Fanconi Anemia
Conditions
Keywords
Fanconi anemia
Brief summary
RATIONALE: A bone marrow or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving combination chemotherapy before a donor stem cell transplant may make the transplant more likely to work. This may be an effective treatment for patients with high risk Fanconi's anemia. PURPOSE: This clinical trial is studying how well combination chemotherapy works in treating high risk patients who are undergoing a donor stem cell transplant for Fanconi's anemia.
Detailed description
OBJECTIVES: Primary * Determine whether the incidence of neutrophil engraftment is acceptable in high-risk patients with Fanconi's anemia treated with busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin followed by allogeneic hematopoietic stem cell transplantation. Secondary * Determine the tolerability of mycophenolate mofetil in these patients. * Determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen. * Determine the incidence of major infections in patients with a history of major infections treated with this regimen. * Determine the incidence of relapse in patients with refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia treated with this regimen * Determine the probability of 1-year survival of patients treated with this regimen. OUTLINE: Patients are stratified according to donor/recipient HLA type (identical vs other). * Cytoreductive combination chemotherapy: Patients receive busulfan intravenously (IV) over 2 hours twice daily on days -7 and -6 and cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes once daily on days -5 to -2. * Graft failure prophylaxis: Patients receive methylprednisolone IV twice daily on days -5 to 30 and anti-thymocyte globulin IV over 4-6 hours twice daily on days -5 to -1. * Graft-vs-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -3 to 100 (if patient has a matched sibling donor) or days -3 to 180 (if patient has another donor type). Patients also receive mycophenolate mofetil orally or IV twice daily on days -3 to 45. * Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT (using bone marrow or umbilical cord blood) on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. After completion of study treatment, patients are followed periodically for 3 years.
Interventions
BIOLOGICALanti-thymocyte globulin
Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
BIOLOGICALfilgrastim
given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10\^9/L)
DRUGbusulfan
Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if \<4 years old)
DRUGcyclophosphamide
10 mg/kg intravenously (IV) on Days -5 through -2.
DRUGfludarabine phosphate
35 mg/m\^2 intravenously (IV) on Days -5 through -2.
DRUGmethylprednisolone
1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
BIOLOGICALHematopoietic stem cell transplantation
Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 44 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be \<45 years of age with a diagnosis of Fanconi anemia with: * Biallelic BRCA2 mutations, or * Aplastic anemia, or advanced myelodysplastic syndrome (MDS) (MDS with ≥5% blasts), or acute leukemia who are ineligible for total body irradiation. Aplastic anemia is defined as having at least one of the following (with or without cytogenetic abnormalities): platelet count \<20 \* 10\^9, - absolute neutrophil count (ANC) \<5 \* 10\^8/L, - Hgb \<8 g/dL * Patients must have an HLA-A, B, DRB1 identical or 1 antigen mismatched related or unrelated BM donor or have an HLA-A, B, DRB1 identical, 1 antigen or 2 antigen mismatched related or unrelated umbilical cord blood (UCB) donor. Patients and donors will be typed for HLA-A and B using serological level typing and for DRB1 using high resolution molecular typing. * Adequate major organ function including: * Cardiac: ejection fraction \>45% * Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites, no cirrhosis) * Karnofsky performance status \>70% or Lansky \>50% * Women of child bearing potential must be using adequate birth control and have a negative pregnancy test.
Exclusion criteria
* Active CNS leukemia at time of HSCT. * Active uncontrolled infection within one week of hematopoietic stem cell transplant (HSCT). * Pregnant or lactating female. Donor Inclusion Criteria: * Donor must be in good health based on review of systems and results of physical examination. * Donor must have a normal hemoglobin, white count, platelet count and partial thromboplastin time (PTT), and a negative diepoxybutane (DEB) test. * HIV-NAT negative, HTLV-1, HTLV-2 negative, Hepatitis B and C negative. * Female donors of childbearing potential must have a negative pregnancy test. * Unrelated donors must agree to peripheral blood stem cell (PBSC) donation Donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Graft Failure | Day 30 | Graft failure is defined as absolute neutrophil count( ANC ) \<5 x 10\^8/L by day 30. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Chronic Graft-Versus-Host Disease | Day 42 | Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host. |
| Number of Participants Experiencing Acute Graft-Versus-Host Disease | 1 year | Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. |
| Number of Participants Experiencing Relapse | 1 Year | Patients with leukemia will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. |
| Number of Participants Experiencing Overall Survival | 1 Year | Overall Survival - Number of patients alive at 1 year post transplant |
| Number of Participants Experiencing Major Infections | Day 1 through 1 year post-transplant | Number of participants experiencing Major Infections by the end of treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Marrow Isolex Bone marrow processed using Isolex300i | 3 |
| USB Arm No processing | 8 |
| Marrow Clinimacs Bone marrow processed using CliniMACS | 2 |
| Sibling withoutCliniMACS sibling donor without use of CliniMACS system | 1 |
| Total | 14 |
Baseline characteristics
| Characteristic | Marrow Isolex | USB Arm | Marrow Clinimacs | Sibling withoutCliniMACS | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 8 Participants | 2 Participants | 1 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 8 Participants | 2 Participants | 1 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 8 Participants |
| Region of Enrollment United States | 3 Participants | 8 Participants | 2 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 1 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 4 / 8 | 1 / 2 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 7 / 8 | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 2 / 3 | 2 / 8 | 1 / 2 | 0 / 1 |
Outcome results
Primary
Number of Participants Experiencing Graft Failure
Graft failure is defined as absolute neutrophil count( ANC ) \<5 x 10\^8/L by day 30.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Graft Failure | 1 Participants |
| USB Arm | Number of Participants Experiencing Graft Failure | 0 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Graft Failure | 0 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Graft Failure | 0 Participants |
Secondary
Number of Participants Experiencing Acute Graft-Versus-Host Disease
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time frame: Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
| USB Arm | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
Secondary
Number of Participants Experiencing Acute Graft-Versus-Host Disease
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
| USB Arm | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 1 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Acute Graft-Versus-Host Disease | 0 Participants |
Secondary
Number of Participants Experiencing Chronic Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| USB Arm | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
Secondary
Number of Participants Experiencing Chronic Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.
Time frame: Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| USB Arm | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Chronic Graft-Versus-Host Disease | 0 Participants |
Secondary
Number of Participants Experiencing Major Infections
Number of participants experiencing Major Infections by the end of treatment
Time frame: Day 1 through 1 year post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Major Infections | 3 Participants |
| USB Arm | Number of Participants Experiencing Major Infections | 8 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Major Infections | 2 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Major Infections | 1 Participants |
Secondary
Number of Participants Experiencing Overall Survival
Overall Survival - Number of patients alive at 1 year post transplant
Time frame: 1 Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Overall Survival | 1 Participants |
| USB Arm | Number of Participants Experiencing Overall Survival | 4 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Overall Survival | 1 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Overall Survival | 1 Participants |
Secondary
Number of Participants Experiencing Relapse
Patients with leukemia will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate.
Time frame: 1 Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Relapse | 0 Participants |
| USB Arm | Number of Participants Experiencing Relapse | 2 Participants |
| Marrow Clinimacs | Number of Participants Experiencing Relapse | 1 Participants |
| Sibling withoutCliniMACS | Number of Participants Experiencing Relapse | 0 Participants |