Effect of Crizanlizumab Infusion during Vaso-Occlusive Crises on Acute Care Utilization for Pain Control

Introduction

Crizanlizumab is a humanized monoclonal antibody which blocks P-selectin, a cellular adhesion molecule expressed on activated endothelium and involved in recruiting leukocytes to sites of inflammation. In patients with sickle cell disease, P-selectin mediates the adhesion of sickle erythrocytes to the endothelium, leading to vessel occlusion, tissue ischemia, and pain. P-selectin is also expressed on activated platelets, which form aggregates with neutrophils that further perturb normal blood flow in sickle cell disease.

The phase 2 SUSTAIN trial presented evidence that crizanlizumab therapy significantly decreases the frequency of sickle cell pain crises compared to placebo (median 2.98 crises per year vs 1.63, p = .01). A limitation of the SUSTAIN trial was that patients with severe vaso-occlusive pain crises (VOC) at the time of crizanlizumab infusion would typically have their medication held due to the potential risk of exacerbating pain symptoms from infusion reactions (personal correspondence with lead trial author). In the post-marketing period, rare painful infusion-related reactions to crizanlizumab have been reported to the drug manufacturer; however, no data are available regarding whether patients had active VOCs prior to infusion (Kanter et al, Blood 2021).

We present the results of a retrospective cohort analysis from a single institution on the effects of crizanlizumab infusion during VOC on acute care utilization (ACU) for pain control. We hypothesized that active VOCs increase the risk of crizanlizumab infusion-related reactions and lead to VOC exacerbation, resulting in higher ACU rates following infusion.

Methods

Patients receiving crizanlizumab infusions were identified and their medical records were reviewed for dates of crizanlizumab infusion, concurrent patient-reported pain scores on a ten-point Likert scale, and episodes of ACU following infusion. Patients reporting a pain score of ≥8 were characterized as having VOC at the time of crizanlizumab infusion, while pain scores ≤7 or otherwise not recorded during the infusion visits were characterized as not having VOC. Eligible episodes of ACU were defined as unplanned infusion center appointments, emergency room visits, and hospital admissions for pain control. Wilcoxon signed rank testing was used to examine paired mean differences in ACU event rates within 14 days of crizanlizumab infusion and event rates beyond 14 days. Chi-squared testing was used to compare the difference in ACU event rates within 14 days of infusion between two groups: patients with VOC at the time of infusion versus those without. An alpha value of 0.05 was chosen for statistical significance. One patient was excluded as an outlier with very high ACU and few out-of-hospital days between crizanlizumab infusions.

Results

Of 124 patients enrolled in the sickle cell disease program, seven were prescribed crizanlizumab and included for analysis. Three were men and four were women, with ages ranging from 21 to 58 years old (median 33). Total number of crizanlizumab infusions per person ranged from 7 to 29 infusions (median 8).

Overall ACU rates ≤14 days and >14 days post-crizanlizumab infusion were not significantly different (p = 0.46). Among patients receiving crizanlizumab during VOC, one of 16 infusion events led to ACU within 14 days. Among patients receiving crizanlizumab without VOC, thirteen of 64 infusion events led to ACU within 14 days. The rates of ACU after crizanlizumab infusion were not significantly different between the two groups (Χ² = 0.91, p = 0.34).

Conclusions

In our retrospective analysis, crizanlizumab infusions during VOC did not significantly increase the rate of acute care utilization for pain control compared to VOC-free infusions. Our results suggest that crizanlizumab does not exacerbate VOC pain, but there are limitations to our study, including a small sample size, unrecorded pain scores during infusion visits, and lacking data on infusion-related VOC exacerbation managed without ACU. These data can lend support to the need for larger prospective studies to examine outcomes in patients receiving crizanlizumab during VOCs to guide clinicians deciding when to give and hold infusions.

No relevant conflicts of interest to declare.