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Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels

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ClinicalTrials.gov Identifier: NCT04008368
Recruitment Status : Recruiting
First Posted : July 4, 2019
Last Update Posted : October 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:

Background:

Sickle cell disease can often be treated with blood stem cell transplants. But for some people the disease returns. This study will give a second transplant to people whose disease has returned but still have some donor cells in their body.

Objective:

To cure people s sickle cell disease by giving a second treatment that makes more room in their bone marrow for donor cells.

Eligibility:

People ages 4 and older with sickle cell disease who had a transplant but the disease returned, and their donor relatives

Design:

Participants will be screened with medical history, physical exam, and blood tests.

Recipients will also be screened with heart and breathing tests, x-rays, a bone marrow sample, and teeth and eye exams. They must have a caregiver.

Donors will have 7-8 visits. They will take a drug for 5-6 days to prepare them for the donation. For the donation, blood is taken from a vein in the arm or groin. The stem cells are collected. The rest of the blood is returned. This may be repeated.

Recipients will get a long IV line in their arm or chest for about 1-2 months. They will take drugs to help their body accept the donor cells. They will get the donor cells and red blood cell transfusions through the line. They will stay in the hospital about 30 days after the transfusion of donor cells.

In first 3 months after the infusion, recipients will have many visits. Then they will have visits every 6 months to 1 year for 5 years. During those visits they will repeat some of the screening tests.


Condition or disease Intervention/treatment Phase
Sickle Cell Disease Device: CliniMACS CD34 Reagent Phase 1 Phase 2

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. An additional protocol is ongoing for patients with high risk of graft rejection which employs pentostatin and oral cyclophosphamide (PC) pre-transplant to further deplete recipient lymphocytes in an attempt to decrease the rate of graft rejection, and to date the engraftment rate has substantially improved. Our first haploidentical transplant protocol showed improving engraftment and success rates with the addition of post-transplant cyclophosphamide, but with a median follow-up of 5 years, the disease-free survival was at best 50%. Our new haploidentical transplant protocol has had some encouraging early results in the first 5 patients transplanted.

Based on 67 patients undergoing HLA-matched sibling or haploidentical PBSC transplants at the NIH, we sought to determine what donor chimerism level is necessary to reverse SCD. Three of the patients had falling donor myeloid chimerism (DMC) levels, and when the DMC level fell below 20%, all 3 patients had return of their SCD. Our mathematical model showed that only 20% DMC (which tracks with donor erythroid chimerism) is necessary due to vast differences in donor and recipient red blood cell (RBC) survival. As all 3 patients had persistent but insufficient donor chimerism levels, we performed a PBSC boost using the same donor and busulfan/alemtuzumab conditioning. Haploidentical patients received CD34-selected PBSCs and HLA-matched sibling patients received unmanipulated PBSCs. All 3 patients now remain free of SCD with DMC levels of 100% at 1, 2.5, and 3.5 years post-transplant. Therefore, in this protocol, we propose repeat PBSC transplants using CD34-selected PBSCs in patients with a haploidentical donor and unmanipulated PBSCs in patients with an HLA-matched sibling donor from the same donor in a population of patients who have falling DMC and return of SCD.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels
Estimated Study Start Date : October 22, 2019
Estimated Primary Completion Date : January 30, 2024
Estimated Study Completion Date : January 1, 2030


Arm Intervention/treatment
1
patients with HLA-matched sibling donors
Device: CliniMACS CD34 Reagent
Haploidentical recipients will receive CD34-selected cells using Miltenyi CliniMACS CD34+ cell selection kits. The target CD34+ cell dose is at least 10 x 106/kg, and the minimum CD34+ cell dose is 5 x 106/kg. All of the cells collected during the apheresis procedure will be given. The cells will be cryopreserved and stored until the day of transplant.

