Cost-Effectiveness of Lovotibeglogene Autotemcel (Lovo-Cel) Gene Therapy for Patients with Sickle Cell Disease and Recurrent Vaso-Occlusive Events in the United States.

BACKGROUND AND OBJECTIVE: Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥ 12 years with ≥ 4 vaso-occlusive events (VOEs) in the past 24 months. METHODS: We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase 1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses. RESULTS: Patients treated with lovo-cel were predicted to survive 23.84 years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40 years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs. CONCLUSIONS: Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.

Pain Frequency and Health Care Utilization Patterns in Women with Sickle Cell Disease Experiencing Menstruation-Associated Pain Crises.

Background: Pain crises in sickle cell disease (SCD) lead to high rates of health care utilization. Historically, women have reported higher pain burdens than men, with recent studies showing a temporal association between pain crisis and menstruation. However, health care utilization patterns of SCD women with menstruation-associated pain crises have not been reported. We studied the frequency, severity, and health care utilization of menstruation-associated pain crises in SCD women. Materials and Methods: A multinational, cross-sectional cohort study of the SCD phenotype was executed using a validated questionnaire and medical chart review from the Consortium for the Advancement of Sickle Cell Research (CASiRe) cohort. Total number of pain crises, emergency room/day hospital visits, and hospitalizations were collected from a subcohort of 178 SCD women within the past 6 months and previous year. Results: Thirty-nine percent of women reported menstruation-associated pain crises in their lifetime. These women were significantly more likely to be hospitalized compared with those who did not (mean 1.70 vs. 0.67, p = 0.0005). Women reporting menstruation-associated pain crises in the past 6 months also experienced increased hospitalizations compared with those who did not (mean 1.71 vs. 0.75, p = 0.0016). Forty percent of women reported at least four menstruation-associated pain crises in the past 6 months. Conclusions: Nearly 40% of SCD women have menstruation-associated pain crises. Menstruation-associated pain crises are associated with high pain burden and increased rates of hospitalization. Strategies are needed to address health care disparities within gynecologic care in SCD.

Global burden of transfusion in sickle cell disease.

Sickle cell disease (SCD) is the most common hereditary hemoglobinopathy. The underlying pathophysiology of the red blood cell (RBC) leads to pan-systemic complications which manifest at an early age. While curative and disease-modifying treatments exist for SCD, a key intervention in the management and treatment of SCD is RBC transfusion, which can alleviate or prevent many complications. SCD patients often require chronic RBC transfusion therapy which can result in complications, such as iron overload, alloimmunization and infection. In low- and middle-income countries (LMICs), SCD patients lack appropriate access to healthcare such as newborn screening, health education, prophylaxis for infection, and treatments to reduce both mortality and SCD-related adverse effects. Poor access to RBCs for transfusion, coupled with donated blood not meeting safety standards set by the World Health Organization, presents a significant barrier for patients requiring chronic transfusions in LMICs. Unmet needs associated with blood collection, blood component processing and recipient matching all pose a serious problem in many LMICs, although this varies depending on geographic location, political organizations and economy. This review aims to provide an overview of the global burden of SCD, focusing on the availability of current treatments and the burden of chronic RBC transfusions in patients with SCD.

Economic and clinical burden of managing transfusion-dependent ß-thalassemia in the United States.

