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

Study Overview
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Brief Summary
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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.

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

Conditions
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Sickle Cell Disease, Thalassemia, Diamond-Blackfan Anemia

Intervention / Treatment
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* Procedure: Bone marrow transplantation
* Biological: Mesenchymal Stromal Cells


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal stromal cells<br> | Procedure: Bone marrow transplantation<br>* Bone marrow transplantation using matched unrelated donors, reduced intensity conditioning regimen, and co-transplanting mesenchymal stromal cells derived from parental bone marrow.<br>Biological: Mesenchymal Stromal Cells<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival 6 Months Following HCT | Overall survival is reported at the count of participants alive 6 months following HCT. | 6 months | 
| Overall Survival 1 Year Following HCT | Overall survival is reported at the count of participants alive 1 year following HCT. | 1 year | 
| Count of Participants With Disease-free Survival 6 Months Following HCT | Disease-free survival is defined as alive without underlying disease. | 6 months | 
| Count of Participants With Disease-free Survival 1 Year Following HCT | Disease-free survival is defined as alive without underlying disease. | 1 year |