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

August 14, 2026 updated by: National Heart, Lung, and Blood Institute (NHLBI)

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Our ongoing nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplant protocol (03-H-0170) for patients with severe sickle cell disease (SCD) and B-thalassemia from HLA-matched family donors has excellent results thus far. Our long term leukocyte engraftment rate is 85-90% with the same disease-free survival. None of the engrafted patients had acute sickle-related events, significant toxicity associated with the conditioning regimen, or any evidence of graft versus host disease (GVHD).

While these results rival the transplant outcomes from low risk transplant patients with B-thalassemia, there are areas for improvement. The first is the 10-15% graft rejection rate, where a majority of these individuals were male donor and female recipient pairs. Another limitation is the significant delay in donor red cell engraftment in one recipient who had pre-existing allo-antibody to donor red cells from previous transfusions. Also we have excluded another group of individuals with preformed antibodies, recipients having major ABO incompatibility to the donors.

To overcome these limitations (and reduce the transplant failure rate) in this new protocol, we will continue our nonmyeloablative approach in the patients with SCD and B-thalassemia with HLA-matched family donors, but using an increased intensity regimen in a subset considered at high risk for transplant failure. This modified regimen consists of pentostatin and oral cyclophosphamide, which we hypothesize will reduce both the T cells that mediate leukocyte rejection and the B/plasma cells that produce anti-donor erythrocyte antibodies. The main transplant backbone will remain as alemtuzumab, low dose total body irradiation of 300 cGy, and sirolimus; the transplant graft will remain as unmanipulated G-CSF mobilized, T-cell replete, PBSC product for hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is the percentage/number of patients who have sustained donor type hemoglobin at 1 year post transplant for male donors - female recipients. The primary endpoint for those with pre-existing antibodies is the presence of donor red cells with reticulocytes greater than or equal to 30 k/uL at 2 years post-transplant. Other endpoints include the toxicity of the pentostatin-cyclophosphamide regimen, the degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related morbidity, as well as disease-free and overall survival. Since SCD and B-thalassemia are non-malignant disorders of red cells, severe GVHD, lack of donor erythrocyte (prolonged donor red cell aplasia), or graft rejection is collectively considered transplant failure.

Study Type

Interventional

Enrollment (Actual)

56

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

-INCLUSION CRITERIA- recipients (must fulfill one disease category in 1 and all of 2)

  1. 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

      2. 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

      • inadequate chelation history (defined as failure to maintain adequate compliance with chelation with deferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week)
      • hepatomegaly of greater than 2cm below the costochondral margin

    Non-disease specific:

    -Age greater than or equal to 4 years

    -6/6 HLA matched family donor available

    • Ability to comprehend and willing to sign an informed consent
    • Negative beta-HCG, when applicable

    EXCLUSION CRITERIA -recipient (any of the following would exclude the subject from participating)

    -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

    INCLUSION CRITERIA -donor

    -6/6 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.

    EXCLUSION CRITERIA -donor

    -None

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor
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
Immunosuppressant
Other Names:
  • Campath
Drug: Sirolimus
Immunosuppressant
Other Names:
  • Rapamune
Drug: Cyclophosphamide
Immunosuppressant
Other Names:
  • Cytoxan
Drug: Pentostatin
Immunosuppressant
Other Names:
  • Deoxycoformycin
Procedure: Radiotherapy
Immunosuppressant and myelosuppressant
Experimental: Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant
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
Immunosuppressant
Other Names:
  • Campath
Drug: Sirolimus
Immunosuppressant
Other Names:
  • Rapamune
Drug: Cyclophosphamide
Immunosuppressant
Other Names:
  • Cytoxan
Drug: Pentostatin
Immunosuppressant
Other Names:
  • Deoxycoformycin
Procedure: Radiotherapy
Immunosuppressant and myelosuppressant
Other: Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor
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
mobilize peripheral blood stem cells for apheresis collection
Other Names:
  • Neupogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients Who Have Sustained Donor Type Hemoglobin at One Year Post Transplant
Time Frame: 1 year
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
Time Frame: 2 years
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean CD34+ Cell Dose
Time Frame: Day 0 up to Day 1
Mean CD34+ cell dose, filgrastim mobilized peripheral blood hematopoietic cells, unselected
Day 0 up to Day 1
Mean CD3+ Cell Dose
Time Frame: Day 0 up to Day 1
Mean CD3+ cell dose, filgrastim mobilized peripheral blood hematopoietic cells, unselected
Day 0 up to Day 1
Median Percent of Donor T-cells and Myeloid Chimerism
Time Frame: day 30, day 60 , day 100, 1 year and 2 year
Median Percent of donor T-cells and myeloid chimerism. Leukocytes are selected by magnetic beads for CD3 (T-cells) and CD14/15 (myeloid cells), then microsatellite PCR analyses are performed to obtain donor chimerism percent.
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
Time Frame: Up to Day 100

Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD.

