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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02105766
Recruitment Status : Recruiting
First Posted : April 7, 2014
Last Update Posted : May 16, 2018
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


- 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.


- To see if low dose radiation (300 rads), oral cyclophosphamide, pentostatin, and sirolimus help a body to better accept donor stem cells.


- People 16 and older with beta-thalassemia or sickle cell disease that can be cured with transplant, and their donors.


  • 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.
  • will have 5 follow-up visits for 3 years after transplant, then annually.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Thalassemia Stem Cell Transplantation Graft vs Host Disease Drug: Alemtuzumab Drug: Sirolimus Drug: Cyclophosphamide Drug: Pentostatin Drug: Radiotherapy Phase 1 Phase 2

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 to30 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  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonmyeloablative Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation For Sickle Cell Disease and Beta-Thalassemia in Individuals With Higher Risk of Transplant Failure
Study Start Date : April 1, 2014
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : August 31, 2021

Intervention Details:
  • Drug: Alemtuzumab
  • Drug: Sirolimus
  • Drug: Cyclophosphamide
  • Drug: Pentostatin
  • Drug: Radiotherapy
    Immunosuppressant and myelosuppressant

Primary Outcome Measures :
  1. Determine regimen failure rate, defined as graft rejection, severe GVHD (acute GVHD grade 3 or higher or extensive chronic GVHD), or prolonged donor red cell aplasia ( greater than 2 years post -HSCT) [ Time Frame: 7 years ]

Secondary Outcome Measures :
  1. Examine the level of chimerism required to maintain both graft survival as well as hematologic normalcy using a regimen containing pentostatin, cyclophosphamide, alemtuzumab, and low total body irradiation. [ Time Frame: 7 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
  • INCLUSION CRITERIA- recipients (must fulfill one disease category in 1.0 and all of 2.0)

1.0 Disease specific

1.1 Patients with sickle cell disease (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 (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 maximal tolerated dose of hydroxyurea (at MTD for at least 6 months)
      • Acute chest syndrome/ 2 prior ACS/ any ACS while on hydroxyurea (at MTD for at least 6 months)
      • 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 (hydroxurea for at least 6 months)

1.2 Patients with 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

2.0 Non-disease specific:

2.1 Age greater than or equal to16 years

2.2 6/6 HLA matched family donor available

2.3 Ability to comprehend and willing to sign an informed consent

2.4 Negative beta-HCG, when applicable

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

  1. ECOG performance status of 3 or more
  2. 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.
  3. Major anticipated illness or organ failure incompatible with survival from PBSC transplant
  4. Pregnant or lactating
  5. We will measure anti-A, anti-B, and/or other red cell antibody titers from the first cohort to determine the feasibility of transplanting patients with pre-existing antibodies (major ABO mismatch or other anti-donor red cell antibody). The information gathered from this cohort of patients will help to determine if the titer or antibody to a specific antigen needs to be incorporated in the exclusion criteria.


  1. 6/6 HLA matched family donor
  2. Weight greater than or equal to 20 kg (insofar that the weight difference between recipient and donor does not exceed a reasonable likelihood of being able to obtain an adequate cell dose from the donor within two aphereses)
  3. Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards no history of congestive heart failure or unstable angina, and no history of stroke)
  4. Ability to comprehend and willing to sign an informed consent; assent obtained from minors

EXCLUSION CRITERIA- donor: (any of the following would exclude the donor from participating)

  1. Pregnant or lactating
  2. HIV positive
  3. Hemoglobin S greater than or equal to 50%, or B-thalassemia intermedia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02105766

Contact: Stephanie N Helwing, R.N. (301) 827-0448
Contact: Matthew M Hsieh, M.D. (301) 402-7687

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Principal Investigator: Matthew M Hsieh, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT02105766     History of Changes
Other Study ID Numbers: 140077
First Posted: April 7, 2014    Key Record Dates
Last Update Posted: May 16, 2018
Last Verified: May 14, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Sickle Cell Disease
Allogeneic Hematopoietic Stem Cell Transplant
Pentostatin (Nipent)
Alemtuzumab (Campath)

Additional relevant MeSH terms:
Anemia, Sickle Cell
Graft vs Host Disease
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Immune System Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Adenosine Deaminase Inhibitors
Enzyme Inhibitors