This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.
OUTLINE: CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -4 to -2. TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) as well as possible chest radiography (x-ray) or computed tomography (CT) at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial. After completion of study treatment, patients are followed up at 1 year from transplant.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Given IV
Given IV
Given IV and PO
Given IV
Given IV
Undergo PBSC
Undergo bone marrow transplant
Ancillary studies
Undergo ECHO
Undergo MUGA
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo blood sample collection
Undergo chest x-ray
Undergo chest CT
Children's Hospital Los Angeles
Los Angeles, California, United States
Rady Children's Hospital/UCSD
San Diego, California, United States
University of California San Francisco
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Children's Healthcare of Atlanta
Atlanta, Georgia, United States
Johns Hopkins University
Baltimore, Maryland, United States
Boston Children's Hospital
Boston, Massachusetts, United States
University of Michigan Medical Center
Ann Arbor, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
St. Louis Children's Hospital
St Louis, Missouri, United States
...and 14 more locations
Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)
The primary endpoint is the incidence of 1-year GVHD free, EFS (GEFS). An event is defined as death due to any cause, primary or secondary graft failure/rejection, or 2nd HCT whichever occurs first. Grade III-IV acute GVHD and chronic GVHD (using National Institutes of Health \[NIH\] consensus criteria) requiring systemic immune suppression will be considered in this estimate.
Time frame: 1 year post-HCT
Overall Survival
Overall survival at day 100 after HCT
Time frame: Day 100 post-HCT
Overall Survival
Overall survival at 6 months after HCT
Time frame: 6 months post-HCT
Overall Survival
Overall survival at 1 year after HCT
Time frame: 1 year post-HCT
Event-Free Survival
Event-free survival will be estimated at 12 months after HCT. An event is defined as death due to any cause, primary or secondary graft failure/rejection, or 2nd HCT, whichever occurs first
Time frame: 1 year post-HCT
Hematologic Recovery: Neutrophil recovery
Hematologic recovery will be assessed according to neutrophil recovery after transplant. Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ to 500/mm3 for 3 consecutive measurements on 3 different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery.
Time frame: Assessed up to 1 year post-HCT
Hematologic Recovery: Platelet recovery
Hematologic recovery will be assessed according to platelet counts recovery after transplant. Platelet recovery is defined as the first day of a minimum of 3 days that the patient has a sustained platelet count ≥ 20,000/mm3 with no platelet transfusions in the preceding 7 days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment.
Time frame: Day 100 post-HCT
Donor Chimerism (CD3 and Myeloid)
Proportions of patients with full (\>95%), mixed (5-95%), or rejection (\<5%) myeloid
Time frame: Day 28 post-HCT
Donor Chimerism (CD3 and Myeloid)
Proportions of patients with full (\>95%), mixed (5-95%), or rejection (\<5%) myeloid
Time frame: Day 100 post-HCT
Donor Chimerism (CD3 and Myeloid)
Proportions of patients with full (\>95%), mixed (5-95%), or rejection (\<5%) myeloid
Time frame: 1 year post-HCT
Primary graft failure/rejection
Defined as never achieving ANC ≥ 500/μL or never achieving ≥ 5% donor myeloid chimerism assessed by peripheral blood chimerism assays by day +42 post-HCT. Second infusion of hematopoietic cells is also considered indicative of primary graft failure by day +42 post-HCT
Time frame: Day 42 post-HCT
Secondary graft failure/rejection post-HCT
Defined as \< 5% donor myeloid chimerism in peripheral blood beyond day +42 post-HCT in patients with prior documentation of hematopoietic recovery with ≥ 5% donor cells by day +42 post-HCT. Second infusion of hematopoietic cells is also considered indicative of secondary graft failure.
Time frame: Assessed up to 1 year post-HCT
Grade II-IV and grade III-IV GVHD at day 100
The cumulative incidences of acute grade II-IV and III-IV GVHD at day 100 after HCT will be determined.
Time frame: Day 100 post-HCT
Grade II-IV and grade III-IV GVHD at day 180
The cumulative incidences of acute grade II-IV and III-IV GVHD at day 100 after HCT will be determined.
Time frame: Day 180 post-HCT
Chronic GVHD
The cumulative incidence of chronic GVHD (using NIH consensus criteria) requiring systemic immune suppression at 1 year after HCT will be determined. Data will be collected directly from providers and chart review as defined by the NIH Consensus Conference Criteria
Time frame: 1 year post-HCT
Incidence of grade 3-5 toxicities
Grade 3-5 toxicities by day 30 after HCT
Time frame: Day 30 post-HCT
Incidence of grade 3-5 toxicities
Grade 3-5 toxicities by day 100 after HCT
Time frame: Day 100 post-HCT
Incidence of grade 2-3 systemic infections
All microbiologically documented infections or significant infections requiring antibiotic/antifungal therapy occurring up to 6 months after HCT
Time frame: 6 months post-HCT
Incidence of Epstein Barr virus (EBV) reactivation requiring therapy
The incidence of EBV reactivation requiring therapy in the first 180 days after HCT, and of EBV-associated lymphoproliferative disorder in the first 180 days after HCT will be evaluated.
Time frame: Day 180 post-HCT
Incidence of EBV-associated lymphoproliferative disorder
Time frame: Day 180 post-HCT
Incidence of cytomegalovirus (CMV) reactivation requiring therapy by day 180 post-HCT
Time frame: Up to day 180 post-HCT
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