Alemtuzumab to Treat Severe Aplastic Anemia
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Anemia |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 2 - 110 |
| Updated: | 10/24/2018 |
| Start Date: | September 15, 2005 |
| End Date: | October 2, 2019 |
A Pilot Study of Alemtuzumab (Campath) in Patients With Relapsed or Refractory Severe Aplastic Anemia
This study will evaluate the safety and usefulness of a new immunosuppressive drug,
alemtuzumab (Campath ), 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.
alemtuzumab (Campath ), 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.
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 ) is a humanized IgG1 monoclonal antibody directed
against the CD52 protein; CD52 is expressed on all lymphocytes and monocytes. Alemtuzumab
(Campath ) 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 )
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.
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 ) is a humanized IgG1 monoclonal antibody directed
against the CD52 protein; CD52 is expressed on all lymphocytes and monocytes. Alemtuzumab
(Campath ) 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 )
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.
- 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:
Known 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
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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