This phase II clinical trial studies how well treosulfan and fludarabine phosphate with or without low dose radiation before donor stem cell transplantation works in treating patients with nonmalignant (noncancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (noncancerous) diseases such as primary immunodeficiency disorders, bone marrow failure syndromes, hemoglobinopathies, and inborn errors of metabolism (metabolic disorders). Powerful chemotherapy drugs and/or radiation are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy and/or radiation which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine phosphate) with or without low dose radiation results in new blood-forming cells (engraftment) of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases.
OUTLINE: CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1. TRANSPLANTATION: Patients receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood (UCB) from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status. IMMUNOSUPPRESSION: Patients receive a combination of immunosuppressive medications to try and prevent graft-versus-host disease. There are 2 regimens depending on the donor. Regimen A: Patients undergoing bone marrow or PBSC transplantation receive tacrolimus daily from day -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Regimen B: Patients undergoing UCB transplantation receive cyclosporine on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil on days 0 to 40 followed by a taper until day 96 in the absence of GVHD. After completion of study treatment, patients are followed up periodically for 5 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
98
Infused IV
Given IV
Given IV or PO
Given IV
Correlative studies
Given IV
Given IV or PO
Infused IV
Given IV or PO
Undergo total body irradiation
Given IV
Single or double unit umbilical cord blood transplant, infused IV
Children's Hospital Colorado
Aurora, Colorado, United States
Oregon Health and Science University
Portland, Oregon, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
Seattle Children's Hospital
Seattle, Washington, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
Preliminary Efficacy
Number of patients engrafted (\>5% donor CD3+ peripheral blood chimerisms) at 1 year following transplant
Time frame: 1 year following transplant
Non-relapse Mortality
Number of patients who experienced non-relapse mortality by 1 year following transplant
Time frame: 1 year following transplant
Number of Patients With Grade II-IV Acute Graft-versus-host Disease
Number of patients diagnosed with overall grade II-IV acute GVHD by Day 100 post transplant
Time frame: Day 100 post transplant
Number of Patients With of Chronic Graft-versus-host Disease
Number of patients diagnosed with chronic GVHD and requiring systemic immunosuppression within 1 year following transplant
Time frame: 1 year following transplant
Donor Chimerism CD3 at 100 Days Post Transplant
Number of patients with peripheral blood donor chimerism for CD3 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant.
Time frame: Day 100 post transplant
Disease Response at One Year Following Hematopoietic Cell Transplantation
Number of patients with no evidence of disease at one year following transplant
Time frame: 1 year following transplant
Immune Reconstitution Following Hematopoietic Cell Transplantation
Number of patients with immune reconstitution (defined by a normal range CD3) at 1 year post transplant
Time frame: 1 year following transplant
Number of Participants With Infections
Number of participants with clinically significant infections (bacterial, fungal, viral) requiring treatment within 100 days following transplant
Time frame: 100 days post transplant
Overall Survival
Number of patients alive at 1 year following transplant
Time frame: 1 year following transplant
Donor Chimerism CD33 at Day 100 Post Transplant
Number of patients with peripheral blood donor chimerism for CD33 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant.
Time frame: 100 days post transplant
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