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

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

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Thalassemia; Diamond-Blackfan Anemia
• Intervention / Treatment: Procedure: Bone marrow transplantation; Biological: Mesenchymal Stromal Cells

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: University of Alabama at Birmingham; University of Minnesota
• Investigators: Principal Investigator: Sandhya Kharbanda, M.D., Stanford University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2009
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: August 12, 2009
• First Submitted That Met QC Criteria: August 12, 2009
• First Posted (Estimate): August 13, 2009

Study Record Updates

• Last Update Posted (Actual): August 6, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Red-Cell Aplasia, Pure; Anemia, Sickle Cell; Thalassemia; Anemia, Diamond-Blackfan
• Other Study ID Numbers: MSC01