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

The Washington University

Status and phase

Enrolling

Phase 2

Phase 1

Conditions

Severe Sickle Cell Disease

Hemoglobinopathies

Metabolic Disorders

Bone Marrow Failure Syndromes

Non-malignant Disorders

Immunologic Disorders

Treatments

Drug: GVHD prophylaxis regimen

Drug: RIC regimen

Study type

Interventional

Funder types

Other

Identifiers

NCT03128996

201611172

Details and patient eligibility

About

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.

Full 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.

Enrollment

29 estimated patients

Sex

All

Ages

1 day to 21 years old

Volunteers

No Healthy Volunteers

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)