Cyclophosphamide Plus Cyclosporine in Treatment-na ve Severe Aplastic Anemia
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Purpose
Background:
- Severe aplastic anemia (SAA) can lead to problems with bone marrow health and result in low blood cell counts, which require frequent transfusions. Standard treatment for SAA involves injections of antithymocyte globulin (ATG) plus cyclosporine (CsA). This regimen has been shown to improve the blood counts in about two-thirds of patients. However, the ATG/CsA regimen has the following limitations: (a) the disease can come back (relapse) in about one-third of patients who improve initially; and (b) in about 10% to 15% of cases, certain types of bone marrow cancer (such as myelodysplasia and leukemia) can develop (called evolution). Experience with other drugs in SAA such as cyclophosphamide suggests that similar response rates to ATG/CsA can be achieved with a lower risk of relapse and clonal evolution. However, cyclophosphamide was found to have significant side effects in SAA when investigated over 10 years ago due to increase risk of fungal infections.
- Better antibiotic drugs against fungus have been developed and are widely used to treat patients who have low white blood cell counts and are at risk of developing infections. In SAA patients in particular, these newer antibiotics have had a large impact in preventing and treating fungus infections. Researchers are revisiting the use of cyclophosphamide in SAA treatment, and plan to give a lower dose of CsA in combination with the immune-suppressing drug cyclophosphamide, as well as antibiotics to protect against infections, as a possible treatment for the disease.
Objectives:
- To determine the safety and effectiveness of the combination of cyclophosphamide and cyclosporine in treating severe aplastic anemia that has not been treated with immunosuppressive therapy.
Eligibility:
- Individuals at least 2 years of age who have severe aplastic anemia that has not been treated with immunosuppressive therapy.
Design:
- After initial screening, medical history, and blood tests, participants will be admitted to the inpatient unit at the National Institutes of Health Clinical Center.
- Participants will receive 4 days of cyclophosphamide, followed by cyclosporine. Cyclosporine treatment will begin the day after the end of cyclophosphamide treatment and will continue for the following 6 months. The doses will be monitored and adjusted in response to frequent blood tests and monitoring.
- Participants will also receive antibiotics and other drugs to protect against bacterial, fungal, and viral infections. Participants will take these drugs regularly until their white blood cell counts improve.
- After discharge from the clinical center, participants will have follow-up evaluations at 3 months, 6 months, and annually for 5 years. Evaluations will include blood samples and periodic bone marrow biopsies.
| Condition | Intervention | Phase |
|---|---|---|
|
Aplastic Anemia Neutropenia Pancytopenia Severe Aplastic Anemia |
Drug: Cyclophosphamide Drug: Cyclosporine |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Cyclophosphamide Plus Cyclosporine in Treatment-Na ve Severe Aplastic Anemia |
- The primary objective is to evaluate the safety and activity profile of Cy/CsA in SAA.
- Secondary endpoints will also be evaluated for the study to include:(a) Hematological response at 3 and 12 months and yearly thereafter; (b) relapse; (c) clonal evolution to PNH, myelodysplasia or acute leukemia; (d) survival.
| Enrollment: | 22 |
| Study Start Date: | August 2010 |
| Estimated Study Completion Date: | June 2014 |
| Estimated Primary Completion Date: | June 2014 (Final data collection date for primary outcome measure) |
-
Drug: Cyclophosphamide
Show Detailed Description Eligibility| Ages Eligible for Study: | 2 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
Severe aplastic anemia characterized by:
Bone marrow cellularity less than 30 percent (excluding lymphocytes)
AND
At least two of the following:
Absolute neutrophil count less than 500/ microL
Platelet count less than 20,000/ microL
Absolute reticulocyte count less than 60,000/ microL
Age greater than or equal to 2 years old
Weight greater than or equal to 12 kg
EXCLUSION CRITERIA:
Diagnosis of Fanconi anemia
Cardiac ejection fraction less than 30 percent (evaluated by ECHO)
Evidence of a clonal hematologic bone marrow disorder on cytogenetics. Patients with the presence of trisomy 8, loss of Y or del(20q) will not be excluded in the absence of dysplastic changes in the marrow. Patients with very severe neutropenia (ANC less than 200 /microL) 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 high dose Cy or ATG
Infection not adequately controlled with appropriate therapy
Serologic evidence of HIV infection
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 30 days is likely
Subjects with cancer who are not considered cured, are on active chemotherapeutic treatment or who take drugs with hematological effects
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 to 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:
| Responsible Party: | National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ) |
| ClinicalTrials.gov Identifier: | NCT01193283 History of Changes |
| Other Study ID Numbers: | 100176, 10-H-0176 |
| Study First Received: | August 31, 2010 |
| Last Updated: | May 1, 2013 |
| Health Authority: | United States: Federal Government |
Keywords provided by National Institutes of Health Clinical Center (CC):
|
Aplastic Anemia Immunosuppression T-Cells |
Hematopoiesis Autoimmunity Severe Aplastic Anemia |
Additional relevant MeSH terms:
|
Anemia Anemia, Aplastic Neutropenia Pancytopenia Hematologic Diseases Bone Marrow Diseases Agranulocytosis Leukopenia Leukocyte Disorders Cyclophosphamide Cyclosporins Cyclosporine Immunosuppressive Agents Immunologic Factors |
Physiological Effects of Drugs Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Enzyme Inhibitors Antifungal Agents Anti-Infective Agents Dermatologic Agents |
ClinicalTrials.gov processed this record on May 22, 2013