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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Undergo allogeneic bone marrow transplantation
Given IV
Given IV
Correlative studies
Given PO
Undergo allogeneic bone marrow transplantation
Given PO
Given IV or PO
Undergo total-body irradiation
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Graft Rejection
Number of patients with graft rejection (CD3 donor chimerisms \<5%).
Time frame: Day 84
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
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
Number of Patients With Transplant Related Mortality
The number of patients with transplant related mortality
Time frame: Day 100 post transplant
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
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
Incidence of Chronic GVHD
Number of patients diagnosed with chronic GVHD by 1 year post transplant
Time frame: 1 year post transplant
Immune Reconstitution
Number of patients with normal range CD3 @ 1 year post transplant
Time frame: 1 year post transplant
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
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.