Nonmyeloablative Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease and Beta-thalassemia in People With Higher Risk of Transplant Failure

NCT02105766 | Active Not Recruiting Phase 2 Results FDA Drug

• 2 other identifiers: 14007714-H-0077
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Some sickle cell disease or beta-thalassemia can be cured with transplant. Researchers want to test a variation of transplant that uses low dose radiation and a combination of immunosuppressive drugs. They want to know if it helps a body to better accept donor stem cells. Objectives: \- To see if low dose radiation (300 rads), oral cyclophosphamide, pentostatin, and sirolimus help a body to better accept donor stem cells. Eligibility: \- People 4 and older with beta-thalassemia or sickle cell disease that can be cured with transplant, and their donors. Design:

• Participants and donors will be screened with medical history, physical exam, blood test, tissue and blood typing, and bone marrow sampling. They will visit a social worker.
• Donors:
• may receive an intravenous (IV) tube in their groin vein.
• will receive a drug injection daily for 5 or 6 days to move the blood stem cells from the bone marrow into general blood circulation.
• will undergo apheresis: an IV is put into a vein in each arm. Blood is taken from one arm, a machine removes the white blood cells that contain blood stem cells, and the rest is returned through the other arm.
• Participants:
• may undergo red cell exchange procedure.
• will remain in the hospital for about 30 days.
• will receive a large IV line that can stay in their body from transplant through recovery.
• will receive a dose of radiation, and transplant related drugs by mouth or IV.
• will receive blood stem cells over 8 hours by IV.
• will take neuropsychological tests and may complete questionnaires throughout the transplant process.
• must stay near NIH for 4 months. They will visit the outpatient clinic weekly.

Conditions

Sickle Cell Disease; Thalassemia; Stem Cell Transplantation; Graft vs Host Disease

Keywords

Sickle Cell Disease; Allogeneic Hematopoietic Stem Cell Transplant; Pentostatin (Nipent); Cyclophosphamide; Alemtuzumab (Campath)

Outcome Measures

Primary Outcomes (2)

• Number of Patients Who Have Sustained Donor Type Hemoglobin at One Year Post Transplant

  Number of patients who have sustained donor type hemoglobin at one year post transplant. Sustained donor type hemoglobin is based on hemoglobin electrophoresis for patients with SCD and transfusion independence for patients with beta-thalassemia

  1 year

• Number of Participants With Donor Red Cells at 2 Years Post Stem Cell Transplant

  Number of participants with donor red cells at 2 years post stem cell transplant. Number of participants with donor red cells is detected by hemoglobin electrophoresis or donor type red cell antigen, and reticulocyte count ≥30 k/uL at 2 years post-transplant.

  2 years

Secondary Outcomes (13)

• Mean CD34+ Cell Dose

  Day 0 up to Day 1

• Mean CD3+ Cell Dose

  Day 0 up to Day 1

• Median Percent of Donor T-cells and Myeloid Chimerism

  day 30, day 60 , day 100, 1 year and 2 year

• Number of Participants Who Developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV

  Up to Day 100

• Number of Participants Who Developed Moderate or Severe Chronic Graft vs Host Disease (GVHD)

  Day 100 up to 2 years

Study Arms (3)

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor

EXPERIMENTAL

Female participants with Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant with male donor. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

Drug: Alemtuzumab; Drug: Sirolimus; Drug: Cyclophosphamide; Drug: Pentostatin; Procedure: Radiotherapy

Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

EXPERIMENTAL

Participants with pre-existing antibodies and Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

Drug: Alemtuzumab; Drug: Sirolimus; Drug: Cyclophosphamide; Drug: Pentostatin; Procedure: Radiotherapy

Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor

OTHER

Participants received filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling.

Drug: Filgrastim

Interventions

Alemtuzumab DRUG

Immunosuppressant

Also known as: Campath

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor; Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

Sirolimus DRUG

Immunosuppressant

Also known as: Rapamune

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor; Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

Cyclophosphamide DRUG

Immunosuppressant

Also known as: Cytoxan

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor; Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

Pentostatin DRUG

Immunosuppressant

Also known as: Deoxycoformycin

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor; Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

Radiotherapy PROCEDURE

Immunosuppressant and myelosuppressant

Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor; Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant

Filgrastim DRUG

mobilize peripheral blood stem cells for apheresis collection

Also known as: Neupogen

Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor

Eligibility Criteria

• Age: 4 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Disease specific
• Patients with severe sickle cell disease (not limited to Hb SS, SC, or S beta-thal) at high risk for disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, C, D, or E) or potentially modifiable complication(s) not ameliorated by hydroxyurea or sickle specific therapy (F):
• A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy; OR
• B. Sickle cell-related renal insufficiency defined by a creatinine level greater than or equal to 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance less than \< 50mL/min OR requiring peritoneal or hemodialysis; OR
• C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 m/s 40, 41 at baseline; OR
• D. Recurrent priapism defined as at least 2 episodes of an erection lasting \>4 hours involving the corpora cavernosa and corpus spongiosa; OR
• E. Sickle hepatopathy defined as EITHER ferritin \>1000mcg/L OR direct bilirubin \>0.4 mg/dL at baseline
• F. Any one of the below complications:
• Complication/ Eligible for hydroxyurea\*/ Eligible for HSCT
• Vaso-occlusive crises/ At least 3 hospital admissions in the last year/ More than one hospital admission in the last year while on therapeutic dose of hydroxyurea or sickle cell therapy
• Acute chest syndrome/ 2 prior ACS/ any ACS while on hydroxyurea
• Osetonecrosis of 2 or more joints/ And significantly affecting their quality of life by Karnofsky score 50-60/ And on hydroxyurea where total hemoglobuin increases less than 1 g/dL or fetal hemoglobin increases less than 2.5 times the baseline level
• Red cell alloimmunization/ Transfusion dependent/ Total hemoglobin increases less than 1g/dL while on hydroxurea
• \. Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:
• \-- portal fibrosis by liver biopsy

You may not qualify if:

• ECOG performance status of 3 or more
• Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant
• Pregnant or lactating
• /6 HLA matched family donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood for research. Matched related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all matched related donors, but is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study.
• None

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead
• National Cancer Institute (NCI): collaborator
• National Institutes of Health Clinical Center (CC): collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Inam Z, Jeffries N, Link M, Coles W, Pollack P, Luckett C, Phang O, Harvey E, Martin T, Farrey T, Tisdale JF, Hsieh MM. Two Nonmyeloablative HLA-Matched Related Donor Allogeneic Hematopoietic Cell Transplantation Regimens in Patients with Severe Sickle Cell Disease. Transplant Cell Ther. 2025 May;31(5):305-318. doi: 10.1016/j.jtct.2025.02.021. Epub 2025 Feb 24.

  PMID: 40010689 DERIVED

• Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.

  PMID: 36240296 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell; Thalassemia; Graft vs Host Disease

Interventions

Alemtuzumab; Sirolimus; Cyclophosphamide; Pentostatin; Radiotherapy; Filgrastim

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Coformycin; Formycins; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors

Results Point of Contact

• Title: Matthew Hsieh M.D.
• Organization: National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

matthewhs@nhlbi.nih.gov

301.402.7687

Study Officials

• Matthew M Hsieh, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2014
• First Posted: April 7, 2014
• Study Start: April 21, 2014
• Primary Completion: December 31, 2023
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 11, 2025
• Results First Posted: November 29, 2024

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: At the time of publication or by the end of the protocol, whichever comes first, and available indefinitely
• Access Criteria: Data will be shared upon request by sending a request to matthewhs@nhlbi.nih.gov

Locations

US (1)