Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
Condition: Sickle Cell Disease; Thalassemia; Diamond-Blackfan Anemia
MeSH terms: Anemia, Sickle Cell; Thalassemia; Anemia, Diamond-Blackfan
Intervention: Bone marrow transplantation; Mesenchymal Stromal Cells
Intervention description: Bone marrow transplantation using matched unrelated donors, reduced intensity conditioning regimen, and co-transplanting mesenchymal stromal cells derived from parental bone marrow.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 1 Year
Maximum age: 25 Years
Healthy volunteers: No

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.
    

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.