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Haploidentical PBMC Transplant for Severe Congenital Anemias

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00977691
Recruitment Status : Active, not recruiting
First Posted : September 16, 2009
Results First Posted : October 14, 2019
Last Update Posted : April 18, 2023
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


Bone marrow transplantation (BMT), which involves transplanting a donor's marrow stem cells, is capable of curing some congenital anemias. BMT usually involves high-intensity treatment with chemotherapy and radiation to kill abnormal cells, which affects all systems of the body.

People with anemias often have damage to other organs such as the kidneys, which can be further damaged by the chemotherapy. Only approximately 20 percent of patients have a full-matched donor, making treatment for many people with anemias unavailable. However, 90 percent of patients may have a half-matched donor, but using a half-matched donor increases the toxicity of BMT.


To determine if a research BMT with half-matched donor cells, low-intensity radiation, immunosuppressant drugs, and no chemotherapy will be effective in patients with sickle cell disease and Beta-thalassemia.

To determine the effectiveness of cyclophosphamide, an immunosuppressant drug, in preventing rejection of the donor cells.


Recipients are individuals at least 18 years of age who have been diagnosed with sickle cell disease and Beta-thalassemia, and who have a family member who is a haploidentical (i.e., half match) tissue match.

Donors are healthy individuals between the ages of 2 and 80 who are found to be suitable donors.


Donors will undergo apheresis, which involves withdrawing blood from one arm vein, passing it through a machine that removes bone marrow stem cells, and returning the remaining blood through the vein in the other arm. Donors will receive a drug that causes the stem cells to be released into the bloodstream prior to the apheresis procedure.

Recipients will undergo routine physical and laboratory examinations, including bone marrow sampling at the beginning of the study. After transplantation, physical and laboratory examinations will occur on a weekly or twice weekly basis at the outpatient clinic. Recipients will be examined every 6 months starting 100 days posttransplant for 5 years.

Recipients will receive low-dose radiation in two treatments 1 and 2 days before the transplant. They will also be given immunosuppressant therapy with alemtuzumab and sirolimus. Another immunosuppressant drug, cyclophosphamide, will be given in the future as needed to subsets of the recipients to prevent rejection of donor cells.

Recipients will receive the donor stem cells through a previously inserted central line. The process takes up to 8 hours.

Recipients will receive blood transfusions as necessary to prevent anemia and bleeding during the posttransplant period. They may also receive intravenous antibiotics to prevent infection.

Condition or disease Intervention/treatment Phase
Sickle Cell Anemia Procedure: PBSC Transplant Drug: Alemtuzumab Drug: Sirolimus Drug: Cyclophosphamide Procedure: Low Dose Irradiation Phase 1 Phase 2

Detailed Description:

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Our ongoing protocol for patients with severe congenital anemias, particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent preliminary results. None of the patients who engrafted had sickle-related events or any evidence of graft versus host disease (GVHD). There was no significant toxicity associated with the conditioning regimen.

Our main limitation has been a lack of HLA-matched sibling donors in the majority of patients. We performed a study in which patients with severe SCD who lacked a suitable donor underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority of patients were not found to have an appropriate alternative donor. We therefore seek to develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that family members can serve as donors and greatly expand the donor pool.

In this protocol, we propose PBSC transplantation in patients with SCD and thalassemia, considered at high risk for complications from or ineligible for standard bone marrow transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant-related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of a relatively low radiation dose for therapeutic radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), and Cyclophosphamide (Cytoxan ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is the percentage of patients who have sustained donor type hemoglobin without significant GVHD for patients with SCD, or who are transfusion-independent and without significant GVHD for patients with thalassemia. Other endpoints include 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia
Actual Study Start Date : December 14, 2009
Actual Primary Completion Date : August 1, 2018
Estimated Study Completion Date : September 10, 2023

Arm Intervention/treatment
Experimental: Cohort 1
PBSC transplant with no post-transplant cyclophosphamide (PT-Cy)
Procedure: PBSC Transplant
PBSC transplant

Drug: Alemtuzumab
Other Name: Campath

Drug: Sirolimus
Other Name: Rapamune

Procedure: Low Dose Irradiation
low dose irradiation

Experimental: Cohort 2
PBSC transplant with 50 mg/kg post-transplant cyclophosphamide (PT-Cy)
Procedure: PBSC Transplant
PBSC transplant

Drug: Alemtuzumab
Other Name: Campath

Drug: Sirolimus
Other Name: Rapamune

Drug: Cyclophosphamide
Other Name: Cytoxan

Procedure: Low Dose Irradiation
low dose irradiation

Experimental: Cohort 3
PBSC transplant with 100 mg/kg post-transplant cyclophosphamide (PT-Cy)
Procedure: PBSC Transplant
PBSC transplant

Drug: Alemtuzumab
Other Name: Campath

Drug: Sirolimus
Other Name: Rapamune

Drug: Cyclophosphamide
Other Name: Cytoxan

Procedure: Low Dose Irradiation
low dose irradiation

Primary Outcome Measures :
  1. Patients With Donor Type Hemoglobin [ Time Frame: 1 year ]
    Percentage of patients post transplant with sustained donor type hemoglobin on hemoglobin electrophoresis

Secondary Outcome Measures :
  1. Chimeric Value That is Required to Maintain Graft Survival and Hematologic Normalcy. [ Time Frame: Up to Year 5 ]

    Define the level of chimerism required to maintain graft survival and hematologic normalcy. Hematologic normalcy may be defined as: being free from sickle cell disease.

