Describing Real-World Use and Voxelotor Adherence Among Youth with Sickle Cell Disease
Authors: Gimba Michelle , Stanek Joseph R , Adelaja Adebimpe , Creary Susan Elizabeth 
Published: December 2024

Background
Sickle cell disease (SCD) is a genetic hemoglobinopathy affecting millions worldwide. SCD leads to a myriad of complications in childhood, including vaso-occlusive pain crises, anemia, and organ damage. While hydroxyurea is a commonly used disease modifying medication (DMM) because it reduces complications, nonadherence has lessened its impact in clinical settings.
As therapies for SCD expand, understanding DMM use and the impact of DMM adherence in clinical practice are needed. For instance, randomized trials show that voxelotor increases hemoglobin (Hb) and reduces hemolytic markers, but real-world tolerability, hematologic response, and adherence to this DMM among youth are unknown. Thus, the aims of this study were to describe use, hematologic outcomes, and electronic prescription adherence during the first year of voxelotor use among youth with SCD at Nationwide Children's Hospital (NCH). We also aimed to compare laboratory changes after one year of use and by adherence category.
Methods
This was a retrospective cohort study of youth (aged 4-21 years) with SCD who started voxelotor between 1/2019-6/2023 and were followed for ≥1 year after initiation. NCH's electronic data warehouse, and diagnostic and pharmacy codes, were used to identify prospective subjects' Electronic medical records (EMR) were manually reviewed to confirm eligibility.
Subjects' demographic, SCD (e.g., genotype), laboratory (at voxelotor initiation and after one year of use), and electronic prescribing data, were abstracted from their EMR. Documented reason(s) for initiation and discontinuation (if applicable) were also recorded. Subjects with prescriptions suggesting voxelotor access for ≥80% of the days during the first year of use were considered adherent. Descriptive statistics and Wilcoxon signed rank tests or linear mixed models were used to compare laboratory data; p-values &lt;0.05 were considered statistically significant.
Results
We identified 27 subjects (54% female; 100% Black; 100% (Hb) SS; 74% public, 7% private, 15% other, 4% no insurance; median age at initiation was 13.3 years (IQR: 11.7-14.6). Severe anemia was the primary reason for voxelotor initiation for 22 subjects (81%) and 7 of those also had additional indication listed besides anemia (i.e., alloimmunization, end organ damage). Voxelotor was also used for silent infracts (n=1) and left ventricular hypertrophy (n=2) and 2 subjects did not have an indication documented. Eight (30%) discontinued voxelotor within the first year for: side effects (n=2), no hematologic effect (n=2), nonadherence (n=2), or other (n=2).
Median Hb at initiation was 7.4 g/dL (7.0-8.1) and significantly increased to 8.1 g/dL (7.4-8.9) after one year (p=0.0135). Median lactate dehydrogenase (LDH), total bilirubin, and absolute reticulocyte counts (ARC) did not significantly change after one year of use (p=0.13, p=0.90 and, p=0.94) respectively.
Of the 27 subjects, 15 (56%) were categorized as adherent. Median Hb at initiation was 7.6 g/dL (7.0-8.4) among adherent patients and 7.4 g/dL (6.9-7.6) among nonadherent patients. Median change in Hb (p=0.86), LDH (p=0.96), total bilirubin (p=0.24) and ARC (p=0.11) after one year were not significantly different between adherence groups.
Discussion
At our center, voxelotor was mainly being used to treat severe anemia in youth with SCD. Consistent with clinical trial and real-world findings in adults, hemoglobin increased with voxelotor in this pediatric cohort, but we did not observe that hemolysis markers improved. While almost a third of children discontinued voxelotor in the first year, indicating potential issues with tolerability, this appears to be at a similar rate as the pediatric clinical trial.
Similar to studies showing poor adherence to hydroxyurea in the real-world setting, voxelotor nonadherence was common. In contrast to hydroxyurea, however, adherence was not associated with laboratory response. This may be related to differences in the adherence level needed to achieve hematologic response between hydroxyurea and voxelotor.
Given our retrospective design, small sample size, shortly study duration, and use of an unvalidated adherence measure, additional studies are warranted to confirm real-world tolerability, best practices on use, and if optimizing voxelotor adherence could have an impact on the outcomes of youth with SCD.