Observational Study to Deeply Phenotype Major Organs in Sickle Cell Disease After Curative Therapies

Observational Study to Deeply Phenotype Major Organs in Sickle Cell Disease After Curative Therapies

Background:

People with sickle cell disease (SCD) have problems with their heart, brain, kidneys, liver, and lungs as they age. These problems may improve after transplant. Researchers want to learn how and why this happens.

Objective:

To study the benefits of treatments that are intended to cure SCD.

Eligibility:

People aged 18 and older with SCD who are either receiving curative therapy in the next 3 months or don t have any plans to receive a curative therapy in the next 2 years.

Design:

At their first visit, participants will be screened with their medical history and a physical exam.

Participants will then have a baseline visit. This will take about a week to complete and will include:

Blood and heart tests

MRI of the brain, heart, and lungs. Participants will lie on a bed that will move into the MRI scanner. Special padding may be placed around their head to keep it still.

Interactive games. Participants will complete computer games that test memory, attention, problem solving, language, spatial orientation, processing speed, and emotion.

Questionnaire rating quality of life

Iothalamate test. An IV catheter will be placed into a vein. A contrast agent will be injected through the IV. Blood will then be collected at different time points.

Lung function tests and a 6-minute walk test

Vibration controlled transient elastography. A probe placed on the abdomen will measure liver scarring.

DOS test. A light attached to the finger or toe will measure blood oxygen.

Participants will have an end-of-study visit about 2 years after their baseline visit. This will include repeats of the baseline visit tests.

Study Description:

This study seeks to evaluate heart, lung, liver, kidney, brain, and neurocognitive function post-hematopoietic stem cell transplant (HSCT) in patients with sickle cell disease (SCD) who undergo curative therapies. Patients who undergo curative therapies will be compared to adults with SCD who receive non-curative therapies at baseline and 2 years later. The primary hypothesis is that diastolic function will improve after successful curative therapy as compared to those receiving non-curative therapies. Secondary analyses will include assessment of cardiopulmonary and kidney function. This study includes assessment of organs before and 2 years after curative and non-curative therapies with deep phenotyping of the heart, lung, liver, brain, cognitive, and kidney function. This protocol will allow us to comprehensively explore sequelae of curative therapies on organ function in patients with SCD.

Objectives:

Primary Objective:

-Evaluate left ventricular end diastolic volume/body surface area (LVEDV/BSA) in patients with SCD who undergo curative therapies as compared to patients who receive non-curative therapies

Secondary Objectives:

• Evaluate other markers of cardiopulmonary function in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies.
• Evaluate change in kidney function over time in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies.

Tertiary Objectives:

• Perform deep phenotyping of heart, lung, liver, kidney, brain and neurocognitive function along with reported genetic variants in adults with SCD who undergo curative therapies as compared to adults with SCD who receive non-curative therapies.
• Assess markers of inflammation in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies.
• Evaluate markers of graft rejection and tolerance induction in patients with SCD who undergo curative therapies.
• Evaluate lipid profiles in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies.
• Evaluate regional oxygenation (rS0(2)) with Near Infrared Spectroscopy (NIRS) in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies.
• Evaluate novel biomarkers of organ damage in patients who receive curative therapies as compared to those who receive non-curative therapies.

Endpoints:

Primary Endpoint:

-Change in LVEDV/BSA

Secondary Endpoints:

• Change in left ventricular end diastolic diameter (LVEDD), ejection fraction, left ventricular mass index, left atrial volume index, global longitudinal strain
• Change in N-terminal pro b-type natriuretic peptide (NTproBNP).
• Change in creatinine, cystatin-C, urine protein to creatinine ratio, urine albumin to creatinine ratio, and estimated glomerular filtration rate (eGFR) using the CKD-EPI equation

Tertiary Endpoints:

• Change in myocardial fibrosis, extracellular volume fraction, processing speed, measured GFR, incidence of stroke/silent infarcts, cerebral blood flow, oxygen extraction fraction, and liver stiffness, and correlation of APOL1 risk alleles with renal function and degree of proteinuria
• Change in c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), inflammatory cytokines (including interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-a), chemokines, GlycA, D-dimer, and haptoglobin
• Change in regulatory cells (including regulatory T cells and myeloid-derived suppressor cells) and proteins (including galectin, platelet factor 4, and thrombospondin-1) and suppressive cytokines (interleukin-10 (IL-10), transforming growth factor beta, and IL-7)
• Change in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle size and number, triglycerides, and apolipoprotein A-I and B
• Change in rS0(2) within the peripheral limb with NIRS
• Correlation of novel genetic biomarkers associated with organ damage in patients with SCD who receive curative therapy or noncurative therapy.

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study

2. Male or female, aged >=18 years

3. Patients with current or previous diagnosis of any type of SCD (including HbSS, HbSC, HbSbeta^0-thal, HbSbeta^+-thal) who:

   1. plan to receive an allogeneic HCT or gene therapy,

      Or

   2. are receiving non-curative treatment (standard of care or investigational) and who do not plan to receive an allogeneic HCT or gene therapy

4. Ability to travel to the NIH Clinical Center

5. Ability of subject to understand a written informed consent document.

6. At least one of the following eligibility criteria:

   • History of stroke (including silent stroke) or abnormal transcranial doppler examination (>= 200 m/s)
   • Progression of central nervous system vasculopathy on MRA
   • History of SCD-related renal insufficiency defined as nephrotic syndrome OR creatinine clearance < 60mL/min OR a creatinine level >=1.3 mg/dL AND kidney biopsy consistent with sickle cell nephropathy
   • Tricuspid regurgitant velocity >= 2.5 m/s
   • Recurrent tricorporal priapism defined as at least 2 episodes of an erection lasting > 4 hours involving the corpora cavernosa and corpus spongiosa
   • SCD-associated liver disease defined as EITHER ferritin > 1000 mcg/L OR direct bilirubin > 0.4 mg/dL
   • > 1 hospitalization per year for vaso-occlusive crises while receiving hydroxyurea treatment
   • A history of 2 or more acute chest syndrome episodes in the participant's lifetime.
   • Avascular necrosis of 2 or more joints
   • Red cell alloimmunization (delayed hemolytic transfusion reaction or significant red blood cell alloimmunization that makes transfusion difficult).
   • Administration of regular red blood cell (RBC) transfusion therapy (>=8 red cell transfusions in the previous 12 months) to prevent SCD complications (i.e. pain, stroke, or acute chest syndrome).
   • Eligible for an allogeneic HCT or gene therapy at an outside transplant center.

EXCLUSION CRITERIA:

All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation.

1. Prior transplantation (including but not limited to HSCT and kidney transplant)
2. Pregnant or breastfeeding
3. Patients with allergy to iodine or iodinated contrast solutions will not undergo Iothalamate or Iohexol GFR clearance testing but can undergo the other deep phenotype testing
4. Implanted metal object that is not compatible with MRI (e.g.: cerebral aneurysm clip, cochlear implant, or pacemaker)
5. Patients with a pacemaker or automated implantable cardioverter defibrillator will not undergo VCTE but can enroll and undergo the other deep phenotype testing as long as the device is compatible with MRI and MRI testing can be performed
6. Patients requiring peritoneal or hemodialysis
7. Uncontrolled infection or acute illness