Haplo T-Cell Depleted Transplantation in High-Risk Sickle Cell Disease (HaploSCD)

• neurological/neurocognitive status [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Change from baseline in neurological/neurocognitive status
• Pulmonary/pulmonary vascular status [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Change from baseline of Pulmonary/pulmonary vascular status
• Health-related quality of life [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Change from baseline of Health-related quality of life

This study is being done to determine the safety and outcome (long-term control) of a high-dose chemotherapy regimen followed by an infusion of CD34 selected (immune cells) stem cells from a partially matched adult family member donor, called haploidentical stem cell transplantation, in high-risk sickle cell disease patients.

Funding Source - FDA OOPD

The purpose of this study is to investigate host myeloimmunosuppressive conditioning followed by familial haploidentical T cell depleted allogeneic stem cell transplantation in patients with high risk Sickle Cell Disease (SCD). It is hypothesized that it will be safe and well tolerated, and result in sustained donor chimerism, acceptable engraftment and immune reconstitution. Also, that it will limit SCD related organ damage resulting in improved and/or stable neurological, neurocognitive, pulmonary and pulmonary vascular function and health related quality of life (QOL).

Patients 2-21 years of age with a diagnosis of high-risk SCD and without an unaffected HLA matched family donor or 8/8 matched unrelated donor, with adequate organ function are eligible.

Inclusion Criteria:

• Homozygous Hemoglobin S Disease, or Hemoglobin S Beta0/+ thalassemia

• Patients must demonstrate one or more of the following Sickle Cell Disease Complications

  1. Clinically significant neurologic event (stroke) or any neurologic deficit lasting >24 hours that is accompanied by an infarct on cerebral MRI
  2. Minimum of two episodes of acute chest syndrome (defined as new pulmonary alveolar consolidation involving at least one complete lung segment associated with acute symptoms including fever >38.5, chest pain, tachypnea, intercostal retractions, nasal flaring, use of accessory muscles of respiration, wheezing, rales, or cough not attributable to asthma or bronchiolitis) in the preceding two year period prior to enrollment that have failed, been non-compliant or declined hydroxyurea treatment,. The acute chest syndrome event occured despite adequate supportive care measures (i.e. despite the use of supportive care and interventions including asthma therapy and/or hydroxyurea; patients who decline hydroxyurea or non-compliant with this therapy are eligible if they meet the other pulmonary criteria defined above for inclusion).
  3. Recurrent painful events (at least 3 in the 2 years prior to enrollment). Pain occurred in typical sites associated with vaso-occlusive painful events and cannot be explained by causes other than sickle cell disease. Pain lasted at least 2-4 hours and required parenteral narcotic treatment, or an equianalgesic dose of oral narcotics or parenteral nonsteroidal anti-inflammatory drugs. These painful events may have been treated in any setting; however, the events, including events that were managed at home, will be considered for eligibility only if there is documentation of the event in a clinical record that may be reviewed by the investigator.
  4. One consecutive abnormal TCD study followed by hypertransfusion therapy or Two consecutive abnormal TCD studies (two months apart) with mean velocities in the MCA, ICA, or ACA of > 200 cm/sec requiring chronic transfusion therapy. .
• A familial haploidentical donor without homozygous sickle cell disease
• Serum creatinine ≤1.5 x upper limit of normal for age and Creatinine clearance >60 ml/min/m2 or radioisotope GFR >100 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range
• Direct bilirubin <2.0 x upper limit of normal for age as per local laboratory and AST or ALT <5.0 x upper limit of normal as per local laboratory
• Shortening fraction ≥27% by echocardiogram or Ejection fraction of >40% by echocardiogram
• Pulse oximetry ≥85% on room air, and DLCO >50% (corrected for hemoglobin) in cooperative patients in whom pulmonary function testing can be performed.
• Karnofsky or Lansky (age appropriate) Performance Score ≥50%
• For all patients receiving chronic transfusions for ≥1 year and a serum ferritin >1000 ng/ml, a liver biopsy will be performed to assess for iron overload.

Exclusion Criteria:

• Females who are pregnant or breast-feeding
• SCD Patients with documented uncontrolled infection
• SCD patients who have an unaffected HLA matched family donor willing to proceed to donation or a willing and acceptable 8/8 matched unrelated donor
• KarnofskyLansky (age appropriate) Performance Score <50% (hemiplegia alone secondary to a previous stroke is not an exclusion)
• Clinically significant fibrosis or cirrhosis of the liver
• Previously received a HSCT

• Children's Hospital & Research Center Oakland
• Medical College of Wisconsin
• Washington University School of Medicine
• Tufts University
• University of California, San Francisco
• Miltenyi Biotec GmbH
• Otsuka Pharmaceutical Development & Commercialization, Inc.
• FDA Office of Orphan Products Development