Mesenchymal Stromal Cells for Haplo Hematopoietic Cell Transplantation for Sickle Cell Disease

Inclusion Criteria:

• Must weigh >25 kg at the time of study entry.
• Must have undergone puberty at the time of study entry to allow pre-transplant fertility preservation to occur, if desired. Puberty will be defined as Tanner III or more in male patients (typically age ≥ 13 years) and menarche in female patients.

• Have severe sickle cell disease (SCD) defined as 1 or more of the following:

  1. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours;
  2. History of ≥2 episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
  3. History of ≥3 severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea);
  4. Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving ≥8 transfusions per year for ≥1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome);
  5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥2.7 m/sec in adult patients.

• Have adequate physical function as measured by:

  1. Lansky or Karnofsky performance score ≥60
  2. Cardiac function: left ventricular ejection fraction (LVEF) >40% or LV shortening fraction > 26% by cardiac echocardiogram or by multigated acquisition (MUGA) scan.
  3. Pulmonary function: pulse oximetry with a baseline O2 saturation of ≥90% and DLCO >40% (corrected for hemoglobin)
  4. Renal function: serum creatinine ≤1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance >70 mL/min/1.73 m2 or glomerular filtration rate (GFR) >70 mL/min/1.73 m2 by radionuclide GFR.
  5. Hepatic function: serum conjugated (direct) bilirubin <2x upper limit of normal for age as per local laboratory and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <5x upper limit of normal as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion are not excluded.
  6. In patients who have received chronic transfusion therapy for ≥1 year and who have clinical evidence of iron overload by serum ferritin or MRI, evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995).
• Must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C and DRB1 and have an available related haploidentical bone marrow donor with 2, 3, or 4 (out of 8) HLA-mismatches. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch.

Exclusion Criteria:

• Availability of an 8 of 8 (HLA-A, B, C and DRB1) human leukocyte antigen (HLA) matched sibling or matched unrelated donor
• Presence of donor directed HLA antibodies.
• Severe pulmonary disease (despite above oxygen saturation and DLCO) including severe and uncontrolled asthma (per 2007 NHLBI Guidelines for the Diagnosis and Treatment of Asthma Expert Panel Report 3; http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report), chronic obstructive pulmonary disease, and/or pulmonary hypertension (PH). A diagnosis of pulmonary hypertension (PH) will be made by finding of mean pulmonary artery pressure (mPAP) <25 mm Hg on right heart catheterization. In patients unable and/or unwilling to undergo cardiac catheterization, patients will be excluded with the following constellation of findings based upon presumptive diagnosis of PH (PPV of 62%): TRJ velocity >2.5 m/sec AND either N-terminal pro-brain natriuretic peptide (NT-pro-BNP) ≥160 pg/ml OR 6-minute walk distance <333 m.
• Uncontrolled bacterial, viral or fungal infection in the 6 week before enrollment
• Seropositivity for human immunodeficiency virus (HIV)
• Previous hematopoietic cell transplantation (HCT)
• Participation in a clinical trial in which the patient received an investigational drug or device or the off-label use of a drug or device within 3 months of enrollment
• Demonstrated lack of compliance with prior medical care
• Unwilling to use approved contraception for at least 6 months following transplant
• Pregnant or breastfeeding females
• Allergy to any component of mesenchymal stromal cell (MSC) suspension (such as human albumin) and/or allergy to any drugs used in HCT conditioning regimen.