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Acute, intermittent vaso-occlusive pain is the hallmark of sickle cell disease (SCD) and is associated with substantial morbidity and impaired quality of life (QOL). The subgroup of adults with SCD who transition from recurrent, acute pain to chronic, persistent pain have even greater QOL impairment and higher rates of healthcare utilization. Self-management is central to SCD management; however, its role in chronic pain management is not established. This qualitative study was conducted to answer the following research questions: (1) What is the chronic pain experience of adults with SCD? (2) What self-management strategies do adults with SCD use for chronic pain? and (3) Do adults with SCD have any needs in the self-management of chronic pain? Eighteen Black adults with SCD completed a demographics questionnaire and an interview. The majority of the participants were 21–30 years of age (mean 33.5, SD 7.6), female (61.1%), employed at least part-time (61.1%), single/never married (72.2%), and had a SCD type of sickle cell anemia (55.5%). Interview analysis revealed three major themes: (1) the chronic pain experience; (2) strategies for managing chronic pain; and (3) challenges and needs in managing chronic pain. Study findings can be used to support chronic pain management among adults with SCD. Further research is needed to devise and implement effective strategies for the prevention and management of chronic SCD pain.

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m2 ) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy associated with severe morbidity, impaired quality of life, and premature mortality. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for patients with SCD and has a >90% event-free survival when a matched related donor is used. However, availability of human leukocyte antigen (HLA)–identical sibling donors for the SCD population is limited. The use of HLA-matched unrelated donors or related haploidentical donors has the potential to expand the donor pool. Methods: We reviewed the current literature on the indications for SCD transplantation, donor options, and the emerging use of gene therapy as a treatment option. Google Scholar and PubMed were searched using the terms SCD, bone marrow transplantation, donor sources, gene therapy, HSCT, and HLA matching. Additional articles were identified from the bibliographies of retrieved articles. All articles were reviewed for pertinent information related to SCD and transplantation. Results: HSCT has the potential to establish donor-derived normal erythropoiesis with stable long-term engraftment, amelioration of symptoms, and stabilization of organ damage. The majority of HSCT has been performed in children from HLA-identical sibling donors and has resulted in excellent rates of survival. The use of alternate donors such as HLA-matched unrelated donors and haploidentical donors has the potential to expand the applicability of HSCT for SCD. Early results in gene therapy for SCD are encouraging. Conclusion: Evaluation of the long-term benefits of curative therapies for SCD requires comparative clinical trials and studies of late effects.

BACKGROUND The role of platelet transfusions in management of Immune Thrombocytopenia (ITP) remains controversial. Current guidelines recommend that platelet transfusions in ITP be reserved for catastrophic hemorrhage or invasive surgical procedures. This study assesses the nationwide platelet transfusion practices in hospitalized children and adults with ITP. STUDY DESIGN AND METHODS We studied hospitalizations with ITP as the primary admitting diagnosis from 2010-2014 in National Inpatient Sample (NIS), the largest all-payer inpatient database. Univariate and multivariable logistic regression analyses were used to determine factors predicting platelet transfusions. Sampling weights were applied to generate nationally representative estimates. Propensity score matching was used to perform sensitivity analyses. RESULTS From 2010 to 2014, there were 78,376 admissions with ITP as the primary admission diagnosis (mean ± SD age: 45 ± 27 years; females 56%, children [age < 18 years] 22%) and 282,285 with ITP as one of all the admission diagnoses. Overall, 27% admissions with ITP as primary (children 4%) and 15% admissions with ITP as one of all the diagnoses documented at least one platelet transfusion. On multivariable adjustment the following factors were associated with worsening disease severity and a higher odds of platelet transfusion, adult age (adjOR = 9.03, 95% CI = 7.40-11.02), male gender (adjOR = 1.21, 95% CI = 1.11-1.31), bleeding occurrence (intracranial/gastrointestinal/genitourinary/epistaxis) (adjOR = 1.78, 95% CI = 1.61-1.96), admission to rural non-teaching hospital (adjOR = 1.85, 95% CI = 1.52-2.22), and small bed-size hospital (adjOR = 1.23, 95% CI = 1.05-1.45). Of admissions reporting platelet transfusions, only 26% reported a bleeding complication, and 11% had a major operating-room surgery/procedure. Overall, 65% of transfused patients had neither bleeding nor a major operative procedure during the hospitalization. Admissions with platelet transfusions had a significantly longer mean length of hospitalization 2.2 days (95% CI = 1.96-2.41, p < 0.001), and accrued higher mean total hospital charges; $31,150 USD (95% CI = 27,644-34,656, p < 0.001). However, platelet transfusions were not associated with in-hospital mortality (adjOR = 1.02, 95% CI = 0.73-1.45, p = 0.892). CONCLUSION Platelets are administered to a small fraction of the hospitalized ITP patients. In a majority of these cases however, platelet usage does not appear to be concordant with the current guidelines or associated with improvement in clinical outcomes.

BACKGROUND Individuals living with sickle cell disease (SCD) may benefit from a variety of disease-modifying therapies, including hydroxyurea, voxelotor, crizanlizumab, L-glutamine, and chronic blood transfusions. However, allogeneic hematopoietic stem cell transplantation (HCT) remains the only nonexperimental treatment with curative intent. As HCT outcomes can be influenced by the complex interaction of several risk factors, HCT can be a difficult decision for health care providers to make for their patients with SCD. OBJECTIVE The aim of this study is to determine the acceptability and usability of a prototype decision support tool for health care providers in decision-making about HCT for SCD, together with patients and their families. METHODS On the basis of published transplant registry data, we developed the Sickle Options Decision Support Tool for Children, which provides health care providers with personalized transplant survival and risk estimates for their patients to help them make informed decisions regarding their patients’ management of SCD. To evaluate the tool for its acceptability and usability, we conducted beta tests of the tool and surveys with physicians using the Ottawa Decision Support Framework and mobile health app usability questionnaire, respectively. RESULTS According to the mobile health app usability questionnaire survey findings, the overall usability of the tool was high (mean 6.15, SD 0.79; range 4.2-7). According to the Ottawa Decision Support Framework survey findings, acceptability of the presentation of information on the decision support tool was also high (mean 2.94, SD 0.63; range 2-4), but the acceptability regarding the amount of information was mixed (mean 2.59, SD 0.5; range 2-3). Most participants expressed that they would use the tool in their own patient consults (13/15, 87%) and suggested that the tool would ease the decision-making process regarding HCT (8/9, 89%). The 4 major emergent themes from the qualitative analysis of participant beta tests include user interface, data content, usefulness during a patient consult, and potential for a patient-focused decision aid. Most participants supported the idea of a patient-focused decision aid but recommended that it should include more background on HCT and a simplification of medical terminology. CONCLUSIONS We report the development, acceptability, and usability of a prototype decision support tool app to provide individualized risk and survival estimates to patients interested in HCT in a patient consultation setting. We propose to finalize the tool by validating predictive analytics using a large data set of patients with SCD who have undergone HCT. Such a tool may be useful in promoting physician-patient collaboration in making shared decisions regarding HCT for SCD. Further incorporation of patient-specific measures, including the HCT comorbidity index and the quality of life after transplant, may improve the applicability of the decision support tool in a health care setting.

Compared with privately insured patients, recipients of Medicaid have been reported to have worse outcomes in several clinical conditions and following various surgical and medical procedures. However, the relationship between health insurance status and allogeneic hematopoietic cell transplantation (alloHCT) outcomes among patients with sickle cell disease (SCD) is not well described. We sought to compare alloHCT outcomes between patients with SCD who underwent alloHCT while enrolled on Medicaid versus those who underwent alloHCT while covered by private health insurance. We conducted a retrospective multicenter study using data reported to the Center for International Blood and Marrow Transplant Research. US patients enrolled on Medicaid or private insurance who underwent a first alloHCT for SCD between 2008 and 2018 were eligible for this study. The primary outcome was event-free survival (EFS), defined as time to death or graft failure. Secondary outcomes included overall survival (OS), graft failure, acute graft-versus-host disease (GVHD), and chronic GVHD. Univariate analysis was performed using the Kaplan-Meier method for EFS and OS. The proportion of patients with graft failure, acute GVHD, and/or chronic GVHD was calculated using the cumulative incidence estimator to accommodate competing risks (ie, death). Cox regression was used to identify factors associated with EFS, OS, graft failure, and acute and chronic GVHD. A total of 399 patients (Medicaid, n = 225; private insurance, n = 174) were included in this study. The median duration of follow-up was 34 months (range, 1.0 to 134.7 months) for the Medicaid group and 38.7 months (range, 0.3 to 139.3 months) for the private insurance group. Compared with the patients with private insurance, those on Medicaid had a significantly lower 3-year EFS (75.4% [95% confidence interval (CI), 69.4% to 81%] versus 82.2% [95% CI, 76.9% to 87.8%]; P = .0279) and a significantly higher 3-year cumulative incidence of graft failure (17.2% [95% CI, 12.5% to 22.5%] versus 10.5% [95% CI, 6.4% to 15.4%]; P = .0372). There were no significant between-group differences in 3-year OS (P = .6337) or in the cumulative incidence of acute GVHD (P = .4556) or chronic GVHD (P = .6878). Cox regression analysis after adjusting for other significant variables showed that the patients enrolled on Medicaid had a lower EFS (hazard ratio [HR], 2.36; 95% CI, 1.44 to 3.85; P = .0006) and a higher cumulative incidence of graft failure (HR, 2.57; 95% CI, 1.43 to 4.60; P = .0015), with no significant between-group differences in OS (HR, 0.99; 95% CI, 0.47 to 2.07; P = .9765), acute GVHD (HR, 0.94; 95% CI, 0.59 to 1.49; P = .7905), or cGVHD (HR, 0.98; 95% CI, 0.65 to 1.48; P = .9331). That EFS is worse in patients on Medicaid compared with privately insured individuals following alloHCT for SCD provides the rationale for research to better understand the mechanisms by which insurance status impacts alloHCT outcomes among patients with SCD.

