Genetic Disorder, Immunodeficiency Syndrome, Severe Aplastic Anemia
Conditions
Brief summary
This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus in treating patients with primary immunodeficiency disorders or noncancerous inherited disorders. Giving low doses of chemotherapy and total-body irradiation before a bone marrow transplant helps prepare the patient's body to accept the incoming donor's bone marrow and decrease the risk that the patient's immune system will reject 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 from a donor can make an immune response against the body's normal cells called graft versus host disease. Giving cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus after the transplant may help decrease this from happening.
Detailed description
PRIMARY OBJECTIVE: I. Determine safety of nonmyeloablative conditioning and hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA)-haploidentical related donors for patients with nonmalignant inherited disorders who do not have an HLA-matched related or unrelated donor. SECONDARY OBJECTIVES: I. Determine whether nonmyeloablative conditioning and HCT from an HLA-haploidentical related donor graft can establish mixed chimerism (\> 5% cluster of differentiation \[CD\]3+ donor T-cell chimerism) in patients with nonmalignant inherited disorders. II. Transplant related mortality at day 100. III. Incidence and severity of graft-versus-host disease (GHVD). IV. Immune reconstitution. V. Infections during the first 200 days after HCT. OUTLINE: NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2; cyclophosphamide IV over 1 hour on days -6 and -5; and undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo allogeneic bone marrow transplant on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on days 3 and 4, and mycophenolate mofetil orally (PO) every 8 hours on days 5-30 then twice daily (BID) to day 40, and then if there is no evidence of active GVHD and donor engraftment is \> 95% (or by principal investigator \[PI\] approval) taper until approximately day 96, or faster at discretion of PI. Patients also receive tacrolimus IV continuously over 22-24 hours starting on day 5 post-transplant and continue on tacrolimus through day 100 followed by a taper to approximately day 180 if there is no evidence of GVHD and their graft is doing well. Patients may convert to oral tacrolimus given BID or three times daily (TID) when the patient is able to take medications orally and has a therapeutic drug level. In addition, patients will receive sirolimus PO beginning on day 5 through day 180 followed by a taper to approximately day 210 if there is no evidence of GVHD and their graft is doing well. After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months, and then annually for 5 years.
Interventions
PROCEDUREAllogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplantation
DRUGCyclophosphamide
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMycophenolate Mofetil
Given PO
PROCEDURENonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic bone marrow transplantation
DRUGSirolimus
Given PO
DRUGTacrolimus
Given IV or PO
RADIATIONTotal-Body Irradiation
Undergo total-body irradiation
Sponsors
National Cancer Institute (NCI)
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 55 Years
Healthy volunteers
No
Inclusion criteria
* Primary immunodeficiency disorder or other nonmalignant inherited disease (except Fanconi anemia) treatable by allogeneic HCT * Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for conventional myeloablative HCT and who do not have HLA-matched related or unrelated donors * Patients with a related donor who is identical for one HLA haplotype * Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows: * Bone marrow cellularity \< 25%, or marrow cellularity \< 50% but with \< 30% residual hematopoietic cells * Two out of three of the following (in peripheral blood): neutrophils \< 0.5 x 10\^9/L; platelets \< 20 x 10\^9/L; reticulocytes \< 20 x 10\^9/L * SAA diagnostic criteria may be applied to assessment at initial diagnosis or follow-up assessments * DONOR: Related donors who are identical for one HLA haplotype * DONOR: Bone marrow will be the only allowed stem cell source
Exclusion criteria
* Fanconi anemia * Suitably HLA-matched related or unrelated donors * Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score \< 70 * Cardiac ejection fraction \< 30% (or, if unable to obtain ejection fraction, shortening fraction \< 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (echo), symptomatic coronary artery disease, or other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction of \< 26% must be seen by cardiology for approval * Poorly controlled hypertension despite anti-hypertensive medications * Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dl, or symptomatic biliary disease * Positive for human immunodeficiency virus (HIV) * Females who are pregnant (beta-human chorionic gonadotropin positive \[beta-HCG+\]) or breast-feeding * Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment * Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B) * DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous * DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10\^8 nucleated cells/kg recipient ideal body weight) * DONOR: HIV-positive donors * DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion * DONOR: \< 6 months old and \> 75 years old
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft Rejection | Day 84 | Number of patients with graft rejection (CD3 donor chimerisms \<5%). |
| Graft Failure | Day 84 | Number of patients with graft failure (grade IV thrombocytopenia and neutropenia after day 21 that lasts \> 2 weeks andn is refractory to growth factor support). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD) | Day 100 post transplant | Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100 |
| Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD) | Day 100 post transplant | Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100 |
| Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism | By day 84 | Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms |
| Immune Reconstitution | 1 year post transplant | Number of patients with normal range CD3 @ 1 year post transplant |
| Number of Patients With Infections | Through day 200 after HCT | Number of patients with clinically significant infections requiring treatment within 200 days after HCT |
| Incidence of Chronic GVHD | 1 year post transplant | Number of patients diagnosed with chronic GVHD by 1 year post transplant |
| Number of Patients With Transplant Related Mortality | Day 100 post transplant | The number of patients with transplant related mortality |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) See Detailed Description
Allogeneic Bone Marrow Transplantation: Undergo allogeneic bone marrow transplantation
Cyclophosphamide: Given IV
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Mycophenolate Mofetil: Given PO
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic bone marrow transplantation
Sirolimus: Given PO
Tacrolimus: Given IV or PO
Total-Body Irradiation: Undergo total-body irradiation | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Treatment (Chemo, Total-body Irradiation, Transplant) |
|---|---|
| Age, Categorical <=18 years | 13 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 10.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 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 | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 14 |
| other Total, other adverse events | 8 / 14 |
| serious Total, serious adverse events | 1 / 14 |
Outcome results
Primary
Graft Failure
Number of patients with graft failure (grade IV thrombocytopenia and neutropenia after day 21 that lasts \> 2 weeks andn is refractory to growth factor support).
Time frame: Day 84
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Graft Failure | 0 Participants |
Primary
Graft Rejection
Number of patients with graft rejection (CD3 donor chimerisms \<5%).
Time frame: Day 84
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Graft Rejection | 1 Participants |
Secondary
Immune Reconstitution
Number of patients with normal range CD3 @ 1 year post transplant
Time frame: 1 year post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Immune Reconstitution | 4 Participants |
Secondary
Incidence of Chronic GVHD
Number of patients diagnosed with chronic GVHD by 1 year post transplant
Time frame: 1 year post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Incidence of Chronic GVHD | 11 Participants |
Secondary
Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)
Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100
Time frame: Day 100 post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD) | 7 Participants |
Secondary
Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)
Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100
Time frame: Day 100 post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD) | 5 Participants |
Secondary
Number of Patients With Infections
Number of patients with clinically significant infections requiring treatment within 200 days after HCT
Time frame: Through day 200 after HCT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Number of Patients With Infections | 11 Participants |
Secondary
Number of Patients With Transplant Related Mortality
The number of patients with transplant related mortality
Time frame: Day 100 post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Number of Patients With Transplant Related Mortality | 0 Participants |
Secondary
Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism
Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms
Time frame: By day 84
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemo, Total-body Irradiation, Transplant) | Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism | 13 Participants |