Details

Details

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

IRB CTN1507

CC 17-900

Hospital Main Campus

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

Description

Description

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

2.2.1.1 Inclusion Criteria for Both Strata (Stratum 1 and Stratum 2)

Participants in both strata must have adequate physical function as measured by all of the following:

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).

a. Patients unable to perform DLCO due to young age or other inability are not required to have a specified threshold but must have no evidence of dyspnea at rest and O2 saturation level must be greater than 88% in room air at baseline.

4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2.

5. Hepatic function:

a. Serum conjugated (direct) bilirubin ≤ 2x upper limit of normal for age as per local laboratory. Participants are not excluded if the serum conjugated (direct) bilirubin is >2x the upper limit of normal for age as per local laboratory and:

i. There is evidence of a hyperhemolytic reaction after a recent RBC transfusion, OR

ii. There is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times ULN and not caused by underlying hepatic disease.

b. ALT and AST < 5x upper limit of normal as per local laboratory.

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. Lack of clinical evidence of overt stroke or transient ischemic attack (TIA) within 180 days prior to enrollment in Segment A. Participants with clinical evidence of an overt stroke or TIA within 180 days prior to enrollment in Segment A will require a cerebral MRI/MRA confirming stabilization of the neurologic event prior to proceeding to enrollment.

8. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, - B, -C, DRB1, and have available:

a. An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype and typing of additional family members is not required. Confirmatory donor HLA typing must be completed < 100 days prior to Segment A enrollment

9. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

2.2.1.2 Inclusion Criteria for Stratum 1: Children Ages 5.00 - 14.99 at enrollment

1. Age 5.00 – 14.99 years at Segment A enrollment

2. Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who have one or more of the following:

a. A neurological event resulting in focal neurologic deficits that lasted ≥ 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both.

b. Abnormal transcranial Doppler (TCD) measurement with a timed average maximum mean velocity of at least 200 cm/sec in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used > 185 cm/sec plus evidence of intracranial vasculopathy.

c. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2-weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s).

d. Acute severe vaso-occlusive pain episodes requiring hospitalization and recalcitrant to maximum medical therapy. Episodes of pain to be adjudicated by selected committee.

e. At least one acute chest syndrome episode resulting in intensive care admission requiring non-mechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), simple nasal cannula, face mask

f. O2 (e.g. ventimask, non-rebreather), CPAP, SiPAP, BiPAP, high flow nasal cannula (HFNC) or invasive mechanical ventilatory support (delivered by ETT or trach).

g. Right heart catherization confirmed pulmonary artery pressure >25 mmHg or mean pulmonary vascular resistance 206(57-421) dyn·s·cm−5.

h. Essential hypertension on antihypertensive medications >95% upper limit of normal for age (as defined according to the American Academy of Pediatrics).

i. Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months) recalcitrant to medical treatment or unable to use hydroxyurea due to SCD phenotype, with the approval of the adjudication committee.

2.2.1.3 Inclusion Criteria for Stratum 2: Adults Ages 15.00 - 45.99 at enrollment

1. Age 15.00-45.99 years at Segment A enrollment

2. Participants with sickle cell anemia (any clinically significant sickle genotype, for example, Hb SS, SC, SD Sβ° Thalassemia, Sβ+ Thalassemia, S-OArab) who have one or more of the following:

a. A neurological event resulting in focal neurologic deficits that lasted ≥ 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both.

b. 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);

c. 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;

d. Administration of regular red blood cell (RBC) transfusion therapy, defined as 8 or more transfusion events per year (in the 12 months before enrollment) to prevent vaso- occlusive clinical complications (i.e. pain, stroke, or acute chest syndrome);

e. 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.