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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
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
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
 (submitted: September 24, 2019)
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
 (submitted: September 15, 2009)
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 ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2009)
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
 
Descriptive Information
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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Anemia
Intervention  ICMJE
  • Procedure: PBSC Transplant
    PBSC transplant
  • Drug: Alemtuzumab
    alemtuzumab
    Other Name: Campath
  • Drug: Sirolimus
    sirolimus
    Other Name: Rapamune
  • Drug: Cyclophosphamide
    cyclophosphamide
    Other Name: Cytoxan
  • Procedure: Low Dose Irradiation
    low dose irradiation
Study Arms  ICMJE
  • Experimental: Cohort 1
    PBSC transplant with no post-transplant cyclophosphamide (PT-Cy)
    Interventions:
    • Procedure: PBSC Transplant
    • Drug: Alemtuzumab
    • Drug: Sirolimus
    • Procedure: Low Dose Irradiation
  • Experimental: Cohort 2
    PBSC transplant with 50 mg/kg post-transplant cyclophosphamide (PT-Cy)
    Interventions:
    • Procedure: PBSC Transplant
    • Drug: Alemtuzumab
    • Drug: Sirolimus
    • Drug: Cyclophosphamide
    • Procedure: Low Dose Irradiation
  • Experimental: Cohort 3
    PBSC transplant with 100 mg/kg post-transplant cyclophosphamide (PT-Cy)
    Interventions:
    • Procedure: PBSC Transplant
    • Drug: Alemtuzumab
    • Drug: Sirolimus
    • Drug: Cyclophosphamide
    • Procedure: Low Dose Irradiation
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 Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 24, 2019)
23
Original Enrollment  ICMJE
 (submitted: September 15, 2009)
192
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
  • 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 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

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
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  
 
Administrative Information
NCT Number  ICMJE NCT00977691
Other Study ID Numbers  ICMJE 090225
09-H-0225
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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
Investigators  ICMJE
Principal Investigator: Courtney D Fitzhugh, M.D. National Heart, Lung, and Blood Institute (NHLBI)
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