Severe Sickle Cell Research Articles

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Severe Sickle Cell Disease

Background: Severe sickle cell disease (SCD), which is characterized by recurrent vaso-occlusive crises (VOCs), has a substantial negative impact on health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, non-viral, ex vivo CRISPR/Cas9 gene-edited autologous cell therapy in phase 3 clinical trials that has been shown to eliminate VOCs. Here, we report HRQoL data from a pre-specified interim analysis of the exa-cel CLIMB SCD-121 study. Methods: CLIMB SCD-121 is an ongoing phase 3 trial of a single dose of exa-cel in patients ages 12-35 years with SCD and a history of ≥2 VOCs/year in each of the 2 years prior to screening. Changes in patient reported outcomes measures EuroQol Quality of Life Scale 5 dimensions 5 levels of severity (EQ-5D-5L, including descriptive system and visual analog scale [VAS]), Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, including FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]), Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), and the 11-point pain Numerical Rating Scale (NRS ) were assessed from baseline through month 24 as a secondary endpoint in the trial. Data is presented as of 10 Feb 2023 for the 17 adult patients (aged ≥18-35 years) who had been followed for ≥16 months after exa-cel infusion. Results: Substantial and clinically meaningful improvements exceeding minimal clinically important difference (MCID) thresholds were observed in all assessed patient reported outcomes measures. At baseline, the EQ-5D-5L health utility US index (n=17; mean [SD]: 0.71 [0.23]) and EQ VAS (63.5 [22.5]) scores were lower than the US general population norm and similar to baseline scores reported for adult SCD patients with recurrent VOCs. By month 6, both EQ-5D-5L health utility US index score and EQ VAS score showed substantial improvements, which were maintained through month 24 (mean changes [SD] at month 24 [n=8]: 0.23 [0.20]; MCID 0.078 and 28.3 [16.2]; MCID 7 to 10, respectively). FACT-G Total Score improved from baseline at month 24 (mean [SD] change at month 24 [n=8]: 29.8 [17.2]; MCID 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, and functional well-being). BMTS score improved by month 6 and was sustained through month 24 (mean [SD] change at month 24 [n=8]: 3.9 [5.7]; MCID 2 to 3). All subscales of the ASCQ-Me, including emotional (mean [SD] change [n=7] 17.7 [9.8]), social (23.8 [6.7]), stiffness (7.9 [12.9]), and sleep impact (8.4 [8.3]), demonstrated clinically meaningful improvements from baseline through month 24. For the ASCQ-Me pain-related subscales evaluating pain impact, pain episode frequency and pain severity, the largest numerical improvement was observed in pain episode frequency (mean [SD] change at month 24 [n=8]: -22.8 [8.2]; MCID -5). Improvements in the pain NRS were observed by month 12 and sustained through Month 24 (mean [SD] change at month 24 [n=8]: -1.8 [3.1]; MCID -1). Conclusion: Adults infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family, and functional well-being, pain experience, and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with SCD.

Renin as a Biomarker of Acute Kidney Injury and Mortality in Children With Severe Malaria or Sickle Cell Disease.

Globally, a very high percentage of acute kidney injury (AKI) occurs in low- and middle-income countries (LMICs) where late recognition contributes to increased mortality. There are challenges with using existing biomarkers of AKI in LMICs. Emerging evidence suggests renin may serve as a biomarker of kidney injury that can overcome limitations in creatinine-based diagnostics. Two study populations in Uganda were assessed. Cohort #1 was a two-site, prospective cohort study enrolling 600 children with severe malaria (SM). Cohort #2 was a prospective cohort study enrolling 185 children with sickle cell disease (SCD) hospitalized with a vaso-occlusive crisis. Plasma or serum renin concentrations were measured in both cohorts of children at the time of hospital admission using Luminex® (Luminex Corporation,Austin, Texas, United States) or enzyme-linked immunosorbent assay (ELISA), respectively. We assessed the ability of renin to discriminate between children with or without AKI and between children who survived and children who died using receiver operating characteristic curves. In both cohorts, renin concentrations were strongly associated with AKI and mortality. Renin was able to discriminate between children with or without AKI with an area under the curve (AUC) of 0.70 (95%CI, 0.65-0.74) in children with SM and 0.72 (95%CI, 0.6co3-0.81) in children with SCD. Renin was able to discriminate between children who survived and children who died with an AUC of 0.73 (95%CI, 0.63-0.83) in children with SM and 0.94 (95%CI, 0.89-0.99) in children with SCD. In Cohort #2, we compared renin against urine neutrophil gelatinase-associated lipocalin (NGAL) as the leading biomarker of AKI, and it had comparable performance in discriminating AKI and predicting mortality. In two independent populations of children at risk of AKI with key differences in the etiology of kidney injury, renin was strongly associated with AKI and mortality and had moderate to good diagnostic performance to predict mortality.

CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease

BackgroundSickle cell disease is caused by a defect in the β-globin subunit of adult hemoglobin. Sickle hemoglobin polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and cause vaso-occlusion that results in progressive organ damage and early death. Elevated fetal hemoglobin levels in red cells protect against complications of sickle cell disease. OTQ923, a clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) product, has a targeted disruption of the HBG1 and HBG2 (γ-globin) gene promoters that increases fetal hemoglobin expression in red-cell progeny.MethodsWe performed a tiling CRISPR-Cas9 screen of the HBG1 and HBG2 promoters by electroporating CD34+ cells obtained from healthy donors with Cas9 complexed with one of 72 guide RNAs, and we assessed the fraction of fetal hemoglobin–immunostaining erythroblasts (F cells) in erythroid-differentiated progeny. The gRNA resulting in the highest level of F cells (gRNA-68) was selected for clinical development. We enrolled participants with severe sickle cell disease in a multicenter, phase 1–2 clinical study to assess the safety and adverse-effect profile of OTQ923.ResultsIn preclinical experiments, CD34+ HSPCs (obtained from healthy donors and persons with sickle cell disease) edited with CRISPR-Cas9 and gRNA-68 had sustained on-target editing with no off-target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice. In the study, three participants received autologous OTQ923 after myeloablative conditioning and were followed for 6 to 18 months. At the end of the follow-up period, all the participants had engraftment and stable induction of fetal hemoglobin (fetal hemoglobin as a percentage of total hemoglobin, 19.0 to 26.8%), with fetal hemoglobin broadly distributed in red cells (F cells as a percentage of red cells, 69.7 to 87.8%). Manifestations of sickle cell disease decreased during the follow-up period.ConclusionsCRISPR-Cas9 disruption of the HBG1 and HBG2 gene promoters was an effective strategy for induction of fetal hemoglobin. Infusion of autologous OTQ923 into three participants with severe sickle cell disease resulted in sustained induction of red-cell fetal hemoglobin and clinical improvement in disease severity. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT04443907.)

Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021

Previous global analyses, with known underdiagnosis and single cause per death attribution systems, provide only a small insight into the suspected high population health effect of sickle cell disease. Completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, this study delivers a comprehensive global assessment of prevalence of sickle cell disease and mortality burden by age and sex for 204 countries and territories from 2000 to 2021. We estimated cause-specific sickle cell disease mortality using standardised GBD approaches, in which each death is assigned to a single underlying cause, to estimate mortality rates from the International Classification of Diseases (ICD)-coded vital registration, surveillance, and verbal autopsy data. In parallel, our goal was to estimate a more accurate account of sickle cell disease health burden using four types of epidemiological data on sickle cell disease: birth incidence, age-specific prevalence, with-condition mortality (total deaths), and excess mortality (excess deaths). Systematic reviews, supplemented with ICD-coded hospital discharge and insurance claims data, informed this modelling approach. We employed DisMod-MR 2.1 to triangulate between these measures-borrowing strength from predictive covariates and across age, time, and geography-and generated internally consistent estimates of incidence, prevalence, and mortality for three distinct genotypes of sickle cell disease: homozygous sickle cell disease and severe sickle cell β-thalassaemia, sickle-haemoglobin C disease, and mild sickle cell β-thalassaemia. Summing the three models yielded final estimates of incidence at birth, prevalence by age and sex, and total sickle cell disease mortality, the latter of which was compared directly against cause-specific mortality estimates to evaluate differences in mortality burden assessment and implications for the Sustainable Development Goals (SDGs). Between 2000 and 2021, national incidence rates of sickle cell disease were relatively stable, but total births of babies with sickle cell disease increased globally by 13·7% (95% uncertainty interval 11·1-16·5), to 515 000 (425 000-614 000), primarily due to population growth in the Caribbean and western and central sub-Saharan Africa. The number of people living with sickle cell disease globally increased by 41·4% (38·3-44·9), from 5·46 million (4·62-6·45) in 2000 to 7·74 million (6·51-9·2) in 2021. We estimated 34 400 (25 000-45 200) cause-specific all-age deaths globally in 2021, but total sickle cell disease mortality burden was nearly 11-times higher at 376 000 (303 000-467 000). In children younger than 5 years, there were 81 100 (58 800-108 000) deaths, ranking total sickle cell disease mortality as 12th (compared to 40th for cause-specific sickle cell disease mortality) across all causes estimated by the GBD in 2021. Our findings show a strikingly high contribution of sickle cell disease to all-cause mortality that is not apparent when each death is assigned to only a single cause. Sickle cell disease mortality burden is highest in children, especially in countries with the greatest under-5 mortality rates. Without comprehensive strategies to address morbidity and mortality associated with sickle cell disease, attainment of SDG 3.1, 3.2, and 3.4 is uncertain. Widespread data gaps and correspondingly high uncertainty in the estimates highlight the urgent need for routine and sustained surveillance efforts, further research to assess the contribution of conditions associated with sickle cell disease, and widespread deployment of evidence-based prevention and treatment for those with sickle cell disease. Bill & Melinda Gates Foundation.

5596737 RETINOPATHY IN EGYPTIAN PATIENTS WITH SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) is a disorder that causes red blood cells to become sticky and rigid. Sickle cells can block blood flow in small blood vessels depriving the eye of oxygen and cause damage. This is called sickle retinopathy that can progress to severe proliferative sickle cell retinopathy, bleeding into the eye, detachment of the retina or even loss of vision. Aim: To assess ocular manifestations and detect frequency of retinopathy in patients with SCD. Methods: Cross-sectional study was conducted on 32 patients with SCD. They were 22 males and 10 females with mean age of 12 years. Routine investigations as well as ophthalmological examination including visual acuity, fluorescein angiography and optical coherence tomography were done. Results: We found that 8 patients (25%) suffered from proliferative retinopathy, 10 patients (31%) showed tortuous retinal veins, while 14 patients (44%) were normal. All patients showed macular thinning on optical coherence tomography examination. Conclusion: We concluded that frequency of retinopathy in patients with SCD is more than expected and it was higher in patients who started transfusion at a later age. More attention should be paid for this problem and close observations and follow up is strongly needed.

Viral Vectors in Gene Therapy: Where Do We Stand in 2023?

Viral vectors have been used for a broad spectrum of gene therapy for both acute and chronic diseases. In the context of cancer gene therapy, viral vectors expressing anti-tumor, toxic, suicide and immunostimulatory genes, such as cytokines and chemokines, have been applied. Oncolytic viruses, which specifically replicate in and kill tumor cells, have provided tumor eradication, and even cure of cancers in animal models. In a broader meaning, vaccine development against infectious diseases and various cancers has been considered as a type of gene therapy. Especially in the case of COVID-19 vaccines, adenovirus-based vaccines such as ChAdOx1 nCoV-19 and Ad26.COV2.S have demonstrated excellent safety and vaccine efficacy in clinical trials, leading to Emergency Use Authorization in many countries. Viral vectors have shown great promise in the treatment of chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, hemophilia, β-thalassemia, and sickle cell disease (SCD). Proof-of-concept has been established in preclinical studies in various animal models. Clinical gene therapy trials have confirmed good safety, tolerability, and therapeutic efficacy. Viral-based drugs have been approved for cancer, hematological, metabolic, neurological, and ophthalmological diseases as well as for vaccines. For example, the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, the oncolytic HSV T-VEC for melanoma, lentivirus-based treatment of ADA-SCID disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease have been approved for human use.