AIMS: To describe clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with transfusion-dependent ß-thalassemia (TDT) in the United States. MATERIALS AND METHODS: Merative MarketScan Databases were used to identify patients with ß-thalassemia between 1 March 2010, and 1 March 2019. Patients were eligible for inclusion with ≥1 inpatient claim or ≥2 outpatient claims for ß-thalassemia and ≥8 red blood cell transfusions (RBCTs) during any 12-month period after and including the date of the first qualifying ß-thalassemia diagnosis code. Matched controls consisted of individuals without ß-thalassemia. Clinical and economic outcomes of patients were assessed during ≥12 months of follow-up, defined as the period from the index date (i.e. the first RBCT) to either the end of continuous enrollment in benefits, inpatient death, or 1 March 2020. RESULTS: Overall, 207 patients with TDT and 1035 matched controls were identified. Most patients received iron chelation therapy (ICT) (91.3%), with a mean of 12.1 (standard deviation [SD] = 10.3) ICT claims per-patient-per-year (PPPY). Many also received RBCTs, with a mean of 14.2 (SD = 4.7) RBCTs PPPY. TDT was associated with higher annual ($137,125) and lifetime ($7.1 million) healthcare costs vs. matched controls ($4183 and $235,000, respectively). Annual costs were driven by ICT (52.1%) and RBCT use (23.6%). Patients with TDT had 7-times more total outpatient visits/encounters, 3-times more prescriptions, and 33-times higher total annual costs than matched controls. LIMITATIONS: This analysis may underestimate the burden of TDT, as indirect healthcare costs (e.g. absenteeism, presenteeism, etc.) were not included. Results may not be generalizable to patients excluded from this analysis, including those with other types of insurance or without insurance. CONCLUSIONS: Patients with TDT have high HCRU and direct healthcare costs. Treatments that eliminate the need for RBCTs could reduce the clinical and economic burden of managing TDT.

Economic and Clinical Burden of Managing Sickle Cell Disease with Recurrent Vaso-Occlusive Crises in the United States.

INTRODUCTION: The aim of this study was to describe the clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in the US. METHODS: Merative MarketScan Databases were used to identify patients with SCD with recurrent VOCs from March 1, 2010, to March 1, 2019. Inclusion criteria were ≥ 1 inpatient or ≥ 2 outpatient claims for SCD and ≥ 2 VOCs per year in any 2 consecutive years after the first qualifying SCD diagnosis. Individuals without SCD in these databases were used as matched controls. Patients were followed for ≥ 12 months, from their second VOC in the 2nd year (index date) to the earliest of inpatient death, end of continuous enrollment in medical/pharmacy benefits, or March 1, 2020. Outcomes were assessed during follow-up. RESULTS: In total, 3420 patients with SCD with recurrent VOCs and 16,722 matched controls were identified. Patients with SCD with recurrent VOCs had a mean of 5.0 VOCs (standard deviation [SD] = 6.0), 2.7 inpatient admissions (SD 2.9), and 5.0 emergency department visits (SD 8.0) per patient per year during follow-up. Compared to matched controls, patients with SCD with recurrent VOCs incurred higher annual ($67,282 vs. $4134) and lifetime ($3.8 million vs. $229,000 over 50 years) healthcare costs. CONCLUSION: Patients with SCD with recurrent VOCs experience substantial clinical and economic burden driven by inpatient costs and frequent VOCs. There is a major unmet need for treatments that alleviate or eliminate clinical complications, including VOCs, and reduce healthcare costs in this patient population.

Burden of disease, treatment utilization, and the impact on education and employment in patients with sickle cell disease: A comparative analysis of high- and low- to middle-income countries for the international Sickle Cell World Assessment Survey.

The international Sickle Cell World Assessment Survey (SWAY) reported a high impact of sickle cell disease (SCD) on patients' daily lives globally. In this study, we analyzed whether the reported burden differed between patients from the USA (n = 384) and other high-income (HI; n = 820) or low- to middle-income (LMI; n = 941) countries. We assessed symptoms and complications, incidence/management of vaso-occlusive crises (VOCs), treatment utilization/satisfaction, and the impact of SCD on education/employment. Certain symptoms (bone aches, insomnia, and joint stiffness) and complications (swollen/painful fingers/toes, gallstones, vision problems, blood clots, and asthma) were reported proportionally more by patients in the USA than in the HI/LMI countries. Self-reported VOCs were more common (mean [SD]: 7.1 [5.7] vs. 5.5 [8.9] and 4.4 [4.6] in the previous 12 months) and were managed more often by hospitalization (52% vs. 24% and 32%) in the USA than the HI and LMI countries. A higher proportion of patients from the USA than the HI/LMI countries reported a negative impact of SCD on their employment/schooling. Although high overall satisfaction with current treatments was reported globally, most patients indicated a strong desire for alternative pain medications. There are likely several reasons for the relatively high patient-reported burden in the USA group compared with the HI/LMI countries, including an older population and differences in newborn screening programs and pediatric/adult transition of care. It is clear that there is an urgent need for improved understanding and management of SCD globally, not just in the USA.

