Expert hematologists comment on the use of crizanlizumab in reducing painful crisis frequency in sickle cell disease and share their experience with the drug in clinical practice.
Jeffrey D. Lebensburger, DO, MSPH: Crizanlizumab is a humanized monoclonal anti–P-selectin antibody. We don’t think of it as just being the red cells getting stuck; we know that there’s a lot more going into this. One of the big players in vaso-occlusion is P-selectin. Crizanlizumab is a medication that’s given IV [intravenously] and blocks P-selectin binding, which can prevent vaso-occlusion. We believe that if you’re blocking vaso-occlusion, you can then reduce the likelihood of having an acute pain event. In the crizanlizumab study, looking at patients who had 2 to 10 pain events per year, they randomized between placebo and crizanlizumab. They showed that crizanlizumab reduced the likelihood of having an earlier sickle cell pain event and reduced the total number of pain events.
John J. Strouse, MD, PhD: This is a more recent analysis of data from the SUSTAIN trial. The SUSTAIN trial led to the approval of crizanlizumab for the treatment of people with sickle cell disease, and vaso-occlusive events requiring health care utilization. It was one of the drugs approved late in 2019, and this is looking at the data from that initial clinical trial, but a different end point. Instead of looking at the rate of vaso-occlusive events published in 2017, they are looking at the use of opiates for the management of pain associated with these vaso-occlusive events. They compared the people who received the dose that was approved for crizanlizumab, which was 5 mg/kg given IV every 2 weeks for the first 2 doses and then every 4 weeks, compared to the placebo group. They showed that the mean annualized days with opiate use in the treated population was decreased by 57% compared to the placebo group. However, that wasn’t statistically significant. They looked at prn [as needed] opiate use, and they showed that was lower in the crizanlizumab compared to the placebo arm, with an absolute reduction of just over 2 days and a relative reduction of 50%. That was statistically significant with a P value of just under .05. What does this mean for patients? In general, patients are getting opiates when they’re having severe pain from their sickle cell disease. This reflects the decreased rate of severe pain in people with the sickle cell disease being treated in these studies. And they were just looking at their opiate use when they were having health care utilization. This doesn’t reflect their home opiate use. But they did show that there was a meaningful reduction. A reduction of 50% for [as needed] opiates and 57% for total opiates in numbers of days means that they’re having less pain and less impact on their life and quality of life.
Sophie M. Lanzkron, MD, MHS: Crizanlizumab has a different mechanism of action than voxelotor and actually affects more of the downstream problems that we see because of the hemolysis and the hemoglobin abnormalities in the red cell. We have an increased expression of adhesion molecules, and crizanlizumab is a P-selectin inhibitor that decreases expression of those adhesion molecules, with the idea that if you decrease the adhesion molecules, you will decrease the stickiness of the environment and you will have fewer crises. The initial study and some follow-up studies have demonstrated that the drug overall is safe and decreases crisis frequency by about 50%. One thing to keep in mind when you look at both the data for voxelotor and for crizanlizumab is that the number of individuals who were in the high-dose arms of those studies was less than 100. A recent ASH [American Society of Hematology] publication did demonstrate that there were no additional safety signals seen with crizanlizumab, but the number of subjects who were studied was small. We know from being in the community and treating patients that there are some patients who can have significant pain when crizanlizumab is infused. But they did demonstrate that there were patients who had pain in the initial studies, but most of those people were able to be treated with Tylenol and Benadryl and their pain improved. In the community in real-world settings with this drug, we have noticed that there are some patients who develop more severe pain. There is a case report published demonstrating a young person who actually ended up hospitalized because of pain that started during their infusion of crizanlizumab. It’s something to be mindful for as a potential adverse effect of the drug. It’s poorly understood at the moment, but something that most of us who take care of people with sickle cell disease are mindful about and keeping an eye on, and talking to patients about the potential that it could cause increased pain. In the short term, most people who are going to have this sort of painful response usually have it after the first or second dose and then after that, they do fine with their infusions.
Jeffrey D. Lebensburger, DO, MSPH: Crizanlizumab is approved by the FDA for patients aged 16 and above. Therefore, we have a little bit less experience in the pediatric setting than we do in the adult. Patients who have had multiple pain events we will try to put on crizanlizumab. In our patients with chronic pain, we still are seeing some pain events, but we’re looking into whether it can reduce the total number of hospitalizations. But the adults are having a little bit more anecdotal success with crizanlizumab in treating patients with pain. Now voxelotor, while it has a benefit for reducing pain events, it also has a benefit of improving hemoglobin through hopefully reducing hemolysis. We have several patients who either are not doing well on their hydroxyurea or are not getting a great hydroxyurea response. I find that patients who have very low hemoglobin, so those who are severely anemic, are at high risk for organ complications. For those patients, I prefer voxelotor because from a mechanism of action standpoint, these are the patients with severe hemolysis for whom we think we need to do something to prevent heme-induced injury. While both of them may have benefits for pain, as somebody who really worries about organ damage because that’s going to lead to mortality in our patients with sickle cell disease, in those situations I’m interested in continued research on voxelotor, to see whether it can reduce pain events, kidney damage, pulmonary hypertension, CNS [central nervous system] events. That’s an exciting opportunity to prevent organ disease, especially for someone who believes in the power or the problem of free hemoglobin.
Transcript edited for clarity.