Background Sickle cell disease (SCD), the most common monogenic disorder, affects more than 300 000 births annually, with 44 000 in India. Although the clinical phenotype of SCD is considered to be milder in aboriginal populations in India, there is a paucity of data on outcomes. To determine the severity of SCD in this population, we studied mortality rates and causes of mortality in a longitudinal cohort of patients with SCD in a remote aboriginal community in India receiving community-based comprehensive care. Procedures Causes of death were analyzed in this cohort from January 2008 to December 2018. Details were collected from hospital records and in case of deaths at home by utilizing the WHO verbal autopsy questionnaire. Results The cohort consisted of 157 patients belonging to the Paniya, Betta Kurumba, Kattunyakan, and Mullu Kurumba tribes. During the study period, there were 22 deaths, all from the Paniya tribe. Twelve deaths (54.5%) occurred in the hospital and the remaining at home (45.5%), reflecting a crude mortality rate of 140 per 1000 population. Twenty-five percent of deaths occurred in the 6-18 age group. There were no deaths in the 0-5 age group. The median age of death was 25 years, which was 30 years less than in the non-SCD aboriginal population. The leading causes of death were acute chest syndrome, anemia, and sepsis among the SCD patients and stroke and suicides in the non-SCD aboriginal population. Conclusion SCD is a severe disease among the Gudalur Valley's aboriginal population with a significant risk of premature mortality.

We performed an assessment to understand perceived decisional needs among those living with sickle cell disease. Additionally, we desired understanding of their preferred methods and quality of learning and sought guidance in development of a web-based patient decision aid.The purpose of this qualitative study was to determine ways patients and caregivers receive education about sickle cell disease and available therapies. We sought to understand preferences for education, quality of current knowledge and information they would like to obtain.Recruitment for the initial needs assessment occurred between October 2013 -April 2014. Further recruitment for clarification of internet-based searches occurred between January 2015 -September 2016. We conducted a total of 201 semi-structured qualitative interviews with patients and caregivers.Six themes emerged: healthcare provider education is good but does not meet all the learning needs of the patient/caregiver; patients/caregivers feel a strong desire to seek information about treatment options on their own; adult patients and parents diverged in their core objectives in seeking information: quality of life (QOL) was the major outcome of interest in considering potential treatment options; experience of peers is preferred source for learning about treatment options; and educational needs may be supplemented with a web-based interactive educational tool.Patients with sickle cell disease and their caregivers are motivated by a desire to improve QOL in seeking treatment options and use many methods to seek education to supplement what they learn from their healthcare providers and may benefit from the use of a web-based decision aid. Impact Educational needs of patients/caregivers with sickle cell disease were identified and provide the basis to inform the design of educational strategies for them. Nurses and others can assist with learning needs by sharing the website and answering questions that arise.目的: 我们进行了一项评估, 以了解镰状细胞病患者的感知决策需求。此外, 我们希望了解他们的首选方法和学习质量, 并寻求在基于网络的患者决策辅助的发展中的指导。 设计: 该项定性研究的目的是确定患者和护理者接受镰状细胞病教育的方式和可用的治疗方法。我们试图了解他们对教育的偏好、当前知识的质量以及他们希望获得的信息。 方法: 在2013年10月至2014年4月期间进行了初步需求评估的招募。在2015年1月至2016年9月期间进行了进一步的招募, 以澄清基于互联网的搜索。我们对患者和护理者进行了共计201次半结构化定性访谈。 结果: 出现了六个主题: 医疗保健提供者受到良好教育, 但不能满足患者/护理者的所有学习需求; 患者/护理人员强烈希望自行寻求有关治疗方案的信息; 成人患者和家长在寻求信息的核心目标上存在分歧: 生活质量 (QOL) 是考虑潜在治疗方案的主要结果; 同龄人的经验是学习治疗方案的首选来源; 教育需求可以通过基于网络的交互式教育工具进行补充。 结论: 镰状细胞病患者及其护理者在寻求治疗方案时, 都渴望改善生活质量, 并使用多种方法寻求教育, 以补充他们从医疗保健提供者那里学到的知识, 并可能受益于基于网络的决策辅助。 影响: 对镰状细胞病患者/护理者的教育需求进行识别, 并为他们的教育策略设计提供了依据。护士及其他人可以通过分享网站和回答出现的问题以辅助学习需求。.

Additional file 1. Semi-structured Interview Guide.

Background Hydroxyurea, chronic blood transfusions, and bone marrow transplantation are efficacious, disease-modifying therapies for sickle cell disease but involve complex risk-benefit trade-offs and decisional dilemma compounded by the lack of comparative studies. A patient decision aid can inform patients about their treatment options, the associated risks and benefits, help them clarify their values, and allow them to participate in medical decision making. Objective The objective of this study was to develop a literacy-sensitive Web-based patient decision aid based on the Ottawa decision support framework, and through a randomized clinical trial estimate the effectiveness of the patient decision aid in improving patient knowledge and their involvement in decision making. Methods We conducted population decisional needs assessments in a nationwide sample of patients, caregivers, community advocates, policy makers, and health care providers using qualitative interviews to identify decisional conflict, knowledge and expectations, values, support and resources, decision types, timing, stages and learning, and personal clinical characteristics. Interview transcripts were coded using QSR NVivo 10. Alpha testing of the patient decision aid prototype was done to establish usability and the accuracy of the information it conveyed, and then was followed by iterative cycles of beta testing. We conducted a randomized clinical trial of adults and of caregivers of pediatric patients to evaluate the efficacy of the patient decision aid. Results In a decisional needs assessment, 223 stakeholders described their preferences, helping to guide the development of the patient decision aid, which then underwent alpha testing by 30 patients and 38 health care providers and iterative cycles of beta testing by 87 stakeholders. In a randomized clinical trial, 120 participants were assigned to either the patient decision aid or standard care (SC) arm. Qualitative interviews revealed high levels of usability, acceptability, and utility of the patient decision aid in education, values clarification, and preparation for decision making. On the acceptability survey, 72% (86/120) of participants rated the patient decision aid as good or excellent. Participants on the patient decision aid arm compared to the SC arm demonstrated a statistically significant improvement in decisional self-efficacy (P=.05) and a reduction in the informed sub-score of decisional conflict (P=.003) at 3 months, with an improvement in preparation for decision making (P Conclusions We have developed a patient decision aid for sickle cell disease with extensive input from stakeholders and in a randomized clinical trial demonstrated its acceptability and utility in education and decision making. We were unable to demonstrate its effectiveness in improving patient knowledge and involvement in decision making. Trial Registration ClinicalTrials.gov NCT03224429; https://clinicaltrials.gov/ct2/show/NCT03224429 and ClinicalTrials.gov NCT02326597; https://clinicaltrials.gov/ct2/show/NCT02326597

Nitya Bakshi,1 Ines Lukombo,1,2 Inna Belfer,3 Lakshmanan Krishnamurti1 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA; 2University of Pittsburgh, Pittsburgh, PA, USA, 3Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA Background: Sickle cell disease (SCD) is an inherited disorder of the red blood cells and is associated with chronic multisystem involvement. While SCD has been associated with poorer health-related quality of life (HRQoL), there is a paucity of data on the relationship of psychological covariates other than anxiety and depression and quality of life (QoL) in children with SCD. Materials and methods: We performed a cross-sectional study of psychological factors, HRQoL, and pain-related outcomes in participants with SCD and race-matched controls as part of a larger study of experimental pain phenotyping. Results: Pain catastrophizing was inversely correlated with HRQoL measured by the PedsQL™ Generic Core Scale in children with SCD, while this was not noted in control participants. Psychological factors, such as anxiety and depressive symptoms, were also associated with poorer HRQoL in both children with SCD and controls. We did not find an association of psychological factors with prior health care utilization. Psychological factors such as anxiety and depressive symptoms were inversely correlated with pain interference, but not pain intensity in SCD. Conclusion: Catastrophizing is associated with poorer HRQoL in SCD, but in this study, it was not associated with pain intensity or interference and health care utilization in children with SCD. Further studies are needed to fully define the association of psychological factors including catastrophizing with QoL, pain burden, and SCD outcomes. Keywords: pain, depressive symptoms, catastrophizing, sickle cell disease, PROMIS, quality of life

Background Vaso-occlusive pain episodes (VOEs) are the hallmark of sickle cell disease (SCD), and our current understanding of disease biology, treatment, and psychological covariates does not adequately explain the variability of pain in SCD. Functional variants in catechol-O-methyltransferase (COMT) gene contribute to variability in pain perception, but their impact on pain perception in African American SCD patients is not well known. Methods We studied COMT single-nucleotide polymorphisms (SNPs) rs6269, rs4633, rs4818, rs4680, and rs165599 to determine their relationship to patient self-reported pain, the number of acute VOEs, and their impact on daily life and health care utilization in 438 hemoglobin SS patients who participated in the walk-PHaSST study. Results In women, two risk SNPs (rs4633 and rs165599) and the corresponding haplotype (ATCAA) were associated with increased frequency of pain-related emergency room visit. Conclusion COMT functional variants may predispose SCD patients to worse acute pain in women. The association of COMT variants with the intensity of self-reported acute pain warrants further genetic study of pain perception in SCD.