SS Sickle Cell Disease and Severe Malaria in Children Aged 0 to 15 Hospitalized in the Pediatric Department of the Donka CHU National Hospital in Conakry, Republic of Guinea

Introduction: The superposition of distribution maps of HbS and plasmodium falciparum is at the origin of several theories on the relationship between sickle cell disease and malaria. Objective: Determine the sociodemographic aspect and identify the main complications of SS sickle cell disease in children with severe malaria at the Donka Pediatrics Department. Methods: Prospective, descriptive study, lasting 12 months from January 01 to December 31, 2021 including all children from 0-15 years hospitalized whose diagnoses of severe malaria and SS sickle cell anemia were retained during the study period. Results: The frequency was 6.65%, The age group of 5-9 years represented 41.93% with a sex ratio (M/F) = 1.3. Frequency peaks were encountered in June, July and August (36.56%). Consanguineous marriage was found in 65.59%. Fever was present in 100% of our patients followed by osteo-articular pain (93.54%). Malaria severity criteria were represented by prostration with 81.7%, followed by anemia (77.42%), hyperparasitaemia (46.23%), respiratory distress (45.16%) and seizures (34.4%). Complications were dominated by bronchopneumopathy, osteomyelitis, dactylitis and necrosis of the femoral head. The evolution was favorable in 95.70% of cases. Conclusion: The prevalence of sickle cell disease associated with severe malaria remains high in the department with consanguinity often found. Reducing these two pathologies will necessarily involve the use of means of prevention against malaria and premarital examinations.

Cerebral Oxygen Metabolism in Patients with Mild and Severe Sickle Cell Disease and Thalassemia

Introduction Studies in patients with severe (HbSS and HbSβ0) sickle cell disease (SCD) have reported reduced oxygen metabolism compared to controls despite the preserved oxygen delivery (OD). Whereas previous studies have found similar lesion load in mild SCD patients (HbSC and HbSβ+), oxygen metabolism has not been studied in this group. Interestingly, we previously showed that CBF values in mild SCD patients were lower compared to severe SCD, and comparable with healthy controls. Here, we assessed the OD, oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and lesion volumes in adult patients with severe and mild SCD and compared our results with thalassemia patients as anemic controls and healthy controls. In addition, the effect of a vasodilatory stimulus on the cerebral parameters was studied to test if increased CBF influences oxygen consumption. Methods In this study, 75 patients with severe SCD (64 HbSS and 11 HbSβ0), 26 patients with mild SCD (16 HbSC and 10 HbSβ+), 17 patients with thalassemia (7 NTDT and 10 TDT) and 30 healthy controls were included. Venous blood T2 was measured using T2-Relaxation-Under-Spin-Tagging (TRUST). Whole brain (WB) CBF was measured using time-encoded pseudo-continuous ASL (te-ASL). TRUST and te-ASL scans were performed before and after acetazolamide (ACZ) administration as a vasodilatory stimulus. Fluid-Attenuated Inversion Recovery (FLAIR) scans were acquired for the assessment and segmentation of lesions. OEF was calculated from arterial saturation measured by pulse oximetry and venous saturation calculated from blood T2 using a sickle cell-specific calibration model and a healthy control model. CMRO2 was calculated from the WB CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). To test the effect of ACZ-induced vasodilation, ∆CBF, ∆OD, ∆OEF and ∆CMRO2 were calculated. A one-way analysis of covariance (ANCOVA) was conducted (or a nonparametric alternative) with posthoc Bonferroni correction to test for statistically significant differences in cerebral parameters between the participating groups controlling for age and sex. For ∆CBF, ∆OD, ∆OEF and ∆CMRO2, baseline values were added as additional covariates. Results CBF was significantly higher in severe SCD compared to other groups and significantly higher in thalassemia patients compared to mild SCD and healthy controls (Table 1). No significant differences were found in OD between the groups. OEF was significantly lower in severe SCD patients compared to other groups and significantly lower in thalassemia patients compared to mild SCD patients and healthy controls (Table 1). CMRO2 was significantly lower in severe SCD and thalassemia patients compared to mild SCD patients and healthy controls (Table 1). ∆CBF upon ACZ administration was not significantly different between the groups. ∆OD was significantly higher in controls compared to severe SCD and thalassemia patients (Table 1). Infusion of ACZ impaired the OEF and CMRO2 more in severe SCD compared to the other groups (Table 1: ∆OEF and ∆CMRO2). Lesion volume was significantly larger in the severe SCD group compared to the healthy controls but no significant differences were found between the other groups (Fig. 1). Conclusion Our results show that OEF and CMRO2 were significantly higher in mild SCD patients, and no different from healthy controls, compared to severe SCD and thalassemia patients, illustrating a more balanced oxygen supply versus demand in these less anemic patients. Furthermore, the finding that ACZ-induced elevated CBF significantly reduced the CMRO2 in severe SCD, but not in the other groups, suggests that functional shunting may play a role in severely affected SCD patients. Despite the large differences in cerebral oxygen metabolism between severe and mild SCD, no difference in lesion volume could be observed between these groups. One possible mechanism that might be responsible for the lesion load in mild SCD patients could be the higher blood viscosity in this group that has been hypothesized to cause other complications such as retinopathy, particularly in patients with HbSC. Another explanation could be that lesion volume is more related to deep brain hypoxia than whole brain oxygen metabolism which could be confirmed by further studies investigating deep brain oxygenation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes in Pregnant HbSS and HbSβ0-Thalassemia Sickle Cell Disease Patients Receiving Scheduled Exchange Transfusions: A Retrospective Study

