Newer Modalities and Updates in the Management of Sickle Cell Disease: A Systematic Review.

Sickle cell disease (SCD), the most common autosomal recessive genetic disorder, affects the hemoglobin (Hb) chains in human red blood cells. It is caused by mutations in the ß-globin genes, leading to the production of hemoglobin S, which results in the formation of sickle-shaped red blood cells (RBCs). These abnormal cells cause hemolysis, endothelial damage, and small vessel occlusion, leading to both acute and long-term complications. According to the World Health Organization's 2008 estimates, SCD affects approximately 2.28 per 1000 individuals globally. Despite this high prevalence, therapeutic advancements have been slow. For many years, the only FDA-approved medications for managing SCD complications were hydroxyurea and deferiprone. However, recent years have seen the approval of several new therapies, including L-glutamine (2017), voxelotor and crizanlizumab (2019), as well as exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) (2023). These treatments have proven effective in managing both the acute and chronic effects of SCD, including hemolytic anemia, chronic pain, stroke, vaso-occlusive crises, and multiple organ damage syndromes. This review explores the mechanisms of action, practical considerations, and side effects of these emerging therapies, drawing from a comprehensive search of databases such as PubMed, Medline, and Cochrane.

Current and emerging drug treatment strategies to tackle sickle cell anemia.

INTRODUCTION: Since its discovery in the early 1900s, sickle cell disease (SCD) has contributed significantly to the scientific understanding of hemoglobin and hemoglobinopathies. Despite this, now almost a century later, optimal medical management and even curative options remain limited. Encouragingly, in the last decade, there has been a push toward advancing the care for individuals with SCD and a diversifying interest in options to manage this disorder. AREAS COVERED: Here, we review the current state of disease modifying therapies for SCD including fetal hemoglobin inducers, monoclonal antibodies, anti-inflammatory modulators, and enzyme activators. We also discuss current curative strategies with specific interest in transformative gene therapies. EXPERT OPINION: SCD is a chronic, progressive disease that despite a century of clinical description, only now is seeing a growth and advance in therapeutic options to improve the lifespan and quality of life for individuals with SCD. We anticipate newly designed and even repurposed therapies that may work as a single agent or combination agents to tackle the progression of SCD. The vast majority of individuals living with SCD are unlikely to receive gene therapy, therefore improved disease management is critical even for those that may ultimately chose to pursue a potentially curative strategy.

Exploring the genetic mechanisms: SELP gene's contribution to alleviating vaso-occlusive crisis in sickle cell disease.

Sickle cell disease is a catastrophic inflammatory disorder characterized by microvascular vaso-occlusion, leading to high morbidity and increased mortality. P-selectin, a cell adhesion molecule, plays a crucial role in the pathogenesis and severity of sickle cell disease. Its expression and binding with its ligand PSGL-1 is involved in various mechanisms that contribute to inflammation and immune response, resulting in complications in sickle cell disease. Preclinical data have verified the efficacy of P-Selectin inhibition in mitigating vaso-occlusive events and severity of disease. Currently clinical trials are ongoing to evaluate the safety and efficiency of P-Selectin-targeted therapies and concede the challenges and limitations associated with their use. Despite of its proven role in reducing severity in sickle cell disease, future research should focus on identifying other novel targets within the adhesion cascade and explore combination therapies. Conducting trials and addressing concerns about accessibility are crucial steps towards fully harnessing the potential of P selectin inhibitors as a groundbreaking treatment option. This review focuses on understanding the role of p selectin and its interactions with molecules involved in inflammation providing insights about the molecular etiology, pathophysiology, and potential therapeutic targets in sickle cell disease.

Potential efficacy of crizanlizumab in treating priapism in sickle cell disease: A case report.

This report documents the treatment of a 41-year-old male with sickle cell disease (SCD) and repeated stuttering priapism using crizanlizumab, which alleviated the priapism but induced a significant vaso-occlusive crisis during the second infusion. Encouragingly, no subsequent vaso-occlusive crises occurred. However, the potential for infusion-related adverse events warrants close supervision. Further research is necessary to explore its full benefits on priapism management.

Cost-effectiveness of l-glutamine versus crizanlizumab for adults with sickle cell disease: model focused on reducing pain episode costs from Qatar's healthcare perspective.

