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

Congenital Hemolytic Anemia research study

What is the primary objective of this study?

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.

Who is eligible to participate?

- INCLUSION CRITERIA: RECIPIENTS: Must fulfill one disease category from below: DISEASE SPECIFIC: 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 OR an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s); 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 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 OR 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 NON-DISEASE SPECIFIC: - 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 DONOR: 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 EXCLUSION CRITERIA: RECIPIENT: (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 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 DONOR: (Any of the following would exclude the donor from participating) Pregnant or breastfeeding HIV positive Hemoglobin S greater than or equal to 50%, or beta-thalassemia intermedia

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Congenital Hemolytic Anemia

Sickle Cell Disease

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Procedure:Peripheral blood hematopoietic progenitor cell (PBPC) transplantPeripheral blood hematopoietic progenitor cell (PBPC) transplant


Procedure:Peripheral blood hematopoieticprogenitor cell ApherisisDonor-Peripheral blood hematopoieticprogenitor cell(PBPC) apheresis


Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.



Study Status


Start Date: July 16, 2004

Completed Date: January 31, 2020

Phase: Phase 1/Phase 2

Type: Interventional


Primary Outcome: treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with thalassemia and DBA.

Secondary Outcome: The level of chimerism required to maintain both graft survival as well as hematologic normalcy. The chimeric status of patients will be measured on days, +30, +60 and +100 by microsatellite analysis of the peripheral blood. More frequent monito...

Study sponsors, principal investigator, and references

Principal Investigator: John F Tisdale, M.D.

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)


More information:

Wayne AS, Schoenike SE, Pegelow CH. Financial analysis of chronic transfusion for stroke prevention in sickle cell disease. Blood. 2000 Oct 1;96(7):2369-72.

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