Introduction: The incidence of feto-maternal complications during pregnancy is high in women with sickle cell disease (SCD) which is the most common inherited hematologic disorder worldwide. Evidence on the impact of transfusions in pregnancy with SCD is lacking with only 12 observational studies and 1 RCT to date that has led to conditional recommendations for transfusional support in pregnant SCD patients. We aim to retrospectively chart review pregnant patients with severe sickle cell disease (HbSS and HbSβ0-thalassemia) and assess if scheduled red cell partial exchanges (RCE) impacted lab values, number of hospital and ED visits, prenatal, perinatal and postnatal outcomes. Methods: We identified 42 adult pregnancies (40 HbSS and 2 HbSβ0-thalassemia) between 04/2012 and 04/2022. HbSC and HbSβ+-thalassemia patients were excluded from the study as most patients did not get RCE due to overall less disease severity. Patients who received RCE had one unit of phlebotomy followed by one unit of packed red cell transfusion every 2 weeks as per the protocol followed at our institution. Collected data included demographics, lab values, number of hospital admissions/ED visits, prenatal, perinatal, and postnatal outcomes. Descriptive statistics as means and percentages, individual samples t-tests for comparison of means, chi-square tests for associations were utilized to report the data. A p value of <0.05 was considered significant. A binary regression model was utilized to adjust for demographics and comorbidities. Results: Mean age in the study group was 24.86±4.28 years. All 42 patients had medicare or medicaid. 11/42 (26.2%) patients received scheduled RCE with 73% compliance rate and no documented evidence of allo-immunization. Only 1/37 (2.7%) patients had venous thromboembolism. Patients who received scheduled RCE had higher hemoglobin (Hb) nadirs (7.80 g/dL vs 6.78 g/dL; p .02), lower number of hospital admissions for painful crises (1.00 vs 3.54; p .02) and higher gestational age in weeks at delivery (37.09 vs 33.64; p .007). The differences in means of other hematological and chemistry lab values were insignificant. Scheduled RCE was associated with lower incidence of preterm deliveries and subsequent NICU admission with unadjusted odds ratios of 0.153 (0.028-0.848) and 0.500 (0.323-0.775) respectively. There was no statistically significant association with respect to other prenatal, perinatal or postnatal outcomes such as preeclampsia, eclampsia, mode of delivery, intrauterine growth restriction or neonatal death. Binary logistic regression did not show any statistically significant associations when adjusted for demographics and comorbidities (Table 1). Conclusions: Pregnant patients with SCD who have had previous pregnancy complications, high hospital admission rates or low Hb nadirs might benefit from scheduled RCE or simple transfusions. Given limited sample size in all 12 reported observational studies, there is a need for multicenter study especially from centers in areas with higher prevalence of SCD. While the TAPS-2 trial was registered in 2019 in the UK and is currently recruiting patients, more trials are necessary to solidify evidence. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Rare Case of Lenalidomide Providing Control of Severe Sickle Cell Anemia in a Patient with Coexisting Multiple Myeloma

