Long-term biological effects in sickle cell disease: insights from a post-crizanlizumab study

Sickle cell disease (SCD) is a multisystem disorder caused by inheritance of a mutated variant of adult haemoglobin (sickle haemoglobin allele [HbS]).1 SCD is characterised by haemolytic anaemia, endothelial damage, and acutely painful vaso-occlusive crises (VOCs) that cause chronic and potentially life-threatening complications.2 Crizanlizumab is approved to reduce VOC frequency in patients aged ≥16 years with SCD. In the phase II SUSTAIN study (ClinicalTrials.gov Identifier: NCT01895361), crizanlizumab reduced the median rate of VOCs by 45% (1·63 vs. 2·98) over placebo.3 SUCCESSOR was a retrospective, non-interventional cohort study of a subset of 48 American patients that evaluated real-world outcomes and treatment patterns after SUSTAIN trial completion. The SUCCESSOR population comprised a subset of SUSTAIN patients who received crizanlizumab 2·5 mg/kg (n = 18), crizanlizumab 5·0 mg/kg (n = 15), or placebo (n = 15) (Figure S1). During SUCCESSOR, patients received neither placebo nor crizanlizumab. Medical records from 52 weeks after SUSTAIN completion were evaluated, and post-SUSTAIN VOCs in patients who received crizanlizumab during SUSTAIN were the primary outcome. Demographics and baseline characteristics are reported in Table SI and Table SII. During SUCCESSOR, the median time to first VOC was 6·1 months in patients who received crizanlizumab 5·0 mg/kg during SUSTAIN, 2·7 months in patients who received crizanlizumab 2·5 mg/kg during SUSTAIN, and 2·6 months in patients who received placebo during SUSTAIN (Fig 1). The time-to-first VOC in the crizanlizumab 5·0 mg/kg group may be reflective of physiological changes induced by P-selectin inhibition. Use of anti-P-selectin drugs has been shown to increase microvascular flow and reduce white blood cell rolling,4 which is known to contribute to a cycle of endothelial injury, inflammation and adhesion.5-8 We hypothesise that the interruption of this cycle through P-selectin inhibition for 1 year during SUSTAIN may have led to endothelial remodelling and reduced inflammation, which may have delayed the time to first VOC during SUCCESSOR; however, additional clinical research is needed to confirm this hypothesis. There is evidence in preclinical animal models demonstrating the effects of inhibiting P-selectin-mediated leucocyte recruitment on decreased inflammation and endothelium remodelling.9 The majority of patients experienced at least one VOC during SUCCESSOR. The respective mean [standard deviation (SD)] annual rates of VOCs during SUSTAIN in patients treated with crizanlizumab 5·0 mg/kg and off-treatment in SUCCESSOR were 2·3 [2·5] and 2·7 [3·3] (Fig 2). The mean (SD) annual rates of VOCs during SUSTAIN in patients treated with crizanlizumab 2·5 mg/kg were 3·8 (2·2) and in SUCCESSOR were 3·9 (4·6) (Fig 2). In the subset of patients treated with placebo during SUSTAIN, the mean (SD) annual rate of VOCs was 4·7 (4·3) and 5·4 (5·4) during SUSTAIN and off treatment during SUCCESSOR, respectively (Fig 2). While patients did not continue crizanlizumab in SUCCESSOR, they were managed as per current standard of care. SCD treatment used during SUCCESSOR is shown in Table SIII. Almost all patients (n = 47/48; 98%) used opioids. Among patients who used opioids, the mean (SD) annual rate of opioid use was 316 (105) days, with 92% of patients receiving opioids for ≥61 days. During SUCCESSOR, 33 patients (69%) used hydroxyurea, with a median annualised duration of usage of 364 days. A total of 10 patients (21%) received blood transfusions for SCD during SUCCESSOR. In SUCCESSOR, patients treated with crizanlizumab 5·0 mg/kg during SUSTAIN visited the emergency department (ED) a mean (SD) of 3·4 (3·6) times. The SUCCESSOR patients who received crizanlizumab 2·5 mg/kg during SUSTAIN visited the ED a mean (SD) of 2·9 (2·5) times. Among patients in the subset treated with placebo during SUSTAIN, the mean (SD) number of ED visits was 4·8 (3·8). The rates of ED use among the patient groups in SUCCESSOR were comparable and higher than the rates seen in other real-world studies. In a retrospective cohort study of state-wide ED databases, the mean number of ED encounters per year for people with SCD was 2·6.10 Of these visits, 1·5 were hospitalisations, and 1·1 did not result in hospitalisation. In another study, ˜39% of patients with SCD visited the ED ≤1/year , 32% 2 or 3/year, and 29% ≥4/year.11 Although valuable real-world data were collected in this study, results should be viewed in the context of the study limitations. Sample selection and limited sample size were two important limitations in this retrospective analysis. As the SUCCESSOR study cohort included only 32% of the original SUSTAIN trial cohort, the results are not generalisable to the patients in SUSTAIN nor the general SCD patient population. The generalisability to the SCD population may be further limited by the recent participation of SUCCESSOR patients in a randomised controlled trial, which may have changed adherence to other medications after rigorous monitoring in the SUSTAIN trial. Furthermore, patients were randomised in the SUSTAIN trial, but the recruitment of a subset of patients for SUCCESSOR resulted in a loss of balance from the original randomisation. Because of this selection bias, no comparison across SUSTAIN treatment arms can be made in SUCCESSOR. The authors also acknowledge the inherent limitations of data availability and quality in medical records review studies. Patients in SUCCESSOR required treatment with opioids