Bone Marrow Failure Syndromes, Hemoglobinopathies, Immunologic Disorders, Metabolic Disorders, Non-malignant Disorders, Severe Sickle Cell Disease
Conditions
Keywords
Bone marrow transplant, Transplant, Transplantation, Reduced Intensity, Familial HLA mismatched
Brief summary
This study is designed to estimate the efficacy and toxicity of familial HLA mismatched bone marrow transplants in patients with non-malignant disease who are less than 21 years of age and could benefit from the procedure.
Detailed description
Patients \< 21 years of age with a non-malignant disorder benefited by hematopoietic stem cell transplant will receive a reduced intensity conditioning regimen consisting of hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. This will be followed by a familial HLA-mismatched bone marrow transplant. The primary objective is to establish safety and donor cell engraftment at 100 days and 1 year post-transplant.
Interventions
DRUGRIC regimen
Days -60 to -21: hydroxyurea (30mg/kg/day po) \>6hrs prior to 1st dose: alemtuzumab (3mg IV) Day -21: alemtuzumab (10mg IV or S/C) Day -20: alemtuzumab (15mg IV or S/C) (10mg if \< 10kg) Day -19: alemtuzumab (20mg IV or S/C) (10mg if \< 10kg) Days -8 to -4: fludarabine (30mg/m2/day IV) Day -4: thiotepa (8mg/kg IV) Day -3: melphalan (140mg/m2) Days -2 to -1: rest days/no therapy Day 0: bone marrow transplant
Day +3 to +4: cyclophosphamide (50mg/kg/day IV) Day +5: Start of tacrolimus \& Start of mycophenolate mofetil (MMF) Days +5, +14, +30, +60, +90: abatacept (IND) (10mg/kg/day IV) Day +90: rituximab (375mg/m2 IV once) Patients \>/= 12 yrs - Days +120 to +180: abatacept (IND) monthly (10mg/kg/day IV) Patients \>/= 12 yrs - Days +210 to +390: abatacept (IND) monthly (5mg/kg/day) Patients \<12 yrs - Days +120 to +390: abatacept (IND) monthly (5mg/kg/day IV)
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 21 Years
Healthy volunteers
No
Inclusion criteria
* Nonmalignant disorder requiring bone marrow transplant including bone marrow failure syndromes, metabolic disorders, immunologic disorders, or hemoglobinopathy * For patients with sickle cell disease, must have one of the following severe manifestations: 1. Overt or silent stroke or persistently elevated transcranial doppler velocities despite transfusion therapy 2. Recurrent acute chest syndrome with significant respiratory compromise each time 3. Sickle nephropathy 4. Recurrent admissions for vaso-occlusive episodes resulting in prolonged opioid use and poor quality of life with interrupted school attendance activity 5. Red cell alloimmunization with the need for chronic transfusions 6. Recurrent osteonecrosis or multiple joint involvement from avascular necrosis * Patients with sickle cell disease must have hemoglobin S \< 30% within 30 days prior to beginning alemtuzumab * Age \</= 20.99 years at the time of enrollment * Performance score \>/= 50 * Left ventricular ejection fraction \> 40% or left ventricular shortening fraction \> 26% by echocardiogram * DLCO \> 40% (corrected for hemoglobin) or pulse oximetry with a baseline O2 saturation of \>/= 90% on room air if too young to perform PFTs * Serum creatinine \</= 1.5x upper limit of normal for age and/or GFR \> 70 mL/min/1.73m2 * Direct bilirubin \< 2x upper limit of normal for age * ALT and AST \< 5x upper limit of normal for age * Participants who have or are receiving \>/= 8 packed red blood cell transfusions for \>/= 1 year or \>/= 20 packed red blood cell transfusions (lifetime cumulative) will undergo liver MRI for estimation of hepatic iron content. 1\. Liver biopsy is indicated for hepatic iron content \>/= 7mg Fe/mg liver dry weight by liver MRI. Histologic examination of the liver must document for the absence of cirrhosis, bridging fibrosis, and active hepatitis * Female subjects of childbearing potential, must agree to practice 2 methods of contraception at the same time from the time of signing of informed consent through 12 months post transplant. Male subjects must agree to practice effective barrier contraception or practice true abstinence from the time of signing informed consent through 12 months post transplant. * Written informed consent must be obtained from all recipients in accordance with the guidelines of the institution's Human Studies Committee.
Exclusion criteria
* Patients who have an HLA-identical sibling who is able and willing to donate bone marrow * Patients with cirrhosis or established bridging fibrosis of the liver or active hepatitis * Uncontrolled bacterial, viral, or fungal infection within 6 weeks prior to enrollment * Evidence of HIV infection or known HIV positive serology * Patients who have received a previous stem cell transplant * Patients who have received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment * Females who are pregnant or breast feeding * Patients with active autoimmune disease (e.g. sarcoidosis, lupus, scleroderma)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Donor engraftment | 100 days and 1 year post-transplant | as measured by chimerism |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to neutrophil engraftment | 100 days post-transplant | as measured by complete blood counts |
| Time to platelet engraftment | 100 days post-transplant | as measured by complete blood counts |
| Effect of BMT on pulmonary function | 90 days, 1 year, and 2 years post-transplant | as measured by pulmonary function tests |
| Effect of BMT on hepatic function | 90 days, 180 days, 1 year, and 2 years post-transplant | as measured by laboratory evaluations |
| Effect of BMT on neurologic function | 90 days, 1 year, and 2 years post-transplant | as measured by cognitive testing and quality of life surveys |
| Effect of BMT on cardiac function | 90 days, 1 year, and 2 years post-transplant | as measured by echocardiograms |
| Effect of BMT on renal function | 90 days, 180 days, 1 year, and 2 years post-transplant | as measured by laboratory evaluations |
| Pharmacokinetics of alemtuzumab | days -19, day 0, day +15, and day +30 | as measured by maximum plasma concentration of alemtuzumab |
| Pharmacokinetics of abatacept | days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant | as measured by maximum plasma concentration of abatacept |
| Incidence of acute graft-versus-host disease (GVHD) | 1 year post-transplant | as measured by protocol grading scale |
| Incidence of chronic graft-versus-host disease (GVHD) | 2 years post-transplant | as measured by protocol grading scale |
| Immune reconstitution | days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant | as measured by research laboratory evaluations |
Countries
United States
Contacts
CONTACTShalini Shenoy, MD
CONTACTIan Snyder, BS, CCRP
PRINCIPAL_INVESTIGATORShalini Shenoy, MD
Washington University School of Medicine
Outcome results
None listed