Background: Multiple myeloma (MM) rarely coexists with Sickle Cell Anemia (Hb-SS-Disease). Whereas MM usually affects those older than 50, Sickle Cell Anemia is a congenital disease with a median life expectancy of 42-47 years. In one recent survey by Zerdan et al (Am J Case reports 2021), there have been 12 cases of coexisting MM with Sickle Cell Disease (including 4 cases of compound sickle cell syndrome). Pareseval et al (J Clin Investigation 2008) has previously shown that the thalidomide analogues Lenalidomide and particularly Pomalidomide are effective inducers of Hgb F in ex-vivo erythroid cells from both healthy donors and patients with SCD. Kutlar et al (Blood 2013) reported on a phase I dose-escalation trial of Pomalidomide given for 12 weeks in patients with SCD, which demonstrated an increase in Hgb F. However, there has not been further progress in exploring this modality of treatment since that time. Here, we report a rare case of a patient with Sickle Cell Anemia who was diagnosed with MM at the age of 38, and is benefiting from Lenalidomide for the treatment of both conditions. Case: 38 y/o M with a history of Sickle Cell Anemia complicated by pulmonary embolism and recurrent deep vein thrombosis, priapism and thrombotic strokes at the ages of 6 and 18 years and follows at hematology clinic for SCD management. Patient was maintained on Hydroxyurea and partial exchange transfusions every 2 weeks with a goal sickle cell hemoglobin (HbS) of 30%. He developed another stroke at the age of 35, and was found to have Moyamoya disease and intracranial bleed which required craniotomy and evacuation. Later, he was incidentally detected to have smoldering multiple myeloma confirmed by bone marrow biopsy which then clinically progressed to MM. He was started on treatment for MM, received a total of 11 cycles of Lenalidomide + Bortezomib + Dexamethasone (RVD regimen) and later transitioned to Lenalidomide alone as maintenance. Around this time, patient was switched to full exchange transfusion, with close monitoring of Hgb S to determine the timing of each exchange. In this context, it was noted that the Hgb F level was steadily rising and peaked at 21% in January 2020, with Hgb S of 41% and transfusion-induced Hgb A of 35%. Once the COVID-19 pandemic set it, the patient stayed at home as a precaution against infection, but the Lenalidomide maintenance was continued, along with Hydroxyurea. He was followed remotely with televisits and home blood draws for the following 2 years. His Hgb F stayed between 25-30% and he had no sickle cell crises and did not require any blood transfusions. He has not had significant side effects from Lenalidomide and the MM has remained controlled, as well. Conclusion: It is interesting to note that our patient with severe Sickle Cell Anemia, with a history of multiple strokes, has had sustained control of his disease for 2 years while on Hydrea and maintenance Lenalidomide (used primarily for prevention of MM relapse), without the need for exchange transfusions. This outcome supports the pre-clinical findings of Parseval et al, and may provide additional basis for advancing clinical research of thalidomide analogues in the management of Sickle Cell Anemia.

