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

  • End date
    Apr 1, 2023
  • participants needed
  • sponsor
    National Heart, Lung, and Blood Institute (NHLBI)
Updated on 26 September 2021
bone marrow transplant
immunosuppressive agents
blood transfusion
conjugated bilirubin
iron overload
acute chest syndrome
chest syndrome
vaso-occlusive crisis
hemoglobin f
tricuspid regurgitant jet velocity


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.



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.

Condition Diamond-Blackfan anemia, Hereditary hemolytic anemia, SICKLE CELL ANEMIA, Sickle Cell Disease
Treatment Radiotherapy, Alemtuzumab (Campath ), Sirolimus (Rapamune ), Sirolimus, alemtuzumab, Peripheral blood hematopoietic progenitor cell (PBPC) transplant, Alemtuzumab + Sirolimus + Peripheral blood hematopoietic progenitor cell (PBPC) transplant, Peripheral blood hematopoieticprogenitor cell Apherisis, Peripheral blood hematopoietic progenitor cell Apherisis
Clinical Study IdentifierNCT00061568
SponsorNational Heart, Lung, and Blood Institute (NHLBI)
Last Modified on26 September 2021


Yes No Not Sure

Inclusion Criteria

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
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
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
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
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
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
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 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
Donor deemed suitable and eligible, and willing to donate per clinical
evaluations, who are additionally willing to donate blood for research and
undergo a neuropsychological test. Donors will be evaluated in accordance with
existing Standard NIH Policies and Procedures for determination of eligibility
and suitability for clinical donation under a separate NHLBI protocol. Note
that participation in this study is offered to all donors, but is not required
for a donor to make a stem cell donation, so it is possible that not all
donors will enroll onto this study

Exclusion Criteria

(Any of the following would exclude the subject from participating)
ECOG performance status of 3 or more or Lansky performance status of less than
Diffusion capacity of carbon monoxide (DLCO) less than 35% 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 35% 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
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