Objectives: Treatment options for preventing vaso-occlusive crises among sickle cell disease patients are on the rise, especially if hydroxyurea treatment has failed. This economic analysis is conducted to assess the comparative clinical effectiveness, safety, and acquisition cost of l-glutamine and crizanlizumab for older adolescents and adults (⩾16 years old) with sickle cell disease in Qatar, with an emphasis on treatment costs and acute pain crises. Methods: We conduct a decision-tree model, where we compare the clinical and economic outcomes of two novel Food and drug administration (FDA)-approved medications which are available in Qatar; l-glutamine and crizanlizumab over a time horizon of 1 year in a hypothetical cohort of adult sickle cell disease patients from a Qatar healthcare perspective. The main outcome is incremental cost per sickle cell disease-related acute pain crises averted. Model clinical parameters were derived from individual drug randomized trials, published literature, whereas cost parameters from Qatar healthcare payer system (2020-2021). A sensitivity analysis was carried out, and the study results were robust around model inputs. Costs were converted to 2020 US dollars. Results: Study results showed that both treatment modalities' costs were the main driver of this analysis, with an average annual cost of the treatments per patient being $189,014 for crizanlizumab (5 mg/kg), $143,798 for crizanlizumab (2.5 mg/kg), and $74,323 for l-glutamine. The probability of no first-time sickle cell disease-related vaso-occlusive crises averted was 0.001/year for glutamine, 0.26/year for crizanlizumab (5 mg/kg), and 0.34/year for crizanlizumab (2.5 mg/kg). Lower dose crizanlizumab (2.5 mg/kg) dominated the higher one (5 mg/kg). The incremental cost-effectiveness ratio of crizanlizumab (2.5 mg/kg), when compared to l-glutamine was $81,265 per sickle cell disease-related vaso-occlusive crises averted. When comparing crizanlizumab (5 mg/kg) and l-glutamine, crizanlizumab (5 mg/kg) showed higher efficacy, yet the crizanlizumab incremental cost-effectiveness ratio was at $459,620 than l-glutamine. Conclusions: Crizanlizumab (2.5 mg/kg) may be a cost-effective intervention, yet it is not the approved dose for preventing vaso-occlusive crises in adolescents and adults with sickle cell disease. Crizanlizumab (5 mg/kg) was more cost-effective than the approved l-glutamine per sickle cell disease vaso-occlusive crisis prevented. Of note, we primarily focused on modeling acute vaso-occlusive pain, which limited our ability to consider other key outcomes in sickle cell disease.

Expert consensus on the management of infusion-related reactions (IRRs) in patients with sickle cell disease (SCD) receiving crizanlizumab: a RAND/UCLA modified Delphi panel.

Crizanlizumab, a monoclonal antibody against P-selectin, has been shown to reduce vaso-occlusive crises (VOCs) compared to placebo in patients ≥ 16 years with sickle cell disease (SCD). However, there have been rare reports of patients experiencing severe pain and subsequent complications within 24 hours of crizanlizumab infusions. These events are defined as infusion-related reactions (IRRs). Informed by current literature and clinical experience, a group of content experts developed clinical guidelines for the management of IRRs in patients with SCD. We used the RAND/University of California, Los Angeles (UCLA) modified Delphi panel method, a valid, reproducible technique for achieving consensus. We present our recommendations for managing IRRs, which depend on patient characteristics including: prior history of IRRs to other monoclonal antibodies or medications, changes to crizanlizumab infusion rate and patient monitoring, pain severity relative to patient's typical SCD crises, and severe allergic symptoms. These recommendations outline how to evaluate and manage IRRs in patients receiving crizanlizumab. Future research should validate this guidance using clinical data and identify patients at risk for these IRRs.

Plant-Produced Therapeutic Crizanlizumab Monoclonal Antibody Binds P-Selectin to Alleviate Vaso-occlusive Pain Crises in Sickle Cell Disease.

