Vaso-Occlusion Definitions Can Impact Efficacy Assessments in Clinical Studies of Sickle Cell Disease

OBJECTIVES: Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs); however, these events have been defined inconsistently across clinical trials. We examined differences in vaso-occlusion definitions from various trials and evaluated the potential impact when assessing treatment efficacy.

METHODS: Clinical trials with endpoints related to vaso-occlusion, including trials of exagamglogene autotemcel (exa-cel), lovotibeglogene autotemcel (lovo-cel), L-glutamine, voxelotor, hydroxyurea, and crizanlizumab, were reviewed. Data from the CLIMB SCD-121 trial of exa-cel (data cut June 14, 2023) were used to analyze different definitions of vaso-occlusion.

RESULTS: Definitions of vaso-occlusion varied across trials, including differences in care setting requirements, care duration, treatments, and complications. The frequency and duration of visits to medical facilities for acute pain showed the greatest differences between trials. For instance, definitions of severe VOCs used in exa-cel trials and sickle cell pain-related crises (SCPCs) used in crizanlizumab and L-glutamine trials include events with medical facility visits of any duration, whereas definitions of severe vaso-occlusive events (VOEs) used in lovo-cel trials require hospital or emergency room (ER) observation unit visits lasting ≥24 hours or ≥2 visits to a day unit or ER lasting ≥72 hours. Based on the definition of severe VOCs used in CLIMB SCD-121, 29/30 patients (96.7%; 95% confidence interval [CI]: 82.8, 99.9) were considered free from severe VOCs for ≥12 consecutive months, whereas based on the definition of severe VOEs, all patients (30/30; 100.0%; 95% CI: 88.4, 100.0) were free from severe VOEs for ≥12 consecutive months.

CONCLUSIONS: Definitions of severe VOCs and SCPCs were more broadly inclusive than those of severe VOEs or painful crisis. This finding was clinically supported by exa-cel trial data showing that the number of patients free from vaso-occlusion changed depending on the vaso-occlusion definition, underscoring the potential impact of varying vaso-occlusion definitions on efficacy assessments of SCD therapies.