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

This study has been completed.
Information provided by (Responsible Party):
Danielle Townsley, M.D., National Institutes of Health Clinical Center (CC) Identifier:
First received: August 20, 2010
Last updated: February 3, 2016
Last verified: February 2016


  • 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.

Condition Intervention Phase
Aplastic Anemia
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:
  • Response Rate at 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    The primary objective is to assess the Flu/Cy hematological response in SAA.The primary endpoint will be response at six months.

Secondary Outcome Measures:
  • Secondary Endpoints Will Evaluated for the Study to Include: (a) Hematologic Response at 3 and 12 Months and Yearly Thereafter; (b) Relapse (c) Clonal Evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplasia or Acute Leukemia; (e) Survival. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

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)
Arms Assigned Interventions
Experimental: Flu/Cy Response at 6 months
The primary objective is to assess Fludarabine/ Cyclophosphamide (Flu/Cy) hematological response in SAA.The primary endpoint will be response at six months.
Drug: Cyclophosphamide
60 mg/kg
Other Name: Cy
Drug: Fludarabine
125 mg/m squared
Other Name: Flu

  Show Detailed Description


Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
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
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 identifier: NCT01187017

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

Responsible Party: Danielle Townsley, M.D., Hematology Clinician, National Institutes of Health Clinical Center (CC) Identifier: NCT01187017     History of Changes
Other Study ID Numbers: 100177  10-H-0177 
Study First Received: August 20, 2010
Results First Received: June 5, 2014
Last Updated: February 3, 2016
Health Authority: United States: Food and Drug Administration

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
Leukocyte Disorders
Bone Marrow Diseases
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents processed this record on October 21, 2016