Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT01193283
First received: August 31, 2010
Last updated: June 25, 2014
Last verified: May 2014
  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: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The primary objective is to evaluate the safety and activity profile of Cy/CsA in SAA. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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. [ Time Frame: 1 to 5 years ]

Enrollment: 22
Study Start Date: August 2010
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Cyclophosphamide
    30 my/kg for 4 days
    Drug: Cyclosporine
    daily to a trough of 100 t0 200 ng/ml
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01193283

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
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: June 25, 2014
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 August 20, 2014