Grades are defined as:

Grade I: Skin = Maculopapular rash< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day.

Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day.

Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day.

Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus.

Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Up to Day 100
Number of Participants Who Developed Moderate or Severe Chronic Graft vs Host Disease (GVHD)
Time Frame: Day 100 up to 2 years

Number of Participants Who Developed Moderate or Severe Chronic Graft vs Host Disease (GVHD) up to 5 years.

Moderate chronic GVHD involves EITHER 3 organs/sites with no clinically significant functional impairment OR a less than or equal to 1 organ/site with clinically significant functional impairment, but no major disability. Severe GVHD is associated with a major disability caused by chronic GVHD.
Day 100 up to 2 years
Number of Participants That Experienced Graft Failure or Graft Rejection, or Red Cell Aplasia at 2 Years After Transplant
Time Frame: Up to 2 years
Number of participants that experienced graft failure or graft rejection, or red cell aplasia at 2 years after transplant. Graft failure or graft rejection is defined as <5% donor cells in both CD3 and myeloid chimerism. Red cell aplasia is defined as reticulocyte <30 k/uL and requiring red cell transfusions.
Up to 2 years
Number of Participants That Experienced Regimen Failure
Time Frame: Up to 2 years
Number of Participants That Experienced Regimen Failure. Regimen failure is defined as those participants that experienced grade 3 or higher acute GVHD, moderate/severe chronic GVHD, graft failure/rejection, or red cell aplasia. Together any one of these count toward the combined endpoint of regimen failure.
Up to 2 years
Number of Participants That Experienced Transplant-related Mortality
Time Frame: Up to 2 years
Number of participants that experienced transplant-related mortality. Transplant-related mortality is defined as death that is at least possibly related to the transplant (GVHD, toxicity, infection, other causes).
Up to 2 years
Percentage of Participant With Disease-free Survival Following Stem Cell Transplant
Time Frame: Up to 2 years
Percentage of participant with disease-free survival following stem cell transplant. Disease-free survival is defined as alive and free acute complications related to sickle cell disease.
Up to 2 years
Percentage of Participant Overall Survival Following Stem Cell Transplant
Time Frame: Up to 2 years
Percentage of Participant Overall Survival up to year 2 following stem cell transplant. Overall survival is defined as being alive following stem cell transplant.
Up to 2 years
Median Day to Neutrophil Recovery
Time Frame: Up to Day 100
Median Day to Neutrophil recovery. Neutrophil recovery is defined as the first of three consecutive days of neutrophil count >0.5 x 10^9 cells/uL.
Up to Day 100
Median Days to Platelet Recovery
Time Frame: Up to Day 120
Median Days to Platelet Recovery. Platelet recovery is defined as count >50 cells/uL and 7 days from the last platelet transfusion.
Up to Day 120
Median Days to Red Cell Recovery
Time Frame: Up to 2 years
Median Days to Red Cell Recovery. Red cell recovery defined as days to recovery of reticulocyte count .30 k/uL, detection of donor red cells, transfusion independence.
Up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

National Institutes of Health Clinical Center (CC)
National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Matthew M Hsieh, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 21, 2014

Primary Completion (Actual)

December 31, 2023

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

April 1, 2014

First Submitted That Met QC Criteria

April 2, 2014

First Posted (Estimated)

April 7, 2014

Study Record Updates

Last Update Posted (Actual)

August 18, 2026

Last Update Submitted That Met QC Criteria

August 14, 2026

Last Verified

August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 140077
  • 14-H-0077

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All IPD that underlie results in a publication

IPD Sharing Time Frame

At the time of publication or by the end of the protocol, whichever comes first, and available indefinitely

IPD Sharing Access Criteria

Data will be shared upon request by sending a request to matthewhs@nhlbi.nih.gov

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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