Acute chest syndrome (ACS) is a frequent cause of acute lung disease in children with sickle cell disease (SCD). Patients may present with ACS or may develop this complication during the course of a hospitalization for acute vaso-occlusive crises (VOC). ACS is associated with prolonged hospitalization, increased risk of respiratory failure, and the potential for developing chronic lung disease. ACS in SCD is defined as the presence of fever and/or new respiratory symptoms accompanied by the presence of a new pulmonary infiltrate on chest X-ray. The spectrum of clinical manifestations can range from mild respiratory illness to acute respiratory distress syndrome. The presence of severe hypoxemia is a useful predictor of severity and outcome. The etiology of ACS is often multifactorial. One of the proposed mechanisms involves increased adhesion of sickle red cells to pulmonary microvasculature in the presence of hypoxia. Other commonly associated etiologies include infection, pulmonary fat embolism, and infarction. Infection is a common cause in children, whereas adults usually present with pain crises. Several risk factors have been identified in children to be associated with increased incidence of ACS. These include younger age, severe SCD genotypes (SS or Sβ0 thalassemia), lower fetal hemoglobin concentrations, higher steady-state hemoglobin levels, higher steady-state white blood cell counts, history of asthma, and tobacco smoke exposure. Opiate overdose and resulting hypoventilation can also trigger ACS. Prompt diagnosis and management with intravenous fluids, analgesics, aggressive incentive spirometry, supplemental oxygen or respiratory support, antibiotics, and transfusion therapy, are key to the prevention of clinical deterioration. Bronchodilators should be considered if there is history of asthma or in the presence of acute bronchospasm. Treatment with hydroxyurea should be considered for prevention of recurrent episodes. This review evaluates the etiology, pathophysiology, risk factors, clinical presentation of ACS, and preventive and treatment strategies for effective management of ACS.

Introduction Sickle cell disease (SCD) is caused by pathologic variants in both alleles of the β-globin gene, affecting ~100,000 patients in the US (Strouse. Handb Clin Neurol 2016;138:311-24). Elevated fetal hemoglobin (HbF) levels ameliorate symptoms and improve survival in patients with SCD (Hebert. Am J Hematol 2020;95:1235-45). SAR445136 (BIVV003) is a novel therapeutic product comprising autologous CD34+ HSPCs modified ex vivo by zinc finger nucleases (ZFN) and targeting the BCL11A gene erythroid-specific enhancer (ESE) to increase endogenous HbF production. Methods PRECIZN-1 (NCT03653247) is an ongoing first-in-human, open label, single arm, multi-site study evaluating safety and tolerability of SAR445136 (n=8; aged 18-40 years), with severe SCD across 6 US sites. Eligible subjects underwent mobilization and apheresis with plerixafor 240 ug/kg/day for up to 3 days to collect autologous CD34+ HSPCs to achieve a minimum of 10 × 10 6 CD34+ HSPC/kg for manufacturing of the SAR445136 dose. Additional apheresis cycles were allowed to achieve the minimum cell dose and rescue aliquots. Autologous HSPCs were transfected ex vivo with ZFN mRNAs targeting the ESE region of the BCL11A locus to manufacture SAR445136. A single IV infusion of 3-20 × 10 6 CD34+ HSPC/kg was administered at least 72 hours after the final busulfan myeloablation dose. Subjects were monitored for stem cell engraftment and hematopoietic recovery, adverse events (AEs), clinical and laboratory hemolysis markers, total Hb and HbF, percentage of F cells and sickle-cell related events post-SAR445136 infusion. Health-related quality of life (HRQoL) was assessed via the PROMIS-57 survey at screening, Weeks 26 and 52, and early termination visit. Results Of the 7 subjects that underwent mobilization and apheresis to date (25 June 2021), 5 achieved successful target yields ranging from 3.4-13.8 x 10 6 CD34+ HSPC/kg per apheresis day (mean: 6.49 x10 6 CD34+ HSPC/kg per apheresis day) in one apheresis cycle (4.45-10.9 x 10 6 CD34+ HSPC/kg per 2-day cycle). One subject failed to mobilize; one discontinued due to intercurrent cholangitis. Baseline patient characteristics of the 4 patients infused are in Table 1. Pre-apheresis peripheral blood WBC ranged from 23.2-36.9 x 10 3/μL (mean: 28.7 x 10 3/μL) and % CD34+ was 0.09-0.36% (0.22%) with absolute CD34+ counts of 20-80/μL (mean: 60/μL). Four of the mobilized subjects were successfully infused with SAR445136 at a single dose ranging from 3.2-9.7 x 10 6 CD34+ HSPC/kg (mean: 5.17 x 10 6 CD34+ HSPC/kg). All 4 subjects engrafted with a median time to neutrophil and platelet recovery of 21.5 and 24.5 days, respectively. No rescue doses were required. All 4 patients improved clinically since SAR445136 infusion, with no recurrence of previous vaso-occlusive crises (VOCs). Total Hb stabilized at 9-10 g/dL by week 26 post SAR445136 infusion along with improvements in the clinical markers of hemolysis in all 4 subjects. Percent HbF levels were 1-11% at screening, increasing to 15-29% by Week 13 in all 4 subjects, to 14-39% by Week 26 in the 3 subjects with at least 26 weeks follow up; and persisting at 35% in 1 subject with 65 weeks follow up (Figure 1). Percent F cells increased to 49-94% in 3 subjects with at least 26 weeks follow up, persisting at 90% in 1 subject with 65 weeks follow up. The fourth subject had 87.5% F cells at 13 weeks follow up. Although preliminary, a trend of improvement exceeding the proposed minimally clinically important difference in all PROMIS-57 HRQoL domains except sleep disturbance was observed in the 3 subjects with 26 weeks follow up, whose scores were "worse" than the norm at baseline (≤2 points per domain). SAR445136 was generally well tolerated with no infusion related reactions. The AEs reported were consistent with plerixafor mobilization and busulfan myeloablation therapy. No AEs or SAEs were reported as related to SAR445136. Conclusions As of 25 June 2021, these preliminary proof-of-concept efficacy and safety results confirm the potential therapeutic value of ZFN-mediated modification of the BCL11A ESE region and SAR445136 infusion to address current unmet needs of patients with SCD. All 4 infused patients had no SCD related events including VOCs following SAR445136 infusion, as well as increases in total Hb, HbF, and %F cells, and clinical improvements in PROMIS-57 domains. SAR445136 is generally well tolerated in the 4 subjects infused to date, with no related AEs or SAEs reported. Figure 1 Figure 1. Disclosures Abedi: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Speakers Bureau; Abbvie: Speakers Bureau. Galeon: Sanofi: Current Employment. Reiner: Sanofi: Current Employment. Smith: Sanofi: Current Employment. Wang: Sanofi: Current Employment. Ramezi: Sanofi: Current Employment. Rendo: Sanofi: Current Employment, Other: May hold shares and/or stock options . Walters: AllCells, Inc: Consultancy; Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy.

