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Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

Primary Purpose

Congenital Hemolytic Anemia, Sickle Cell Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Peripheral blood hematopoietic progenitor cell (PBPC) transplant
Alemtuzumab
Peripheral blood hematopoietic progenitor cell Apherisis
Sirolimus
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Hemolytic Anemia focused on measuring Stem Cell Transplant, Low Dose Radiation, Alemtuzumab (Campath), Sirolimus (Rapamune), Donor Apheresis, Sickle Cell Anemia, SCA, Thalassemia, Diamond-Blackfan Anemia, DBA

Eligibility Criteria

2 Years - 80 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

INCLUSION CRITERIA: RECIPIENTS: Must fulfill one disease category from below: DISEASE SPECIFIC: Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F): A. Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s); 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 nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis OR Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit of normal serum creatinine 1.2mg/dl Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis, OR D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR F. Any one of the below complications: Vaso-occlusive crisis: 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 Acute Chest Syndrome (ACS): Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma Eligible for HSCT: any ACS while on hydroxyurea* Osteonecrosis of 2 or more joints: Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60 Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level Red cell alloimmunization: Eligible for hydroxyurea: Transfusion dependent Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on hydroxyurea* hydroxyurea at maximum tolerated dose Patients with beta-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 desferoxamine 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 2 cm below the costochondral margin NON-DISEASE SPECIFIC: Ages greater than or equal to 4 years 6/6 HLA matched family donor available Ability to comprehend and willing to sign an informed consent, assent obtained from minors Negative serum beta-HCG Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation DONOR: Donor deemed suitable and eligible, and willing to donate per clinical evaluations, who are additionally willing to donate blood for research and undergo a neuropsychological test. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation under a separate NHLBI protocol. Note that participation in this study is offered to all donors, but is not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study. EXCLUSION CRITERIA: RECIPIENT: (Any of the following would exclude the subject from participating) ECOG performance status of 3 or more or Lansky performance status of less than 40. Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for hemoglobin and alveolar volume) Baseline oxygen saturation or less than 85 % or PaOa2 less than 70 Left ventricular ejection fraction: less than 35% estimated by ECHO. Transaminases greater than 5 times the upper limit of normal for age 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 Major anticipated illness or organ failure incompatible with survival from PBSC transplant. Pregnant or lactating Major ABO mismatch DONOR: None

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

1

2

Arm Description

donor

recipient

Outcomes

Primary Outcome Measures

treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with thalassemia and DBA.
This trial is designed to estimate treatment success, which is anticipated to be about 80%. The study started with a sample size of 25 and this will allow us to estimate the success of engraftment. For example, if the estimated rate is .80, the 95% confidence interval would be approximately (.64, .96). This would allow us to rule out rate of treatment success of less than .64. If the estimated rate is .70, the 95% confidence interval would be approximately (.52, .88) and we could rule out rate of treatment success below .50. If the lower bound of the 95% confidence interval is raised to 0.7, the number of subjects needed to accrue with respect to success rate is listed below.

Secondary Outcome Measures

Transplant-related mortality
The level of chimerism required to maintain both graft survival as well as hematologic normalcy. The chimeric status of patients will be measured on days, +30, +60 and +100 by microsatellite analysis of the peripheral blood. More frequent monito...
Quality of life and neuropsychologic function post-transplant (see Addendum B)
Incidence of acute and chronic GVHD or relapse rate. GvHD or relapse together count together toward the combined endpoint for regimen failure
Immunologic function post-transplant
Effect of transplant on end-organ function (e.g. renal function, see Addendum A)
Disease-free survival and overall survival

Full Information

First Posted
May 29, 2003
Last Updated
July 6, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00061568
Brief Title
Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias
Official Title
Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease (SCD) and B-Thalassemia
Study Type
Interventional

