cooperative assessment of late effects for scd curative therapies

Conditions: Sickle Cell Disease; Pulmonary Disease; Renal Disease; Heart Disease

Summary: sickle cell disease is one of the most common genetic diseases in the united states, occurring in approximately 1 in 400 births. approximately 100,000 individuals are diagnosed with scd in the united states. mortality for children with scd has decreased substantially over the past 4 decades, with \>99% of those born in high resource settings, including the united states, france, and england, now surviving to 18 years of age. however, the life expectancy of adults with scd is severely shortened. dysfunction of the heart, lung, and kidney is directly associated with decreased life expectancy. with the variety of curative therapies that are now available for scd, long-term health outcomes studies are time-sensitive. as of now, efforts to determine long-term health outcomes following curative therapies for scd have been limited. though curative therapies initially should provide a cure for symptoms of scd, there is the risk of late health outcomes to consider. defining health outcomes following curative therapy is essential to improve personalized decision-making when considering curative versus disease-modifying therapeutic options. the primary goal of this study is to determine whether curative therapies for individuals with scd will result in improved or worsening heart, lung, and kidney damage when compared to individuals with scd receiving standard therapy. the investigators will also explore whether certain genes are associated with a good or bad outcome after curative therapy for scd.

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 clinical studies exist to determine the long-term health outcomes following curative therapies for scd. with emerging curative therapies for scd (allogeneic \[allo\] hematopoietic stem cell transplant \[hsct\], gene therapy/editing), long-term health outcomes studies are critical to inform personalized choices. unfortunately, adverse outcomes have started to emerge after scd curative therapy. thus, risks of a cure in scd must be measured against the benefits of a 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, the investigators 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. the investigators 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, 3) evaluate the prevalence, incidence and evolution of clonal hematopoiesis of indeterminate potential (chip) concerning therapy-related myeloid neoplasm development following non-myeloablative hsct or myeloablative gene editing in adults and children with scd, and 4) evaluate accuracy and gaps involved in collecting clinical health record data directly from patients and family members in comparison to clinical health record data collected by research coordinators.

Eligibility criteria:
inclusion criteria * confirmed laboratory diagnosis of scd * ability to give informed consent * ability to provide pre- and post-curative therapy data * treated with either one hsct or with standard disease-modifying therapy exclusion criteria •history of non-compliance

Keywords: myeloablative autologous gene editing myeloablative autologous gene therapy myeloablative allo-hsct nonmyeloablative allo-hsct disease-modifying therapy