Pain Burden in the CASiRe International Cohort of Sickle Cell Patients: United States and Ghana.

OBJECTIVES: Sickle Cell Disease (SCD) is a genetic blood disorder affecting over 1 million people globally. The aim of this analysis is to explore the pain burden of patients with SCD in two countries: the United States and Ghana. METHODS: The Consortium for the Advancement of Sickle Cell Research (CASiRe) was created to better understand the clinical severity of patients with SCD worldwide. Data regarding gender, SCD genotype, prior medical diagnoses, and validated pain burden measures were analyzed from the CASiRe database. The Sickle Cell Pain Burden Interview (SCPBI) was used to assess pain burden, the impact of pain on physical, emotional, and social function. RESULTS: Most subjects identified as Black/African American (n = 298, 97.0%). Patient ages ranged from 6 to 73 years. 35.9% resided in the United States, 64.1% resided in Ghana, 40.9% were men, and 58.7% were women. The mean SCPBI score for US SCD patients was 6.53(±5.89) vs 4.04(±5.10) for Ghanaian patients, P <0.001. Pain burden was higher in US men vs Ghanaian men (6.74(±5.68) vs 3.54(±4.46), P = .003) and in US women vs Ghanaian women (6.37 ± 6.06 vs 4.44(±5.54), P = .032). Pain burden was higher in US patients than Ghanaian patients for both the Hb SC/SBeta+ genotype (5.40(±5.29) vs 2.82(±4.86), P = .054) and Hb SS/SBeta0 genotype (6.79(±6.01) vs 4.49(±5.13), P = .003). Pain burden was significantly higher in SCD patients with comorbid conditions independent of geographic origin including stroke, cholecystectomy, gallstones, depression, and headache. DISCUSSION: US patients with SCD have a higher pain burden than Ghanaian patients. Further studies should investigate underlying contributors to pain burden in these populations and further explore the etiology of geographic differences in pain.

Global geographic differences in healthcare utilization for sickle cell disease pain crises in the CASiRe cohort.

BACKGROUND: Sickle cell disease (SCD) is characterized by frequent, unpredictable pain episodes and other vaso-occlusive crises (VOCs) leading to significant healthcare utilization. VOC frequency is often an endpoint in clinical trials investigating novel therapies for this devastating disease. PROCEDURE: The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaboration investigating clinical severity in SCD using a validated questionnaire and medical chart review standardized across four countries (United States, United Kingdom, Italy and Ghana). RESULTS: This study, focused on pain crisis incidence and healthcare utilization, included 868 patients, equally represented according to age and gender. HgbSS was the most common genotype. Patients from Ghana used the Emergency Room/Day Hospital for pain more frequently (annualized mean 2.01) than patients from other regions (annualized mean 1.56 U.S.; 1.09 U.K.; 0.02 Italy), while U.K. patients were hospitalized for pain more often (annualized mean: U.K. 2.98) than patients in other regions (annualized mean 1.98 U.S.; 1.18 Ghana; Italy 0.54). Italy's hospitalization rate for pain (annualized mean: 0.57) was nearly 20 times greater than its emergency room/day hospital only visits for pain (annualized mean: 0.03). When categorized by genotype and age, similar results were seen. CONCLUSIONS: Geographic differences in pain crisis frequency and healthcare utilization may correlate with variable organization of healthcare systems among countries and should be considered regarding trial design, endpoints, and analysis of results when investigating novel agents for clinical benefit.

Age of first pain crisis and associated complications in the CASiRe international sickle cell disease cohort.