Sickle Cell Disease (SCD) is a severe genetic disorder causing vascular occlusion and pain by upregulating the adhesion molecule P-selectin on endothelial cells and platelets. It primarily affects infants and children, causing chronic pain, circulatory problems, organ damage, and complications. Thus, effective treatment and management are crucial to reduce SCD-related risks. Anti-P-selectin antibody Crizanlizumab (Crimab) has been used to treat SCD. In this study, the heavy and light chain (HC and LC) genes of anti-P-Selectin antibody Crimab were cloned into a plant expression binary vector. The HC gene was under control of the duplicated 35S promoter and nopaline synthase (NOS) terminator, whereas the LC gene was under control of the potato proteinase inhibitor II (PIN2) promoter and PIN2 terminator. Agrobacterium tumefaciens LBA4404 was used to transfer the genes into the tobacco (Nicotiana tabacum cv. Xanthi) plant. In plants the genomic PCR and western blot confirmed gene presence and expression of HC and LC Crimab proteins in the plant, respectively. Crimab was successfully purified from transgenic plant leaf using protein A affinity chromatography. In ELISA, plant-derived Crimab (CrimabP) had similar binding activity to P-selectin compared to mammalian-derived Crimab (CrimabM). In surface plasmon resonance, the KD (dissociation binding constant) and response unit values were lower and higher than CrimabP, respectively. Taken together, these results demonstrate that the transgenic plant can be applied to produce biofunctional therapeutic monoclonal antibody.

Real-world experience of patients with sickle cell disease treated with crizanlizumab.

In 2019, crizanlizumab was approved by the Food and Drug Administration (FDA) to reduce the rate of vaso-occlusive crisis in patients with sickle cell disease (SCD). We aimed to study the real-world effectiveness of crizanlizumab in our comprehensive sickle cell center. This was a retrospective cohort analysis of patients with SCD who received at least two consecutive doses of crizanlizumab. Clinically significant improvement was captured using the patient global impression of change scale (PGI-C). As of December 2022, there were 18 patients eligible for analysis with a median age of 30.5 years. Eight patients had the HbSS genotype, 7 HbSC, and 3 HbSB null genotype. Median duration of exposure to crizanlizumab was 53.6 weeks, and 16 (88.9%) patients received crizanlizumab for ≥26 weeks. Crizanlizumab was very well tolerated with no serious adverse events (grade ≥3) related to treatment. There was no significant difference in laboratory parameters. There was a remarkable improvement in patients' subjective response to crizanlizumab infusion. The median PGI-C score of our patients was 5, signifying moderately better with slight but noticeable changes. The morphine equivalent daily doses (MEDD) were lower after crizanlizumab infusion. MEDD prior to crizanlizumab was 90; after ≥2 consecutive crizanlizumab doses, it was 60. There was also a reduction in the hospital admissions, emergency, and urgent care visit for acute pain crisis in 6 (28%) patients. This study shows that crizanlizumab was associated with improvement in patients' response, both directly and indirectly related to the reduction of opioids used, which is consistent with results from the SUSTAIN trial.

Sickle cell disease: combination new therapies vs. CRISPR-Cas9 potential and challenges - review article.

In 2022, sickle cell disease (SCD) continues to affect the lives of millions of people, being one of the most frequently inherited blood disorders worldwide. Recently, several new therapies have been FDA approved for the treatment of SCD. The complexity of the pathophysiology of sickling has given opportunity to the evolution of several modalities of therapies. Nonetheless, the potential for complementary targeting of HbS polymerization, vasocclusion, and other inflammatory pathways remains controversial. None of these drugs can be considered a single curative line of treatment. With the advancement of CRISPR/Cas9 technology, autologous transplant of gene-edited hematopoietic stem cells could possibly provide a cure for most patients with SCD. The advantage of this approach over the conventional stem cell transplantation is that it decreases the need for immuno-suppressive drugs and the risk of graft-versus-host disease. In addition, recent technological advances can reduce the off-target effects, but long-term monitoring is needed to ensure the reliability of these methods in the clinical setting. This review explores the efficacy and safety of combination therapies and contrasting this alternative with the challenges that exist with sickle cell gene therapy using CRISPR.

Crizanlizumab in sickle cell disease.

Vaso-occlusion in sickle cell disease (SCD) leads to a myriad of manifestations driving morbidity and mortality in patients with SCD. Increased leucocyte adhesion and P-selectin expression on platelets and endothelial cells is an inciting event that leads to obstruction of microcirculation by adhesion with rigid sickled red blood cells. Crizanlizumab is a first-in-class monoclonal antibody that inhibits P-selectin and has been shown to decrease the frequency of vaso-occlusive pain crises in patients with SCD in clinical trials. The role of crizanlizumab in other manifestations of SCD still needs further investigation.