and blood transfusions and had high rates of ED utilisation, suggesting an increase of P-selectin production after crizanlizumab discontinuation. These results demonstrate a high unmet medical need for continuous, efficacious prevention of perceptible vaso-occlusive events in patients with SCD. Long-term P-selectin inhibition may be necessary to durably suppress vaso-occlusion and benefit patients with SCD. Despite the outlined limitations, results from SUCCESSOR have complemented data from the SUSTAIN trial. SUCCESSOR provided insights on the outcomes of patients enrolled in SUSTAIN who stopped receiving crizanlizumab or placebo upon completion of the SUSTAIN trial. Based on the results of SUCCESSOR, long-term P-selectin inhibition may be necessary to provide sustained suppression of VOCs, thereby benefitting patients with SCD. Further research is needed to validate the findings of this study. The SUCCESSOR study was supported by research funding from Novartis Pharmaceuticals Corporation. The authors would like to acknowledge Jincy Paulose, MD, Dramane Lainé, PhD, Savita Nandal, MD and Das Purkayastha, PhD for their contributions to the study design and data analysis. Editorial support in the preparation of this manuscript was provided by Phase Five Communications, supported by Novartis Pharmaceuticals Corporation. All authors were involved in the medical records review and agreed on the final selection. All authors extracted data from the selected studies. They also assessed the quality of the included studies and performed a cross-check for data accuracy. All authors contributed to the writing of the manuscript and approved the final version. Darla K. Liles has no conflicts to disclose. Nirmish R. Shah, reports consultancy fees and research funding from Novartis Pharmaceuticals Corporation and Global Blood Therapeutics; consultancy fees at CSL Behring and bluebird bio; speaker’s bureau participation at Global Blood Therapeutics and Novartis Pharmaceuticals Corporation, outside of the submitted work. Brigid Scullin, reports honoraria from PHAR, LLC, and Novartis Pharmaceuticals Corporation, outside of the submitted work. Victor R. Gordeuk, reports grant support from Novartis Pharmaceuticals Corporation during conduct of the study; grant support from Global Blood Therapeutics, Imara, Inc., Takeda, Ironwood, Incyte, CSL Behring, and Pfizer; consultancy fees from CSL Behring, Forma Therapeutics, and Novartis Pharmaceuticals Corporation, outside of the submitted work. Wally R. Smith, reports research funding from consultancy fees from National Heart Lung and Blood institute, Novartis Pharmaceuticals Corporation, Patient-Centered Outcomes Research Institute, and the United States Department of Health and Human Services/Health Resources and Services Administration, Pfizer Inc., Novartis Pharmaceuticals Corporation, Emmaus Medical, Inc., Imara Inc., and Shire; consultancy fees from Global Blood Therapeutics, Emmaus Medical, Inc., Pfizer Inc., and Novartis Pharmaceuticals Corporation, outside of the submitted work. Julie Kanter, reports funding from Novartis Pharmaceuticals Corporation during the conduct of the study, and honoraria from Novartis Pharmaceuticals Corporation, outside of the submitted work. Maureen M. Achebe has no conflicts to disclose. Ralph Boccia has no conflicts to disclose. Shelley E. Crary has no conflicts to disclose. Walter K. Kraft, reports grant support from Novartis Pharmaceuticals Corporation during the conduct of the study. Natasha Archer, reports grant support from Novartis Pharmaceuticals Corporation during the conduct of the study; grant support from Global Blood Therapeutics and from the American Society of Hematology/Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Award, outside of the submitted work. Vince Cataldo has no conflicts to disclose. Brandon M. Hardesty, reports fees for research from Global Blood Therapeutics and Novartis Pharmaceuticals Corporation, outside the submitted work. Modupe Idowu, reports grant support from UT Health McGovern Medical School, Houston, Texas, outside of the submitted work. Payal C. Desai, reports grant support from Selexys during the conduct of the study. Alan Ikeda has no conflicts to disclose. Geetha Puthenveetil has no conflicts to disclose. Kathryn L. Hassell, reports fees from Selexys and Novartis Pharmaceuticals Corporation during the conduct of the study; fees from Pfizer Inc., outside of the submitted work. Sharada Sarnaik has no conflicts to disclose. Abdullah Kutlar, reports consultancy fees, during the conduct of the study, and personal fees for participation in clinical trials from Novartis Pharmaceuticals Corporation; personal fees for participation in clinical trials and speaker program from Global Blood Therapeutics; honoraria from Blueprint Research Group, Saudi Society of Blood and Marrow Transplantation, MUH Life Sciences, and Vindico Medical Education; personal fees (DSMB membership) for bluebird bio, Inc. and Micelle BioPharma, Inc., outside of the submitted work. Fig S1. SUCCESSOR study design. Table SI. Demographics and baseline characteristics of SUSTAIN patients and SUCCESSOR patients previously treated with crizanlizumab or placebo. Table SII. Baseline characteristics of SUSTAIN patients previously treated with crizanlizumab or placebo. Table SIII. Concomitant sickle cell disease treatment in SUCCESSOR patients previously treated with crizanlizumab or placebo. Table SIV. Concomitant sickle cell disease treatment in SUCCESSOR patients previously treated with crizanlizumab or placebo. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.