Immunodeficiency Syndrome, Non-Cancer Diagnosis
Conditions
Brief summary
This phase II trial studies fludarabine phosphate and total-body irradiation with or without alemtuzumab followed by donor stem cell transplant to see how well it works in treating patients with immunodeficiency or other nonmalignant inherited disorders. Giving chemotherapy, such as fludarabine phosphate, a monoclonal antibody such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells.
Detailed description
PRIMARY OBJECTIVES: I. Improve donor chimerism levels in patients with inherited nonmalignant disorders undergoing hematopoietic cell transplantation (HCT) using a reduced intensity conditioning regimen either through the addition of Campath (alemtuzumab) or a slightly higher dose of total-body irradiation (TBI). SECONDARY OBJECTIVES: I. Decrease the incidence and severity of acute and chronic graft-versus-host disease (GVHD) through use of marrow as the stem cell source and Campath. II. Assess disease response following HCT. III. Immune reconstitution following HCT. IV. Incidence of infections. V. Overall survival. VI. Percent of patients with cluster of differentiation (CD)33/CD19 donor chimerism \> 50%. OUTLINE: CONDITIONING REGIMEN: Patients with no life-threatening viral or fungal infections within 1 month before the planned hematopoietic cell transplantation (HCT) receive alemtuzumab intravenously (IV) over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with hemophagocytic lymphohistiocytosis (HLH), immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0. HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV or orally (PO) 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96. After completion of HCT, patients are followed up at day 84, at 6, 12, 18 and 24 months post-transplantation, and then once a year for 3 years.
Interventions
BIOLOGICALAlemtuzumab
Given IV
PROCEDUREAllogeneic Bone Marrow Transplantation
Undergo HCT
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo HCT
DRUGCyclosporine
Given PO or IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative study
DRUGMycophenolate Mofetil
Given PO or IV
RADIATIONTotal-Body Irradiation
Undergo low dose TBI
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 54 Years
Healthy volunteers
No
Inclusion criteria
* Primary immunodeficiency disorder or other nonmalignant inherited disease (except aplastic anemia and 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 a conventional myeloablative HCT * Donors: Related donor who is human leukocyte antigen (HLA) genotypically identical at least at one haplotype and may be genotypically or phenotypically identical for serological typing for HLA-A, B, -C, and at the allele level for -DRB1 and -DQB1; related donors must be a match or a single allele mismatch at HLA-A, B, and C (at highest resolution available at the time of donor selection) and matched at DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing * Donors: Unrelated donors who are prospectively: * Matched for HLA-A, B, C, DRB1 and DQB1 by DNA typing at the highest resolution routinely available at the time of donor selection * Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing (no mismatching for DRB1 or DQB1 is allowed)
Exclusion criteria
* Patients with Aplastic anemia and Fanconi anemia * 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 of \< 26%) on multi-gated acquisition (MUGA) scan or cardiac echo, symptomatic coronary artery disease, 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 \< 26% may be enrolled if approved by a cardiologist * 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 \> 3mg/dl, or symptomatic biliary disease (Patients will be allowed on to the protocol with liver problems if gastroenterology approves the patient for HCT) * Patients who are positive for human immunodeficiency virus (HIV) * Females who are pregnant 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) * Donors: Identical twin * Donors: Pregnancy * Donors: HIV positive * Donors: A positive anti-donor cytotoxic cross match is absolute donor exclusion * Donors: If a patient is homozygous at a particular loci, mismatching at that loci is not allowed due to an isolated graft rejection vector, i.e., patient A\*0101 and the donor is A\*0101, A\*0201; such a mismatch may increase the risk of graft rejection; if patient and donor pairs are both homozygous at a mismatched loci, they are considered a two-HLA antigen mismatch, i.e., the patient is A\*0101 and the donor is A\*0201, and this type of mismatch is not allowed * Donor: Donor \< 6 months old, \> 75 years old
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Achieve Greater Than 50% Donor T-cell Chimerism | At 1 year post transplant | The study will be considered a success and the protocol worthy of further study if there is sufficient evidence that this rate is greater than the 50% rate observed in the most recently transplanted patients with nonmalignant disorders. Analyses will be carried out separately for the alemtuzumab recipients and the TBI recipients. We will be 80% confidence of success if a one-sided 80% confidence interval for the proportion of patients with successful chimerism exceeds 50%. Cumulative incidence will be used to evaluate the probability of chimerism. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune Reconstitution by 1 Year Post Transplant | 1 year | Number of patients with normal range CD3 at 1 year post transplant |
| Disease Response by 1 Year Post Transplant | 1 year | Number of patients at 1 year with disease response (defined as no clinical evidence of active disease and/or sufficient level of donor chimerisms to prevent disease recurrence) |
| Greater Than 50% CD33+ Donor Chimerisms at 1 Year Post Transplant | 1 year | Number of patients who achieve greater than 50% CD33+ donor chimerisms at 1 year post transplant. |
| Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant | 1 year | Number of Patients Who Achieve Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant |
| Overall Survival | 1 year | Number of patients alive at 1 year |
| Number of Patients Diagnosed With Acute GVHD | Day 100 | Number of patients diagnosed with acute GVHD by Day 100 post transplant |
| Number of Patients Diagnosed With Overall Grade 1 or Grade 2 Acute GVHD | Day 100 | Number of patients diagnosed with overall grade I or grade II acute GVHD by Day 100 post transplant |
| Number of Patients Diagnosed With Overall Grade III or Grade IV Acute GVHD | Day 100 | Number of patients diagnosed with overall Grade III or Grade IV Acute GVHD by Day 100 post transplant |
| Number of Patients Diagnosed With Chronic GVHD | 1 year | Number of patients diagnosed with chronic GVHD within 1 year post transplant |
| Clinical Significant Infection, Requiring Treatment, Within 100 Days Post Transplant | 100 days | Number of patients who experienced a clinical significant infection, requiring treatment, within 100 days post transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) CONDITIONING REGIMEN: \*Patients with no life-threatening viral or fungal infections within 1 month before the planned HCT receive alemtuzumab IV over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with HLH, IPEX syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0.
HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV or PO 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96.
Alemtuzumab: Given IV Allogeneic Bone Marrow Transplantation: Undergo HCT Allogeneic Hematopoiet | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy, Low Dose Radiation) |
|---|---|
| Age, Categorical <=18 years | 24 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 28 |
| other Total, other adverse events | 13 / 28 |
| serious Total, serious adverse events | 10 / 28 |
Outcome results
Primary
Number of Patients Who Achieve Greater Than 50% Donor T-cell Chimerism
The study will be considered a success and the protocol worthy of further study if there is sufficient evidence that this rate is greater than the 50% rate observed in the most recently transplanted patients with nonmalignant disorders. Analyses will be carried out separately for the alemtuzumab recipients and the TBI recipients. We will be 80% confidence of success if a one-sided 80% confidence interval for the proportion of patients with successful chimerism exceeds 50%. Cumulative incidence will be used to evaluate the probability of chimerism.
Time frame: At 1 year post transplant
Population: Excludes 9 patients who expired prior to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Number of Patients Who Achieve Greater Than 50% Donor T-cell Chimerism | 13 Participants |
Secondary
Clinical Significant Infection, Requiring Treatment, Within 100 Days Post Transplant
Number of patients who experienced a clinical significant infection, requiring treatment, within 100 days post transplant.
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Clinical Significant Infection, Requiring Treatment, Within 100 Days Post Transplant | 21 Participants |
Secondary
Disease Response by 1 Year Post Transplant
Number of patients at 1 year with disease response (defined as no clinical evidence of active disease and/or sufficient level of donor chimerisms to prevent disease recurrence)
Time frame: 1 year
Population: Excludes 9 patients who expired prior to 1 year time point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Disease Response by 1 Year Post Transplant | 15 Participants |
Secondary
Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant
Number of Patients Who Achieve Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant
Time frame: 1 year
Population: Excludes 9 patients who expired prior to 1 year time point
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant | 16 Participants |
Secondary
Greater Than 50% CD33+ Donor Chimerisms at 1 Year Post Transplant
Number of patients who achieve greater than 50% CD33+ donor chimerisms at 1 year post transplant.
Time frame: 1 year
Population: Excludes 9 patients who expired prior to 1 year time point
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Greater Than 50% CD33+ Donor Chimerisms at 1 Year Post Transplant | 8 Participants |
Secondary
Immune Reconstitution by 1 Year Post Transplant
Number of patients with normal range CD3 at 1 year post transplant
Time frame: 1 year
Population: Excludes 16 patients: 13 patients who did not achieve 1 year time point (9 expired, 4 went to second transplant) and 3 patients for whom no data was sent at 1 year from external site
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Immune Reconstitution by 1 Year Post Transplant | 7 Participants |
Secondary
Number of Patients Diagnosed With Acute GVHD
Number of patients diagnosed with acute GVHD by Day 100 post transplant
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Number of Patients Diagnosed With Acute GVHD | 18 Participants |
Secondary
Number of Patients Diagnosed With Chronic GVHD
Number of patients diagnosed with chronic GVHD within 1 year post transplant
Time frame: 1 year
Population: Excludes 6 patients who expired prior to Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Number of Patients Diagnosed With Chronic GVHD | 8 Participants |
Secondary
Number of Patients Diagnosed With Overall Grade 1 or Grade 2 Acute GVHD
Number of patients diagnosed with overall grade I or grade II acute GVHD by Day 100 post transplant
Time frame: Day 100
Population: Excludes 10 patients who were not diagnosed with acute GVHD
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Number of Patients Diagnosed With Overall Grade 1 or Grade 2 Acute GVHD | 12 Participants |
Secondary
Number of Patients Diagnosed With Overall Grade III or Grade IV Acute GVHD
Number of patients diagnosed with overall Grade III or Grade IV Acute GVHD by Day 100 post transplant
Time frame: Day 100
Population: Excludes 10 patients who were not diagnosed with acute GVHD
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Number of Patients Diagnosed With Overall Grade III or Grade IV Acute GVHD | 6 Participants |
Secondary
Overall Survival
Number of patients alive at 1 year
Time frame: 1 year
Population: Excludes 3 patients with graft rejection and second transplant prior to 1 year.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Low Dose Radiation) | Overall Survival | 19 Participants |