Aplastic Anemia, Bone Marrow Failure, Immunosuppression, Severe Aplastic Anemia
Conditions
Keywords
immunosuppression, nonmyeloablative, non-myeloablative, allogeneic, tacrolimus, bone marrow, bone marrow transplant, cyclophosphamide, thymoglobulin, ATG, fludarabine
Brief summary
Our primary objective is to determine if it is feasible for previously untreated severe aplastic anemia (SAA) patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide.
Detailed description
This is a clinical trial of upfront bone marrow transplantation for patients with SAA who do not have a fully human leukocyte antigen (HLA) matched donor. The trial uses a conditioning regimen which has been successful in the refractory and relapsed setting to maximize engraftment and post transplant therapy to minimize graft versus host disease (GVHD). This would be used here in patients who have not yet undergone immunosuppressive therapy for their SAA or are thought to be unlikely to respond to immunosuppressive therapy for SAA.
Interventions
DRUGThymoglobulin
Day -9: 0.5 mg/kg Days -8 and -7: 2 mg/kg daily
DRUGFludarabine
Days -6 through -2: 30 mg/m\^2 IV daily
DRUGCyclophosphamide
Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
RADIATIONTotal body irradiation
Day -1: 200 centigray (cGy) in a single fraction
DRUGTacrolimus
Start on Day 5 through Day 365
DRUGMycophenolate mofetil
Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of inherited or acquired severe aplastic anemia (SAA) * One of the following available donors: 1. HLA-haploidentical relative 2. If recipient is \>= 40 years old, may use HLA-matched related donor 3. For recipients with inherited bone marrow failure syndromes (IBMFS) with clear evidence of same disorder in potential related donors, may use 10/10 matched unrelated donor * Recipient and/or legal guardian must sign protocol informed consent * Donor must be willing to donate bone marrow * Left ventricular ejection fraction (LVEF) \>= 40%. For recipients \< 13 years old, shortening fraction \>= 26% may be used instead. * Bilirubin \< 3 x upper limit of normal (ULN) for age, unless patient has Gilbert's disease * aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 5 x ULN for age * For patients \>= 13 years old: estimated creatinine clearance \> 50 mL/min using Cockcroft-Gault formula and actual body weight * For patients \>= 1 but \< 13 years old: glomerular filtration rate (GFR) estimated by updated Schwartz formula \>= 90 mL/min/1.73 m\^2. If estimated GFR is \< 90 mL/min/1.73 m\^2, 24-hour measured creatinine clearance must be \> 50 mL/min/1.73 m\^2. * For patients \>= 8 years old, diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) \> 40%; forced expiratory volume at one second (FEV1) \> 50%; forced vital capacity (FVC) \> 50% * For patients \< 8 years old or unable to undergo pulmonary function testing: no evidence of dyspnea at rest; no need for supplemental oxygen; oxygen saturation \> 92% on room air * Karnofsky/Lansky status (depending on age) \>= 70% * Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time. If unwilling, they must agree to complete abstinence.
Exclusion criteria
* Previous administration of immunosuppressive therapy for SAA. * Fanconi anemia. At minimum, this diagnosis must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow in patients \< 30 years old. * Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on bone marrow examination * Presence of anti-donor antibodies * Prior allogeneic stem cell transplant * Prior solid organ transplant * Uncontrolled bacterial, viral, or fungal infection * HIV seropositivity * Active hepatitis B or C infection determined by serology and/or nucleic acid testing (NAT) * Pregnancy or active breastfeeding * Prior malignancies except: resected basal carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent \> 5 years previously. Other prior cancers will not be allowed unless approved by the PI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival and Engraftment at One Year | 1 year | Number of enrolled participants who receive BMT, achieve engraftment, and are alive at one year post bone marrow transplant (BMT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Neutrophil Recovery as Assessed by the Number of Participants Who Have Recovered Neutrophil Counts | 1 year | Probability of neutrophil recovery will be assessed by the number of participants who have recovered neutrophil counts at 1 year (\>500 ANC). |
| Probability of Platelet Recovery as Assessed by Number of Participants Who Have Recovered Platelet Counts | 1 year | Probability of platelet recovery will be assessed by the number of participants who have recovered platelet counts at 1 year. |
| Number of Participants Who Experience Primary Graft Failure | 1 year | Number of participants who experience primary graft failure by one year after BMT. |
| Number of Participants Who Experience Secondary Graft Failure | 1 year | Number of participants who experience secondary graft failure by one year after BMT. |
| Number of Participants Who Experience Grades II-IV Acute GVHD | Day 100 | Number of participants who experience grade II, III, or IV acute GVHD by Day 100. |
