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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Given IV
Undergo HCT
Undergo HCT
Given PO or IV
Given IV
Correlative study
Given PO or IV
Undergo low dose TBI
Children's Hospital and Research Center at Oakland
Oakland, California, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
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
Overall Survival
Number of patients alive at 1 year
Time frame: 1 year
Immune Reconstitution by 1 Year Post Transplant
Number of patients with normal range CD3 at 1 year post transplant
Time frame: 1 year
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
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
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
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
Number of Patients Diagnosed With Acute GVHD
Number of patients diagnosed with acute GVHD by Day 100 post transplant
Time frame: Day 100
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
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
Number of Patients Diagnosed With Chronic GVHD
Number of patients diagnosed with chronic GVHD within 1 year post transplant
Time frame: 1 year
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