)
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(Registered Trademark), r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H(Registered Trademark)). 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.
Eligibility| Ages Eligible for Study: | 2 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
- 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.
Contacts and Locations| United States, Maryland | |
| National Institutes of Health Clinical Center, 9000 Rockville Pike | |
| Bethesda, Maryland, United States, 20892 | |
| Principal Investigator: | Danielle M Townsley, M.D. | National Heart, Lung, and Blood Institute (NHLBI) |
More Information
Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ) |
| ClinicalTrials.gov Identifier: | NCT00065260 History of Changes |
| Other Study ID Numbers: | 030249, 03-H-0249 |
| Study First Received: | July 18, 2003 |
| Last Updated: | May 1, 2013 |
| Health Authority: | United States: Federal Government |
Keywords provided by National Institutes of Health Clinical Center (CC):
|
Alemtuzumab (Campath-1H) Rabbit ATG Severe Aplastic Anemia Cyclosporine Thrombocytopenia |
Leukopenia Neutropenia Autoimmunity Relapse Anemia |
Additional relevant MeSH terms:
|
Anemia Anemia, Aplastic Hematologic Diseases Bone Marrow Diseases Antilymphocyte Serum Cyclosporins Cyclosporine Campath 1G Alemtuzumab Immunosuppressive Agents Immunologic Factors |
Physiological Effects of Drugs Pharmacologic Actions Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antifungal Agents Anti-Infective Agents Therapeutic Uses Dermatologic Agents Antirheumatic Agents Antineoplastic Agents |
ClinicalTrials.gov processed this record on May 23, 2013