Crizanlizumab Improves Prevention of Vaso-occlusive Crises in Patients With Sickle Cell Disease

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For the first time in more than 20 years, patients with sickle cell disease may have another treatment option to reduce painful vaso-occlusive crises, according to data presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1

Results of the phase II, randomized, double-blind, placebo-controlled SUSTAIN study published this past year showed that crizanlizumab (administered at 5.0 mg/kg) provided significant benefit over placebo, nearly halving the median annual rate of vaso-occlusive crises, doubling the time to first crisis, and doubling the number of patients who experienced no vaso-occlusive crises during treatment in the intent-to-treat population, despite comparable drug exposure. Now, a post hoc analysis has found the beneficial effect of crizanlizumab on vaso-occlusive crises to be even more pronounced in the per-protocol population.

Study Background

“Patients in the per-protocol population who received at least 12 of 14 assigned doses saw a significant reduction in the number of vaso-occlusive crises experienced and had a longer time to first painful crisis,” said Darla K. Liles, MD, Interim Chief of the Hematology-Oncology Division at East Carolina University, in Greenville, North Carolina. “The sickle cell community has been waiting for more than 20 years for something in addition to hydroxyurea to help patients modify their disease…. This is an exciting time for patients and providers to see so many researchers working on different mechanisms and targeting different problems associated with the disease.”

Darla K. Liles, MD

Darla K. Liles, MD

As Dr. Liles reported, painful vaso-occlusive crises are the hallmark of sickle cell disease and the leading cause of hospitalization for patients with the disease. Although hydroxyurea is the current mainstay for the reduction of vaso-occlusive crises, said Dr. Liles, adherence to treatment remains suboptimal and can lead to decreased quality of life, more frequent complications, and increased costs and health-care utilization.

In the SUSTAIN study, patients with sickle cell disease who had experienced between 2 and 10 vaso-occlusive crises in the previous 12 months were randomly assigned to receive crizanlizumab, a humanized monoclonal antibody that blocks P-selectin, at doses of 5.0 mg/kg, 2.5 mg/kg, or placebo administered intravenously 14 times over 52 weeks. Initial published results showed that crizanlizumab significantly reduced the median annual rate of vaso-occlusive crises leading to health-care utilization by 45.3% compared to placebo (P = .01).2 In this post hoc analysis from SUSTAIN, Dr. Liles and colleagues evaluated key endpoints related to vaso-occlusive crises in the 5.0-mg/kg crizanlizumab and placebo groups in the per-protocol population, comprising patients who received at least 12 of 14 assigned doses.

Reduced Number of Crises and Increased Time to First Crisis

As Dr. Liles reported, in the 5.0-mg/kg crizanlizumab and placebo groups, there were 67 and 65 patients in the intent-to-treat population, and 40 and 41 patients in the per-protocol population, respectively. Initial analysis of the intent-to-treat population showed a median annual rate of 1.63 vaso-occlusive crises in the crizanlizumab group vs 2.98 in the placebo group (P = .01). The median time to first on-treatment crisis was 4.07 months vs 1.38 months in the crizanlizumab and placebo groups, respectively (P = .001).

In the per-protocol population, post hoc analysis showed that the median annual rate of vaso-occlusive crises dropped to 1.04 with crizanlizumab at 5.0 mg/kg vs 2.18 with placebo (P = .02), and the median time to first on-treatment crisis increased to 6.55 months in the treatment arm vs 1.58 months with placebo (P < .001). Overall, 15 of 40 patients (37.5%) in the crizanlizumab group and 5 of 41 patients (12.2%) in the placebo group did not experience any vaso-occlusive crises during treatment (P = .008).


  • Post hoc analysis from the phase II SUSTAIN study has demonstrated a more pronounced benefit with crizanlizumab in the per-protocol population than the originally analyzed intent-to-treat population.
  • The median annual rate of vaso-occlusive crises in the per-protocol population was 1.04 with crizanlizumab at 5.0 mg/kg vs 2.18 with placebo (P = .02).
  • The median time to first on-treatment vaso-occlusive crisis was 6.55 months with crizanlizumab at 5.0 mg/kg and 1.58 months with placebo (P < .001).

Researchers also noted that overall incidences of adverse events and serious adverse events were similar among patients treated with crizanlizumab and placebo. Despite manageable toxicity, however, Dr. Liles acknowledged that adherence to treatment was a key challenge. This post hoc analysis was a way to assess the effect in patients who were able to follow the standard treatment regimen.

“Compliance with treatment is a challenge whenever you have a disease with such a heavy symptom burden,” said Dr. Liles. “Some patients with sickle cell disease are in the hospital four or five times a year. On days that they’re feeling good, they might not want to come and receive an infusion, especially if they might be getting a placebo.”

At the time of writing, hydroxyurea, an oral medication taken daily, and L-Glutamine, an oral powder that is mixed into a beverage and administered twice daily, are the only medications approved by the U.S. Food and Drug Administration to modify the sickle cell disease process and reduce complications of disease.

Dr. Liles noted that hydroxyurea requires at least 6 to 12 months before a noticeable change in vaso-occlusive crises occurs. The availability of an additional medication to ease patients’ symptom burden would be a welcome addition to the armamentarium, she observed, adding that crizanlizumab and hydroxyurea appear to work synergistically without any cross-reactivity.

“The group that performed best in our study consisted of patients already taking hydroxyurea who received crizanlizumab as well,” said Dr. Liles. “Crizanlizumab is able to decrease the number of crises on its own, so patients who are intolerant of hydroxyurea will get the benefit of this medicine. But if you can tolerate both hydroxyurea and crizanlizumab, these data suggest you will do even better.”

Given the low levels of toxicity with both 2.5-mg/kg and 5.0-mg/kg doses of crizanlizumab, Dr. Liles and colleagues are conducting another trial at multiple sites comparing crizanlizumab at 5.0 mg/kg to an increased dose of 7.5 mg/kg. The study has completed accrual, and data are currently being analyzed.

Better Biomarkers Needed

Patrick C. Hines, MD, PhD, Associate Professor of Pediatric Critical Care Medicine at the Children’s Hospital of Michigan and Associate in the Department of Physiology at Wayne State University School of Medicine, Detroit, was encouraged by the outcomes reported with crizanlizumab but emphasized the need for improved biomarkers and surrogate endpoints in sickle cell disease.

Patrick C. Hines, MD, PhD

Patrick C. Hines, MD, PhD

“The lack of reliable biomarkers has made the development of sickle cell–modifying therapies much more difficult because clinicians are depending on subjective clinical endpoints,” said Dr. Hines, who is developing a standardized P-selectin flow adhesion bioassay.3 “Ultimately, we are trying to determine whether we can treat and manage patients based on lab values as opposed to having to wait until they have clinical issues, because pain in sickle cell disease is equivalent to organ damage ischemia.”

Patients with sickle cell disease have been waiting for decades for new medications to come along, Dr. Hines added, but providers will still need tools to assess and predict vaso-occlusive episodes to help them deploy these medications effectively.

“As opposed to waiting for clinical issues to occur, we can hopefully treat patients much more upstream, when the cellular changes are happening, and work on more of a health-maintenance prevention model,” he concluded. 

DISCLOSURE: This study was sponsored by Novartis Pharmaceuticals. Dr. Liles reported no conflicts of interest. Dr. Hines is the founder of Functional Fluidics, which is developing a standardized platform for measuring sickle erythrocyte adhesion and other critical blood function properties for investigators and clinicians.


1. Liles DK, Cancado R, Kanter J, et al: Established prevention of vaso-occlusive crises with crizanlizumab is further improved in patients who follow the standard treatment regimen: Post-hoc analysis of the phase II Sustain study. 2018 ASH Annual Meeting & Exposition. Abstract 1082. Presented December 1, 2018.

2. Ataga KI, Kutlar A, Kanter J, et al: Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376:429-439, 2017.

3. Liu K, Gao X, White J, et al: Longitudinal evaluation of a standardized P-selectin flow adhesion bioassay: Potential role for the assessment and prediction of vaso-occlusive episodes in sickle cell disease. 2018 ASH Annual Meeting & Exposition. Abstract 1096. Presented December 1, 2018.