A Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With SCD

Prior treatment

• Patients with donor-specific antibodies (DSA) against the potential stem cell donor by either
  • Cell-based crossmatched assays (Complement-dependent cytotoxicity; CDC) or
  • Flow cytometry crossmatch test or
  • Solid-phase immunoassays (SPI) or
  • Modified SPI such as C4d and C1q assays Whichever method the participating center is experienced in.
• Prior autologous or allogeneic hematopoietic stem cell transplant
• Vaccination with a live virus vaccine during the trial
• Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study

Other illness

• History of uncontrolled autoimmune disease or on active treatment
• HIV infection
• Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction)

Lab values

• Cardiac function:
  • Ejection fraction at rest \<45.0% on echocardiography or
  • Shortening fraction of \<27.0% by echocardiogram or radionuclide scan (MUGA)
  • Patients with \> grade II hypertension by Common Toxicity Criteria (CTC)
• Renal function:
  • Estimated creatinine clearance (for patients \> 12 years) greater than 50.0 mL/minute
  • for pediatric patients (\> 1 year to 12 years), GFR estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m2. If \< 90 mL/min/1.73 m2, renal function must be measured by 24-hour creatinine clearance or nuclear GFR and must be \> 70.0 mL/min/1.73 m2 or
  • Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard
• Pulmonary function:
  • DLCO \>50% (adjusted for hemoglobin), and FVC and FEV1≥50%; children unable to perform for PFTs, O2 saturation \<92% on room air.
• Liver function:
  • Total bilirubin \> 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and ALT/AST \> 2.5x the upper limit of normal.
  • Chronic active viral hepatitis
• Women who are pregnant (positive serum or urine βHCG) or breastfeeding. Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.

Other

• Karnofsky or Lansky Performance Score \< 70%
• Patients with major AB0 incompatibility defined according to EBMT Handbook, Edition 2019 Tab 23.1.:
  • ABO incompatibility Recipient Donor Major O A O B O AB A AB B AB
• Adults of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter,
• Patient unable to comply with the treatment protocol
• Patients unwilling or unable to comply with the protocol or unable to give informed consent.

• Age 2yrs to 35yrs
• Homozygous hemoglobin S disease or heterozygous hemoglobin SC or S 0/+
• Study specific consent given
• Preexisting severe or moderate SCD related complications:
  • Clinically significant neurological event (stroke) or deficit
  • Silent crisis, neurocognitive deficit
  • Pathological angio-MRI with TOF Sequence
  • TCD velocity \>200 cm/s at 2 occasions \>1 month apart
  • More than 5 vaso-occlusive crises (VOC) in the past 1 year or more than 20 VOC in a lifetime
  • Two or more episodes of acute chest syndrome (ACS) in a lifetime or one episode of ACS in the past 24 months
  • Chronic transfusion requirement or more than 8 transfusions or one exchange transfusion in a lifetime
  • Transfusion-refractory allo-immunization
  • More than five SCD-related hospitalizations in a lifetime
  • Beginning pulmonary hypertension
  • Osteonecrosis at more than 2 sites
  • Beginning SCD Nephropathy
  • Recurrent priapism (\>2)