Aplastic Anemia
Conditions
Brief summary
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
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.
Interventions
DRUGcyclophosphamide
Given IV
BIOLOGICALanti-thymocyte globulin
Given IV
DRUGcyclosporine
Given IV or PO
PROCEDUREallogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplantation
DRUGmethotrexate
Given IV
GENETICDNA analysis
Correlative studies
OTHERflow cytometry
Correlative studies
GENETICpolymorphism analysis
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Chronic GVHD | 2 years | Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days to Neutrophil Recovery to >500/uL | 100 days post-transplant | First of 3 consecutive days of neutrophils \>500/uL |
| Overall Survival | From the time of enrollment until death from any cause up to one year | Number of patients alive at one year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis) |
|---|---|
| Age, Continuous | 15 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 5 / 21 |
Outcome results
Primary
Incidence of Chronic GVHD
Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events.
Time frame: 2 years
Population: All Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Receive a Conditioning Regimen Comprising Cyclophosph | Incidence of Chronic GVHD | 5 number participants with chronic GVHD |
Secondary
Number of Days to Neutrophil Recovery to >500/uL
First of 3 consecutive days of neutrophils \>500/uL
Time frame: 100 days post-transplant
Population: All patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Receive a Conditioning Regimen Comprising Cyclophosph | Number of Days to Neutrophil Recovery to >500/uL | 26 days |
Secondary
Overall Survival
Number of patients alive at one year
Time frame: From the time of enrollment until death from any cause up to one year
Population: All Patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients Receive a Conditioning Regimen Comprising Cyclophosph | Overall Survival | 21 Participants |