Bone Marrow Failure Syndromes, Severe Aplastic Anemia
Conditions
Keywords
bone marrow transplant, thymoglobulin, cyclophosphamide, fludarabine, tacrolimus, Mycophenolic Acid Mofetil, chemotherapy, GVHD, haploidentical
Brief summary
Our primary objective is to determine if it is feasible for SAA patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide with partially HLA-mismatched donors.
Detailed description
This research is being done to find out if bone marrow transplantation (BMT) followed by chemotherapy will help people with aplastic anemia who have failed other treatments. You have a severe, life threatening disease (severe aplastic anemia) in your bone marrow. Your disease has come back or not responded after receiving one or more immunosuppressive treatments. High dose chemotherapy followed by bone marrow transplantation (BMT) has been used to treat blood diseases like yours but complications from Graft vs. Host disease (GVHD) and graft failure have limited the survival for those people. A small study done at Johns Hopkins has shown that in subjects with other diseases (blood cancers) some immunosuppressive drugs given after the BMT have decreased how often subjects had complications of GVHD and engraftment failure. People with aplastic anemia who have refractory disease (not responding to standard treatment) may join.
Interventions
PROCEDUREBone marrow transplant
Day 0
DRUGThymoglobulin
0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7
DRUGFludarabine
30 mg/M2 IV on days -6 to -2
DRUGCyclophosphamide
14.5 mg/kg IV on days -6, -5, 3, 4
RADIATIONTBI
200 cGy on day -1
DRUGMesna
40 mg/kg IV on days 3, 4
DRUGTacrolimus
For patients 18 years or older, tacrolimus will be given per institutional standards; may be increased or later changed to a PO BID schedule. Treatment to continue until Day 365 or longer if GVHD present
DRUGMycophenolic acid mofetil
15 mg/kg PO/IV TID beginning on day 5 through day 35
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
Age
No minimum to 73 Years
Healthy volunteers
No
Inclusion criteria
* Patients with relapsed or refractory SAA or very SAA defined: * Bone marrow (\< 25% cellular) * Peripheral cytopenias (at least 2 of 3) * ANC \< 500 per ml * Platelets \< 20,000 per ml * Absolute retic \< 60,000 or corrected retic \< 1% * Very severe: as above, but ANC \< 200 * Disease may be designated as acquired or inherited if previous counts known (these other bone marrow failure disorders that are characterized by aplastic anemia may go by additional names such as dyskeratosis congenita or PNH) * Failed at least one course of immunosuppressive therapy (if presumed acquired disease). Patients with inherited disease will be characterized as refractory and do not require immunosuppressive first. * Age 0- upper age limit as determined by current institutional standards * Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100) * Patients and donors must be able to sign consent forms (or if a minor the parent will sign). Donors should be willing to donate. * Patients must be geographically accessible and willing to participate in all stages of treatment. * Adequate end-organ function as measured by: 1. Left ventricular ejection fraction \> or = to 35%, or shortening fraction \> 25% (For pediatric patients, a normal ejection fraction is required) 2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST ≤ 5 x ULN 3. FEV1 and FVC \> or = to 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation \>92% on room air
Exclusion criteria
* Patients will not be excluded on the basis of sex, racial or ethnic background. * Prior transfusions from selected donor (as this could have cause recipient alloimmunization against the donor) * Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception. * Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow up. * Uncontrolled viral, bacterial, or fungal infections (HIV infection permitted if viral load undetectable)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe? | 1 year | Feasibility will be met with the following conditions: the patient has the transplant, is assessed for the safety endpoint, and survives one year. The safety monitoring plan is included to monitor graft failure (day 60), grade 2-4 acute graft versus host disease (day100), 6 month mortality (day 180), and chronic graft versus host disease (day 180). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant | 60 days | Donor chimerism will be measured in the peripheral blood around day 30 and day 60. Patients with \>5% donor chimerism around day 60 will be considered as having engrafted. |
| Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant | 1 year | — |
| Number of Participants With Major Toxicities Related to Transplant | 1 year | — |
| Number of Patients That Expired Due to Transplant Related Mortality | 1 year | — |
| Number of Patients That Have Survived at One Year | 1 year | — |
| Number of Participants With Grade II-IV or Grade III-IV Acute GVHD | 1 year | Participants were graded during clinical visits based on evidence and extent of skin rash, liver involvement, and GI tract involvement |
