Haploidentical PBMC Transplant for Severe Congenital Anemias
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|ClinicalTrials.gov Identifier: NCT00977691|
Recruitment Status : Active, not recruiting
First Posted : September 16, 2009
Results First Posted : October 14, 2019
Last Update Posted : March 29, 2021
|First Submitted Date ICMJE||September 15, 2009|
|First Posted Date ICMJE||September 16, 2009|
|Results First Submitted Date ICMJE||August 23, 2019|
|Results First Posted Date ICMJE||October 14, 2019|
|Last Update Posted Date||March 29, 2021|
|Study Start Date ICMJE||September 9, 2009|
|Actual Primary Completion Date||August 1, 2018 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Patients With Donor Type Hemoglobin [ Time Frame: 1 year ]
Percentage of patients post transplant with sustained donor type hemoglobin on hemoglobin electrophoresis
|Original Primary Outcome Measures ICMJE
||1 year post-transplant w/ sustained donor type hemoglobin for pts w/sickle cell dx or are transfusion-independent for pts w/thalassemia and not have severe graft-versus-host disease. [ Time Frame: 1 year ]|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE
||1) The level of chimerism required to maintain both graft survival as well as hematologic normalcy; 2) Incidence of acute and chronic GVHD; 3) Disease-free survival and overall survival; 4) Relapse rate and graft rejection rate.|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Haploidentical PBMC Transplant for Severe Congenital Anemias|
|Official Title ICMJE||Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia|
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.
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.
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.
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.
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. Our ongoing protocol for patients with severe congenital anemias, particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent preliminary results. None of the patients who engrafted had sickle-related events or any evidence of graft versus host disease (GVHD). There was no significant toxicity associated with the conditioning regimen.
Our main limitation has been a lack of HLA-matched sibling donors in the majority of patients. We performed a study in which patients with severe SCD who lacked a suitable donor underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority of patients were not found to have an appropriate alternative donor. We therefore seek to develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that family members can serve as donors and greatly expand the donor pool.
In this protocol, we propose PBSC transplantation in patients with SCD and thalassemia, considered at high risk for complications from or ineligible for standard bone marrow transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor 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 a relatively low radiation dose for therapeutic radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), and Cyclophosphamide (Cytoxan ) 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 (G-CSF)-mobilized PBSC will be used to establish hematopoietic and lymphoid reconstitution.
The primary endpoint of this study is the percentage of patients who have sustained donor type hemoglobin without significant GVHD for patients with SCD, or who are transfusion-independent and without significant GVHD for patients with thalassemia. Other endpoints include degree of donor-host chimerism necessary for long term graft survival and disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related morbidity, as well as disease-free and overall survival.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Sickle Cell Anemia|
|Study Arms ICMJE||
|Publications *||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.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Actual Enrollment ICMJE
|Original Enrollment ICMJE
|Estimated Study Completion Date ICMJE||September 10, 2021|
|Actual Primary Completion Date||August 1, 2018 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Recipients (must fulfill one disease category in 5.1.1 and all of 5.1.2)
5.1.1 Disease specific
220.127.116.11 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
18.104.22.168 Patients with thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:
5.1.2 Non-disease specific:
22.214.171.124 Age greater than or equal to 18 years
126.96.36.199 Haploidentical relative donor available
188.8.131.52 Ability to comprehend and willing to sign an informed consent
184.108.40.206 Negative Beta-HCG
Recipient (any of the following would exclude the subject from participating)
5.2.1 6/6 HLA-matched with or without an ABO minor mismatched sibling donor
5.2.2 ECOG performance status of 3 or more
5.2.3 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.
5.2.4 Major anticipated illness or organ failure incompatible with survival from PBSC transplant
5.2.5 Pregnant or lactating
5.2.6 Major ABO mismatch
5.3.1 Haploidentical relative donor
5.3.2 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)
5.3.3 Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)
5.3.4 No history of congestive heart failure or unstable angina, and no history of stroke)
5.3.4 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)
5.4.1 Pregnant or lactating
5.4.2 HIV positive
5.4.3 Hemoglobin S greater than or equal to 50 percent, or beta
|Ages ICMJE||2 Years to 80 Years (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00977691|
|Other Study ID Numbers ICMJE||090225
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )|
|Study Sponsor ICMJE||National Heart, Lung, and Blood Institute (NHLBI)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||March 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP