Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia
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| ClinicalTrials.gov Identifier: NCT00260689 |
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Recruitment Status :
Completed
First Posted : December 1, 2005
Results First Posted : June 8, 2017
Last Update Posted : June 8, 2017
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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%.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Immunosuppresion Thrombocytopenia Pancytopenia Neutropenia | Biological: Anti-thymocyte globulin (rabbit) Biological: Anti-thymocyte globulin (horse) Drug: Cyclosporine Drug: Alemtuzumab | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 136 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Study Start Date : | November 28, 2005 |
| Actual Primary Completion Date : | May 4, 2016 |
| Actual Study Completion Date : | May 4, 2016 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Horse ATG/CsA taper
h-ATG (Anti-thymocyte globulin (horse)) + 6 months CsA (Cyclosporine) followed by an 18 month CsA taper
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Biological: Anti-thymocyte globulin (horse) Drug: Cyclosporine |
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Experimental: Rabbit ATG/CsA
r-ATG (Anti-thymocyte globulin (rabbit)) + 6 months CsA (Cyclosporine)
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Biological: Anti-thymocyte globulin (rabbit) Drug: Cyclosporine |
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Experimental: Alemtuzumab
Alemtuzumab administered for 10 days
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Drug: Alemtuzumab
Other Name: Campath |
- Hematologic Response [ Time Frame: 3 months ]
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.
- Hematologic Response [ Time Frame: 6 months ]
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.
- Hematologic Response [ Time Frame: 12 months ]
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.
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| Ages Eligible for Study: | 2 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
-INCLUSION CRITERIA:
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00260689
| 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) |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Heart, Lung, and Blood Institute (NHLBI) |
| ClinicalTrials.gov Identifier: | NCT00260689 |
| Other Study ID Numbers: |
060034 06-H-0034 ( Other Identifier: NIH ) |
| First Posted: | December 1, 2005 Key Record Dates |
| Results First Posted: | June 8, 2017 |
| Last Update Posted: | June 8, 2017 |
| Last Verified: | May 15, 2017 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NIH Biomedical Translational Research Information System (BTRIS) |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Immunosuppression T-cells Hematopoiesis Autoimmunity |
Thrombocytopenia Severe Aplastic Anemia SAA |
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Anemia Thrombocytopenia Neutropenia Anemia, Aplastic Pancytopenia Hematologic Diseases Blood Platelet Disorders Agranulocytosis Leukopenia Leukocyte Disorders Bone Marrow Diseases Cyclosporine Alemtuzumab Cyclosporins |
Antilymphocyte Serum Thymoglobulin Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antifungal Agents Anti-Infective Agents Dermatologic Agents Antirheumatic Agents Calcineurin Inhibitors Antineoplastic Agents, Immunological Antineoplastic Agents |