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Ataga KI, et al. "Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease". The New England Journal of Medicine. 2017. 376(5):429-439.

Clinical Question

In patients with sickle cell disease, how does the P-selectin inhibitor crizanlizumab (SelG1) impact the rate of sickle cell-related pain crises compared to placebo?

Bottom Line

In patients with sickle cell disease, the P-selectin inhibitor crizanlizumab reduces the rate of sickle cell-related pain crises without a measurable improvement in quality of life.

Major Points

Crizanlizumab is a monoclonal antibody targeting P-selectin, an adhesion molecule thought to be important in the pathogenesis of sickle cell disease-related vasoocclusive events. In the randomized phase 2 SUSTAIN trial, 192 patients with sickle cell disease complicated by ≥2 painful crises in the prior year (63% with 2-4 crises) and on a stable medication regimen (62% receiving hydroxyurea) were randomized in a 1:1:1 fashion to high-dose crizanlizumab, low-dose crizanlizumab, or placebo. Treatment was given on week zero, week two, and then every four weeks thereafter for a total of one year. The primary endpoint was the annual rate of pain crises, defined as a vasoocclusive episode resulting in treatment with a parenteral analgesic; types of crises included acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism although these latter types of crises were rare. In the intention-to-treat analysis, patients in the high-dose crizanlizumab group had a median crisis rate per year of 1.63 compared to 2.98 in the placebo group, representing a 45% relative reduction. There was no significant difference in the rate of crises between the low-dose crizanlizumab group and the placebo group. The proportion of patients without any sickle cell pain crises during the year-long study period was higher in the high-dose crizanlizumab group compared to placebo (36% vs. 17%). In subgroup analyses considering genotype, baseline hydroxyurea use, and baseline frequency of crises, patients in the crizanlizumab group consistently appeared to benefit more than those in the placebo group.[1][2] High-dose crizanlizumab was generally well tolerated, with a higher proportion of patients experiencing arthralgias (18%), pyrexia (11%), and diarrhea (11%) compared to those in the placebo group. Additionally, the package insert for crizanlizumab suggests monitoring for infusion-related reactions and indicates that platelet clumping may occur. Quality of life (QOL) data were collected during the study period; figures were not reported in the manuscript or supplement, but the authors reported that between-group differences tended to be small.

On the basis of the SUSTAIN trial, crizanlizumab at the 5 mg/kg dose was FDA approved in November 2019 with an indication to reduce the frequency of vasoocclusive crises in patients 16 years and older. The agent was approved under priority review, breakthrough therapy, and orphan drug designations. Significant concerns have been raised regarding crizanlizumab, particularly related to its high cost (approximately $100,000 per year[3]) and lack of demonstrable improvement in hard endpoints such as survival or QOL. In a 2020 report by the Institute for Clinical and Economic Review, crizanlizumab was found to be cost-effective for a population of patients with 10 pain crises per year at a threshold of $150,000 per quality adjusted life-year gained (QALY).[3]


As of December 2020, no guidelines have been published that reflect the results of this trial.


  • Randomized, double-blind, placebo controlled phase 2 trial
  • N=198 patients with sickle cell disease
    • Crizanlizumab 5.0 mg/kg (n=67)
    • Crizanlizumab 2.5 mg/kg (n=66)
    • Placebo (n=65)
  • Setting: Outpatients in the US, Brazil, and Jamaica
  • Enrollment: 2013-2015
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: Sickle cell-related crises


Inclusion Criteria

  • Age 16-65 years
  • Sickle cell disease, defined as one of:
    • HbSS
    • HbSC
    • HbS/β0-thalassemia
    • HbS/β+-thalassemia
    • Other genotype
  • 2-10 sickle cell-related pain crises in the prior 12 months
  • For patients receiving hydroxyurea and/or erythropoiesis-stimulating agents:
    • Must have been receiving for ≥6 months
    • Dose must have been stable for the most recent ≥3 months

