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Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 21, 2017 by 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) ) Identifier:
First received: May 29, 2003
Last updated: April 20, 2017
Last verified: March 21, 2017

People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults.

The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons.

To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused.

Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling.

Condition Intervention Phase
Congenital Hemolytic Anemia
Diamond-Blackfan Anemia
Procedure: Radiotherapy
Drug: Alemtuzumab (Campath )
Drug: Sirolimus (Rapamune )
Phase 2

Study Type: Interventional
Study Design: Masking: Single Blind (masked role unspecified)
Primary Purpose: Treatment
Official Title: Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation For Severe Congenital Anemias Including Sickle Cell Disease (SCD) and Beta-Thalassemia

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Rate of engraftment [ Time Frame: 5 years ]

Estimated Enrollment: 124
Study Start Date: May 19, 2003
Estimated Study Completion Date: January 31, 2018
Estimated Primary Completion Date: January 31, 2018 (Final data collection date for primary outcome measure)
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. Preliminary data have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe graft-versus-host-disease (GVHD) leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration.

In this protocol, we propose transplantation in patients with severe beta-globin disorders including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for complications from or ineligible for standard BMT, with allogeneic PBSCs from an HLA identical sibling 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 low dose radiation, Alemtuzumab (Campath ) and Sirolimus (Rapamune ) 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 (filgrastim, G-CSF) mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with beta-thalassemia. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft-vs-host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.


Ages Eligible for Study:   2 Years to 80 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes


Must fulfill one disease category from below:


Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI


an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);


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 nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis


Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl

Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl

Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit of normal serum creatinine 1.2mg/dl

Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl

C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis, OR

D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR

E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR

F. Any one of the below complications:

  1. Vaso-occlusive crisis:

    • 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
  2. Acute Chest Syndrome (ACS):

    • Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma
    • Eligible for HSCT: any ACS while on hydroxyurea*
  3. Osteonecrosis of 2 or more joints:

    • Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60
    • Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level
  4. Red cell alloimmunization:

    • Eligible for hydroxyurea: Transfusion dependent
    • Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on hydroxyurea*

      • hydroxyurea at maximum tolerated dose

    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 desferoxamine 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 2 cm below the costochondral margin


    • Ages greater than or equal to 4 years
    • 6/6 HLA matched family donor available
    • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
    • Negative serum beta-HCG
    • Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation


    6/6 HLA identical family donor

    Weight greater than or equal to 20 kg (in so far that 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)

    Fit to receive G-CSF and give peripheral blood stem cells (adequate blood counts, stable blood pressure, and no history of stroke)

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



    (Any of the following would exclude the subject from participating)

    ECOG performance status of 3 or more or Lansky performance status of less than 40.

    Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted. (corrected for hemoglobin and alveolar volume)

    Baseline oxygen saturation or less than 85 % or PaOa2 less than 70

    Left ventricular ejection fraction: less than 40% estimated by ECHO.

    Transaminases greater than 5 times the upper limit of normal for age

    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

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

    Pregnant or lactating

    Major ABO mismatch


    (Any of the following would exclude the donor from participating)

    Pregnant or lactating

    HIV positive

    Hemoglobin S greater than or equal to 50%, or beta-thalassemia intermedia

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00061568

Contact: Mary E. Link, R.N. (301) 402-3087
Contact: John F Tisdale, M.D. (301) 402-6497

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 Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: John F Tisdale, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT00061568     History of Changes
Other Study ID Numbers: 030170
Study First Received: May 29, 2003
Last Updated: April 20, 2017

Keywords provided by National Institutes of Health Clinical Center (CC):
Stem Cell Transplant
Low Dose Radiation
Alemtuzumab (Campath)
Sirolimus (Rapamune)
Donor Apheresis
Graft-Versus-Host Disease
Host-Donor Chimerism
Peripheral Blood Stem Cells
Low Dose Irradiation
Sickle Cell Anemia
Diamond-Blackfan Anemia

Additional relevant MeSH terms:
Anemia, Diamond-Blackfan
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Red-Cell Aplasia, Pure
Bone Marrow Diseases
Genetic Diseases, Inborn
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs processed this record on April 24, 2017