There are more than 100,000 people in the USA living with sickle cell anemia, which is a form of the inherited blood disorder, sickle cell disease. Patients with sickle cell anemia are typically diagnosed through newborn screening programs. They are also diagnosed during times of vaso-occlusive pain crisis, where patients present with severe pain without an obvious cause, and also through hemolytic anemia, a disorder in which red blood cells are destroyed faster than they can be made. While children typically survive into adulthood, the life expectancy of those with sickle cell remains shorter secondary to the after-effects of chronic sickling, where the hemoglobin inside red blood cells sticks or clumps together, causing the cell to become fragile. The associated complications of chronic sickling include pulmonary hypertension (high blood pressure in the arteries of the lung and the right side of the heart), heart failure, stroke, liver dysfunction and splenic infarction, where the blood flow to the spleen is compromised. Crizanlizumab is a new therapy targeting P-selectin, a protein that blocks interaction with p-selectin glycoprotein ligand, and has shown promise in reducing vaso-occlusive crises.

The Role of Non-genetic Therapies to Reduce the Incidence of Sickle Cell Crisis: A Systematic Review.

Sickle cell anemia is a hemoglobinopathy that causes complications such as Vaso-Occlusive Crisis (VOC), stroke, priapism, Acute Chest Syndromes (ACS), and bone infarcts due to blood vessel occlusion, resulting in hypoxia, ischemia, and inflammation. Preventing these incidents improves the quality of life and lowers mortality rates in Sickle Cell Disease (SCD) patients. This systematic review aims to describe the drugs, their mechanisms of action, dosages, changes in hemoglobin parameters, decrease in VOCs, delay the time for the next VOC, decrease in the length of hospital stay, and side effects associated with these drugs. This review adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. For this review, we searched the PubMed, Google Scholar, and Cochrane databases and screened them for full free texts published in English and studied in humans in the last five years beginning in 2018. Randomized clinical trials (RCT), observational studies, meta-analyses, systemic reviews, and traditional reviews were all included in the search. According to the type of study, quality assessment tools are used, and eight papers are chosen. Full-text articles from these papers are studied, analyzed, and tabulated. We discussed seven interventions that are used to treat sickle cell disease. Voxelotor, crizanlizumab, L-glutamate, long-term blood transfusions, Zinc (Zn), Niprisan®, and Ciklavit* were found to reduce the number and severity of VOC. We discovered that VOCs containing L -glutamate reduced the length of hospitalization. Magnesium (Mg) did not affect the number and severity of VOCs. This review includes a few articles for the study. Future papers on this subject should include a large sample size and many papers. More clinical trials are required to evaluate the dosages and outcomes of using these drugs in combination to prevent VOCs.

Advancements in Sickle Cell Disease (SCD) Treatment: A Review of Novel Pharmacotherapies and Their Impact on Patient Outcomes.

Sickle cell disease (SCD) is a genetic hereditary blood disease that disrupts normal beta-globin production. Patients with SCD experience a broad range of symptoms ranging from anemia, pain crises, and jaundice to acute coronary syndrome and stroke. SCD has been treated with hydroxyurea since 1998. Three important pharmacotherapies have been approved by the Food and Drug Administration (FDA) in the past few years. L-Glutamine has shown efficacy in reducing vaso-occlusive pain crises and hospitalization. Crizanlizumab has also shown positive outcomes in patients with SCD. Voxelotor has been studied to be effective in improving hemolytic anemia and the quality of life in SCD patients. These drugs can be used alone or in conjunction with hydroxyurea. Trials have shown that these therapies have significant efficacy. The events of pain, hemolytic anemia, vaso-occlusive crises, and hospitalizations have been reduced by using these agents. In this editorial, we will discuss these advanced treatment options for patients with SCD.

Successful Treatment of SCD-Related Priapism With Crizanlizumab: A Case Series.

Priapism, an unwanted, painful, prolonged erection that is unrelated to sexual stimulation, is a common complication of sickle cell disease (SCD). Priapic events in SCD are stuttering, meaning they occur repeatedly with intervening periods of detumescence. Without health care intervention, repeated episodes can lead to erectile dysfunction. There are limited treatment options for SCD-related priapism and no approved targeted therapies. Crizanlizumab is a monoclonal antibody that binds to P-selectin and is used to reduce the frequency of vaso-occlusive crises in patients with SCD. Here, we report the cases of 3 patients with SCD-related priapism who were treated with crizanlizumab. All patients were African American men who experienced numerous priapic episodes that interfered with their daily lives. Upon treatment with crizanlizumab, priapic events were reduced in all 3 patients. These successful cases suggest a potential role for crizanlizumab in the prevention of SCD-related priapism.

