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

NCT01187017 | Completed Phase 1 Results DMC

• 2 other identifiers: 10017710-H-0177
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

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 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. Objectives: \- 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.

Conditions

Aplastic Anemia; Neutropenia; Pancytopenia; Severe Aplastic Anemia

Keywords

Severe Aplastic Anemia; Aplastic Anemia; Immunosuppression; Immunosuppressive Therapy; T-Cells

Outcome Measures

Primary Outcomes (1)

• Response Rate at 6 Months

  The primary objective is to assess hematologic response of Refractory Severe aplastic anemia (SAA) subjects to who have received fludarabine and cyclophosphamide. Subjects blood counts will be evaluated at 6 months to assess a hematologic response. The hematologic response will be defined as complete, partial or no response.

  6 months

Secondary Outcomes (4)

• Number of Participants With Hematologic Response

  3 months

• Number of Patients Who Experienced Disease Relapse

  6 months

• Number of Participants With Clonal Evolution

  6 months

• Participant Survival Following Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia

  6 months

Study Arms (1)

Fludarabine/Cyclophosphamide in Participants with Severe Aplastic Anemia

EXPERIMENTAL

Participants with Severe Aplastic Anemia will receive Fludarabine at 125 mg/m squared plus Cyclophosphamide at 60 mg/kg (Flu/Cy).

Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

Cyclophosphamide DRUG

60 mg/kg

Also known as: Cy

Fludarabine/Cyclophosphamide in Participants with Severe Aplastic Anemia

Fludarabine DRUG

125 mg/m squared

Also known as: Flu

Fludarabine/Cyclophosphamide in Participants with Severe Aplastic Anemia

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Severe aplastic anemia characterized by:
• Bone marrow cellularity \< 30 percent (excluding lymphocytes)
• AND
• At least two of the following:
• Absolute neutrophil count \< 500/ microL
• Platelet count \< 20,000/ microL
• Absolute reticulocyte count \< 60,000/ microL
• 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
• Refractory SAA unresponsive to both horse and rabbit ATG-based regimens
• Age greater than or equal to 2 years old
• Weight greater than or equal to 12 kg

You may not qualify if:

• Diagnosis of Fanconi anemia
• Cardiac ejection fraction \< 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 \< 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
• 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 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

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003 Mar 5;289(9):1130-5. doi: 10.1001/jama.289.9.1130.

  PMID: 12622583 BACKGROUND

• Passweg JR, Perez WS, Eapen M, Camitta BM, Gluckman E, Hinterberger W, Hows JM, Marsh JC, Pasquini R, Schrezenmeier H, Socie G, Zhang MJ, Bredeson C. Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia. Bone Marrow Transplant. 2006 Apr;37(7):641-9. doi: 10.1038/sj.bmt.1705299.

  PMID: 16489361 BACKGROUND

• Marsh JC, Hows JM, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC. Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood. 1987 Oct;70(4):1046-52.

  PMID: 3651599 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic; Neutropenia; Pancytopenia

Interventions

Cyclophosphamide; fludarabine; Influenza Vaccines

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Agranulocytosis; Leukopenia; Cytopenia; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Viral Vaccines; Vaccines; Biological Products; Complex Mixtures

Results Point of Contact

• Title: Bhavisha Patel, MD
• Organization: NIHNHLBI

bhavisha.patel@nih.gov

301.402.3477

Study Officials

• Danielle M Townsley, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2010
• First Posted: August 23, 2010
• Study Start: August 1, 2010
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2012
• Last Updated: July 2, 2021
• Results First Posted: March 2, 2016

Record last verified: 2016-02

Locations

US (1)