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

NCT ID: NCT03128996

Last Updated: 2026-01-07

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-20
• Study Completion Date: 2033-04-30

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

RIC Prep Regimen & GVHD Prophylaxis

Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen

Group Type: EXPERIMENTAL

RIC regimen

Intervention Type: DRUG

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

GVHD prophylaxis regimen

Intervention Type: DRUG

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)

Interventions

RIC 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

Intervention Type: DRUG

GVHD prophylaxis regimen

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)

Intervention Type: DRUG

Other Intervention Names

Transplant Preparative Regimen; Transplant Conditioning Regimen; Graft versus Host Disease prophylaxis regimen

Eligibility Criteria

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)

• Minimum Eligible Age: 1 Day
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Shalini Shenoy, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Yale School of Medicine

New Haven, Connecticut, United States

Site Status: RECRUITING

Nemours Children's Health

Wilmington, Delaware, United States

Site Status: RECRUITING

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States

Site Status: RECRUITING

Washington University School of Medicine

St Louis, Missouri, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Shalini Shenoy, MD

Role: CONTACT

shalinishenoy@wustl.edu

314-454-6018

Ian Snyder, BS, CCRP

Role: CONTACT

ian.s@wustl.edu

314-273-5953

Facility Contacts

Lakshmanan Krishnamurti, MD

Role: primary

Emi Caywood, MD

Role: primary

(800) 416-4441

Troy Quigg, DO

Role: primary

Shalini Shenoy, MD

Role: primary

shalinishenoy@wustl.edu

314-454-6018

Ian Snyder, BS, CCRP

Role: backup

ian.s@wustl.edu

314-273-5953

References

Ngwube A, Shah N, Godder K, Jacobsohn D, Hulbert ML, Shenoy S. Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease. Blood Adv. 2020 Aug 25;4(16):3894-3899. doi: 10.1182/bloodadvances.2020002236.

Reference Type: DERIVED

PMID: 32813873 (View on PubMed)

Other Identifiers

201611172

Identifier Type: -

Identifier Source: org_study_id