Pain is a hallmark of Sickle Cell Disease (SCD) affecting patients throughout their life; the first pain crisis may occur at any age and is often the first presentation of the disease. Universal newborn screening identifies children with SCD at birth, significantly improving morbidity and mortality. Without early screening, diagnosis is generally made after disease manifestations appear. The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaborative group evaluating the clinical severity of subjects with SCD using a validated questionnaire and medical chart review, standardized across 4 countries (United States, United Kingdom, Italy and Ghana). We investigated the age of first pain crisis in 555 sickle cell subjects, 344 adults and 211 children. Median age of the first crisis in the whole group was 4 years old, 5 years old among adults and 2 years old among children. Patients from the United States generally reported the first crisis earlier than Ghanaians. Experiencing the first pain crisis early in life correlated with the genotype and disease severity. Early recognition of the first pain crisis could be useful to guide counseling and management of the disease.

An Analysis of Racial and Ethnic Backgrounds Within the CASiRe International Cohort of Sickle Cell Disease Patients: Implications for Disease Phenotype and Clinical Research.

Millions are affected by sickle cell disease (SCD) worldwide with the greatest burden in sub-Saharan Africa. While its origin lies historically within the malaria belt, ongoing changes in migration patterns have shifted the burden of disease resulting in a global public health concern. We created the Consortium for the Advancement of Sickle Cell Research (CASiRe) to understand the different phenotypes of SCD across 4 countries (USA, UK, Italy, and Ghana). Here, we report the multi-generational ethnic and racial background of 877 SCD patients recruited in Ghana (n = 365, 41.6%), the USA (n = 254, 29%), Italy (n = 81, 9.2%), and the UK (n = 177, 20.2%). West Africa (including Benin Gulf) (N = 556, 63.4%) was the most common geographic region of origin, followed by North America (N = 184, 21%), Caribbean (N = 51, 5.8%), Europe (N = 27, 3.1%), Central Africa (N = 24, 2.7%), and West Africa (excluding Benin Gulf) (N = 21, 2.4%). SCD patients in Europe were primarily West African (73%), European (10%), Caribbean (8%), and Central African (8%). In the USA, patients were largely African American (71%), Caribbean (13%), or West African (10%). Most subjects identified themselves as Black or African American; the European cohort had the largest group of Caucasian SCD patients (8%), including 21% of the Italian patients. This is the first report of a comprehensive analysis of ethnicity within an international, transcontinental group of SCD patients. The diverse ethnic backgrounds observed in our cohort raises the possibility that genetic and environmental heterogeneity within each SCD population subgroup can affect the clinical phenotype and research outcomes.

Impact of sickle cell disease on patients' daily lives, symptoms reported, and disease management strategies: Results from the international Sickle Cell World Assessment Survey (SWAY).

Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso-occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient-reported impact of SCD on QoL. This cross-sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1-7 for some questions; 5-7 indicated "high severity/impact." Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0-6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded "high severity" by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patients' QoL and emotional wellbeing, and the high prevalence of self-reported VOCs and other symptoms.

Annual Academy of Sickle Cell and Thalassaemia (ASCAT) conference: a summary of the proceedings.

The fourteenth annual ASCAT conference was held 21-23 October 2019. The theme of the conference was 'Sickle Cell and Thalassaemia disorders new treatment horizon; while ensuring patient safety and delivering excellence in routine patient care.' Over the three-day conference, topics on current and novel models of care, advances in bone marrow transplant and gene therapy, as well as the psychosocial aspects of mind, body and health related quality of life were discussed. In addition, blood transfusion, apheresis, iron chelation therapy and acute haemolytic complications were presented. Quality standards in the diagnosis and treatment of sickle cell and thalassaemia were reviewed. Experts from Europe, the United Kingdom, the Middle East, the United States and Africa reported up-to-date scientific data, guides to comprehensive care, and current research into developing cures and advancing current therapy were described. In addition, oral and poster presentations on novel research from all over the world were shown during the conference.

Deep learning-based cell identification and disease diagnosis using spatio-temporal cellular dynamics in compact digital holographic microscopy.

