Clinical

Taking the hammer to sickle pain crises


 

 

Clinical question: Are any novel medicines designed to interrupt the pathophysiology of vaso-occlusion available to reduce the frequency and severity of pain crises in sickle cell anemia?

Background: Hypoxemia-dependent HbS polymerization is just the initiating step in a complex cascade of events leading to sickle pain crises. Animal studies have suggested that blockade of P-selectin, an adhesion molecule expressed by endothelium, blunts the aggregation of sickled erythrocytes, leukocytes and activated platelets and may reduce progression to vaso-occlusive crises.



Study Design: Multicenter, double-blinded, randomized placebo-controlled trial.

Setting: International (60 study sites in 3 countries) from August 2013 to January 2015.

Synopsis: Crizanlizumab is a humanized monoclonal antibody directed against P-selectin. A total of 198 patients aged 16-65 with HbSS, HbSC, HbSbeta+ and select other genotypes experiencing 2-10 pain crises in the 12 months prior to trial were block randomized to receive high-dose crizanlizumab, low-dose crizanlizumab, or placebo. Roughly 62% of enrolled patients in all three arms were already taking hydroxyurea – for which dose changes during trial period were forbidden. Patients not already on hydroxyurea could not initiate treatment during the trial period. The primary outcome was annualized rate of sickle pain crises (defined as pain without other demonstrable cause requiring medical facility visit and treatment with oral or parenteral narcotics or NSAIDs), including acute chest, hepatic or splenic sequestration crises and priapism. Secondary outcomes were annualized rates of hospital days, rates of uncomplicated crises, time to first and second crises, rates of acute chest syndrome and Brief Pain Inventory questionnaire. Primary outcome data were processed via intention-to-treat analysis.

For high-dose crizanlizumab, there were a median 1.63 crises per year compared to 2.98 in the placebo group, representing a 45.3% lower rate (P = .01). The protective effect of crizanlizumab was more pronounced in the per-protocol analysis (1.04 crises per year for the high dose group). In the subgroup of patients on concomitant hydroxyurea, the median annualized crisis rate among high dose versus placebo was 2.43 compared to 3.58, representing a 32.1% lower rate. In the non-hydroxyurea subgroup, the median annualized crisis rate for high dose versus placebo was 1.0 vs. 2.0, representing a 50% lower rate. Secondary endpoints similarly trended in favor of crizanlizumab in a dose-dependent fashion, although statistical significance was mixed.

Bottom line: Crizanlizumab, a humanized monoclonal antibody that blocks the action of the endothelial adhesion molecule P-selectin, is promising as a novel medication to reduce frequency of vaso-occlusive crises in patients with HbS-related disease.

Citation: Ataga KI, Kutler A, Kanter J, et al. Crizanlizumab for prevention of pain crises in sickle cell disease. N Engl J Med. 2016 Dec. 3. doi: 10.1056/NEJMoa1611770.

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