A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia

A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
This study has been completed.

First Received on August 20, 2010.  
Last Updated on July 26, 2012  
History of Changes
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Information provided by: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01187017


  • Severe aplastic anemia (SAA) can lead to problems with bone marrow health and result in low blood cell counts, which require frequent transfusions. Standard initial treatment for SAA involves injections of antithymocyte globulin (ATG) plus cyclosporine (CsA). Patients with SAA who do not respond to initial treatment with ATG (refractory) have a high risk of dying without additional treatment. In these cases, for those who do not have a matched bone marrow transplant donor there is no well-defined standard therapy. In our experience with patients who do not respond to horse ATG + CsA, only about one-third of patients who are re-treated with rabbit ATG + CsA improve. Experience with cyclophosphamide in the treatment of refractory severe aplastic anemia suggests that this drug is able to improve blood counts in about 50% of cases. However, the cyclophosphamide regimen has been associated with a significant infection risk (mostly caused by fungus) in studies conducted over 10 years ago due to the lowering of the white blood cell levels.
  • 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 at lower doses to minimize its side effects given in combination with another immune suppressant, fludarabine.


– To determine the safety and effectiveness of the combination of fludarabine plus cyclophosphamide in treating severe aplastic anemia that has not responded to initial treatments.


– Individuals at least 2 years of age who have severe aplastic anemia that has not improved after treatment with horse ATG or both horse and rabbit ATG.


  • 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 2 days of cyclophosphamide, followed by 5 days of fludarabine.
  • 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
Severe Aplastic Anemia
Refractory Severe Aplastic Anemia
Drug: Cyclophosphamide
Drug: Fludarabine
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: A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory 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 Flu/Cy in SAA.-The primary safety endpoint will be toxicity profile in the 6 months following Flu/Cy-The primary efficacy endpoint is response rate at 6 months

Secondary Outcome Measures:

  • Secondary endpoints will also be evaluated for the study to include: (a) hematologic response at 3 and 12 months and yearly thereafter; (b) relapse (c) clonal evolution to PNH, myelodysplasia or acute leukemia; (e) survival.

Enrollment: 1
Study Start Date: August 2010
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Intervention Details:

    Drug: Cyclophosphamide


    Drug: Fludarabine


Show Detailed Description


Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


  1. Severe aplastic anemia characterized by:

    Bone marrow cellularity < 30 percent (excluding lymphocytes)


    At least two of the following:

    • Absolute neutrophil count < 500/ microL
    • Platelet count < 20,000/ microL
    • Absolute reticulocyte count < 60,000/ microL
  2. Failure to respond to an initial course of h-ATG/CsA at least 3 months post-treatment or a suboptimal response to initial h-ATG/CsA defined by both platelet and reticulocyte count < 50,000 /microL at 3 months post-treatment


  3. Refractory SAA unresponsive to both horse and rabbit ATG-based regimens
  4. Age greater than or equal to 2 years old
  5. Weight greater than or equal to 12 kg


  1. Diagnosis of Fanconi anemia
  2. Cardiac ejection fraction < 30 percent (evaluated by ECHO)
  3. 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 < 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)
  4. Prior immunosuppressive therapy with high dose Cy
  5. Infection not adequately controlled with appropriate therapy
  6. Serologic evidence of HIV infection
  7. 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
  8. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects
  9. Current pregnancy or unwillingness to take oral contraceptives or refrain from pregnancy if of childbearing potential
  10. Not able to understand the investigational nature of the study or to give informed consent
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01187017

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Principal Investigator: Danielle M Townsley, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:


Responsible Party: Phillip Scheinberg, M.D./National Heart, Lung, and Blood Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT01187017    
History of Changes
Other Study ID Numbers: 100177, 10-H-0177
Study First Received: August 20, 2010
Last Updated: July 26, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Severe Aplastic Anemia
Aplastic Anemia
Immunosuppressive Therapy

Additional relevant MeSH terms:

Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Leukocyte Disorders
Fludarabine monophosphate
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
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on August 21, 2012

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