| Participants With Chronic GVHD at One Year | 1 year | — |
| Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant | 1 year | CBC drawn daily with a WBC differential once the total WBC is greater than 100 until ANC \> 500 for three days or two consecutive measurements over a three day period; then CBC drawn weekly with differential. |
| Participants That Were GVHD Free, Relapse Free Survival (GRFS) | 1 year | — |
| Number of Patients With Primary or Secondary Graft Failure Following Transplant | 1 year | Graft failure: \< 5% donor chimerism in blood and/or bone marrow on \ Day 30 or after and on all subsequent measurements. Primary graft failure: \< 5% donor chimerism in blood and/or bone marrow by \ Day 56 Secondary graft failure: achievement of \> 5% donor chimerism, followed by sustained \<5% donor chimerism in blood and/or bone marrow. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bone Marrow Transplant Thymoglobulin on days -9 to -7 Fludarabine on days -6 to -2 Cyclophosphamide on days -6, -5, 3, 4 TBI on day -1 BMT on day 0 Mesna on days 3, 4 Tacrolimus on days 5-365 Mycophenolic acid mofetil on days 5-35
Bone marrow transplant: Day 0
Thymoglobulin: 0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7
Fludarabine: 30 mg/M2 IV on days -6 to -2
Cyclophosphamide: 14.5 mg/kg IV on days -6, -5, 3, 4
TBI: 200 cGy on day -1
Mesna: 40 mg/kg IV on days 3, 4
Tacrolimus: For patients 18 years or older, tacrolimus will be given per institutional standards; may be increased or later changed to a PO BID schedule. Treatment to continue until Day 365 or longer if GVHD present
Mycophenolic acid mofetil: 15 mg/kg PO/IV TID beginning on day 5 through day 35 | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Bone Marrow Transplant |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 30 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 18 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 7 / 18 |
Outcome results
Primary
Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe?
Feasibility will be met with the following conditions: the patient has the transplant, is assessed for the safety endpoint, and survives one year. The safety monitoring plan is included to monitor graft failure (day 60), grade 2-4 acute graft versus host disease (day100), 6 month mortality (day 180), and chronic graft versus host disease (day 180).
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe? | 18 Participants |
Secondary
Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant
CBC drawn daily with a WBC differential once the total WBC is greater than 100 until ANC \> 500 for three days or two consecutive measurements over a three day period; then CBC drawn weekly with differential.
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bone Marrow Transplant | Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant | 18.85 days |
Secondary
Number of Participants With Grade II-IV or Grade III-IV Acute GVHD
Participants were graded during clinical visits based on evidence and extent of skin rash, liver involvement, and GI tract involvement
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants With Grade II-IV or Grade III-IV Acute GVHD | 17 Participants |
Secondary
Number of Participants With Major Toxicities Related to Transplant
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Participants With Major Toxicities Related to Transplant | 0 Participants |
Secondary
Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant | 0 Participants |
Secondary
Number of Patients That Expired Due to Transplant Related Mortality
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Patients That Expired Due to Transplant Related Mortality | 0 Participants |
Secondary
Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant
Donor chimerism will be measured in the peripheral blood around day 30 and day 60. Patients with \>5% donor chimerism around day 60 will be considered as having engrafted.
Time frame: 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant | 7 Participants |
Secondary
Number of Patients That Have Survived at One Year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Patients That Have Survived at One Year | 18 Participants |
Secondary
Number of Patients With Primary or Secondary Graft Failure Following Transplant
Graft failure: \< 5% donor chimerism in blood and/or bone marrow on \ Day 30 or after and on all subsequent measurements. Primary graft failure: \< 5% donor chimerism in blood and/or bone marrow by \ Day 56 Secondary graft failure: achievement of \> 5% donor chimerism, followed by sustained \<5% donor chimerism in blood and/or bone marrow.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Number of Patients With Primary or Secondary Graft Failure Following Transplant | 17 Participants |
Secondary
Participants That Were GVHD Free, Relapse Free Survival (GRFS)
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Participants That Were GVHD Free, Relapse Free Survival (GRFS) | 14 Participants |
Secondary
Participants With Chronic GVHD at One Year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bone Marrow Transplant | Participants With Chronic GVHD at One Year | 3 Participants |