Congenital Hemolytic AnemiaPhase 1/2NCT00061568
Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias
A Phase 1/2 study testing Peripheral blood hematopoietic progenitor cell (PBPC) transplant, Alemtuzumab and Peripheral blood hematopoietic progenitor cell Apheresis in people with Congenital Hemolytic Anemia and Sickle Cell Disease, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 2 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Congenital Hemolytic Anemia, Sickle Cell Disease
- What is being tested?
- Peripheral blood hematopoietic progenitor cell (PBPC) transplant, Alemtuzumab and Peripheral blood hematopoietic progenitor cell Apheresis
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 130 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jul 2004to 20 Jan 2028
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 80 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- 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):
- Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI
- OR
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- an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);
- OR
- 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 age the 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
- 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
- Recurrent tricorporal priapism 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
- 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
- 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 therapeutic 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 than 1 g/dL while on hydroxyurea*
- hydroxyurea at therapeutic 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:
- 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.
Who cannot join
- 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.
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- 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:
- None
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease (SCD) and B-Thalassemia
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.
Read more
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.
Read the 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.
- Conditions
- Congenital Hemolytic Anemia, Sickle Cell Disease
- Being tested
- Peripheral blood hematopoietic progenitor cell (PBPC) transplant, Alemtuzumab, Peripheral blood hematopoietic progenitor cell Apheresis, Sirolimus
- Keywords
- Stem Cell Transplant, Low Dose Radiation, Alemtuzumab (Campath), Sirolimus (Rapamune), Donor Apheresis, Sickle Cell Anemia (SCA), Beta-Thalassemia
- Medical subject headings
- Anemia, Hemolytic, Congenital, Anemia, Sickle Cell, beta-Thalassemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Peripheral blood hematopoietic progenitor cell (PBPC) transplantProcedure or surgery
Peripheral blood hematopoietic progenitor cell (PBPC) transplant
AlemtuzumabDrug
Also called Campath
Alemtuzumab
Peripheral blood hematopoietic progenitor cell ApheresisProcedure or surgery
Donor-Peripheral blood hematopoietic progenitor cell (PBPC) apheresis
SirolimusDrug
Also called Rapamune
Sirolimus
| Study group | Role | What they receive |
|---|---|---|
| Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants | Experimental | Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings. Receives: Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant; Drug: Alemtuzumab; Drug: Sirolimus |
| Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor | Experimental | Participants received Filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling. Receives: Procedure: Peripheral blood hematopoietic progenitor cell Apheresis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants That Experience Treatment Success Following Stem Cell Transplant
Number of participants that experience treatment success at one year following stem cell transplant. Treatment success is defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with sickle cell disease and transfusion-independence for patients with beta-thalassemia.
Measured: Up to 1 year
Secondary outcomes (7)
Mean Myeloid Chimerism Level
Mean Myeloid Chimerism Level in participants following stem cell transplant.
Measured: up to 2 years
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.
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.
Measured: Up to 1 year
Number of Participants Who Developed Limited or Extensive Chronic GVHD
Number of participants who developed Limited or Extensive 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.
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
Measured: Day 100 up to 3 Years
Number of Participants With Regimen Failure
Number of participants with regimen failure. Regimen failure is defined as those participants that experienced graft verses host disease or relapse of sickle cell disease or beta-thalassemia.
Measured: Up to 1 year
Number of Participants With Disease-free Survival
Number of participants with disease-free survival, as defined by: alive and free of acute complications related to sickle cell disease or beta-thalassemia.
Measured: Up to 2 year
Number of Participants Overall Survival
Number of participants overall survival at year 1 and year 2. Overall survival is defined as participants alive at 1 and 2 years following stem cell transplant.
Measured: 1 year and 2 year
Number of Participants That Experienced a Transplant-related Mortality
Number of participants that experienced a transplant related mortality, as defined as death from causes other than relapse (such as: GVHD, toxicity, infection, other and unknown causes).
Measured: Up to 2 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2003 (estimated)
- Study start16 Jul 2004
- Primary completion20 Jan 2023
- Study completion20 Jan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Congenital Hemolytic AnemiaStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 130 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- John F Tisdale, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00061568
- Sponsor's protocol ID
- 030170
- Other IDs
- 03-H-0170
- Status last verified
- Aug 2026
- First submitted
- 29 May 2003
- Last updated
- 9 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Protocol is available to be shared upon request to PI.
Publications
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.
PubMed 11001885Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. doi: 10.1056/NEJM199406093302303.
PubMed 7993409Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. doi: 10.1056/NEJM199505183322001.
PubMed 7715639Kern KC, Inam Z, Hsieh MM, Tisdale JF, Fitzhugh CD, Limerick EM, Gebremeskel ASK, White T, Jordan LC, Lynch JK. Hematopoietic Stem Cell Transplant and Brain Volume Changes in Adults With Sickle Cell Disease. Neurology. 2026 Jun 9;106(11):e218050. doi: 10.1212/WNL.0000000000218050. Epub 2026 May 14.
PubMed 42133908Inam Z, Jeffries N, Link M, Coles W, Pollack P, Luckett C, Phang O, Harvey E, Martin T, Farrey T, Tisdale JF, Hsieh MM. Two Nonmyeloablative HLA-Matched Related Donor Allogeneic Hematopoietic Cell Transplantation Regimens in Patients with Severe Sickle Cell Disease. Transplant Cell Ther. 2025 May;31(5):305-318. doi: 10.1016/j.jtct.2025.02.021. Epub 2025 Feb 24.
PubMed 40010689Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.
PubMed 36240296Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 Jul 2;312(1):48-56. doi: 10.1001/jama.2014.7192.
PubMed 25058217Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009 Dec 10;361(24):2309-17. doi: 10.1056/NEJMoa0904971.
PubMed 20007560