We demonstrate a successful deep learning strategy for cell identification and disease diagnosis using spatio-temporal cell information recorded by a digital holographic microscopy system. Shearing digital holographic microscopy is employed using a low-cost, compact, field-portable and 3D-printed microscopy system to record video-rate data of live biological cells with nanometer sensitivity in terms of axial membrane fluctuations, then features are extracted from the reconstructed phase profiles of segmented cells at each time instance for classification. The time-varying data of each extracted feature is input into a recurrent bi-directional long short-term memory (Bi-LSTM) network which learns to classify cells based on their time-varying behavior. Our approach is presented for cell identification between the morphologically similar cases of cow and horse red blood cells. Furthermore, the proposed deep learning strategy is demonstrated as having improved performance over conventional machine learning approaches on a clinically relevant dataset of human red blood cells from healthy individuals and those with sickle cell disease. The results are presented at both the cell and patient levels. To the best of our knowledge, this is the first report of deep learning for spatio-temporal-based cell identification and disease detection using a digital holographic microscopy system.

Building access to care in adult sickle cell disease: defining models of care, essential components, and economic aspects.

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a medically and socially complex, multisystem illness that affects individuals throughout the lifespan. Given improvements in care, most children with SCD survive into adulthood. However, access to adult sickle cell care is poor in many parts of the United States, resulting in increased acute care utilization, disjointed care delivery, and early mortality for patients. A dearth of nonmalignant hematology providers, the lack of a national SCD registry, and the absence of a centralized infrastructure to facilitate comparative quality assessment compounds these issues. As part of a workshop designed to train health care professionals in the skills necessary to establish clinical centers focused on the management of adults living with SCD, we defined an SCD center, elucidated required elements of a comprehensive adult SCD center, and discussed different models of care. There are also important economic impacts of these centers at an institutional and health system level. As more clinicians are trained in providing adult-focused SCD care, center designation will enhance the ability to undertake quality improvement and compare outcomes between SCD centers. Activities will include an assessment of the clinical effectiveness of expanded access to care, the implementation of SCD guidelines, and the efficacy of newly approved targeted medications. Details of this effort are provided.

A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis.

Vasculopathy is a hallmark of sickle cell disease ultimately resulting in chronic end organ damage. Leg ulcer is one of its sequelae, occurring in ~ 5-10% of adult sickle cell patients. The majority of leg ulcer publications to date have emanated from single center cohort studies. As such, there are limited studies on the geographic distribution of leg ulcers and associated risk factors worldwide. The Consortium for the Advancement of Sickle Cell Research (CASiRe) was formed to improve the understanding of the different phenotypes of sickle cell disease patients living in different geographic locations around the world (USA, UK, Italy, Ghana). This cross-sectional cohort sub-study of 659 sickle cell patients aimed to determine the geographic distribution and risk factors associated with leg ulcers. The prevalence of leg ulcers was 10.3% and was associated with older age, SS genotype, male gender, and Ghanaian origin. In fact, the highest prevalence (18.6%) was observed in Ghana. Albuminuria, proteinuria, increased markers of hemolysis (lower hemoglobin, higher total bilirubin), lower oxygen saturation, and lower body mass index were also associated with leg ulceration. Overall, our study identified a predominance of leg ulcers within male hemoglobin SS patients living in sub-Saharan Africa with renal dysfunction and increased hemolysis.

Paediatric to adult transition care for patients with sickle cell disease: a global perspective.

Sickle cell disease is a life-threatening inherited condition designated as a public health priority by WHO. Increased longevity of patients with sickle cell disease in high-income, middle-income, and low-income countries present unprecedented challenges for all settings; however, a globally standardised solution for patient transition from paediatric to adult sickle cell disease health care is unlikely to address the challenges. We established a task force of experts from a multicountry (the USA, Europe, Middle East, and Africa) consortium. We combined themes from the literature with viewpoints from members of the task force and invited experts to provide a global overview of transition care practice, highlighting barriers to effective transition care and provide baseline recommendations that can be adapted to local needs. We highlighted priorities to consider for any young person with sickle cell disease transitioning from paediatric to adult health care: skills transfer, increasing self-efficacy, coordination, knowledge transfer, linking to adult services, and evaluating readiness (the SICKLE recommendations). These recommendations aim to ensure appropriate benchmarking of transition programming, but multisite prospective studies are needed to address this growing public health need.