    The chimeric status of patients will be measured on days +14 (or when subject starts to engraft), +30, +60 and +100, and periodically after day +100, by microsatellite analysis of the peripheral blood.

    Engraftment of donor cells was assessed with the use of methods that detect informative polymorphisms in regions known to contain short tandem repeats. Peripheral-blood CD3+ T cells and CD14+CD15+ myeloid cells were selected for analysis with the use of immunomagnetic beads (Dynal).

  2. Number of Participants Who Developed Acute GVHD Grades I, II, III, IV [ Time Frame: Day100 ]

    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.

  3. Number of Participants Who Developed Limited Chronic GVHD [ Time Frame: Year 5 ]

    Number of incidences of participants who developed Limited Chronic Graft vs Host Disease (GVHD).

    Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction.

    Limited disease is associated with a favorable outcome without systemic therapy, while extensive disease patients have an unfavorable outcome.

  4. Number of Participants Who Develop Extensive GVHD [ Time Frame: Year 5 ]

    Number of participants with extensive, Chronic Graft vs Host Disease (GVHD). Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD.

    Extensive disease presents either with generalized skin involvement, or with localized skin involvement or hepatic dysfunction plus at least one of the following:

    • Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis
    • Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and classification of Sjögren's syndrome")
    • Involvement of minor salivary glands or oral mucosa (as demonstrated on labial or mucosal biopsy specimen)
    • Involvement of any other target organ

  5. Number of Participants With Disease-free Survival [ Time Frame: Year 5 ]
    Number of participants with disease-free survival, as defined by: alive and free acute complications related to sickle cell disease.

  6. Number of Participants Overall Survival [ Time Frame: Up to Year 5 ]
    Number of participants overall survival by year 5

  7. Number of Participants With Graft Failure [ Time Frame: Up to Year 5 ]
    Number of participants with graft failure by year 5. Graft failure is defined by return of sickle cell disease.

  8. Number of Participants That Experienced a Transplant-related Mortality [ Time Frame: Year 1 ]
    Number of participants that experienced a transplant related mortality, as defined as death from causes other than relapse (GVHD, toxicity, infection, other and unknown causes).

  9. Number of Stem Cell Transplant Participants That Experienced Rejection at Each Dose of Post-transplant Cyclophosphamide [ Time Frame: Year 5 ]
    Number of stem cell transplant participants that experienced rejection at each dose of post-transplant cyclophosphamide. Determine whether post-transplant cyclophosphamide is required and will reduce the incidence and severity of regimen failure.

  10. Participants Who Engrafted or Rejected and Type of Haploidentical Donors [ Time Frame: Up to Year 5 ]
    Determine whether specific haploidentical donors (i.e. parent versus sibling versus child) will decrease the incidence of regimen failure

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Recipients (must fulfill one disease category in 5.1.1 and all of 5.1.2)

5.1.1 Disease specific Patients with sickle cell disease (HB SS, SC, or SBeta(0)-thal) at high risk for disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, C, or D) or potentially modifiable complication(s) not ameliorated by hydroxyurea (E):

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. Pulmonary hypertension defined as tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 m/s at baseline (without vaso-occlusive crisis); OR

D. Sickle hepatopathy defined as EITHER ferritin greater than 1000mcg/L OR direct bilirubin greater than 0.4 mg/dL AND platelet count less than 250,000/microL at baseline (without vaso-occlusive crisis)

E. Any one of the below complications:

-Complication: Vaso-occlusive crises;

Eligible for hydroxyurea*: At least 3 hospital admissions in the last year.

Eligible for HSCT: More than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea*

-Complication: Acute chest syndrome

Eligible for hydroxyurea*: 2 prior ACS

Eligible for HSCT: any ACS while on hydroxyurea*

*hydroxyurea at maximum tolerated dose for at least 6 months 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

5.1.2 Non-disease specific: Age greater than or equal to 18 years Haploidentical relative donor available Ability to comprehend and willing to sign an informed consent Negative Beta-HCG


Recipient (any of the following would exclude the subject from participating)

5.2.1 6/6 HLA-matched with or without an ABO minor mismatched sibling donor

5.2.2 ECOG performance status of 3 or more

5.2.3 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.

5.2.4 Major anticipated illness or organ failure incompatible with survival from PBSC transplant

5.2.5 Pregnant or lactating

5.2.6 Major ABO mismatch



5.3.1 Haploidentical relative donor

5.3.2 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)

5.3.3 Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)

5.3.4 No history of congestive heart failure or unstable angina, and no history of stroke)

5.3.4 Ability to comprehend and willing to sign an informed consent; assent obtained from minors


Donor: (any of the following would exclude the donor from participating)

5.4.1 Pregnant or lactating

5.4.2 HIV positive

5.4.3 Hemoglobin S greater than or equal to 50 percent, or beta

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 ClinicalTrials.gov identifier (NCT number): NCT00977691

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Courtney D Fitzhugh, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT00977691    
Other Study ID Numbers: 090225
First Posted: September 16, 2009    Key Record Dates
Results First Posted: October 14, 2019
Last Update Posted: April 18, 2023
Last Verified: October 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Sickle Cell Anemia
Peripheral Blood Stem Cell Transplantation
Graft-Versus-Host Disease
Sirolimus (Rapamune )
Alemtuzumab (Campath )
Sickle Cell Disease
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Genetic Diseases, Inborn
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
Antineoplastic Agents, Immunological