Alemtuzumab to Treat Severe Aplastic Anemia
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Purpose
This study will evaluate the safety and usefulness of a new immunosuppressive drug, alemtuzumab (Campath(Registered Trademark)), in patients with severe aplastic anemia (SAA). SAA is a rare and serious blood disorder in which the bone marrow stops making red blood cells, white blood cells and platelets. Alemtuzumab is a monoclonal antibody that attaches to and kills white blood cells called lymphocytes. In certain types of aplastic anemia, lymphocytes are responsible for the destruction of stem cells in the bone marrow, leading to a decrease in blood counts. Because alemtuzumab destroys lymphocytes, it may be effective in treating aplastic anemia. Alemtuzumab is currently approved to treat chronic lymphocytic leukemia and is also helpful in other conditions that require immunosuppression, such as rheumatoid arthritis and immune cytopenias.
Patients 2 years of age and older with severe aplastic anemia whose disease does not respond to immunosuppressive therapy or has recurred following immunosuppressive therapy may be eligible for this study. Participants undergo the following tests and procedures:
- Pretreatment evaluation: Patients have a medical history, physical examination, blood tests, electrocardiogram (EKG), echocardiogram, 24-hour Holter monitor (continuous 24-hour monitoring of electrical activity of the heart), bone marrow biopsy (withdrawal through a needle of a small sample of bone marrow for analysis).
- Placement of a central line, if needed: An intravenous line (tube) is placed into a major vein in the patient's chest. It can stay in the body for the entire treatment period and be used to give chemotherapy or other medications, including antibiotics and blood transfusions, if needed, and to withdraw blood samples.
- Alemtuzumab therapy: Patients are admitted to the NIH Clinical Center for the first few injections for close monitoring of side effects. After receiving an initial small test dose, patients begin the first of ten daily injections under the skin, each lasting about 2 hours. Once patients tolerate the infusions with minimal or no side effects, they may be given the remaining infusions on an outpatient basis. Patients who relapse after their initial response to alemtuzumab are given cyclosporine to see if this drug will boost their immune response.
- Patients receive transfusions, growth factors, and antibiotic therapy, as needed.
- Infection therapy: Patients are given aerosolized pentamidine to protect against lung infections and valacyclovir to protect against herpes infections.
- A blood test is done and vital signs are measured every day while patients receive alemtuzumab.
- Patients have an echocardiogram and 24-hour Holter monitor after the last dose of alemtuzumab.
- Blood tests are done weekly for the first 3 months after alemtuzumab administration, then every other week until 6 months.
Patients return to the NIH for follow-up visits 1 month, 3 months, 6 months, and yearly for 5 years after the last dose of alemtuzumab for the following tests and evaluations:
- Blood test
- Repeat echocardiogram at 3-month visit
- Repeat bone marrow biopsy 6 months and 12 months after alemtuzumab, then as clinically indicated for 5 years.
| Condition | Intervention | Phase |
|---|---|---|
|
Relapsed or Refractory Severe Aplastic Anemia Severe Aplastic Anemia |
Drug: Alemtuzumab (Campath(Registered Trademark)) |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Pilot Study of Alemtuzumab (Campath) in Patients With Relapsed or Refractory Severe Aplastic Anemia |
- Response rate at six months, defined as no longer satisfying blood count criteria for SAA. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Relapse, robustness of the hematopoietic recovery at three and six months, three months responses, survival, and clonal evolution to myelodysplasia and acute leukemia. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 67 |
| Study Start Date: | September 2005 |
| Estimated Study Completion Date: | July 2013 |
| Estimated Primary Completion Date: | July 2013 (Final data collection date for primary outcome measure) |
-
Drug: Alemtuzumab (Campath(Registered Trademark))
Hematopoietic stem cell destruction in many human bone marrow failure syndromes is now recognized to be secondary to immune mechanisms. Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens. However, a significant minority of patients with SAA fail to respond to a single course of horse antithymocyte globulin and cyclosporine, and other patients experience relapse, especially on discontinuation of therapy. Pancytopenia secondary to refractory or relapsed aplastic anemia has a poor prognosis, with death usually resulting from infectious complications. Alemtuzumab (Campath(Registered Trademark)) is a humanized IgG1 monoclonal antibody directed against the CD52 protein; CD52 is expressed on all lymphocytes and monocytes. Alemtuzumab (Campath(Registered Trademark)) produces profound and persistent lymphopenia. The antibody has been used to treat a wide range of autoimmune diseases, lymphoid malignancies, and in solid organ and hematopoietic stem cell transplantation. In our limited experience with alemtuzumab for the treatment of SAA refractory to horse antithymocyte globulin, meaningful hematologic responses have been observed and toxicity has been modest.
We therefore propose a non-randomized pilot phase II study of this humanized monoclonal antibody in SAA relapsed or refractory to ATG. Commercially available alemtuzumab (Campath(Registered Trademark)) will be administered at 10 mg per day subcutaneously for 10 days total.
The primary end point of the study is the response rate at 6 months, defined as no longer satisfying blood count criteria for SAA.
Relapse, robustness of the hematopoietic recovery at 3 and 6 months, 3 months responses, survival, and clonal evolution to myelodysplasia and acute leukemia will be secondary end points.
Eligibility| Ages Eligible for Study: | 2 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
Relapsed severe aplastic anemia after initial hematologic response to a prior course of h-ATG or r-ATG based immunosuppression
Or
Refractory severe aplastic anemia not responding to both horse-ATG and rabbit ATG-based immunosuppression
The criteria for severe aplastic anemia are two of the three criteria:
- Absolute neutrophil count less than or equal to 500 /mm(3)
- Platelets to less than or equal to 20,000/mm(3)
- Absolute reticulocyte count less than 60,000 /microL
Age greater than or equal to 2 years old and greater than 12 kg
Prospective subjects or their parent(s)/responsible guardian(s) must be able to comprehend and be willing to sign an informed consent.
EXCLUSION CRITERIA:
Diagnosis of Fanconi's anemia
Evidence of a clonal disorder on cytogenetics. In the refractory disease setting, prospective subjects with super severe neutropenia (ANC less than 200 /microL) will not be excluded if results of cytogenetics are not available or pending.
Infection not adequately responding to appropriate therapy
HIV positivity
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
Previous hypersensitivity to alemtuzumab or its components
Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
Current pregnancy, or unwilling 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
Contacts and Locations| Contact: Olga J Rios, R.N. | (301) 496-4462 | riosj@mail.nih.gov |
| Contact: Danielle M Townsley, M.D. | (301) 402-3477 | townsleydm@nhlbi.nih.gov |
| United States, Maryland | |
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
| Bethesda, Maryland, United States, 20892 | |
| Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 prpl@mail.cc.nih.gov | |
| 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: | NCT00195624 History of Changes |
| Other Study ID Numbers: | 050242, 05-H-0242 |
| Study First Received: | September 16, 2005 |
| Last Updated: | May 1, 2013 |
| Health Authority: | United States: Federal Government |
Keywords provided by National Institutes of Health Clinical Center (CC):
|
Immunosuppression Alemtuzumab/Campath Severe Aplastic Anemia T-Cells Hematopoiesis |
Autoimmunity Thrombocytopenia Neutropenia SAA |
Additional relevant MeSH terms:
|
Bone Marrow Diseases Anemia Anemia, Aplastic Hematologic Diseases Alemtuzumab Campath 1G |
Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 23, 2013