Abstract Topic: 26. Sickle cell disease
Background: Frequent episodes of vaso-occlusion are a clinical hallmark of sickle cell disease (SCD). Vaso-occlusion results from blood flow blockages that deprive tissues and organs of adequate oxygen and nutrients, resulting in severe pain and contributing to progressive organ dysfunction and failure. A variety of therapeutic options are aimed at reducing or eliminating these episodes; however, the definition of vaso-occlusion is not consistent across different clinical trials. As the SCD treatment landscape evolves, and includes the promise of potentially curative therapies, it is important to understand differing definitions for vaso-occlusion episodes to understand efficacy outcome data.
Aims: To compare definitions of episodes of vaso-occlusion as endpoints in clinical trials for various therapies, including genetic therapies.
Methods: This study reviewed recently completed and currently ongoing clinical trial protocols and published articles that included endpoints assessing reductions or elimination in episodes of vaso-occlusion. Clinical trials included those on: (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across several variables including setting of care, duration of care, treatments, and complications.
Results: We found differing terminology for endpoints associated with episodes of vaso-occlusion: vaso-occlusive crises (VOC, voxelotor), painful crises (hydroxyurea) and sickle-cell related pain crises (SCPC, crizanlizumab, L-glutamine), severe vaso-occlusive crises (severe VOCs, exa-cel), and severe vaso-occlusive events (VOEs, lovo-cel). The most substantial differences in endpoint definitions were associated with duration of medical facility visits and complications. The definitions of severe VOC, SCPC, and VOC include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of event (VOC), whereas the definition of severe VOE requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours and the definition of painful crisis requires a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion while others require only a single visit.
Conclusions:
The definitions of episodes of vaso-occlusion in clinical trial endpoints vary across studies, especially with respect to medical facility visit requirements. For genetic therapies that offer the potential of eliminating episodes of vaso-occlusion, it is important that the definition for these endpoints be broad and inclusive. We found that the definitions of health care facility visits for severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and included events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis, creating the potential for episodes of vaso-occlusion to be undercounted by these latter endpoints. Overall, these differences in definitions for endpoints of vaso-occlusion in clinical trials have the potential to significantly impact assessments of efficacy across therapies for SCD.
Keywords: Vasoocclusive crisis, Gene therapy, Clinical outcome, Sickle cell disease