Cyclophosphamide and Anti-thymocyte Globulin Followed By Methotrexate and Cyclosporine in Preventing Chronic Graft-Versus-Host Disease in Patients With Severe Aplastic Anemia Undergoing Donor Bone Marrow Transplant

Cyclophosphamide and Antithymocyte Globulin Conditioning Regimen for Marrow Transplantation From HLA-Matched Family Members for Severe Aplastic Anemia: Effect of Marrow Cell Dose on Chronic Graft-vs.-Host Disease: A Multi-Center Trial

This clinical trial is studying how well giving cyclophosphamide together with anti-thymocyte globulin followed by methotrexate and cyclosporine works in preventing chronic graft-vs-host disease (GVHD) in patients with severe aplastic anemia undergoing donor bone marrow transplant. Giving low doses of chemotherapy, such as cyclophosphamide, before a donor bone marrow transplant helps stop the growth of abnormal cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before and methotrexate and cyclosporine after transplant may stop this from happening

Study Overview

• Status: Completed
• Conditions: Aplastic Anemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: flow cytometry; Drug: cyclophosphamide; Drug: methotrexate; Genetic: DNA analysis; Genetic: polymorphism analysis; Procedure: allogeneic bone marrow transplantation; Biological: anti-thymocyte globulin; Drug: cyclosporine

Detailed Description

PRIMARY OBJECTIVES:

I. Minimize the incidence of chronic GVHD by restricting the transplanted marrow dose to 2.0-2.5 x 10^8 nucleated cells/kg.

SECONDARY OBJECTIVES:

I. Engraftment and overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or orally (PO) twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

After completion of study treatment, patients are followed up at on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Any patient who has aplastic anemia with marrow failure involving 2 of the three following criteria: granulocytes < 500/uL; a corrected reticulocyte count of < 1%; platelet count of < 20,000/uL
• Availability of an human leukocyte antigen (HLA)-matched family member
• DONOR: Family member who is HLA-matched
• DONOR: If more than one HLA-matched family member is available, priority will be given to a donor who is genotypically HLA-identical, of appropriate cytomegalovirus (CMV) serology, ABO compatible, and, in case of a female donor, non-parous

Exclusion Criteria:

• Severe disease other than aplastic anemia that would severely limit the probability of survival during the graft procedure:

  • Patients who have developed clonal cytogenetic abnormalities or myelodysplastic syndrome (preleukemia)
  • Patients with Fanconi's anemia
  • Aplasia secondary to radiation or cytotoxic chemotherapy
  • Patients with paroxysmal nocturnal hemoglobinuria who have not developed aplastic anemia

• Severe organ toxicities:

  • Cardiac insufficiency requiring treatment or symptomatic coronary artery disease;
  • Severe hypoxemia , partial pressure of oxygen (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted;
  • Impaired renal function (creatinine > 2 times upper limit of normal or estimated creatinine clearance < 60 ml/min)
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• Human immunodeficiency virus (HIV)-positive patients
• Females who are pregnant or breast-feeding
• DONOR: Donors who have increase anesthetic risk and are not able psychologically and medically to tolerate the procedure
• DONOR: HIV-positive donors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (conditioning regimen, transplant, GVHD prophylaxis); Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

Other: laboratory biomarker analysis; Correlative studies; Other: flow cytometry; Correlative studies; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: methotrexate; Given IV; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Genetic: DNA analysis; Correlative studies; Genetic: polymorphism analysis; Correlative studies; Procedure: allogeneic bone marrow transplantation; Undergo allogeneic bone marrow transplantation; Other Names: bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow; Biological: anti-thymocyte globulin; Given IV; Other Names: ATGAM; ATG; Thymoglobulin; lymphocyte immune globulin; Drug: cyclosporine; Given IV or PO; Other Names: ciclosporin; cyclosporin; cyclosporin A; CYSP; Sandimmune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Chronic GVHD	Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Days to Neutrophil Recovery to >500/uL	First of 3 consecutive days of neutrophils >500/uL	100 days post-transplant
Overall Survival	Number of patients alive at one year	From the time of enrollment until death from any cause up to one year

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Rainer Storb, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: June 22, 2006
• First Submitted That Met QC Criteria: June 22, 2006
• First Posted (Estimate): June 23, 2006

Study Record Updates

• Last Update Posted (Actual): April 13, 2017
• Last Update Submitted That Met QC Criteria: March 16, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Immunoglobulins; Methotrexate; Thymoglobulin; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2054.00; P01HL036444 (U.S. NIH Grant/Contract); NCI-2010-01781 (Registry Identifier: CTRP (Clinical Trial Reporting Program))