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Clinical and genetic risk factors associated with adverse long-term health outcomes after curative therapies in individuals with sickle cell disease

Award Number: U01HL156620
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $757,751 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	001	5	3/25/2025	NON-COMPETING CONTINUATION	$757,751
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	000	4	12/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $757,751

Issue Date FY: 2024 ( Subtotal = $827,619 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	000	4	2/29/2024	NON-COMPETING CONTINUATION	$760,058
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$67,561
														Subtotal = $827,619

Issue Date FY: 2023 ( Subtotal = $849,699 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	000	3	2/27/2023	NON-COMPETING CONTINUATION	$849,699
														Subtotal = $849,699

Issue Date FY: 2022 ( Subtotal = $854,865 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	000	2	3/23/2022	NON-COMPETING CONTINUATION	$769,376
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	002	2	6/13/2022	NON-COMPETING CONTINUATION	$85,489
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	001	2	3/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $854,865

Issue Date FY: 2021 ( Subtotal = $691,115 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	001	1	3/30/2021	NEW	$0
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Blood Diseases and Resources Research	000	1	3/12/2021	NEW	$691,115
														Subtotal = $691,115

Grand Total All Awards = $3,981,049

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Clinical and genetic risk factors associated with adverse long-term health outcomes after curative therapies in individuals with sickle cell disease

Award Number: U01HL156620

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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