免费获得国外相关药品，最快 1 个工作日回馈药物信息
Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels
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 |
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.
| 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 |
| Actual Study Start Date : | October 24, 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.
|
- 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.
- 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
| Ages Eligible for Study: | 4 Years to 80 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
- INCLUSION CRITERIA:
Inclusion criteria- recipient
- Patient with history of SCD who underwent allogeneic hematopoietic stem cell transplantation (HSCT)
- 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)
- Persistent donor chimerism levels
- Age greater than or equal to 4 years
- Negative beta-HCG
- Ejection fraction greater than or equal to 35%
- DLCO greater than or equal to 35%
Inclusion- donor
- Original donor from the patient s prior transplant
- Age greater than or equal to 18 years
- Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)
- Ability to comprehend and willing to sign an informed consent
EXCLUSION CRITERIA:
Exclusion criteria- recipient
- ECOG performance status of 3 or more (see Appendix B)
- Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to signing the consent
- Patients with fever or suspected minor infection should await resolution of symptoms before signing the consent
- Major anticipated illness or organ failure incompatible with survival from PBSC transplant
- Pregnant or breastfeeding
- Baseline alanine aminotransferase or direct bilirubin >3x upper limit of normal
- History of liver cirrhosis
- History of secondary malignancies (other than localized skin cancer)
Exclusion- donor
- Pregnant or breastfeeding
- HIV positive
- Hemoglobin S >50%
- History of congestive heart failure, unstable angina, or stroke
| Contact: Julia M Varga | (301) 402-3595 | julia.varga@nih.gov |
| 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 | |
| Principal Investigator: | Courtney D Fitzhugh, M.D. | National Heart, Lung, and Blood Institute (NHLBI) |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | July 3, 2019 | ||||
| First Posted Date ICMJE | July 5, 2019 | ||||
| Last Update Posted Date | May 13, 2021 | ||||
| Actual Study Start Date ICMJE | October 24, 2019 | ||||
| Estimated Primary Completion Date | January 30, 2024 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
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.
|
||||
| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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
|
||||
| Original Secondary Outcome Measures ICMJE |
|
||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels | ||||
| Official Title ICMJE | Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels | ||||
| 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.... |
||||
| 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. |
||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 1 Phase 2 |
||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment |
||||
| Condition ICMJE | Sickle Cell Disease | ||||
| Intervention ICMJE | 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.
|
||||
| Study Arms ICMJE |
|
||||
| Publications * | Not Provided | ||||
|
* 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 | Recruiting | ||||
| Estimated Enrollment ICMJE |
30 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | January 1, 2030 | ||||
| Estimated Primary Completion Date | January 30, 2024 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion criteria- recipient
Inclusion- donor
EXCLUSION CRITERIA: Exclusion criteria- recipient
Exclusion- donor
|
||||
| Sex/Gender ICMJE |
|
||||
| Ages ICMJE | 4 Years to 80 Years (Child, Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||
| Contacts ICMJE |
|
||||
| Listed Location Countries ICMJE | United States | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT04008368 | ||||
| Other Study ID Numbers ICMJE | 190118 19-H-0118 |
||||
| 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 | ||||
| Investigators ICMJE |
|
||||
| PRS Account | National Institutes of Health Clinical Center (CC) | ||||
| Verification Date | May 11, 2021 | ||||
|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
|||||