Exclusion Criteria

  • Receiving or planned to receive chronic transfusions, HbA >20% of total hemoglobin
  • Acute finding on baseline CXR
  • Hemoglobin <4 g/dL
  • Major surgery planned during study period
  • Planning to initiate, terminate, or alter hydroxyurea dosing
  • Receiving chronic anticoagulation (aspirin allowed)
  • Active and poorly controlled disease unrelated to sickle cell disease
  • Creatinine ≥1.2 mg/dL, direct bilirubin ≥2.0 mg/dL, ALT ≥3×ULN
  • Non-melanomatous skin cancer diagnosis within the prior 5 years
  • Planned or recent receipt of investigational therapy
  • Stroke within prior 2 years
  • HIV
  • Positive urine drug test at screening for cocaine, PCP, or amphetamines
  • Serious mental or physical illness (eg, impaired mental capacity, alcoholism)
  • Any condition which study physician judges would preclude safe participation

Baseline Characteristics

Baseline characteristics were well distributed between crizanlizumab groups and placebo. Shown are placebo group characteristics.

  • Age 26 years (median), range 16-56
  • Female 58%
  • Race: Black 92%, White 5%, Other 3%
  • HbSS genotype 72%
  • Concurrent hydroxyurea use: 62%
  • Sickle cell-related pain crises in prior 12 months:
    • 2-4 crises 63%
    • 5-10 crises 37%


The study consisted of 3 phases:

  • 30-day screening
  • 52-week treatment
  • 6-week follow-up evaluation

Randomization was stratified by:

  • Number of crises in the prior year (2-4 vs. 5-10)
  • Hydroxyurea use (yes vs. no)

1:1:1 randomization to:

  • Crizanlizumab 5.0 mg/kg
  • Crizanlizumab 2.5 mg/kg
  • Placebo

Treatment was administered on day 1 and 15 (loading), and then every 4 weeks thereafter (maintenance).[1]


Outcomes are presented as high-dose crizanlizumab vs. low-dose crizanlizumab vs. placebo.

Primary Outcome

Sickle cell-related crises
1.63 vs. 2.01 vs. 2.98 per year
45.3% lower rate with high-dose crizanlizumab compared to placebo (P=0.01)
32.6% lower rate with low-dose crizanlizumab compared to placebo (P=0.18)

Secondary Outcomes

Patients without sickle cell-related crises during the study treatment phase
36% vs. 18% vs. 17%
Median days hospitalized per year
4.0 vs. 6.87 vs. 6.87 (no significant difference)
Median time to first crisis
4.07 vs. 2.20 vs. 1.38 months (HR 0.50 between high-dose crizanlizumab and placebo; P=0.001)
Median time to second crisis
10.32 vs. 9.2 vs. 5.09 (HR 0.53 between high-dose crizanlizumab and placebo; P=0.02)
Annual rate of uncomplicated pain crises
1.08 vs. 2.00 vs. 2.91
Annual rate of acute chest syndrome
0 events in each group
Quality of life as assessed by the Brief Pain Inventory questionnaire
Exact figures not reported in manuscript. The authors report that "differences tended to be small" and "there were no significant difference from baseline in the least-squares means during the trial."
Markers of hemolysis
No difference between groups

Subgroup Analysis

Sickle cell-related crises among patients receiving hydroxyurea
2.43 per year in high-dose crizanlizumab group vs. 3.58 in placebo
32.1% lower rate with high-dose crizanlizumab compared to placebo
Sickle cell-related crises among patients not receiving hydroxyurea
1.0 per year in high-dose crizanlizumab group vs. 2.0 in placebo
50% lower rate with high-dose crizanlizumab compared to placebo

Adverse Events

Number of patients with ≥1 serious adverse event (SAE)
26% vs. 33% vs. 27%
Most frequent SAE
Pyrexia (3% vs. 0 vs. 2%)
Influenz (0 vs. 5% vs. 0)
Pneumonia (5% vs. 3% vs. 5%)
Number of patients with ≥1 adverse event
86% vs. 88% vs. 89%
Most frequent adverse events
Arthralgia (18% vs. 14% vs. 8%)
Pyrexia (11% vs. 9% vs. 6%)
Diarrhea (11% vs. 8% vs. 3%)


  • Quality of life data not reported


Supported by Selexys Pharmaceuticals, grants from NHLBI, and the Orphan Prodcuts Grant Program of the FDA.

Further Reading

  1. Kutlar A et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. Am J Hematol 2019. 94:55-61.
  2. Kutlar AJH 2018 Supplemental Appendix
  3. 3.0 3.1 Bradt P, et al. "Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: Effectiveness and Value." Prepared for New England Comparative Effectiveness Public Advisory Council, an ICER program. March 12, 2020.