"REAL Answers" (Registry Expansion Analyses to Learn)

Sickle cell disease (SCD) is an inherited disorder of human adult hemoglobin, which primarily afflicts Americans of African descent. The mutant hemoglobin, Hb S, polymerizes upon deoxygenation, leading to impaired red blood cell rheology, microvascular occlusion, chronic inflammatory state, and chronic hemolytic anemia, culminating in chronic organ damage and a shortened life expectancy. SCD is an orphan disease, with an estimated ~110,000 patients in the U.S. who suffer from disparities and discrimination and increased health care utilization. Until recently, the management of the disease has been largely confined to symptom control, with pain management and transfusions. In 1998, the U.S. FDA approved hydroxyurea (HU) as the first disease modifying therapy for SCD. Subsequent studies in children and adults with SCD has confirmed the beneficial effects of HU, with prevention of organ damage and decrease in mortality. In the past five years, three additional disease modifying drugs (L-glutamine, voxelotor, and crizanlizumab) targeting different mechanisms in disease pathophysiology have been approved by the FDA, broadening the available therapeutic armamentarium for SCD. Although this is a welcomed development, knowledge gaps exist on the choice of the most effective disease modifying therapy or combinations, based on a spectrum of sub- phenotypes of the disease. This gap is unlikely to be filled by knowledge gained from randomized clinical trials involving the use of FDA approved therapies. This application seeks to meet this unmet need by taking advantage of the infrastructure (prospective Registry of 2400 SCD patients) provided by the NHLBI funded Sickle Cell Disease Implementation Consortium (2016-2022) consisting of eight Centers throughout U.S. We propose to approach this problem by enrolling 1200 patients (150 patients from each Center) by applying the following specific aims: 1) Compare the effect of novel disease modifying therapies (L-glutamine, voxelotor, and crizanlizumab) on clinical outcomes in individuals with SCD. We will follow these individuals prospectively for 5 years, emulating data collection protocols and eligibility from key, interventional phase III SCD trials, and monitor organ injury NT-proBNP for heart and lung injury, urine albumin/creatinine ratio for kidney function, hemolysis score for blood, as well as symptom burden (ASCQ-Me) 2) Identify genetic and genomic predictors of response to disease modifying therapies, by a) whole exome sequencing and b) RNA seq (mononuclear cells, retics, platelets); and 3) integrate study data into the CureSCi metadata catalog to enhance future cross study analyses.