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis.

Background: Crizanlizumab was approved by the United States Food and Drug Administration agency in 2019 for decreasing vaso-occlusive events (VOEs) in sickle cell disease (SCD). Data regarding the use of crizanlizumab in the real-world setting are limited. Our goal was to identify patterns of crizanlizumab prescriptions in our SCD program and evaluate the benefits and identify barriers to its use in our SCD clinic. Methods: We conducted a retrospective analysis of patients who received crizanlizumab at our institution between July 2020 and January 2022. We compared acute care usage patterns before and after initiation of crizanlizumab, adherence to treatment, discontinuation and reasons for discontinuation. High utilizers of hospital-based services were defined as those with more than one visit to the emergency department (ED) per month or more than three visits to the day infusion program per month. Results: Fifteen patients received at least one dose of crizanlizumab 5 mg/kg of actual body weight during the study period. The average number of acute care visits decreased following crizanlizumab initiation but was not statistically significant (20 visits vs. 10 visits, P = 0.07). Among high users of hospital-based services, the average number of acute care visits decreased after initiation of crizanlizumab (40 vs. 16, P = 0.005). Only five patients included in this study remained on crizanlizumab 6 months after initiation. Conclusion: Our study suggests that crizanlizumab use may be helpful in decreasing acute care visits in SCD, particularly among high utilizers of hospital-based acute care services. However, the discontinuation rate in our cohort was extremely high, and further evaluation of efficacy and causes contributing to discontinuation in larger cohorts is warranted.

Recurrence of acute chest syndrome post stopping Crizanlizumab, the dilemma of stopping vs continuation in patient with sickle cell disease: case report.

Sickle cell disease (SCD) is one of the most common hematological diseases, which results in variable complications. The treatment of SCD is evolving but limited options are available for now. Acute chest syndrome (ACS) is one of the serious complications observed in SCD and a challenging one in prevention. Crizanlizumab is a monoclonal antibody that binds to P-selectin and improves blood flow by preventing sickle cell adhesion to endothelium, resulting in improvement of vaso-oclusive crises (VOC). It is not well evaluated in terms of ACS prevention. Here we report a 23-year-old patient with SCD and recurrent ACS; she was started on Crizanlizumab and she had no more ACS, but once she was off Crizanlizumab she developed ACS again, later Crizanlizumab was re-started, and the patient has improved significantly.

Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial.

BACKGROUND: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19. METHODS: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry. RESULTS: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio <1.2) of 98% and a posterior probability of inferiority (odds ratio <1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 deaths (12.8%) in the standard-of-care arm (hazard ratio, 1.33 [95% CrI, 0.85-2.21]; [probability of hazard ratio>1] = 0.879). CONCLUSIONS: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04505774.

Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease.

Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years.    Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non ß0/ß0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).

Real-world characteristics of patients with sickle cell disease who initiated crizanlizumab therapy.

OBJECTIVE: To provide real-word evidence of patients with SCD initiating crizanlizumab, their use of other SCD treatments, and crizanlizumab treatment patterns. METHODS: Using IQVIA's US-based, Longitudinal Patient-Centric Pharmacy and Medical Claims Databases patients with a diagnosis of SCD between November 1, 2018, and April 30, 2021, and ≥1 claim for crizanlizumab (date of first claim = index date) between November 1, 2019, and January 31, 2021 who were ≥16 years of age, and had ≥12 months of pre-index data were selected for analysis. Two cohorts were identified based on available follow-up time (3- and 6-month cohorts). Patient characteristics were reported along with pre- and post-index SCD treatments and crizanlizumab treatment patterns (e.g. total doses received, gap-days between doses, days on therapy, discontinuation, and restarts). RESULTS: 540 patients met the base inclusion criteria (345 in the 3-month cohort and 262 in the 6-month cohort. Most patients (64%) were female with a mean (SD) age of 35 (12) years overall. Concomitant hydroxyurea use was observed in 19-39% of patients, while concomitant L-glutamine use was observed for 4-8% of patients. 85% of 3-month cohort patients received at least two doses of crizanlizumab, while 66% of the 6-month cohort received at least 4 doses of crizanlizumab. The median number of gap days between doses was 1 or 2. CONCLUSIONS: 66% of patients who receive crizanlizumab receive at least 4 doses within 6-months. The low median number of gap days suggests high adherence.