2
patients with haploidentical donors
Device: CliniMACS CD34 Reagent
Haploidentical recipients will receive CD34-selected cells using Miltenyi CliniMACS CD34+ cell selection kits. The target CD34+ cell dose is at least 10 x 106/kg, and the minimum CD34+ cell dose is 5 x 106/kg. All of the cells collected during the apheresis procedure will be given. The cells will be cryopreserved and stored until the day of transplant.




Primary Outcome Measures :
  1. dichotomous positive/negative outcome where a positive response is defined by absence of graft rejection [ Time Frame: 5 years ]
    The primary endpoint for each individual is a dichotomous positive/negative outcome where a positive response is defined by absence of graft rejection, and absence of severe acute GVHD (grade 3 and higher), or moderate to severe chronic GVHD evaluated 100 days post-transplant.


Secondary Outcome Measures :
  1. Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  2. Incidence of acute and chronic GVHD [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  3. The level of chimerism required to maintain both graft survival as well as hematologic normalcy. [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  4. Incidence of donor type hemoglobin at 1 year post-transplant in SCD patients who have not been transfused in the previous 3 months. [ Time Frame: at 1 year post-transplant ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  5. Incidence of viral reactivation and disease [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  6. Disease-free survival and overall survival [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  7. Relapse rate and graft rejection rate [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  8. Transplant-related mortality [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  9. Effects of transplant on organ function [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction

  10. Biomarkers associated with tolerance induction [ Time Frame: 5 years ]
    1) Incidence of graft rejection defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait 2) Incidence of acute and chronic GVHD3) The level of chimerism required to maintain both graft survival as well as hematologic normalcy.4) Incidence of donor type hemoglobin at 1 year posttransplant in SCD patients who have not been transfused in the previous 3 months.5) Incidence of viral reactivation and disease6) Disease-free survival and overall survival7) Relapse rate and graft rejection rate8) Transplant-related mortality9) Effects of transplant on organ function10) Biomarkers associated with tolerance induction



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Inclusion criteria- recipient

  1. Patient with history of SCD who underwent allogeneic hematopoietic stem cell transplantation (HSCT)
  2. Patient with recurrent SCD defined as HbS greater than or equal to 50% for donors with sickle cell trait and greater than or equal to 10% for donors with HbAA with recurrent clinical manifestations (for example but not limited to recurrent painful crises, acute chest syndrome, priapism, or severe anemia)
  3. Persistent donor chimerism levels
  4. Age greater than or equal to 4 years
  5. Negative beta-HCG
  6. Ejection fraction greater than or equal to 35%
  7. DLCO greater than or equal to 35%

Inclusion- donor

  1. Original donor from the patient s prior transplant
  2. Age greater than or equal to 18 years
  3. Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)
  4. Ability to comprehend and willing to sign an informed consent

EXCLUSION CRITERIA:

Exclusion criteria- recipient

  1. ECOG performance status of 3 or more (see Appendix B)
  2. Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to signing the consent
  3. Patients with fever or suspected minor infection should await resolution of symptoms before signing the consent
  4. Major anticipated illness or organ failure incompatible with survival from PBSC transplant
  5. Pregnant or breastfeeding
  6. Baseline alanine aminotransferase or direct bilirubin >3x upper limit of normal
  7. History of liver cirrhosis
  8. History of secondary malignancies (other than localized skin cancer)

Exclusion- donor

  1. Pregnant or breastfeeding
  2. HIV positive
  3. Hemoglobin S >50%
  4. History of congestive heart failure, unstable angina, or stroke

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04008368


Contacts
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Contact: For more information Office of Patient Recruitment (OPR) (800) 411-1222 prpl@cc.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Courtney D Fitzhugh, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT04008368     History of Changes
Other Study ID Numbers: 190118
19-H-0118
First Posted: July 4, 2019    Key Record Dates
Last Update Posted: October 17, 2019
Last Verified: October 7, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Graft-Versus-Host Disease
Donor Apheresis
Host-Donor Chimerism
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn