Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia

ID: NCT00977691
Status: Active, not recruiting
Phase: Phase 1/Phase 2
Start Date: September 09, 2009
First Submitted: September 15, 2009
Last Updated: February 22, 2018
Results: N/A
Sponsors & Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
Location: United States
Conditions: Peripheral Blood Stem Cell Transplantation, Anemia, Sickle Cell, Graft-Versus-Host Disease, Sirolimus (Rapamune ), Alemtuzumab (Campath )
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

Study Description

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.

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. 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.
Condition or disease Intervention/treatment Phase

Alemtuzumab (Campath )

Anemia, Sickle Cell

Graft-Versus-Host Disease

Peripheral Blood Stem Cell Transplantation

Sirolimus (Rapamune )

Procedure: PBMC Transplant
Other Names
Drug: Alemtuzumab (Campath )
Other Names
Drug: Sirolimus (Rapamune )
Other Names
Drug: Cyclophosphamide (Cytoxan )
Other Names
Procedure: Low Dose Irradiation
Other Names
Phase 1/Phase 2

Tracking Information

First Submitted DateSeptember 15, 2009
Last Update Posted DateFebruary 22, 2018
Start DateSeptember 09, 2009
Anticipated Completion DateAugust 01, 2018
Primary Completion DateAugust 01, 2018
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • 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]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • 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.

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleNonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia
Official TitleNonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia
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.

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. 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 TypeInterventional
Study PhasePhase 1/Phase 2
Estimated Enrollment
56
Allocation
Non-Randomized
Interventional Model
Single Group Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Alemtuzumab (Campath )
Anemia, Sickle Cell
Graft-Versus-Host Disease
Peripheral Blood Stem Cell Transplantation
Sirolimus (Rapamune )
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Procedure: PBMC Transplant

Other Names
Drug: Alemtuzumab (Campath )

Other Names
Drug: Sirolimus (Rapamune )

Other Names
Drug: Cyclophosphamide (Cytoxan )

Other Names
Procedure: Low Dose Irradiation

Other Names
Study Groups/Cohorts
Not Available
Study Arms
Not Available
Arm Intervention/Treatment

Recruitment Information

Recruitment Status:Active, not recruiting
Enrollment56
Completion DateAugust 01, 2018
Eligibility Criteria: - INCLUSION CRITERIA:
Recipients (must fulfill one disease category in 5.1.1 and all of 5.1.2)
5.1.1 Disease specific
5.1.1.1 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
5.1.1.2 Patients with 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 deferoxamine 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 2cm below the costochondral margin
5.1.2 Non-disease specific:
5.1.2.1 Age greater than or equal to 18 years
5.1.2.2 Haploidentical relative donor available
5.1.2.3 Ability to comprehend and willing to sign an informed consent
5.1.2.4 Negative Beta-HCG
EXCLUSION CRITERIA:
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
INCLUSION CRITERIA:
Donor
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 Ability to comprehend and willing to sign an informed consent; assent obtained from minors
EXCLUSION CRITERIA:
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
thalassemia intermedia
GenderAll
Age2 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT00977691
Other Study ID Numbers
090225
09-H-0225
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborators
Not Available
Investigators
Principal Investigator
Courtney D Fitzhugh, M.D.
National Heart, Lung, and Blood Institute (NHLBI)