Background: Sickle cell disease (SCD) is characterized by painful vaso-occlusive events (VOEs), progressive vasculopathy, hemolytic anemia, and organ damage resulting in frequent hospitalizations and decreased quality of life (QoL). The ongoing phase 1/2 HGB-206 study is evaluating the efficacy and safety of LentiGlobin for SCD (bb1111) gene therapy and has demonstrated complete resolution of severe VOEs, near-normalization of key hemolysis markers, and normalization of total hemoglobin up to 24 months post-LentiGlobin infusion in Group C. In addition, LentiGlobin for SCD also showed clinically meaningful improvements in QoL in adult patients. Here we present patient-reported QoL outcomes up to 24 months post-LentiGlobin infusion in Group C of the HGB-206 study. Methods: Patients (≥12-≤50 years of age) with severe SCD and recurrent severe VOEs underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and LentiGlobin infusion. In addition to laboratory and clinical assessments, patients were monitored for patient-reported outcomes (PROs) at baseline and every 6 months post-infusion through Month 24 using PRO Measurement Information System (PROMIS)-57, a QoL-monitoring tool that has been validated in SCD. PROMIS-57 uses a collection of short forms to assess 7 PROMIS domains of relevance to patients' physical, mental, and social wellbeing (Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, Physical Function, Satisfaction with Participation in Social Roles) as well as a 0-10 Pain Intensity numeric rating scale (NRS). Available data were analyzed for 25/35 Group C patients (median age: 25 [19-38]; 40% female) who completed PROMIS-57 assessments at baseline with up to 24 months of follow-up as of February 17, 2021. For each domain, patients from the overall population were stratified into 2 subgroups depending on whether their baseline score was "better or near" or "worse" than the population norm, to account for potential differences over time in QoL changes relative to baseline status, and their means and standard deviations were plotted over time. The US general population norm is a standardized T-score of 50 for all domains and a 2.6 for Pain Intensity NRS. Meaningful change, a minimal response deemed meaningful to the patient, was interpreted at group level as at least a 5-point change from baseline for domains and a 2-point change for the NRS, as based on PROMIS guidelines and published literature. Results: In general, patients with baseline scores "worse" than the population norm reported improvements in all domains at Month 6 up to Month 24. Of note, mean pain interference decreased from 64.2 (n=16) to 44.5 (n=5), pain intensity decreased from 6.5 (n=15) to 1.8 (n=5) from baseline to Month 24 and fatigue decreased from 64.6 (n=8) to 46.9 (n=1) from baseline to Month 18, respectively (Figure). In patients with baseline scores "better or near" population norm, scores generally remained stable through Month 24. For example, mean pain interference scores were 46.4 (n=8) and 45.9 (n=4), pain intensity scores were 2.0 (n=9) and 2.8 (n=4), and fatigue scores were 47.7 (n=16) and 43.4 (n=9) at baseline and last visit, respectively. When considering mean differences, values for patients overall showed meaningful change in all domains and the Pain Intensity NRS, with the exception of Anxiety. Expected variability due to the small sample size limits interpretation. Mean values over time will be presented for all domains. Summary: In Group C of the HGB-206 study, patients with baseline scores "worse" than population norm had improved scores across all PROMIS-57 domains that were established early post-infusion and sustained up to Month 24. Patients with baseline scores "better or near" population norm were stable, and not worse up to Month 24. Mean values for patients overall indicate meaningful change at latest follow-up for all domains and Pain Intensity NRS, with the exception of Anxiety. These data show LentiGlobin for SCD not only improved hematologic parameters and resulted in complete resolution of severe VOEs, as presented elsewhere, but also provide sustained and clinically meaningful QoL benefit for patients. Continued follow-up and analysis of patient-reported outcomes is needed to evaluate the long-term impact of LentiGlobin for SCD. Figure 1 Figure 1. Disclosures Walters: Vertex pharmaceuticals: Consultancy; BioLabs, Inc: Consultancy; Ensoma, Inc.: Consultancy; AllCells, Inc: Consultancy. Kwiatkowski: Silence Therapeutics: Consultancy; Sangamo: Research Funding; Bioverativ: Research Funding; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy; Imara: Consultancy, Research Funding; Celgene: Consultancy; Agios: Consultancy; bluebird bio,Inc.: Consultancy, Research Funding. Aygun: Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Heart, Lung, Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Global Blood Therapeutics: Consultancy. Gallagher: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson: Graphite Bio: Research Funding; Agios: Consultancy; Novartis: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; Beam: Consultancy; CRISPR Therapeutics: Research Funding; Celgene/BMS: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Vertex: Research Funding; Editas: Research Funding. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Introduction Recipients of Hematopoietic Cell Transplantation (HCT) are at risk for treatment related late effects including cardiovascular disease and diabetes. Physical fitness including mobility and muscle strength are important predictors of cardiovascular health and quality of life. Physical fitness has been described in children and adults who are long term survivors of HCT for malignant disease [1]. Patients with sickle cell disease (SCD) are likely to be subject to unique morbidity post-HCT as a consequence of the pathophysiology of SCD which is characterized by anemia, inflammation, pain, bone infarcts and neurological complications. A systematic assessment of physical fitness is required to understand some of the long-term outcomes HCT for SCD. Methods We enrolled patients with SCD ≥ 1-year post-HCT in Sickle Transplantation Evaluating Long Term And Late Effects Registry (STELLaR). We assessed physical fitness including mobility using the timed up and go (TUG) test, and muscle strength using the handgrip strength (HGS) test. TUG scores were compared with published normative data for children (mean 9.2s; SD = 0.8) and young adults (mean 10.5s, SD = 1.1) [2]. TUG scores ≥ mean+ 2SD were considered abnormal (children: ≥10.8s, young adults ≥12.7s). The HGS of each patient was compared to published normative data of children and adults [3,4]. Patients ≤12 years were abnormal if they had a HGS of two standard deviations below the mean. Patients ≥13 years were considered abnormal if they had a HGS lower than the lower limit of the 85% age-sex standard. Additionally, patients were also assessed for chronic graft versus host disease (cGvHD) by means of the Lee Chronic GvHD Symptom Scale [5]. Patients rated their extent of being bothered by cGvHD symptoms on a scale from 1 to 5, with 1 being not at all and 5 being extremely. These scores were then organized into 7 categories of cGVHD symptoms and normalized to a 0-100 scale. We report the results of an interim analysis of physical fitness in these HCT recipients. Results Out of 121 patients enrolled in the study, 37 HCT recipients were assessed for mobility using the TUG test, and for muscle strength using the HGS test. Children were defined as being below the age of 18 and young adults between 18 and 40 years of age. Patient demographic and clinical results for TUG and HGS are presented in Table 1. Young adult participants were more likely to have abnormal TUG and HGS results than pediatric study participants. Patient self-reporting of overall (summary) cGvHD symptoms was found to be statistically significant between children and young adults (p=0.037) with young adults iappearing to be slightly more bothered by GvHD symptoms. There was no correlation in length of time in years between a patient's transplant and whether or not there was abnormal physical fitness (TUG and HGS) for both the young adult and children cohorts. Conclusions These data suggest the existence of impaired physical fitness in the long term in SCD patients who are HCT recipients. They provide the rationale for systematic evaluation of physical fitness and other risk factors for cardiovascular disease post-HCT. References 1. Slater, M. E., Steinberger, J., Ross, J. A., Kelly, A. S., Chow, E. J., Koves, I. H., ... & Baker, K. S. (2015). Physical activity, fitness, and cardiometabolic risk factors in adult survivors of childhood cancer with a history of hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 21(7), 1278-1283. 2. Mangano, G. R., Valle, M. S., Casabona, A., Vagnini, A., & Cioni, M. (2020). Age-related changes in mobility evaluated by the timed up and go test instrumented through a single sensor. Sensors, 20(3), 719. 3. Omar, M. T., Alghadir, A. H., Zafar, H., & Al Baker, S. (2018). Hand grip strength and dexterity function in children aged 6-12 years: A cross-sectional study. Journal of Hand Therapy, 31(1), 93-101. 4. Webb, A. R., Newman, L. A., Taylor, M., & Keogh, J. B. (1989). Hand grip dynamometry as a predictor of postoperative complications reappraisal using age standardized grip strengths. Journal of Parenteral and Enteral Nutrition, 13(1), 30-33. 5. Lee, S. J., Cook, E. F., Soiffer, R., & Antin, J. H. (2002). Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 8(8), 444-452 Figure 1 Figure 1. Disclosures Guilcher: BlueBirdBio: Research Funding; Project Sickle Cure Study: Other: Principal Investigator, Research Funding.

Background: The ongoing Phase 1/2 HGB-206 study (NCT02140554) of LentiGlobin for SCD (bb1111) GT uses a modified human β-globin gene that expresses an anti-sickling hemoglobin (HbA T87Q). The relationships between biological outcomes, clinical outcomes, and clonality in the initial cohort (Group A) and the cohort treated after substantial changes were made to the study protocol and manufacturing process to improve clinical benefit (Group C) are presented here. Methods: Patients (pts; ≥18 in Group A and ≥12-≤50 yrs in Group C) with SCD and recurrent severe vaso-occlusive events (VOEs), overt stroke, or tricuspid regurgitant jet velocity of >2.5 m/s, were enrolled. The initial protocol (cell collection and target busulfan dose) and manufacturing process in Group A was modified to improve cell dose, transduction efficiency, HbA T87Q expression, and clinical benefit. CD34+ cells (collected by bone marrow [BM] harvesting in Group A and plerixafor mobilization/apheresis in Group C) were transduced with BB305 lentiviral vector (LVV). LentiGlobin was infused after myeloablative busulfan conditioning. Transduction, SCD-related outcomes, clonality, and safety were assessed; data are median (min-max) unless otherwise stated. Results: As of 17 February 2021, there were 61.5 (55.5-66.1) months of follow-up post-LentiGlobin infusion in Group A (n=7) and 17.3 (3.7-37.6) months in Group C (n=35). After protocol and manufacturing modifications, median drug product vector copy number (DP VCN) and transduction efficiency were increased in Group C (3.7 c/dg with 80.3% transduced cells) compared with Group A (0.6 c/dg with 27.7% transduced cells). Peripheral blood (PB) VCN stabilized by Month 6 post-infusion and was sustained throughout follow up in both groups; however, the median PB VCN was correspondingly higher in Group C than in Group A (1.45 c/dg vs 0.09 c/dg). A higher DP VCN, %LVV+, and PB VCN in Group C generated increased HbA T87Q of 5.2 (2.6-8.8) g/dL (n=30) compared with HbA T87Q of 0.5 (0.1-1.8) g/dL (n=7) in Group A at Month 6. This was associated with near pancellular expression of HbA T87Q at ≥6 months post-infusion in Group C with a mean of 87% of red blood cells containing β A-T87Q by 18 months (n=14). Group C featured significantly higher median unique insertion sites (UIS) than Group A (p = 1.43 x 10 -12;Fig 1), consistent with increased polyclonality. Critically, median UIS also correlated strongly with PB VCN (Spearman rho = 0.97; Fig 1) and HbA T87Q at Month 6 post-infusion and was associated with improved clinical efficacy in Group C, with complete resolution of severe VOEs and near normal levels of key hemolysis markers. In Group C, the only treatment (tx) emergent serious adverse events (TESAEs) reported in >1 pt were abdominal pain, nausea, opioid withdrawal syndrome, and vomiting (n=2, 5.7% each). No events of malignancy were reported in Group C. One event of sudden death, considered unlikely related to LentiGlobin, occurred >18 months post-tx in a patient with significant baseline SCD-related cardiopulmonary disease. In Group A, the most common TESAE was sickle cell anemia with crisis (n=4, 57%). Two events of acute myeloid leukemia (AML) were reported in Group A pts at 3 and 5 years post-tx, both of which were considered unlikely related to the LVV. Both pts had classic AML driver mutations identified post-diagnosis. One pt died of AML and the second pt is receiving therapy for AML. The modifications made in Group C are anticipated to reduce risk of AML. To monitor safety, BM and PB will be screened for the presence of AML driver mutations prior to treatment, and patients already treated will have regular cytogenetic screening in addition to BB305 LVV integration site analysis. Summary: Alterations to the protocol and manufacturing process in HGB-206 resulted in improved cell dose, transduction efficiency, HbA T87Q expression, and clinical outcomes in Group C compared with Group A. Polyclonality was strongly correlated to PB VCN and HbA T87Q production, indicating that superior engraftment of LVV-transduced cells leads to favorable clinical outcomes. The safety profile post-LentiGlobin for all treated patients with SCD remains generally consistent with the risks of autologous stem cell transplant, myeloablative busulfan conditioning, and underlying SCD. Figure 1 Figure 1. Disclosures Thompson: Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Kwiatkowski: Bluebird Bio: Other: Consultancy Fees; Imara: Other: Consultancy Fees; Celgene: Honoraria; Silence Therapeutics: Honoraria; Agios: Honoraria; ApoPharma: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Sangamo: Research Funding; Terumo BCT: Research Funding. Aygun: National Heart, Lung, Blood Institute: Research Funding; Global Blood Therapeutics: Consultancy; National Institute of Nursing Research: Research Funding; Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt: GeneWerk GmbH, Heidelberg, Germany: Current equity holder in publicly-traded company; German Cancer Research Center, Heidelberg, Germany: Current Employment. Pierciey: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rogers: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Nnamani: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Foos: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Miller: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Lynch: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters: Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy; AllCells, Inc: Consultancy. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Bonner: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company.

