Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/II Trial of Reduced Intensity Conditioning and Familial HLA-Mismatched Bone Marrow Transplantation in Children With Non-Malignant Disorders

Conditions
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Metabolic Disorders, Severe Sickle Cell Disease, Bone Marrow Failure Syndromes, Immunologic Disorders, Hemoglobinopathies, Non-malignant Disorders

Intervention / Treatment
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* Drug: RIC regimen
* Drug: GVHD prophylaxis regimen


Participation Criteria
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Eligibility Criteria
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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: Overt or silent stroke or persistently elevated transcranial doppler velocities despite transfusion therapy Recurrent acute chest syndrome with significant respiratory compromise each time Sickle nephropathy Recurrent admissions for vaso-occlusive episodes resulting in prolonged opioid use and poor quality of life with interrupted school attendance activity Red cell alloimmunization with the need for chronic transfusions 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)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RIC Prep Regimen & GVHD Prophylaxis<br>Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen | Drug: RIC regimen<br>* 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<br>* Other names: Transplant Conditioning Regimen;Drug: GVHD prophylaxis regimen<br>* 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) Days +120 to +390: abatacept (IND) monthly (5mg/kg/day IV)<br>* Other names: Graft versus Host Disease prophylaxis regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor engraftment | as measured by chimerism | 100 days and 1 year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil engraftment | as measured by complete blood counts | 100 days post-transplant | 
| Time to platelet engraftment | as measured by complete blood counts | 100 days post-transplant | 
| Effect of BMT on pulmonary function | as measured by pulmonary function tests | 90 days, 1 year, and 2 years post-transplant | 
| Effect of BMT on hepatic function | as measured by laboratory evaluations | 90 days, 180 days, 1 year, and 2 years post-transplant | 
| Effect of BMT on neurologic function | as measured by cognitive testing and quality of life surveys | 90 days, 1 year, and 2 years post-transplant | 
| Effect of BMT on cardiac function | as measured by echocardiograms | 90 days, 1 year, and 2 years post-transplant | 
| Effect of BMT on renal function | as measured by laboratory evaluations | 90 days, 180 days, 1 year, and 2 years post-transplant | 
| Pharmacokinetics of alemtuzumab | as measured by maximum plasma concentration of alemtuzumab | days -19, day 0, day +15, and day +30 | 
| Pharmacokinetics of abatacept | as measured by maximum plasma concentration of abatacept | days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant | 
| Incidence of acute graft-versus-host disease (GVHD) | as measured by protocol grading scale | 1 year post-transplant | 
| Incidence of chronic graft-versus-host disease (GVHD) | as measured by protocol grading scale | 2 years post-transplant | 
| Immune reconstitution | as measured by research laboratory evaluations | days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone marrow transplant, Transplant, Transplantation, Reduced Intensity, Familial HLA mismatched