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Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs

Primary Purpose

Sickle Cell Disease, Thalassemia, Diamond-Blackfan Anemia

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Bone marrow transplantation

Mesenchymal Stromal Cells

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

1 Year - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with sickle cell disease (SCD) 1-25 years of age with an HLA-identical, but unrelated, donor or 1 human leukocyte antigen (HLA) allele mismatched bone marrow or up to 2 HLA antigen mismatched umbilical cord blood (UCB) donor with one or more of the following:
- Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours.
- Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions.
- Recurrent vaso-occlusive pain, 3 or more episodes per year for 3 years or more years; or recurrent priapism.
- Impaired neuropsychological function and/or abnormal cerebral MRI scan or abnormal transcranial Doppler (TCD).
- Stage I or II sickle lung disease.
- Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate (GFR) 30-50% of the predicted normal value).
- Bilateral proliferative retinopathy and major visual impairment in at least one eye.
- Osteonecrosis of multiple joints with documented destructive changes.
- Requirement for chronic transfusions but with RBC alloimmunization >2 antibodies during long term transfusion therapy.
- Failure of hydroxyurea (HU) therapy.
Patients aged 0-21 years with transfusion dependent alpha- or beta-thalassemia who have an HLA-identical or 1 HLA allele mismatched bone marrow or up to 2 HLA mismatched UCB donor.
Patients aged 0-21 years with Diamond-Blackfan anemia who have an HLA-identical or 1 HLA allele mismatched bone marrow or up to 2 HLA mismatched UCB donor. Diamond- Blackfan anemia patients will only be eligible if they have failed steroid therapy.

Exclusion Criteria:

Patients with one or more of the following:
- Karnofsky or Lansky performance score <70 (See Appendices I and II).
- Stage III-IV lung disease (Appendix III).
- GFR<30% predicted normal values.
- Pregnant or lactating females.
- Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry.
- Any patient with AIDS or HIV seropositivity.
- Any patient with invasive aspergillus infection within one year of study entry.
- Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance.

Sites / Locations

Children's Hospital of Alabama
University of Minnesota

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Mesenchymal stromal cells

Arm Description

Outcomes

Primary Outcome Measures

Count of Participants With Stable Engraftment Post Hematopoietic Cell Transplantation (HCT)

Stable engraftment was defined as absolute neutrophil count (ANC) >500 cells /µL for 3 consecutive days and platelet count >50,000 for one week without transfusion; subsequently stable engraftment was measured by percentage of donor cells.

Secondary Outcome Measures

Overall Survival 6 Months Following HCT

Overall survival is reported at the count of participants alive 6 months following HCT.

Overall Survival 1 Year Following HCT

Overall survival is reported at the count of participants alive 1 year following HCT.

Count of Participants With Disease-free Survival 6 Months Following HCT

Disease-free survival is defined as alive without underlying disease.

Count of Participants With Disease-free Survival 1 Year Following HCT

Disease-free survival is defined as alive without underlying disease.

Full Information

NCT ID

NCT00957931

First Posted

August 12, 2009

Last Updated

July 9, 2018

Sponsor

Stanford University

Collaborators

University of Minnesota, University of Alabama at Birmingham

1. Study Identification

Unique Protocol Identification Number

NCT00957931

Brief Title

Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs

Official Title

Pilot Study MUD HCT:Pts High Risk Sickle Cell,Other Non-Malignant RBC Disorders- Reduced Intensity Preparative Regimen, HAPLO-Identical Mesenchymal Stromal Cells

Study Type

Interventional

2. Study Status

Record Verification Date

July 2018

Overall Recruitment Status

Completed

Study Start Date

March 2009 (Actual)

Primary Completion Date

August 2013 (Actual)

