Fanconi Anemia
Conditions
Keywords
Fanconi anemia
Brief summary
RATIONALE: Giving chemotherapy, such as cyclophosphamide and fludarabine, before a donor stem cell transplant helps to remove the patient's cells to allow for the transplant cells to take and grow. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells can make an immune response against the body's normal cells. Giving antithymocyte globulin and removing the T cells from the donor cells before transplant and giving cyclosporine before and after transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects of cyclophosphamide, fludarabine, and antithymocyte globulin followed by donor stem cell transplant and to see how well it works in treating patients with Fanconi anemia.
Detailed description
OBJECTIVES: Primary * To determine the probability of engraftment in patients with Fanconi anemia treated with cyclophosphamide, fludarabine phosphate, and antithymocyte globulin followed by HLA-genotypically identical sibling donor hematopoietic stem cell transplantation that is T-cell depleted. Secondary * To evaluate the incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in patients treated with this regimen. * To evaluate the incidence of regimen-related toxicity in these patients. * To evaluate the 1-year survival of patients treated with this regimen. * To evaluate the incidence of late secondary malignancies (e.g., squamous cell carcinoma of the head and neck or cervix) in patients treated with this regimen. OUTLINE: * Preparative cytoreductive therapy: Patients receive cyclophosphamide IV over 2 hours on days -6 to -3 and fludarabine phosphate IV over 30 minutes and anti-thymocyte globulin IV over 4-6 hours on days -6 to -2. * T-cell depleted donor hematopoietic stem cell transplantation: Patients undergo T-cell depleted donor bone marrow or umbilical cord blood stem cell transplantation on day 0. Patients also receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover. * Graft-versus-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper. Patients will receive Mycophenolate Mofetil (MMF) therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count \[ANC\] \> 0.5 x 10\^9/L. After completion of study therapy, patients are followed periodically.
Interventions
BIOLOGICALAnti-Thymocyte Globulin
30 mg/kg/day will be administered after MP on days -6, -5, -4, -3 and -2.
DRUGCyclophosphamide
5 mg/kg is to be given as a 2 hour infusion, Days -6 through -3.
DRUGFludarabine
35 mg/m\^2 intravenously (IV) on days -6 through -2.
PROCEDUREHematopoietic Stem Cell Transplantation
Bone marrow or umbilical cord blood infusion on day 0.
DRUGMethylprednisolone
Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -6 until day -2 as a premedication for ATG.
DRUGFilgrastim
5 mcg/kg per day intravenously (IV) continue until Absolute neutrophil count \> or = 2.5 x 10\^9/L
DRUGCyclosporine
Cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper.
DRUGMycophenolate Mofetil
Day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count \[ANC\] \> 0.5 x 10\^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours PO (to a maximum dose of 1 gram).
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 59 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be \<60 years of age with a diagnosis of Fanconi Anemia (FA). * Patients must have an HLA-A, B, DRB1 identical sibling donor. Patients and donors will be typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing. * Patients with FA must have moderately severe aplastic anemia (AA), early myelodysplastic syndrome (MDS) with no excess blasts with or without chromosomal abnormalities. * In patients \<18 years of age, moderately severe aplastic anemia is defined as having at least one of the following: * platelet count \<40 x 10\^9/L * absolute neutrophil count (ANC) \<10 x 10\^8/L * Hgb \<9 g/dL * In patients 18-60 years of age, moderately severe aplastic anemia is defined as having at least one of the following: * platelet count \<20 x 10\^9/L * absolute neutrophil count ANC \<5 x 10\^8/L * Hgb \<8 g/dL * Early myelodysplastic syndrome, with multilineage dysplasia with \< 5% blasts, with or without chromosomal anomalies. * Adequate major organ function including: * Cardiac: ejection fraction \>45% * Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites) * Karnofsky performance status \>70% or Lansky \>50% * Women of child bearing age must be using adequate birth control and have a negative pregnancy test.
Exclusion criteria
* Active bacterial infection within one week of hematopoietic cell transplant (HCT) * Active fungal infection at time of HCT. * Late MDS with greater than 5% blasts in bone marrow. * Acute myelogenous leukemia (AML) or history of AML * Malignant solid tumor (e.g. squamous cell carcinoma of the head/neck/cervix) within 2 years of HCT. * Pregnant or lactating female.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Graft Failure | From Day 1 to event, assessed up to100 days | graft failure = absolute neutrophil count (ANC) \<5 x 10\^8/L and an acellular bone marrow aspirate/biopsy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Acute Graft-Versus-Host Disease (GVHD) | Day 42 | 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 Overall Survival | 1 Year | The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from enrollment to date of death or censored at the date of last documented contact for patients still alive. |
| Number of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 1 Year | Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host. |
| Number of Participants With Transplant Related Deaths | Day 100 | In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Marrow Isolex bone marrow processed using Isolex 300i (for patients enrolled through April 2010) | 16 |
| UCB Arm No processing | 9 |
| Marrow Clinimax bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version) | 6 |
| Total | 31 |
Baseline characteristics
| Characteristic | Marrow Isolex | UCB Arm | Marrow Clinimax | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 9 Participants | 4 Participants | 26 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 8 Participants | 6 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 7 Participants | 3 Participants | 22 Participants |
| Region of Enrollment United States | 16 participants | 9 participants | 6 participants | 31 participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 5 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 1 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 1 / 9 | 1 / 6 |
| other Total, other adverse events | 9 / 16 | 6 / 9 | 5 / 6 |
| serious Total, serious adverse events | 0 / 16 | 0 / 9 | 1 / 6 |
Outcome results
Primary
Number of Participants Experiencing Graft Failure
graft failure = absolute neutrophil count (ANC) \<5 x 10\^8/L and an acellular bone marrow aspirate/biopsy
Time frame: From Day 1 to event, assessed up to100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Graft Failure | 0 Participants |
| UCB Arm | Number of Participants Experiencing Graft Failure | 0 Participants |
| Marrow Clinimax | Number of Participants Experiencing Graft Failure | 0 Participants |
Secondary
Number of Participants Experiencing Overall Survival
The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from enrollment to date of death or censored at the date of last documented contact for patients still alive.
Time frame: 1 Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants Experiencing Overall Survival | 15 Participants |
| UCB Arm | Number of Participants Experiencing Overall Survival | 8 Participants |
| Marrow Clinimax | Number of Participants Experiencing Overall Survival | 5 Participants |
Secondary
Number of Participants With Acute Graft-Versus-Host Disease (GVHD)
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 With Acute Graft-Versus-Host Disease (GVHD) | 0 Participants |
| UCB Arm | Number of Participants With Acute Graft-Versus-Host Disease (GVHD) | 0 Participants |
| Marrow Clinimax | Number of Participants With Acute Graft-Versus-Host Disease (GVHD) | 0 Participants |
Secondary
Number of Participants With Chronic Graft-Versus-Host Disease (GVHD)
Chronic Graft-Versus-Host Disease is a severe long-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 With Chronic Graft-Versus-Host Disease (GVHD) | 2 Participants |
| UCB Arm | Number of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 0 Participants |
| Marrow Clinimax | Number of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 0 Participants |
Secondary
Number of Participants With Transplant Related Deaths
In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Isolex | Number of Participants With Transplant Related Deaths | 1 Participants |
| UCB Arm | Number of Participants With Transplant Related Deaths | 0 Participants |
| Marrow Clinimax | Number of Participants With Transplant Related Deaths | 1 Participants |