source: American Society of Hematology

year: 2017

authors: Julie Kanter, Abdullah Kutlar, Darla Liles, Rodolfo Cançado, Andreas Bruederle, Michael Shi, Zewen Zhu, Kenneth I Ataga

In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo, crizanlizumab 5.0 mg/kg significantly reduced the frequency of sickle cell pain crises (SCPCs) versus placebo (1.6 vs 3.0, P=0.01) and increased the time to first on-treatment SCPC (4.1 vs 1.4 months, P=0.001) in patients with sickle cell disease (SCD) (Ataga KI et al. N Engl J Med 2017;376:429–39). Due to heterogeneity in disease severity and differences in medications used for the treatment of SCD and various other factors, treatment responses may vary between individuals with SCD. Differences in the response to crizanlizumab observed in defined subgroups of patients are of interest to increase understanding of this treatment, and the role of P-selectin in SCD. Aims: This post hoc analysis evaluated the time to first SCPC in subgroups of the SUSTAIN study population to further assess the efficacy of crizanlizumab 5.0 mg/kg and differences in treatment response between those subgroups.

Methods: SUSTAIN was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361). Patients aged 16–65 years with SCD (HbSS, HbSC, HbSβ0–thalassemia, HbSβ+–thalassemia or other genotype) were included if they had experienced 2–10 SCPC events in the previous 12 months. Concomitant use of hydroxyurea (HU) was permitted if the patient had been using it for ≥6 months and at a stable dose for ≥3 months. Patients were randomized 1:1:1 to receive intravenous crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo; however, this abstract focuses on the 5.0 mg/kg dose of crizanlizumab versus placebo. Study treatments were administered on days 1 and 15, then every 4 weeks to week 50; the final study visit of the treatment phase was at week 52, with an additional follow-up visit at week 56. The median time to first SCPC after the first dose of study treatment was summarized for patients treated with crizanlizumab 5.0 mg/kg or placebo in the following subgroups: 2–4 or 5–10 SCPC events in the previous 12 months; HbSS or non-HbSS genotype; and HU use (yes or no) at baseline. Hazard ratios (HRs) for crizanlizumab 5.0 mg/kg versus placebo were calculated based on Cox regression analysis, with treatment as a covariate.

Results: 67 patients in the intent-to-treat population received crizanlizumab 5.0 mg/kg and 65 received placebo. Overall, more patients who had experienced 2–4 SCPCs (63% in both groups) than 5–10 SCPCs (37% in both groups) in the previous year were enrolled. HbSS was the most common genotype (crizanlizumab 5.0 mg/kg: 70%; placebo: 72%), and more than half of patients were taking HU at baseline (crizanlizumab 5.0 mg/kg: 63%; placebo: 62%). In almost all the subpopulations evaluated, crizanlizumab 5.0 mg/kg significantly (P<0.05) increased the time to first SCPC versus placebo by two-fold or greater (Table). The effect was present in both SCPC subgroups (2–4 and 5–10 SCPCs in the previous year). The largest treatment difference was observed in patients with the HbSS genotype, with a 3.7-fold increase in time to first SCPC observed for crizanlizumab 5.0 mg/kg versus placebo (4.1 vs 1.1 months; HR: 0.50). It is also notable that in patients taking HU who experienced 2–10 SCPCs in the previous year, the time to first on-study SCPC was longer with crizanlizumab 5.0 mg/kg versus placebo (2.4 vs 1.2 months; HR: 0.58).

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