2. Study Status

Record Verification Date
July 1, 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 16, 2004 (Actual)
Primary Completion Date
January 20, 2023 (Actual)
Study Completion Date
January 20, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults. The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons. To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused. Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling. ...
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. Preliminary data have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe graft versus host disease (GVHD) leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration. In this protocol, we propose transplantation in patients with severe beta-globin disorders including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for complications from or ineligible for standard BMT, with allogeneic PBSCs from an HLA identical sibling 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 low dose radiation, Alemtuzumab (Campath ) and Sirolimus (Rapamune ) 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 (filgrastim, G-CSF) mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution. The primary endpoint of this study is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with beta-thalassemia. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft-vs-host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Hemolytic Anemia, Sickle Cell Disease
Keywords
Stem Cell Transplant, Low Dose Radiation, Alemtuzumab (Campath), Sirolimus (Rapamune), Donor Apheresis, Sickle Cell Anemia, SCA, Thalassemia, Diamond-Blackfan Anemia, DBA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
donor
Arm Title
2
Arm Type
Experimental
Arm Description
recipient
Intervention Type
Procedure
Intervention Name(s)
Peripheral blood hematopoietic progenitor cell (PBPC) transplant
Intervention Description
Peripheral blood hematopoietic progenitor cell (PBPC) transplant
Intervention Type
Drug
Intervention Name(s)
Alemtuzumab
Intervention Description
Alemtuzumab
Intervention Type
Procedure
Intervention Name(s)
Peripheral blood hematopoietic progenitor cell Apherisis
Intervention Description
Donor-Peripheral blood hematopoietic progenitor cell (PBPC) apheresis
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
Sirolimus
Primary Outcome Measure Information:
Title
treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with thalassemia and DBA.
Description
This trial is designed to estimate treatment success, which is anticipated to be about 80%. The study started with a sample size of 25 and this will allow us to estimate the success of engraftment. For example, if the estimated rate is .80, the 95% confidence interval would be approximately (.64, .96). This would allow us to rule out rate of treatment success of less than .64. If the estimated rate is .70, the 95% confidence interval would be approximately (.52, .88) and we could rule out rate of treatment success below .50. If the lower bound of the 95% confidence interval is raised to 0.7, the number of subjects needed to accrue with respect to success rate is listed below.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Transplant-related mortality
Time Frame
1 year, 2 year
Title
The level of chimerism required to maintain both graft survival as well as hematologic normalcy. The chimeric status of patients will be measured on days, +30, +60 and +100 by microsatellite analysis of the peripheral blood. More frequent monito...
Time Frame
+30, +60, +100, 1year, 2year
Title
Quality of life and neuropsychologic function post-transplant (see Addendum B)
Time Frame
1year, 2 year
Title
Incidence of acute and chronic GVHD or relapse rate. GvHD or relapse together count together toward the combined endpoint for regimen failure
Time Frame
1 year
Title
Immunologic function post-transplant
Time Frame
1 year
Title
Effect of transplant on end-organ function (e.g. renal function, see Addendum A)
Time Frame
1 year
Title
Disease-free survival and overall survival
Time Frame
1year, 2 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA: RECIPIENTS: Must fulfill one disease category from below: DISEASE SPECIFIC: Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F): A. Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s); 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 nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis OR Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit of normal serum creatinine 1.2mg/dl Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis, OR D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR F. Any one of the below complications: Vaso-occlusive crisis: 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 Acute Chest Syndrome (ACS): Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma Eligible for HSCT: any ACS while on hydroxyurea* Osteonecrosis of 2 or more joints: Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60 Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level Red cell alloimmunization: Eligible for hydroxyurea: Transfusion dependent Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on hydroxyurea* hydroxyurea at maximum tolerated dose Patients with beta-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 desferoxamine 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 2 cm below the costochondral margin NON-DISEASE SPECIFIC: Ages greater than or equal to 4 years 6/6 HLA matched family donor available Ability to comprehend and willing to sign an informed consent, assent obtained from minors Negative serum beta-HCG Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation DONOR: Donor deemed suitable and eligible, and willing to donate per clinical evaluations, who are additionally willing to donate blood for research and undergo a neuropsychological test. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation under a separate NHLBI protocol. Note that participation in this study is offered to all donors, but is not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study. EXCLUSION CRITERIA: RECIPIENT: (Any of the following would exclude the subject from participating) ECOG performance status of 3 or more or Lansky performance status of less than 40. Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for hemoglobin and alveolar volume) Baseline oxygen saturation or less than 85 % or PaOa2 less than 70 Left ventricular ejection fraction: less than 35% estimated by ECHO. Transaminases greater than 5 times the upper limit of normal for age 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 Major anticipated illness or organ failure incompatible with survival from PBSC transplant. Pregnant or lactating Major ABO mismatch DONOR: None
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Priscilla S Pollack, R.N.
Phone
(301) 496-1781
Email
priscilla.pollack@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
John F Tisdale, M.D.
Phone
(301) 402-6497
Email
johntis@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John F Tisdale, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY dial 711
Email
ccopr@nih.gov

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
11001885
Citation
Wayne AS, Schoenike SE, Pegelow CH. Financial analysis of chronic transfusion for stroke prevention in sickle cell disease. Blood. 2000 Oct 1;96(7):2369-72.
Results Reference
background
PubMed Identifier
7993409
Citation
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. doi: 10.1056/NEJM199406093302303.
Results Reference
background
PubMed Identifier
7715639
Citation
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. doi: 10.1056/NEJM199505183322001.
Results Reference
background
PubMed Identifier
25058217
Citation
Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 Jul 2;312(1):48-56. doi: 10.1001/jama.2014.7192.
Results Reference
derived
PubMed Identifier
20007560
Citation
Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009 Dec 10;361(24):2309-17. doi: 10.1056/NEJMoa0904971.
Results Reference
derived
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2003-H-0170.html
Description
NIH Clinical Center Detailed Web Page

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Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

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