Study Completion Date

August 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Stanford University

Collaborators

University of Minnesota, University of Alabama at Birmingham

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The main purpose of this project is to cure patients with high risk Sickle cell disease and other red cell disorders including thalassemia and diamond-blackfan anemia by bone marrow transplantation. The patients enrolled in this study will be those who lack matched sibling donors and therefore have no other option but to undergo bone marrow transplantation using matched but unrelated bone marrow or umbilical cord blood from the national marrow donor program registry. Since bone marrow transplantation for these disorders using matched unrelated donors has two major problems i.e. engraftment, or , the process of new marrow being accepted and allowed to grow in the the patient; and graft-versus-host disease, or the process where the new marrow "rejects" the host or the patient, this study has been devised with methods to overcome these two problems and thus make transplantation from unrelated donors both successful in terms of engraftment and safe in terms of side effects, both acute and long term. In order to accomplish these two goals, two important things will be done. Firstly, patients will get three medicines which are considered reduced intensity because they are not known to cause the serious organ damage seen with conventional chemotherapy. These medicines, however, do cause intense immune suppression so these can cause increased infections. Secondly, in addition to transplantation of bone marrow from unrelated donors, patients will also transplanted with mesenchymal stromal cells derived from the bone marrow of their parents. Mesenchymal stromal cells are adult stem cells that are normally found in the bone marrow and are thought to create the right background for the blood cells to grow. They have been shown in many animal and human studies to improve engraftment. In addition, they have a special property by which they prevent and are now even considered to treat graft versus host disease. Therefore, by using a reduced intensity chemotherapy regimen before transplant and transplanting mesenchymal stromal cells, we hope to improve engraftment while at the same time decrease the potential for severe side effects associated with a conventional transplant which uses extremely high doses of chemotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sickle Cell Disease, Thalassemia, Diamond-Blackfan Anemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mesenchymal stromal cells

Arm Type

Experimental

Intervention Type

Procedure

Intervention Name(s)

Bone marrow transplantation

Intervention Description

Bone marrow transplantation using matched unrelated donors, reduced intensity conditioning regimen, and co-transplanting mesenchymal stromal cells derived from parental bone marrow.

Intervention Type

Biological

Intervention Name(s)

Mesenchymal Stromal Cells

Primary Outcome Measure Information:

Title

Count of Participants With Stable Engraftment Post Hematopoietic Cell Transplantation (HCT)

Description

Time Frame

Up to 1 year

Secondary Outcome Measure Information:

Title

Overall Survival 6 Months Following HCT

Description

Overall survival is reported at the count of participants alive 6 months following HCT.

Time Frame

6 months

Title

Overall Survival 1 Year Following HCT

Description

Overall survival is reported at the count of participants alive 1 year following HCT.

Time Frame

1 year

Title

Count of Participants With Disease-free Survival 6 Months Following HCT

Description

Disease-free survival is defined as alive without underlying disease.

Time Frame

6 months

Title

Count of Participants With Disease-free Survival 1 Year Following HCT

Description

Disease-free survival is defined as alive without underlying disease.

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with sickle cell disease (SCD) 1-25 years of age with an HLA-identical, but unrelated, donor or 1 human leukocyte antigen (HLA) allele mismatched bone marrow or up to 2 HLA antigen mismatched umbilical cord blood (UCB) donor with one or more of the following: Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours. Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions. Recurrent vaso-occlusive pain, 3 or more episodes per year for 3 years or more years; or recurrent priapism. Impaired neuropsychological function and/or abnormal cerebral MRI scan or abnormal transcranial Doppler (TCD). Stage I or II sickle lung disease. Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate (GFR) 30-50% of the predicted normal value). Bilateral proliferative retinopathy and major visual impairment in at least one eye. Osteonecrosis of multiple joints with documented destructive changes. Requirement for chronic transfusions but with RBC alloimmunization >2 antibodies during long term transfusion therapy. Failure of hydroxyurea (HU) therapy. Patients aged 0-21 years with transfusion dependent alpha- or beta-thalassemia who have an HLA-identical or 1 HLA allele mismatched bone marrow or up to 2 HLA mismatched UCB donor. Patients aged 0-21 years with Diamond-Blackfan anemia who have an HLA-identical or 1 HLA allele mismatched bone marrow or up to 2 HLA mismatched UCB donor. Diamond- Blackfan anemia patients will only be eligible if they have failed steroid therapy. Exclusion Criteria: Patients with one or more of the following: Karnofsky or Lansky performance score <70 (See Appendices I and II). Stage III-IV lung disease (Appendix III). GFR<30% predicted normal values. Pregnant or lactating females. Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or HIV seropositivity. Any patient with invasive aspergillus infection within one year of study entry. Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sandhya Kharbanda, M.D.

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Children's Hospital of Alabama

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35233

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24370862

Citation

Kharbanda S, Smith AR, Hutchinson SK, McKenna DH, Ball JB, Lamb LS Jr, Agarwal R, Weinberg KI, Wagner JE Jr. Unrelated donor allogeneic hematopoietic stem cell transplantation for patients with hemoglobinopathies using a reduced-intensity conditioning regimen and third-party mesenchymal stromal cells. Biol Blood Marrow Transplant. 2014 Apr;20(4):581-6. doi: 10.1016/j.bbmt.2013.12.564. Epub 2013 Dec 24.

Results Reference

result

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Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs

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