A Study of Immune Suppression Treatment for People With Sickle Cell Disease or β-Thalassemia Who Are Going to Receive an Allogeneic Hematopoietic Cell Transplantation (HCT)

Pre-Transplant Immune Suppression With Hematopoietic Cell Transplantation From Haploidentical Donors for Adults and Children With Sickle Cell Disease or ß-Thalassemia (Haplo PTCy)

Hematopoietic Cell Transplantation/HCT involves receiving healthy blood-forming cells (stem cells) from a donor to replace the diseased or damaged cells in participants' bone marrow. The researchers think giving participants treatment with fludarabine and dexamethasone, drugs that lower the activity of the body's immune system (immune suppression), before standard conditioning therapy and HCT may help prevent serious side effects, including graft failure and GvHD. In this study, depending on how participants' body responds to the fludarabine and dexamethasone, the study doctor may decide participants should receive another drug, called cyclophosphamide, instead of fludarabine. In addition, depending on the results of participants' routine blood tests, participants may receive the drugs bortezomib and rituximab, which also help with immune suppression.

Inclusion Criteria:

• Age ≥ 2 and ≤ 50 years

• Suitable haploidentical donor.

• Performance score ≥ 70% by Karnofsky Performance Scale or 0 to 1 by ECOG (age > 16 years), or Lansky Play-Performance Scale ≥ 70% (age ≤ 16 years).

• Adequate major organ system function as demonstrated by:

  • For patients ≥ 18 years of age:
  • eGFR ≥ 50 mL/min by Cockcroft-Gault formula Formula: ((140 - Age) x Weight (kg)) / (72 x Serum Creatinine (mg/dL) Female Adjustment: Multiply result by 0.85
  • For patients < 18 years of age:
  • Serum creatinine clearance: glomerular filtration rate [GFR]) must be >50 mL/min/1.73 m2 as calculated by the Schwartz formula

• Conjugated (direct) bilirubin less than 3x upper limit of normal.

• ALT or AST ≤ 3 times institutional upper limit of normal.

• Left ventricular ejection fraction ≥ 50%.

• Diffusing capacity for carbon monoxide (DLCO) ≥ 50% predicted, corrected for hemoglobin. For children < 7 years of age who are unable to perform PFT, oxygen saturation > 92% on room air by pulse oximetry.

• For SCD patients: HbSS, HbSC, HbS/β° with one or more of the following complications:

  • Acute chest syndrome: 2 or more episodes in the 2 years preceding enrollment
  • Vaso-occlusive episodes: 3 or more episodes in the 2 years preceding enrollment
  • Recurrent priapism: 2 or more episodes in the 2 years preceding enrollment
  • History of osteomyelitis or osteonecrosis
  • Cerebrovascular disease:

• Imaging evidence of prior overt or silent stroke

• History of a neurologic event resulting in focal neurologic deficits lasting > 24 hours

• Abnormal transcranial Doppler: Timed average maximum mean velocity ≥ 200 cm/sec in terminal portion of the carotid or proximal portion of the middle cerebral artery or > 185 cm/sec plus evidence of intracranial vasculopathy if imaging TCD is used

  • Pulmonary hypertension: Confirmed by right heart catheterization with mean pulmonary arterial pressure ≥ 25 mmHg or mean pulmonary vascular resistance > 2 Wood units
  • Red blood cell alloimmunization (> 3 alloantibodies)

• For thalassemia patients: Any genotype, with all of the following:

  • Onset of red blood cell transfusion dependence during the first 3 years of life
  • RBC transfusion history > 225 mL/kg/year or > 15 lifetime RBC transfusions
  • Pre-transfusion hemoglobin ≤ 7 g/dL
  • Hepatosplenomegaly

• Patient or the patient's legal representative, parent(s) or guardian should be able to provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.

• For sexually active men and women of childbearing potential, must agree to use a form of contraception considered effective and medically acceptable by the Investigator.

Exclusion Criteria:

• Prior myeloablative allogeneic HCT.
• Overt stroke or CNS instrumentation (e.g. for Moyamoya disease) within 6 months of enrollment.
• Liver cirrhosis. Mild fibrosis will be permitted, i.e. fine reticulin or grade 1 of 4, with bridging fibrosis.
• Hepatic iron content ≥ 3 mg Fe/g liver dry weight, if applicable
• Active hepatitis B or C.
• Other uncontrolled infections.
• Other malignancy/cancer diagnosis unless in remission after definitive therapy for a minimum of 2 years. Exceptions: Ductal carcinoma in situ, basal cell carcinoma, cervical intraepithelial neoplasia.
• Positive pregnancy test in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
• Inability to comply with medical therapy or follow-up.
• Known history of allergic reactions to any constituents of the stem cell product, including a known history of allergic reactions to DMSO.