Pilot Study PBSCT With TCRab Depletion For Hemoglobinopathies

This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo TCRαβ+ T cell and CD19+ B cell depletion of URD grafts using the CliniMACS device in patients with SCD and BTM. Apart from CliniMACS-based cell processing, PSCT will be performed according to current standards of care in the Children's Hospital of Philadelphia (CHOP) Cell Therapy and Transplant Section, including the use of a standard chemotherapy conditioning regimen and standard follow-up laboratory assessments. The study will determine efficacy of this strategy in terms of engraftment, rates of acute and chronic Graft versus Host Disease (GvHD), and one-year overall and event-free survival.

Inclusion criteria

Severe Sickle Cell Disease

• Genotype: Hemoglobin SS, Hemoglobin SC, Hemoglobin SD, SOArab, or Hemoglobin SBeta thalassemia
• Must have at least one of the following disease manifestations
• Clinically symptomatic neurologic event (stroke) or any neurologic deficit lasting greater than 24 hours at any time prior to enrollment
• History of two or more episodes of vaso-occlusive events (VOE) per year in the 2 years preceding enrolment. Patients must be refractory to hydroxyurea, defined as developing VOE despite receiving hydroxyurea for at least 6 months. Patients who are intolerant of hydroxyurea may also be enrolled.

Vaso-occlusive events include:

• Acute chest syndrome
• Pain episodes requiring intravenous pain management and/or hospitalization
• Priapism
• Splenic sequestration (defined as a 2 g/dL drop in hemoglobin in the setting of an acutely enlarging spleen. This will be determined as part of clinical care and prior to the research)
• Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving ≥ 8 RBC transfusions in the year preceding enrollment to prevent sickle cell-related complications of any kind per treating hematologist's judgment.

Beta Thalassemia Major

• Genotype: Confirmed Beta Thalassemia genotype by molecular genetic testing (May include E/Beta0 and Beta0/Beta+ genotypes)
• Must meet clinical diagnosis of transfusion-dependent thalassemia, defined as need for ≥ 8 RBC transfusions per year in the two years preceding study enrollment.

Exclusion criteria

• Patients who do not meet disease, organ or infectious criteria.
• Previous Hematopoietic stem cell transplant (HSCT)
• Patients with no suitable unrelated donor available. Patients with suitable fully matched related donor are also not eligible.
• Pregnant females. All females of childbearing potential must have negative pregnancy test.
• Participation in a clinical trial in which the patient receives an investigational drug must be discontinued prior to the time of initiation of transplant therapy. Specifically transplant chemotherapy should not begin until at least 3 half-lives after last use of the investigational drug.
• Severe RBC alloimmunization, defined as inability to receive packed RBC transfusion therapy due to anti-RBC antibodies. Patients with high titer anti-donor human leukocyte antigen (HLA) antibodies detected on screening may be enrolled if they are willing to undergo HLA antibody desensitization therapy.