Title Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease

IRB CTN 1507

CC 17-900

Hospital Main Campus

Disease Blood & Marrow Transplant (BMT), Sickle Cell Disease (SCD)



Primary Objective
  • The primary objective is to estimate event-free survival (EFS) at 2 years after a reduced intensity conditioning regimen and human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (haploBMT) in children with SCD and adults with severe SCD.
Secondary Objectives
  1. Estimate overall survival at one year and two years after enrollment and after haploBMT.
  2. Estimate EFS at one year after haploBMT.
  3. Estimate incidence of primary and secondary graft rejection at one and two years after haploBMT.
  4. Estimate incidence and severity of acute GVHD until Day 100 then chronic GVHD at six months, one year, 18 months, and two years post-transplant.
  5. Characterize donor hematopoietic chimerism in peripheral blood at days 28, 100, and 180 and at 1 and 2 years after haploBMT.
  6. Characterize hematologic and non-hematologic toxicities of haploBMT, including the incidence and severity of acute and chronic graft-versus-host disease; time to and probability of red blood cell, neutrophil, and platelet recovery; hepatic veno-occlusive disease (VOD); idiopathic pneumonia syndrome (IPS); central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS], hemorrhage, and seizures); cytomegalovirus (CMV) infection; adenovirus infection; Epstein Barr virus post-transplant lymphoproliferative disease (EBV PTLD); invasive fungal infection.
  7. Evaluate if sickle vasculopathy is halted by successful transplantation as determined by comparing brain MRI pre- and 2 years post-haploBMT. Cerebral MRI/MRA is required for all pediatric patients to assess progression of CNS disease. For adults with where the indication for the transplant is a stroke, cerebral MRI/MRA is required after transplant to assess progression of CNS disease.
  8. Evaluate sickle-related events and end organ function in all recipients after haploBMT to determine if severe and debilitating vaso-occlusive pain and cerebral infarction are stabilized after transplantation.
  9. Evaluate patient-reported quality of life (pain and fatigue domains) pre- and 1 and 2 years post-haploBMT in the adult stratum
  10. Lung function pre- and 2 years post-haploBMT
  11. TRJV pre- and 1 and 2 years post-haploBMT
  12. 6 min walk distance pre- and 1 and 2 years post-haploBMT
  13. Pain intensity assessed by an electronic pain diary at baseline, 1 and 2 years post-haploBMT for patient ≥ 13.00 years of age at time of enrollment
  14. Hematological outcomes at 2 years (hgb, retic, %HbS, LDH, bili, last date of red blood cell transfusion)
  15. Viral mold infections/bacterial or fungal sepsis at anytime up to 2 years post transplant
  16. Proportion on immunosuppression at 2 years post-haploBMT
Inclusion Criteria

Inclusion Criteria

  1. A Karnofsky/Lansky performance score of ≥ 60.
  2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.
  3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and DLCO > 40% (corrected for hemoglobin).
  4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age
  5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory; ALT and AST < 5 times upper limit of normal as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.
  6. Liver MRI using a validated methodology per institutional preference (T2* or R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 10 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis[1], and active hepatitis.
  7. Participants must have a first-degree related HLA-haploidentical related donor who is willing and able to donate bone marrow. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Children Ages 5.00 - 14.99 years of age at enrollment

  1. Participants (Hb SS or Sβo Thalassemia) with overt stroke ischemia based on neuroimaging, clinical evidence of permanent neurological injury lasting for 24 hours, or both. If there is clinical or radiologic evidence of a recent cerebral infarct by cerebral MRI/MRA within 30 days prior to enrollment, participants will be deferred for ≥ 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation.

Adults Ages 15.00 - 45.99 at enrollment

Participants with sickle cell anemia (Hb SS or Sβo Thalassemia) who are 15.00 - 45.99 years of age at enrollment AND who have one or more of the following:

  1. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours;
  2. History of two or more 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 three or more severe vaso-occlusive 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); painful episodes related to priapism, osteonecrosis or any sickle-related complication are acceptable;
  4. Administration of regular RBC transfusion therapy, defined as receiving ≥8 packed red blood cell transfusions per year for ≥ 1 year in the 12 months before enrollment to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome);
  5. An echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) ≥ 2.7 m/sec.

Exclusion Criteria

Exclusion Criteria

  1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donor are not excluded.
  2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
  3. Evidence of HIV infection or known HIV positive serology.
  4. Participants who have received a previous HCT.
  5. Participants who have participated in another clinical trial in which the patient received an investigational or off-label use of a drug or device within 3 months of enrollment.
  6. Females who are pregnant or breastfeeding.
  7. Participants with clinically significant, uncontrolled autoimmune disease, requiring active medical management (immunosuppressive therapy or chemotherapy), which, in the judgment of the local Principal Investigator, indicates that the patient could not tolerate transplantation.
  8. Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized), who do not agree to practice two (2) effective methods of contraception at the same time, or do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-transplant.
  9. Males (even if surgical sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-transplant.
  10. Anti-donor specific HLA antibodies: Positive anti-donor HLA antibody is defined as a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A, -B, -C, or -DRB1 with mean fluorescence intensity >3000 by solid phase immunoassay. This will be measured before the final donor selection, and at least 180 days or less before HCT.