| Overall Survival at One Year | 1 year | Number of participants alive at one year after BMT. |
| Number of Participants Who Experience Chronic GVHD | 2 years | Number of participants who experience chronic GVHD by two years after BMT. |
| Number of Participants With Full Donor Chimerism | Day 60 | Number of participants with full donor chimerism at Day 60. |
| GVHD-free Relapse-free Survival (GRFS) | 1 year | Number of participants alive, without relapse, and without GVHD at 1 year. |
| Transplant-related Mortality | 1 year | Number of participants deceased for reasons related to BMT at 1 year. |
| Number of Participants Who Experience Grades III-IV Acute GVHD | Day 100 | Number of participants who experience grade III or IV acute GVHD by Day 100. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bone Marrow Transplant Non-myeloablative bone marrow transplant with a Thymoglobulin (ATG), fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Thymoglobulin: Day -9: 0.5 mg/kg Days -8 and -7: 2 mg/kg daily
Fludarabine: Days -6 through -2: 30 mg/m\^2 IV daily
Cyclophosphamide: Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
Total body irradiation: Day -1: 200 centigray (cGy) in a single fraction
Tacrolimus: Start on Day 5 through Day 365
Mycophenolate mofetil: Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day) | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Bone Marrow Transplant |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 25 years |
| Race/Ethnicity, Customized African American | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 14 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 21 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 21 |
| other Total, other adverse events | 0 / 21 |
| serious Total, serious adverse events | 2 / 21 |
Outcome results
Primary
Overall Survival and Engraftment at One Year
Number of enrolled participants who receive BMT, achieve engraftment, and are alive at one year post bone marrow transplant (BMT).
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Overall Survival and Engraftment at One Year | 19 Participants |
Secondary
GVHD-free Relapse-free Survival (GRFS)
Number of participants alive, without relapse, and without GVHD at 1 year.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | GVHD-free Relapse-free Survival (GRFS) | 19 Participants |
Secondary
Number of Participants Who Experience Chronic GVHD
Number of participants who experience chronic GVHD by two years after BMT.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants Who Experience Chronic GVHD | 1 Participants |
Secondary
Number of Participants Who Experience Grades III-IV Acute GVHD
Number of participants who experience grade III or IV acute GVHD by Day 100.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants Who Experience Grades III-IV Acute GVHD | 2 Participants |
Secondary
Number of Participants Who Experience Grades II-IV Acute GVHD
Number of participants who experience grade II, III, or IV acute GVHD by Day 100.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants Who Experience Grades II-IV Acute GVHD | 4 Participants |
Secondary
Number of Participants Who Experience Primary Graft Failure
Number of participants who experience primary graft failure by one year after BMT.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants Who Experience Primary Graft Failure | 21 Participants |
Secondary
Number of Participants Who Experience Secondary Graft Failure
Number of participants who experience secondary graft failure by one year after BMT.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants Who Experience Secondary Graft Failure | 19 Participants |
Secondary
Number of Participants With Full Donor Chimerism
Number of participants with full donor chimerism at Day 60.
Time frame: Day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants With Full Donor Chimerism | 21 Participants |
Secondary
Overall Survival at One Year
Number of participants alive at one year after BMT.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Overall Survival at One Year | 19 Participants |
Secondary
Probability of Neutrophil Recovery as Assessed by the Number of Participants Who Have Recovered Neutrophil Counts
Probability of neutrophil recovery will be assessed by the number of participants who have recovered neutrophil counts at 1 year (\>500 ANC).
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Probability of Neutrophil Recovery as Assessed by the Number of Participants Who Have Recovered Neutrophil Counts | 21 Participants |
Secondary
Probability of Platelet Recovery as Assessed by Number of Participants Who Have Recovered Platelet Counts
Probability of platelet recovery will be assessed by the number of participants who have recovered platelet counts at 1 year.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Probability of Platelet Recovery as Assessed by Number of Participants Who Have Recovered Platelet Counts | 20 Participants |
Secondary
Transplant-related Mortality
Number of participants deceased for reasons related to BMT at 1 year.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Transplant-related Mortality | 2 Participants |