Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503)
Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503)
This is a clinical trial that will compare survival and sickle related outcomes in
 adolescents and young adults with severe sickle cell disease after bone marrow
 transplantation and standard of care. The primary outcome is 2-year overall survival.
This is a prospective phase II multi-center trial of hematopoietic stem cell transplantation
 or standard of care based on availability of HLA-matched related or unrelated donor after
 confirmation of clinical eligibility. In order to minimize bias assignment to either
 treatment arm, clinical eligibility to both treatment arms are similar and donor availability
 is not known at referral. HLA typing and donor search is initiated upon confirmation of
 clinical eligibility for the study. Additionally, all analyses of primary and secondary
 endpoints will follow the Intent-to-Treat principle to address potential bias introduced by
 participants with donors not proceeding to transplantation or those without a matched donor
 receiving transplantation with less well-matched donors.

 The primary outcome is 2-year overall survival. Our hypothesis is that patients who receive
 bone marrow transplantation will experience early deaths but that this will plateau by 2
 years after transplantation. Patients who receive standard of care will not experience early
 death but will succumb to their disease at a rate much higher than the general population.
 Therefore, the goal of the study is to establish that the difference in the proportion of
 patients surviving is not significantly more than 15% lower in the donor arm at 2-years after
 assignment to treatment arm.

 Secondary endpoints will compare changes in sickle cell disease related events (pulmonary
 hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and
 functional outcomes [6-minute walk distance (6MWD), health-related quality of life, cardiac
 function, pulmonary function, and mean pain intensity as assessed by a multidimensional
 electronic pain diary] from baseline to 2-years after assignment to treatment arms.

 Additionally for patients assigned to the donor arm and expected to undergo transplantation,
 hematopoietic recovery, graft rejection, acute and chronic graft-versus-host disease, other
 significant transplant-related complications and disease-free survival will be reported.
Inclusion Criteria:

 1. Age ≥ 15 and < 41 years

 2. Severe sickle cell disease [Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC) or Hemoglobin
 SBeta thalassemia (Hb Sβ) genotype] with at least 1 of the following manifestations
 (a-e):

 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);

 3. An average of three or more pain crises per year in the 2-year period preceding
 enrollment (required intravenous pain management in the outpatient or inpatient
 hospital setting). Clinical documentation of pain management in the inpatient or
 outpatient setting is required.

 4. Administration of regular RBC transfusion therapy, defined as receiving 8 or more
 transfusion events per 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 (TRJ) velocity ≥
 2.7 m/sec.

 6. Ongoing high impact chronic pain on a majority of days per month for ≥ 6 months
 as defined as ONE or more of the following: Chronic pain without contributory SCD
 complications, OR Mixed pain type in which chronic pain is occurring at site(s)
 (arms, back, chest, or abdominal pain) unrelated to any sites associated with
 Contributory SCD complications (e.g. leg ulcers and/or avascular necrosis).

 i. High impact chronic pain is identified as those reporting "severe interference"
 with life activities OR "usually or always" experiencing a limitation of their life or
 work activities including household chores. (See guidelines for identifying HICP in
 the BMT CTN 1503 Manual of Procedures) ii. Contributory SCD complications are defined
 as clinical signs (e.g. presence of leg ulcers) or clinical assessments (e.g. imaging
 confirmation of splenic infarct or avascular necrosis). Chronic pain attributed solely
 to contributory SCD complications is excluded.

 3. Adequate physical function as measured by all of the following:

 1. Karnofsky/Lansky performance score ≥ 60

 2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV
 shortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition
 Scan (MUGA).

 3. Pulmonary function:

 a. Pulse oximetry with a baseline O2 saturation of ≥ 85% b. Diffusing capacity of the
 lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin) d. 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; or GFR > 70 mL/min/1.73 m2 by
 radionuclide Glomerular Filtration Rate (GFR).

 e. Hepatic function:

 1. 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:
 There is evidence of a hyperhemolytic reaction after a recent RBC transfusion, OR
 there is evidence of moderate direct hyperbilirubinemia defined as direct serum
 bilirubin < 5 times ULN and not caused by underlying hepatic diseasePatients

 2. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 times
 upper limit of normal as per local laboratory.

 Additional inclusion required for donor arm participants to proceed with transplant

 1. Liver MRI (≤ 90 days prior to initiation of transplant conditioning) to document
 hepatic iron content is required for participants who are currently receiving ≥8
 packed red blood cell transfusions for ≥1 year or have received ≥20 packed red blood
 cell transfusions (cumulative). Participants who have hepatic iron content ≥7 mg Fe/ g
 liver dry weight by liver MRI must have a liver biopsy and histological
 examination/documentation of the absence of cirrhosis, bridging fibrosis and active
 hepatitis (≤ 90 days prior to initiation of transplant conditioning).

 2. Lack of clinical or radiologic evidence of a recent neurologic event (such as stroke
 or transient ischemic attack) by Cerebral MRI/MRA within 30 days prior to initiating
 transplant conditioning. Subjects with clinical or radiologic evidence of a recent
 neurologic event will be deferred for ≥ 6 months with repeat cerebral MRI/MRA to
 ensure stabilization of the neurologic event prior to proceeding to transplantation

 3. Documentation of participant's willingness to use approved contraception method until
 discontinuation of all immunosuppressive medications is to be documented in the
 medical record corresponding with the consent conference.

 Exclusion Criteria:

 1. HLA typing with a donor search prior to referral (consultation with HCT physician).

 1. If a subject has had HLA typing and a related donor search that did not identify
 a suitably matched relative (i.e., sibling) at any time, and also did not have an
 unrelated donor search, the patient will be considered eligible.

 2. If a subject has had HLA typing and a related donor search that did not identify
 a suitably matched relative (i.e., sibling) at any time and had an unrelated
 donor search that did not identify a suitably matched unrelated donor ≥ 1 year
 prior to enrollment, the patient will be considered eligible.

 3. If a subject has had HLA typing with no related donor search and had an unrelated
 donor search that did not identify a suitably matched unrelated donor ≥ 1 year
 prior to enrollment, the patient will be considered eligible.

 4. Subjects with a known HLA-identical sibling or HLA-matched unrelated donor are
 excluded

 2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.

 3. Seropositivity for HIV.

 4. Previous HCT or solid organ transplant.

 5. Participation in a clinical trial in which the patient received an investigational
 drug or device must be discontinued at enrollment.

 6. A history of substance abuse as defined by version IV of the Diagnostic & Statistical
 Manual of Mental Disorders (DSM IV).

 7. Demonstrated lack of compliance with prior medical care as determined by referring
 physician.

 8. Pregnant or breast feeding females.

 9. Inability to receive HCT due to alloimmunization, defined as the inability to receive
 packed red blood cell (pRBC) transfusion therapy.