Haploidentical PBMC Transplant for Severe Congenital Anemias

NCT00977691 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: 09022509-H-0225
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Background: 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. Objectives: 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. Eligibility: 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. Design: 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.

Conditions

Sickle Cell Anemia

Keywords

Sickle Cell Anemia; Peripheral Blood Stem Cell Transplantation; Graft-Versus-Host Disease; Sirolimus (Rapamune ); Alemtuzumab (Campath ); Thalassemia; Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• Patients With Donor Type Hemoglobin

  Percentage of patients post transplant with sustained donor type hemoglobin on hemoglobin electrophoresis

  1 year

Secondary Outcomes (10)

• Chimeric Value That is Required to Maintain Graft Survival and Hematologic Normalcy.

  Up to Year 5

• Number of Participants Who Developed Acute GVHD Grades I, II, III, IV

  Day100

• Number of Participants Who Developed Limited Chronic GVHD

  Year 5

• Number of Participants Who Develop Extensive GVHD

  Year 5

• Number of Participants With Disease-free Survival

  Year 5

Study Arms (3)

Cohort 1

EXPERIMENTAL

PBSC transplant with no post-transplant cyclophosphamide (PT-Cy)

Procedure: PBSC Transplant; Drug: Alemtuzumab; Drug: Sirolimus; Procedure: Low Dose Irradiation

Cohort 2

EXPERIMENTAL

PBSC transplant with 50 mg/kg post-transplant cyclophosphamide (PT-Cy)

Procedure: PBSC Transplant; Drug: Alemtuzumab; Drug: Sirolimus; Drug: Cyclophosphamide; Procedure: Low Dose Irradiation

Cohort 3

EXPERIMENTAL

PBSC transplant with 100 mg/kg post-transplant cyclophosphamide (PT-Cy)

Procedure: PBSC Transplant; Drug: Alemtuzumab; Drug: Sirolimus; Drug: Cyclophosphamide; Procedure: Low Dose Irradiation

Interventions

PBSC Transplant PROCEDURE

PBSC transplant

Cohort 1; Cohort 2; Cohort 3

Alemtuzumab DRUG

alemtuzumab

Also known as: Campath

Cohort 1; Cohort 2; Cohort 3

Sirolimus DRUG

sirolimus

Also known as: Rapamune

Cohort 1; Cohort 2; Cohort 3

Cyclophosphamide DRUG

cyclophosphamide

Also known as: Cytoxan

Cohort 2; Cohort 3

Low Dose Irradiation PROCEDURE

low dose irradiation

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 2 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Recipient (any of the following would exclude the subject from participating)
• /6 HLA-matched with or without an ABO minor mismatched sibling donor
• ECOG performance status of 3 or more
• 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.
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant
• Pregnant or lactating
• Major ABO mismatch
• Donor
• Haploidentical relative donor
• 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)
• Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)
• No history of congestive heart failure or unstable angina, and no history of stroke)
• 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)
• Pregnant or lactating

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Fitzhugh CD, Hsieh MM, Taylor T, Coles W, Roskom K, Wilson D, Wright E, Jeffries N, Gamper CJ, Powell J, Luznik L, Tisdale JF. Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Blood Adv. 2017 Apr 19;1(11):652-661. doi: 10.1182/bloodadvances.2016002972. eCollection 2017 Apr 25.

  PMID: 29296707 BACKGROUND

• Limerick E, Hsieh M, Queen J, Grecco ML, Varga J, Brooks J, Coles W, Jeffries N, Fitzhugh CD. Nonmyeloablative pentostatin-cyclophosphamide preconditioning improves rates of engraftment in adults undergoing haploidentical HCT for sickle cell disease. PLoS One. 2026 Mar 23;21(3):e0332282. doi: 10.1371/journal.pone.0332282. eCollection 2026.

  PMID: 41871072 DERIVED

• Leonard 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.

  PMID: 36240296 DERIVED

• Bhat DK, Olkhanud PB, Gangaplara A, Seifuddin F, Pirooznia M, Biancotto A, Fantoni G, Pittman C, Francis B, Dagur PK, Saxena A, McCoy JP, Pfeiffer RM, Fitzhugh CD. Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease. Front Immunol. 2021 Nov 30;12:757279. doi: 10.3389/fimmu.2021.757279. eCollection 2021.

  PMID: 34917079 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell; Graft vs Host Disease; Thalassemia

Interventions

Alemtuzumab; Sirolimus; Cyclophosphamide; Radiation

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Physical Phenomena

Results Point of Contact

• Title: Courtney Fitzhugh, MD, Investigator
• Organization: National Heart Lung and Blood Institute

courtney.fitzhugh@nih.gov

+1 301 402 6496

Study Officials

• Courtney D Fitzhugh, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2009
• First Posted: September 16, 2009
• Study Start: December 14, 2009
• Primary Completion: August 1, 2018
• Study Completion (Estimated): September 10, 2026
• Last Updated: April 23, 2026
• Results First Posted: October 14, 2019

Record last verified: 2026-04

Locations

US (1)