U01HL156620

Clinical and Genetic Risk Factors Associated with Adverse Long-Term Health Outcomes After Curative Therapies in Individuals with Sickle Cell Disease - Summary

Our primary objective is initiating a personalized approach to curative therapies in children and adults with sickle cell disease (SCD) to maximize benefits and limit adverse outcomes. Limited systematic efforts exist to elucidate long-term health outcomes following curative therapies for SCD. The paradigm of focusing only on the initial cure is analogous to what occurred in pediatric oncology in the 1980s with successful curative therapies. Subsequently, curative therapies were associated with increased risk for organ dysfunction and malignancies, leading to a new field, survivorship in pediatric oncology.

With emerging curative therapies for SCD (allogeneic [allo] hematopoietic stem cell transplant [HSCT], gene therapy/editing), long-term health outcomes studies are time-sensitive and critical to inform personalized choices. Unfortunately, adverse outcomes have started to emerge after SCD curative therapy. Specifically, 10% of the deaths following HSCT occur more than 5 years after HSCT. Further, our group has demonstrated therapy-related myeloid neoplasms and clonal hematopoiesis of indeterminate potential (CHIP) may occur when graft rejection/mixed chimerism is present (seen in 5 of 76 patients with SCD after HSCT). Thus, risks of cure in SCD must be measured against the benefits of cure, including stabilization of lung function (FEV1) and improved tricuspid regurgitant jet velocity [TRJV].

Ultimately, the shortened lifespan of individuals with SCD, attributable to declining heart (elevated TRJV), lung (decreased FEV1), and kidney (decreased eGFR) function, for which curative therapies were designed to ameliorate, must be measured against favorable and unfavorable late outcomes.

In our multicenter retrospective-prospective cohort, we will test the following hypotheses:

1A): Myeloablative curative therapies for children with SCD will result in progressive pulmonary and renal dysfunction when compared to children with SCD receiving standard therapy;
1B): Nonmyeloablative HSCT for adults with SCD will result in no significant change in FEV1% predicted, but will lead to accelerated decline in eGFR when compared to adults receiving standard therapy;
2) Nonmyeloablative HSCT for adults with SCD will be associated with a clinically significant improvement in TRJV following HSCT; and
3) In adults with SCD, proliferative and genotoxic stress uniformly related to nonmyeloablative allo-HSCT and myeloablative gene editing will lead to post-HSCT therapy-related myeloid neoplasm of recipient origin.

We will address these hypotheses with the following aims:

1) Evaluate the incidence of pulmonary and renal function in 1A: children with SCD receiving myeloablative curative therapies; and 1B: adults with SCD receiving nonmyeloablative allo-HSCT, compared to a pre-existing cohort of children and adults with SCD;
2) Determine whether there is a clinically significant improvement in TRJV in adults with SCD, at least half having TRJV > 2.5 m/s, following nonmyeloablative allo-HSCT; and
3) Evaluate the prevalence, incidence, and evolution of CHIP following non-myeloablative HSCT or myeloablative gene editing in adults with SCD.

Vanderbilt University Medical Center

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Nashville, Tennessee 37203 United States

Single Zip Code

Opportunities for Collaborative Research at the NIH Clinical Center (U01 Clinical Trial Optional) (PAR-18-951)

Amendment Since initial award the total obligations have increased 488% from $691,115 to $4,065,243.