Background Individuals living with sickle cell disease (SCD) may benefit from a variety of disease-modifying therapies, including hydroxyurea, voxelotor, crizanlizumab, L-glutamine, and chronic blood transfusions. However, allogeneic hematopoietic stem cell transplantation (HCT) remains the only nonexperimental treatment with curative intent. As HCT outcomes can be influenced by the complex interaction of several risk factors, HCT can be a difficult decision for health care providers to make for their patients with SCD. Objective The aim of this study is to determine the acceptability and usability of a prototype decision support tool for health care providers in decision-making about HCT for SCD, together with patients and their families. Methods On the basis of published transplant registry data, we developed the Sickle Options Decision Support Tool for Children, which provides health care providers with personalized transplant survival and risk estimates for their patients to help them make informed decisions regarding their patients’ management of SCD. To evaluate the tool for its acceptability and usability, we conducted beta tests of the tool and surveys with physicians using the Ottawa Decision Support Framework and mobile health app usability questionnaire, respectively. Results According to the mobile health app usability questionnaire survey findings, the overall usability of the tool was high (mean 6.15, SD 0.79; range 4.2-7). According to the Ottawa Decision Support Framework survey findings, acceptability of the presentation of information on the decision support tool was also high (mean 2.94, SD 0.63; range 2-4), but the acceptability regarding the amount of information was mixed (mean 2.59, SD 0.5; range 2-3). Most participants expressed that they would use the tool in their own patient consults (13/15, 87%) and suggested that the tool would ease the decision-making process regarding HCT (8/9, 89%). The 4 major emergent themes from the qualitative analysis of participant beta tests include user interface, data content, usefulness during a patient consult, and potential for a patient-focused decision aid. Most participants supported the idea of a patient-focused decision aid but recommended that it should include more background on HCT and a simplification of medical terminology. Conclusions We report the development, acceptability, and usability of a prototype decision support tool app to provide individualized risk and survival estimates to patients interested in HCT in a patient consultation setting. We propose to finalize the tool by validating predictive analytics using a large data set of patients with SCD who have undergone HCT. Such a tool may be useful in promoting physician-patient collaboration in making shared decisions regarding HCT for SCD. Further incorporation of patient-specific measures, including the HCT comorbidity index and the quality of life after transplant, may improve the applicability of the decision support tool in a health care setting.

Objectives To determine the acceptability, feasibility and safety of yoga for chronic pain in sickle cell disease. Design and Setting In Part A of this two-part study, adolescents with SCD and chronic pain (Group 1) and their parent (Group 2) completed a survey designed to capture pain characteristics, attitudes and practices related to yoga, and potential acceptability of a yoga program. In Part B, the study assessed the feasibility and safety of an instructor-led group yoga program. The study was registered on clinicaltrials.gov (NCT03694548). Intervention Eight instructor-led group yoga sessions Main Outcome Measures Feasibility and safety outcomes were chosen a priori, as follows: 1) Proportion of adolescent patients with SCD and chronic pain approached that consent to participate in Part A, 2) Proportion of adolescent participants enrolled in Part A that consent to participate in Part B, 3) Proportion of participants enrolled in Part B that attend at least 6 of 8 yoga sessions, 4) Proportion of participants enrolled in Part B with an ED visit or a hospitalization for pain within 24 hours of completion of each yoga session, 5) Proportion of participants in Part B who complete all study assessments before, and at the end of the yoga program, 6) Adherence to submission of pain diary. Results The median age of 15 patient participants in Part A was 16 (IQR 14-17), and 14 parents was 43.5 (IQR 42-51). Most participants were female. Most participant responses indicated a positive opinion of yoga. Nine adolescents (60%) from Part A participated in Part B of the study. The median age of 9 participants in Part B was 17 (IQR 15-18), and 5 of the 9 participants were female (53.3%). Only one participant was able to attend 3 of the 8 yoga sessions offered, and did not experience any ED visits or hospitalizations following the yoga sessions. None of the other feasibility endpoints were met in this study. Conclusions Patients with SCD and chronic pain overall have a positive opinion of yoga, but there are challenges with recruitment and retention of participants in a clinical trial of yoga, and barriers to feasibility of an in-person group yoga intervention.

Sickle cell disease (SCD) is associated with episodes of severe vaso-occlusive pain beginning in infancy with a subset of patients with SCD transitioning to chronic pain. Response to experimental pain using quantitative sensory testing in these patients suggests altered pain processing. The objectives of this study were to characterize sensitivity to multiple modalities of experimental pain stimuli and to interrogate the relationship of psychological covariates, clinical pain burden, and pain-related outcomes to experimental pain sensitivity in children with SCD compared with healthy individuals of similar age and sex. Cross-sectional assessments of psychological characteristics were performed, and quantitative sensory testing methods were used to measure experimental pain sensitivity in children age 8 to 21 years. Anxiety, depressive symptoms, catastrophizing, and somatization were found to be associated with increased sensitivity to experimental pain stimuli. Increased frequency of painful episodes in SCD was associated with decreased sensitivity to heat pain and decreased mechanical temporal summation. These data suggest that careful consideration be given to psychological factors, age, sex, and clinical burden of pain when studying response to experimental pain in SCD. Perspective In this study of patients with SCD, a condition associated with recurrent acute or chronic pain, psychological factors such as depression, anxiety, and catastrophizing are associated with increased sensitivity to experimental pain stimuli. Further study is need to delineate the role of these factors in chronic SCD pain.

Background Available modalities for the longitudinal capture and analysis of pain intensity in patients with sickle cell disease (SCD) limit our ability to study intraindividual and interindividual variation in pain and the factors influencing the transition from acute to chronic pain in patients with SCD. Objectives The objectives of this study were to determine the feasibility of electronic capture of longitudinal outpatient pain intensity data and to test the applicability of novel metrics in the study of intraindividual and interindividual variation in pain in patients with SCD. Materials and methods Twenty SCD patients aged 13 to 21 submitted 2045 diary days of pain intensity data over 229 days using a web-based electronic pain diary or through text message. Results Participants reported pain (11-point Numerical Rating Score >0) on 1559 diary days (76.2%) suggesting a significant outpatient pain burden. In addition to mean maximum daily pain (MMDP), using maximum daily pain (MDP) scores, we calculated the ninetieth percentile (p90) of MDP, proportion of pain-free days (PPFD), Standard Deviation (SD) of MDP and coefficient of variation (CV) of MDP. Although p50 of MDP and p90 of MDP correlated positively with MMDP, PPFD correlated negatively with MMDP and both MMDP and PPFD correlated poorly with the SD of MDP. Examination of graphic representation of pain trends demonstrated how patients with similar MMDP had varying p90, PPFD, SD/coefficient of variation, and ultimately burden of pain over time. Missing data rates were lowest in the first 30 days of reporting and increased over time. Study participants reported a positive experience with momentary pain reporting and improved communication with health care providers regarding pain. Conclusions The longitudinal collection of pain data with the inclusion of hospital data during periods of hospitalization is feasible and acceptable in patients with SCD over periods of 30 to 60 days. Long-term collection of pain diary data, while informative, is associated with higher rates of missing data. Novel metrics of pain have the potential to better describe intraindividual and interindividual variation in pain, inform studies of the transition from acute to chronic pain as well as contribute patient-reported end points of pain for interventional clinical trials of pain in SCD.

Hematopoietic cell transplantation (HCT) is the only cure for sickle cell disease (SCD), but engraftment remains challenging in patients lacking matched donors. Infusion of mesenchymal stromal cells (MSCs) at the time of HCT may promote hematopoiesis and ameliorate graft-versus-host disease. Experimental murine models suggest MSC major histocompatibility complex compatibility with recipient impacts their in vivo function, suggesting autologous MSCs could be superior to third-party MSCs for promoting HCT engraftment. Here we tested whether bone marrow (BM)-derived MSCs from SCD subjects have comparable functionality compared with MSCs from healthy volunteers. SCD MSC doubling time and surface marker phenotype did not differ significantly from non-SCD. Third-party and autologous (SCD) T cell proliferation was suppressed in a dose-dependent manner by all MSCs. SCD MSCs comparably expressed indoleamine-2,3-dioxygenase, which based on transwell and blocking experiments appeared to be the dominant immunomodulatory pathway. The expression of key genes involved in hematopoietic stem cell (HSC)–MSC interactions was minimally altered between SCD and non-SCD MSCs. Expression was, however, altered by IFN-γ stimulation, particularly CXCL14, CXCL26, CX3CL1, CKITL, and JAG1, indicating the potential to augment MSC expression by cytokine stimulation. These data demonstrate the feasibility of expanding BM-derived MSCs from SCD patients that phenotypically and functionally do not differ per International Society of Cell Therapy essential criteria from non-SCD MSCs, supporting initial evaluation (primarily for safety) of autologous MSCs to enhance haploidentical HSC engraftment in SCD.

Background Sickle cell disease (SCD) is caused by abnormal sickle hemoglobin (HbS) and results in chronic hemolytic anemia, painful vaso-occlusive events (VOEs), and progressive vasculopathy that lead to significant morbidity. While acute vaso-occlusive pain is a defining clinical feature, chronic daily pain also contributes significantly to poor quality of life in many adult patients. The ongoing Phase 1/2 HGB-206 Study (NCT02140554) evaluating safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT) uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbAT87Q). Data from Group C patients including red blood cell (RBC) physiology, clinical outcomes, and patient-reported pain intensity are presented here. Methods Patients (≥12 and ≤50 years) with SCD and stroke or severe VOEs, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for laboratory evaluations including Hb levels and hemolysis markers, SCD-related outcomes, pain intensity using the Patient Reported Outcomes Measurement Information System (PROMIS)-57, and adverse events (AEs). Data are median (min-max) unless otherwise stated. Results As of 3 March 2020, 40 Group C patients (23.5 [12-38] years) initiated cell collection; 25/40 were treated with LentiGlobin and followed for 12.1 (2.8-24.8) months. Neutrophil and platelet engraftment were achieved at 19 (12-27) days and 28 (19-136) days, respectively. All patients stopped RBC transfusions by 90 days post-treatment. In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 (9.6-16.2) g/dL, with HbAT87Q contribution of 5.2 (2.7-9.4) g/dL, HbS of 6.1 (4.9-7.8) g/dL, and median HbS ≤ 60% of total Hb. Exploratory assays showed near pancellular expression of HbAT87Q ≥6 months post-treatment (N=9 patients), with ~90% of RBCs containing βA-T87Q by 18 months, and reduction in sickling propensity comparable to sickle cell trait. At last visit post-treatment, key hemolysis markers were trending towards normalization with median (quartile [Q]1-Q3) lactate dehydrogenase of 212 (201-287) U/L, reticulocyte count of 178 (146.5-236.3) ×109/L, and total bilirubin of 19 (15.4-27.4) µmol/L (all for n=25). In 14 patients with ≥6 months of follow-up and history of vaso-occlusive crisis (VOC) or ACS, the annualized VOC+ACS rate was 4.0 (2.0-14.0) in the 2 years prior to treatment. Post-treatment, no ACS or serious VOCs were observed in these patients. One non-serious Grade 2 VOC occurred ~3.5 months after LentiGlobin infusion, resulting in a 99.5% (95% confidence interval, 92.4%-100%) mean reduction in the annualized VOC+ACS rate post-treatment (Figure 1). Patients with PROMIS-57 pain intensity scores "worse" than the population norm at baseline reported clinically meaningful improvements in pain reduction at 12 months post-treatment (n=5). Patients with scores near or "better" than the population norm at baseline (n=5) remained stable over time (Figure 2). The most common non-hematologic Grade ≥3 AEs post-treatment were stomatitis (n=15) and febrile neutropenia (n=11). Serious AEs reported in ≥2 patients post-treatment were nausea, opioid withdrawal syndrome, and vomiting (all for n=2); 3 patients had LentiGlobin-related nonserious Grade ≤2 AEs. There has been one death, unlikely related to LentiGlobin, >18 months post-treatment in a patient with significant baseline SCD-related cardiopulmonary disease. There have been no events of graft failure, vector-mediated replication-competent lentivirus, or clonal dominance. Summary LentiGlobin for SCD GT results in near pancellular βA-T87Q expression and reduced HbS expression, which impacts the pathophysiology of SCD as demonstrated by reduced RBC sickling and hemolysis and increased total Hb. Complete resolution of VOC/ACS was observed in almost all patients, with 99.5% mean reduction in the annualized VOC+ACS rate post-treatment. In addition, patients overall reported an improved pain intensity score. The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD. Longer follow-up and additional patients will be presented. Disclosures Thompson: CRISPR/Vertex: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding. Walters:AllCells, Inc: Consultancy; Veevo Biomedicine: Consultancy; Editas: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo Corp: Research Funding; Sangamo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Bristol Myers Squibb: Consultancy. Aygun:Patient-Centered Outsomes Research Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt:German Cancer Research Center, Heidelberg, Germany: Current Employment; GeneWerk GmbH, Heidelberg, Germany: Other: Equity ownership. DelCarpini:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Pierciey:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Miller:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Gallagher:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Chen:bluebird bio, Inc.: Consultancy. Goyal:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Kanter:Wells Fargo: Honoraria; Cowen: Honoraria; Jeffries: Honoraria; AGIOS: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; GLG: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Guidepoint Global: Honoraria.

Introduction: Comprehensive management for patients with hemophilia has drastically improved outcomes, quality of care, and longevity. Because of increases in life span, patients with hemophilia may be at risk for other chronic conditions including cardiovascular disease (CVD). Though initially it was thought that hemophilia might have been protective for cardiovascular disease further research has shown that CVD remains a significant risk for the aging hemophilia population. This study aims to determine the prevalence of risk factors and outcomes for CVD in hospitalized adult and pediatric patients with the discharge diagnosis of Hemophilia A or B compared to patients without Hemophilia. We examine longitudinal changes over the previous decade. WMethods: The Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (HCUP-NIS) was utilized for analysis of years 2007 and 2017. The NIS uses a stratified probability sample of 20% of all inpatient discharges (representing more than 97% of the US population). Hemophilia-A and B were identified using ICD-9 code 286.0 and 286.1, ICD-10 codes D66 and D67 respectively and sampling weights were applied to generate nationally representative estimates. Cardiovascular risk factors and outcomes were determined by evaluating ICD-9 codes for 2007 data and ICD-10 codes for 2017 data. For comparative historical data, 2007 NIS data from a prior published study [Goel et al., Hemophilia (2012), 18, 688-692] were used. The NIS is a de-identified, publicly available data set. This study was deemed exempt from review from the Johns Hopkins Institutional Review Board. This analysis was conducted in accordance with the HCUP data use agreement guidelines. Results: In 2017, there were 10,555 admissions with Hemophilia A or B listed as one of all diagnoses. The mean age of hemophilia patients was 44.31 years compared to 49.57. years for all admissions. The most prevalent risk factor in 2017 was hypertension (32.4% for admissions with hemophilia as compared to 35.3% for all admissions) followed by hyperlipidemia (19.4% compared to 27.5%), diabetes (17.4% compared to 22.8%) and obesity (10.8% compared to 14.4%). CVD outcomes, in descending order of frequency were atherosclerotic coronary artery disease (11.6% for admissions with hemophilia compared to 16.9% for all admissions), heart failure (10.2% compared to 14.2%), acute myocardial infarction (AMI) (2.2% compared to 3.9%), and stroke (2.2% compared to 2.4% respectively). Comparing to 10 year prior data, in 2007, there were 9,737 admissions with Hemophilia A or B listed as one of all diagnoses. The mean age of hemophilia patients was 30.89 years compared to 47.16 years for all admissions. The most prevalent risk factor in 2007 was hypertension (27.0% in admissions with hemophilia compared to 36.7% for all admissions); followed by diabetes (11.2% compared to 18.5%), hyperlipidemia (9.5% compared to 17%), and obesity (3.6% compared to 5.8%). CVD outcomes, in descending order of frequency were, atherosclerotic coronary artery disease (10.1% compared to 16.7%), heart failure (6.6% compared to 10.8%), AMI (2.1% compared to 2.4%), and stroke (2.0% compared to 1.7%). Between 2007 and 2017 the crude prevalence rates of all CVD risk factors as well as CVD outcomes generally increased for admissions with hemophilia as well as all-cause hospitalizations. Conclusions: The frequency of all CVD risk factors (obesity, diabetes, hypertension, and hyperlipidemia) as well as CVD outcomes (atherosclerosis, congestive heart failure, AMI, and stroke) increased between 2007 and 2017 in hospitalized patients both with and without hemophilia. While the unadjusted prevalence rates for all CVD risk factors and CVD outcomes were less in hospitalized patients with hemophilia compared to the general hospitalized population in both 2007 and 2017, CVD remains a significant risk for the hemophilia population. An improved understanding of the various risk factors will help to improve CVD outcomes in the aging hemophilia population. Disclosures Takemoto: Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB Aplastic Anemia Trial.

Introduction Allogeneic hematopoietic stem cell (HSC) transplantation (allo-HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT-related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB-205 and -206, and cerebral adrenoleukodystrophy (CALD) using Lenti-D in ALD-102. The safety outcomes following autologous gene modified HSCT in these ongoing studies are summarized. Methods HSCs are collected using disease-appropriate procedures, then CD34+ cells are transduced with LVV encoding disease-specific therapeutic transgenes. After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD), patients are infused with LVV-transduced CD34+ HSCs. Patients are followed for two years and offered participation in long term follow-up studies (LTF-303 [NCT02633943] or LTF-304 [NCT02698579]). Results Across all 6 studies, 110 patients have been treated as of most recent analyses (Table 1). Patients have been followed for 2 years follow-up. No patient experienced primary or secondary graft failure. One patient with CALD experienced disease progression and died 22 months after drug product (DP) infusion of disease complications. Two additional patients with CALD withdrew from the study after DP infusion and were referred for allo-HSCT. All other patients with CALD, TDT, and SCD remain alive. Most (107/110) patients had ≥ one grade 3 or 4 adverse event (AE) attributed to conditioning; most common AEs were cytopenia, febrile neutropenia, and stomatitis. Myelodysplastic syndrome was reported in one patient with SCD. After investigation for LVV insertion in malignant cells, the AE was assessed as not related to LentiGlobin insertion or transgene expression. AEs reported as related to the DP are shown in Table 1. There was no GVHD and no clinically relevant clonal dominance or LVV-mediated replication competent lentivirus. Summary Data from 110 patients followed for up to 5 years supports that the safety profile of gene-modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long-term immunosuppression attendant to allo-HSCT. While the safety profile beyond 5-years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of complications from allo-HSCT, such as those who lack a suitable donor or are more advanced in age.

Introduction LentiGlobin for SCD GT contains autologous CD34+ hematopoietic stems cells (HSCs) encoding β-globin with the anti-sickling T87Q mutation (βA-T87Q) and is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554) in patients with SCD. Levels of GT-derived hemoglobin (HbAT87Q) in 7 initial patients (Group A) were suboptimal but were maintained for ≥ 30 months of follow-up post-treatment, suggesting durable transgene expression. To increase HbAT87Q production, protocol and manufacturing changes were made (Group B; N=2). In addition, HSC collection by plerixafor mobilization and apheresis was instituted in Group C. Objective Provide an update on safety and efficacy of LentiGlobin for SCD in HGB-206 Group C. Methods Adults with severe SCD (including recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were enrolled. CD34+ HSCs were harvested by apheresis following plerixafor mobilization and transduced with BB305 lentiviral vector (LVV). Patients received myeloablative busulfan conditioning, were infused with LentiGlobin drug product (DP) and monitored for adverse events (AEs), Hb fractions, and other parameters. LVV presence in transduced cells (%LVV+) was measured by qPCR of individual colonies from colony-forming unit assays from pre-infusion DP) and post-infusion from CD34+ bone marrow (BM) HSCs and peripheral blood mononuclear cells (PBMCs). Data are shown as median (min-max). Results As of 7 March 2019, 13 Group C patients received DP, with follow-up of 9.0 (1.0-15.2) months. All but 1 patient had neutrophil and platelet engraftment as of the data cut date. Median HbS was ≤50% of total Hb in those with ≥6 months follow-up (n=8; Figure 1). Total unsupported Hb at last visit in patients with ≥6 months of follow-up was 11.5 (10.2-15.0) g/dL, with HbAT87Q levels of 5.3 (4.5-8.8) g/dL. Six of these 8 patients had a history of VOCs or ACS; the annualized VOC+ACS rate decreased from 5.3 (3-14) pre-treatment to 0 (0-2) post-treatment (Figure 2). A decrease in hemolysis markers was also seen post-DP. Most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7). Serious AEs occurred in 6 patients; the most frequent were nausea and vomiting. To date, there have been no cases of DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. The %LVV+ colonies from PBMCs at 9 months and BM at 12 months post-DP infusion (n=5) were 79.2 (67.0-88.4) % and 81.5 (60.6-88.1) %, respectively, indicating stable engraftment of transduced cells from DP (%LVV+ was 80 [71-88] %). Conclusions Patients in HGB-206 Group C show stable LentiGlobin engraftment, with median total Hb >10 g/dL and median HbS ≤50% of total Hb in those with ≥6 months follow-up. The decrease in SCD-related complications and hemolysis in this cohort demonstrate a strong therapeutic benefit of LentiGlobin in patients with SCD.

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.

Sickle cell disease is an inherited disorder that affects over 5 million people worldwide. Current maintenance therapy has been successful in reducing complications and enhancing life expectancy; yet subclinical complications persist. To date, allogeneic haematopoietic stem cell transplant (HSCT) remains the only available curative therapy for sickle cell disease. With declining incidences of rejection and transplant- related mortality, disease-free survival after human leucocyte antigen-identical sibling transplant exceeds 90%. However, the majority of individuals with sickle cell disease do not have an human leucocyte antigen (HLA)-identical sibling; therefore, research is expanding to focus on new approaches to alternative donor transplant. Advances in supportive care and conditioning regimens have led to expansion of the pool of donors to unrelated donors and haploidentical donors. Challenges remain in improving the safety and efficacy of HSCT from alternate donors. Early results from gene therapy may provide another curative option in patients with sickle cell disease. These approaches show early promise, but larger, longitudinal studies are needed to better determine the optimal clinical circumstances for transplant in sickle cell disease.

Although a number of published trials exist of HLA-identical sibling hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) that span 2decades, when and for whom this therapy should be pursued is a subject of debate. Assessments of the risks of transplant-related complications that include infertility and debilitating graft-versus-host disease and long-term quality of life after successful HCT are difficult to perform without prospective trials in transplant and nontransplant cohorts. However, it is possible to assess the risk of mortality and to compare published rates of survival in individuals with SCD treated and not treated by HCT. In this brief review, projections about mortality risk based on recent published reports are reviewed and summarized. The published data show overall survival and event-free survival rates of 95% and 92%, respectively, in children treated by HLA-identical sibling HCT. The overall survival rates in the Center for International Blood and Marrow Transplant Research (N=412) and European Blood and Marrow Transplant (N=487) registries were 91% and 95%, respectively. These results provide broad support for the therapeutic value of HLA-identical sibling HCT for children with SCD and serve as the basis for a strong recommendation in favor of the option of HCT when a suitable donor is available. The experience of HLA-identical sibling HCT in adults with SCD is limited but appears to be similar to results in children. These preliminary observations, however, warrant further investigation.

Background In patients with sickle cell disease (SCD), health-related quality of life (HRQoL) is worse than in the general population and comparable or worse than in patients with other chronic or painful diseases such as cystic fibrosis or cancer. Targeting SCD pathophysiology may significantly improve HRQoL in addition to clinical outcomes. In the ongoing phase 1/2 HGB-206 Study (NCT02140554), which evaluates the safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT), the most recently treated cohort of patients (Group C) have demonstrated improvements in laboratory assessments, including a trend toward normalization in key hemolysis markers and improvements in total hemoglobin values, and near resolution of vaso-occlusive crises and acute chest syndrome (ACS), suggesting a fundamental effect on sickle cell pathophysiology. Patient-reported HRQoL outcomes through 12 months post-treatment are presented here. Methods Patients (≥12 and ≤50 years of age) with SCD and history of stroke or severe vaso-occlusive events, including acute episodes of pain and ACS, were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. In addition to laboratory and clinical assessments, patients were monitored for patient-reported outcomes (PROs) using the PRO Measurement Information System (PROMIS)-57. PROMIS-57 assesses HRQoL using collection of short forms containing 8 questions for each of the 7 PROMIS domains (Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, in which a lower score denotes improvement, and Physical Function, Satisfaction with Participation in Social Roles, in which a higher score denotes improvement) and a 0-10 Pain Intensity numeric rating scale (NRS). PROMIS-57 has been validated in patients with SCD. Data were analyzed for ten Group C patients who had at least 12 months of follow-up and had completed PROMIS-57 assessments as of March 3, 2020. For each domain, patients were stratified into 2 sub-groups based on baseline scores and population norm (i.e., baseline scores "better" than or near the population norm and baseline scores "worse" than the population norm). The stratification was built upon the premise that patients with baseline scores "better" or near the population norm would not be expected to improve. The US general population norm was 2.6 for Pain Intensity and a T-score of 50 for all other domains. The minimal clinically importance difference (2-point difference for pain intensity NRS and 5-point difference for other domains) was selected based on the PROMIS guidelines and literature. Results Patients who had baseline scores "worse" than the population norm reported improvements in all domains at Month 6, which were sustained through Month 12. These patients reported clinically meaningful improvement in 6/8 domains; mean T-scores at baseline and Month 12 were 6 and 2.4 for Pain Intensity (n=5); 63 and 48 for Pain Interference (n=7); 62 and 48 for Anxiety (n=3); 62 and 44 for Depression (n=4); 39 and 60 for Satisfaction with Social Roles (n=5); and 40 and 56 for Physical Function (n=4), respectively. Only 1 patient was included in the analysis of Fatigue and Sleep Disturbance domains, thereby limiting the conclusions in these 2 domains (Figure 1). Patients who had baseline scores that were "better" or near than the population norm reported clinically meaningful improvements in the Physical Function (n=6) and Fatigue domains (n=9); mean scores at baseline and Month 12 were 49 and 55 for Physical Function and 50 and 43 for Fatigue, respectively. Among patients in this sub-group, Pain Intensity (n=5) and Pain Interference (n=3) scores were stable from Month 6 through Month 12; there was no clinically meaningful change for the Anxiety (n=7) and Depression (n=6) domains, however, worsening was observed in the Satisfaction with Social Role (n=4) and Sleep Disturbance (n=9) domains (Figure 1). Summary LentiGlobin for SCD GT improved HRQoL in all domains of PROMIS-57 for patients whose baseline scores were "worse" than the population norm, including clinically meaningful improvements in all evaluable (6/8) domains. Larger sample sizes are required to clarify the impact of LentiGlobin for SCD for some PROMIS-57 domains. Disclosures Kanter: SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria. Kwiatkowski:Terumo Corp: Research Funding; Imara: Consultancy; Celgene: Consultancy; Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Novartis: Research Funding; Sangamo: Research Funding; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy. Chen:bluebird bio, Inc.: Consultancy. Gallagher:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Ding:bluebird bio, Inc.: Current Employment, Other: Salary. Goyal:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Paramore:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; CRISPR/Vertex: Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Walters:AllCells, Inc: Consultancy; Veevo Biomedicine: Consultancy; Editas: Consultancy.

Importance Bone marrow transplant (BMT) is a potentially curative treatment for sickle cell disease (SCD). Patient and caregiver attitudes toward BMT for SCD and the willingness to accept risks of BMT vary, but these attitudes are not well understood. Objective To understand patient and caregiver perceptions of and attitudes toward BMT for SCD and decision-making about BMT. Design, Setting, and Participants Qualitative study of interview transcripts from a convenience sample. Transcripts were from adults with SCD and caregivers of patients with SCD recruited from national and regional SCD conferences, symposia, and sickle cell clinics in 2 cities. Interview transcripts were used from the needs assessment phase to develop a patient-decision aid in 2013 to 2014 (group 1) and from the baseline point in 2015 to 2016 (group 2) of the parent trial, a randomized clinical trial of adults and caregivers of patients with SCD to evaluate the effectiveness of a patient decision aid. Main Outcomes and Measures Participant perspectives on decision-making regarding BMT for SCD. Results Fifty-seven transcripts from adults with SCD and 50 transcripts from caregivers of patients with SCD were included. Median (interquartile range [IQR]) age of adults with SCD was 34 (21-50) years in group 1 and 30 (23-38) years in group 2. The median (IQR) age of caregivers was 42.5 (31-52) years in group 1 and 41 (35-46.5) years in group 2. Most transcripts from adults with SCD (75.0% in group 1 and 72.4% in group 2) and caregivers of patients with SCD (76.7% in group 1 and 85.0% in group 2) were from female participants. Bone marrow transplant was perceived as a treatment option associated with serious risks. Reported attitudes toward BMT occurred on a continuum ranging from unfavorable to favorable. Participants reported serious decisional dilemma regarding BMT for SCD. Most participants expressed interest in learning about BMT or curative treatments. Conclusions and Relevance This qualitative study found a continuum in attitudes toward BMT for SCD and highlights the complexity of decision-making in BMT for SCD. Patients and families with SCD expressed an interest in learning about BMT. Future prospective studies of patient decision-making regarding BMT, especially in the context of emerging curative and novel disease-modifying therapies for SCD, are warranted.

Background Hematopoietic stem cell transplantation (HCT) from matched sibling donors has been associated with excellent outcomes in patients with SCD but has been limited by the availability of HLA identical related donors and acceptability of HCT. Improved outcomes and the availability of clinical trials of HCT from haploidentical related donors and HLA matched unrelated donors and autologous hematopoietic progenitor cells modified by gene addition and gene editing has expanded the applicability of HCT for SCD. The objective of this study was to determine from the perspective of the parent about what motivates parents of a child with SCD to consider HCT/gene therapy in the setting of alternate donors and gene modification? Methods We conducted semi-structured qualitative interviews with at least one parent of a child with SCD who had scheduled a BMT consultation. Interviews were conducted pre-consultation and a second time post-consultation Audio recordings were transcribed verbatim. Data were analyzed using open and axial coding stages of grounded theory methodology. Results We interviewed 22 parents and one caregiver (18 mothers, 2 fathers, and 1 grandmother). Six participants were only available for the post-consultation interview. The median age of caregivers was 43 years (range 31 to 64 years.) Median age of the child was 13 years (range 14 months to 18 years). Three main themes relevant to the research question emerged. First, the child's quality of life, limitations placed by the disease and the concern for future potential to live independently because of SCD complications. Second, knowledge acquired by parents about curative options through multiple sources. Third, recent disease exacerbation or new SCD complication. Conclusion These results provide insight into the factors that prompt parents of children with SCD to HCT and gene therapy and have the potential to inform efforts to raise awareness about curative options for patients with SCD.

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Nitya Bakshi,1 Ines Lukombo,1,2 Inna Belfer,3 Lakshmanan Krishnamurti1 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 2University of Pittsburgh, 3Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA Introduction: Sickle cell disease (SCD) is an inherited blood disorder characterized by abnormally shaped sickle cells. The hallmark of this disease is intermittent, painful vaso-occlusive episodes (VOE), but a subset of individuals with SCD experience chronic pain. The mechanism of transition to chronic pain is not well understood in SCD, but there is evidence of altered pain processing in individuals with SCD. The impact of VOE on pain sensitivity is not established. The objective of this study was to determine the feasibility and tolerability of quantitative sensory testing (QST) in SCD following a VOE to better understand the contribution of VOE to the development of chronic pain. Methods: As part of a larger pain sensitivity study, pediatric patients with SCD were offered QST following a VOE-related Emergency Room visit or inpatient hospitalization. The feasibility of recruitment and completion of QST was measured, and tolerability of QST was determined using post-QST assessments of pain, and compared with measurements at steady state. Results: Ten participants completed QST following a VOE. The median age was 16.5, and 60% were female. Overall, 10 of 16 (62.5%) patients approached for QST following VOE completed QST. This included 8 of 12 patients who had previously completed QST at steady state. There were no statistically significant differences in pain intensity and Gracely Box scores after QST following a VOE, when compared to steady-state QST. Conclusion: QST is feasible and is well-tolerated following a VOE in patients with SCD. Large prospective studies are needed to determine the impact of VOE on experimental pain sensitivity and must take into account all factors contributing to pain sensitivity. Keywords: quantitative sensory testing, sickle cell disease, pain

Despite its efficacy, the uptake of HU in adults with sickle cell disease (SCD) is poor likely due to a combination of system, provider, and patient-related factors. We investigated attitudes of adult patients towards HU by conducting qualitative interviews with 95 adult SCD patients (age 18 to 67 years old, 71 were female). While 53% of all participants reported that they were currently taking HU, patients ranging in age 18-30 years (Group 1) were more likely to report current HU use as compared to those (Group 2) ranging in age 31-67 years (65% vs. 41% P = 0.01). Most Group 1 participants who reported currently taking HU indicated that the decision to start HU was made by a parent, though some made the decision themselves as a young adult. Group 1 participants expressed trust in the efficacy of HU as well as trust that their physician adequately shared risks and benefits for the medication. The Group 2 participants, who were not currently on HU, were skeptical that all the risks and benefits of HU were known, were concerned that the efficacy of HU was not proven, and that they were not receiving complete information about its potential side effects. Of Group 2 participants who reported currently being on HU, 25% were concerned about the side effects and efficacy of HU and reported continuing HU because of a lack of effective alternatives. These data suggest that there are significant differences by age in adult SCD patients' attitudes towards, utilization and understanding of the risks and benefits of HU.

Background Allogeneic HSCT is a well-established treatment for children with AL. For pts lacking a compatible matched related or unrelated donor, HLA-haplo-HSCT represents an alternative. Promising results were reported with selective depletion of αβ T and B cells (Locatelli, Blood 2017). PX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. BPX-501 provides broad virus and tumor-specific immunity; the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid. Aims Evaluate the safety and efficacy of BPX-501 in pediatric pts with AL by determining whether BPX-501 infusion can increase efficacy outcomes through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods A subset of pts had high-risk ALs. BPX-501 was planned to be infused on day14±4 after the allograft with no post-transplant GvHD prophylaxis allowed. Pts who developed steroid-resistant GvHD could receive ≥1 dose of rimiducid. Results As of June 30, 2018, 100 pts with AL (described in Table 1) were efficacy evaluable. Median time for neutrophil and platelet engraftment was 16 and 12 days, respectively. Four pts (4.1%) experienced primary graft failure. Of 96 evaluable pts, 5 (3.1%) developed Grade III-IV aGvHD. Of 82 evaluable pts, 12 developed cGvHD (18.1%), with 3 moderate-severe. Rimiducid was administered to 10 pts. Best overall clinical response (CR/PR) post-rimiducid was 80% (8 pts). Among responding patients, 7 (87.5%) had a CR. Six (6.6%) pts died after transplantation. Efficacy outcomes in AL subsets are in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. Conclusion BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a highly effective transplantation strategy for pediatric pts with AL. Rimiducid was an effective treatment for pts with steroid-resistant GvHD.

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037.Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase.Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults.GlaxoSmithKline.

The National Collegiate Athletic Association (NCAA) requires all student-athletes have their sickle cell trait (SCT) status confirmed prior to athletic participation. The NCAA approved the screening program in 2010 for institutions participating in Division I athletics and extended it in subsequent years to institutions at Division II and III levels. Ethical concerns about the controversial policy focus on its mandatory nature and potential impact on student-athletes, particularly through stigmatization of and discrimination against those with SCT. Organizations, such as the American Society of Hematology (ASH), oppose the imposition of SCT testing and instead recommend universal precautions that would protect the entire student-athlete population without revealing student-athletes' SCT statuses. This paper discusses these issues and offers recommendations, including genetic counseling, which would improve the current SCT screening program. It argues that implementation of universal precautions would ensure that the most ethically sound practices are afforded to every student-athlete.

While platelets are primary mediators of hemostasis, there is emerging evidence to show that they may also mediate pathologic thrombogenesis. Little data are available on risks and benefits associated with platelet transfusions in thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT) and immune thrombocytopenic purpura (ITP). This study utilized the Nationwide Inpatient Sample to evaluate the current in-hospital platelet transfusion practices and their association with arterial/venous thrombosis, acute myocardial infarction (AMI), stroke, and in-hospital mortality over 5 years (2007-2011). Age and gender-adjusted odds ratios (adjOR) associated with platelet transfusions were calculated. There were 10 624 hospitalizations with TTP; 6332 with HIT and 79 980 with ITP. Platelet transfusions were reported in 10.1% TTP, 7.1% HIT, and 25.8% ITP admissions. Platelet transfusions in TTP were associated with higher odds of arterial thrombosis (adjOR = 5.8, 95%CI = 1.3-26.6), AMI (adjOR = 2.0, 95%CI = 1.2-3.3) and mortality (adjOR = 2.0,95%CI = 1.3-3.0), but not venous thrombosis. Platelet transfusions in HIT were associated with higher odds of arterial thrombosis (adjOR = 3.4, 95%CI = 1.2-9.5) and mortality (adjOR = 5.2, 95%CI = 2.6-10.5) but not venous thrombosis. Except for AMI, all relationships remained significant after adjusting for clinical severity and acuity. No associations were significant for ITP. Platelet transfusions are associated with higher odds of arterial thrombosis and mortality among TTP and HIT patients.

Sickle cell disease (SCD) is an inherited blood disorder that primarily affects African-American and other ethnic minority populations. There are three available disease-modifying therapies for sickle cell disease: hydroxyurea (HU), bone marrow transplantation (BMT), and chronic blood transfusion (CBT). Since these treatments vary in their therapeutic intent, efficacy in preventing progression of the disease, short and long-term adverse effects, costs and patient burden, the decision-making process regarding these therapies is complicated for both the patient and healthcare provider. While previous research has focused on the patient perspective of treatment-related decision making, there is a paucity of research investigating the physician perspective of treatment-related decision making. We conducted a qualitative study with physicians who were experts in the field of SCD. Interviews focused on physician perceptions of patient decisional needs as well as physicians' approach to decision making regarding disease-modifying therapies in SCD. Thirty-six physician interviews were analyzed, with a focus on their perspectives regarding available treatment options and on how they approach decision making with patients. We identified two narrative approaches. The Collaborative approach (CA) was characterized by emphasizing the need to discuss all possible treatment options to ensure that the patient and/or family was equipped to make an informed decision. The Proponent approach (PA) was characterized by strongly advocating a pre-determined treatment plan and providing patients/families with information, with the objective of convincing them to accept the treatment. An interplay of patient-related and disease-related factors, decision type and physician-related factors, as well as institutional frameworks, influenced physician perspectives on treatment options and decision making regarding these therapies. These findings point to the potential value of developing systems to foster patient engagement as a way of facilitating shared decision making.