COVID-19 in Adults with Sickle Cell Disease: Data from Cerner Real-World Database

Introduction Sickle cell disease (SCD) is the most common inherited hemoglobinopathy and is estimated to affect more than 100,000 Americans. A voluntary clinical reported registry of COVID-19 infections in patients with SCD reported both high hospitalization rates (69%) and case fatality rates (7%) (Panepinto, 2020), but only reported data from March 20-May 21, 2020. We hypothesize that the rate of hospitalizations among patients with SCD and COVID 19 decreased with time as vaccinations became available and COVID-19 treatment improved. We report on all patients, both ambulatory and hospitalized, with SARS-CoV-2 and SCD at institutions contributing data to the Cerner Real-World DataTM (CRWD) database. The CRWD is a de-identified cloud-based data source of electronic health records from more than 100 health systems in the United States. Methods Exempted retrospective review was approved by ChristianaCare IRB. We obtained access to the CRWD, which included data for all patients with SARS-CoV-2 and SCD as documented by ICD 10 D57.XX and positive lab result or ICD-10 U07.X from 3/1/2020-10/15/2021. Those with sickle cell trait were excluded. The final dataset included 896 patients, after excluding patients <18 years and those without prior health care encounters. We used Wilcoxon rank sum test to compare the characteristics between ambulatory and hospitalized patients and examined the trend in hospitalizations between 2020 quarter 1 and 2021 quarter 3. Results: The final data set included 896 adult patients, 371 of whom were hospitalized. There was no difference in sex or insurance status between the 2 groups. Those hospitalized were more likely to have at least 1 AHRQ comorbidity (80.3% vs. 72.8% p=0.01), notably coronary artery disease, hypertension, renal failure, and congestive heart failure and be considered immunocompromised as defined by AHRQ (reference?). The median length of stay [IQR]was 5 days [3;9]. A total of 35/371 (9.43%) patients were admitted to the ICU and 25/371 (6.74%) were treated with invasive ventilation for a median of 15 days; 28/371 patients died (7.5%) and 5 were discharged to hospice care. When evaluated by quarter, the hospitalization rate peaked in 2020 Q2 at 46.9% then remained stable with an average over the next 5 quarters of 40.9%. Discussion Ambulatory patients were slightly younger and had fewer prior encounters, potentially representing less severe sickle cell phenotypes. Death rate is similar to other COVID cohorts. Geographic variability of patients- some zip code areas had relatively few, corresponds to areas with low patient density. Contrary to what we expected, after a peak in 2020Q2, the rate of hospitalizations remained stable until 2021Q3 at approximately 41%. There are several limitations to this study: it only draws from Cerner EMR institutions, representing a 26% market share and does not include data from the Omicron wave which started after October 2021. The vaccination status relied on import of external data and is likely incomplete. Finally, we could not adequately gauge severity of COVID-19 disease given notable variations in institutional resources. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Background: Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients with sickle cell disease (SCD). Exagamglogene autotemcel (exa-cel; formerly known as CTX001) is a cell therapy designed to reactivate HbF via non-viral, ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). Recent data from the pivotal CLIMB SCD-121 (NCT03745287) trial showed that a single dose of exa-cel increased HbF and total hemoglobin (Hb) sufficiently to eliminate vaso-occlusive crises (VOCs) in patients with severe SCD. Here, we report efficacy and safety data from the first 31 patients dosed with exa-cel in the ongoing CLIMB SCD-121 trial. Methods: Patients aged 12 to 35 years with severe SCD and a history of ≥2 VOCs per year in the previous 2 years before screening were eligible. Following pharmacokinetic-adjusted, busulfan myeloablation and infusion of exa-cel, patients are monitored for engraftment, total Hb, HbF, BCL11A-edited alleles, transfusions, VOCs, and adverse events (AEs). The primary endpoint is the proportion of patients who have not experienced a severe VOC for at least 12 months after the infusion of exa-cel, starting 60 days after their last RBC transfusion. Updated efficacy and safety results on all dosed patients will be included in the presentation. Data are reported as mean (min-max), unless noted. Results: At the most recent data cut in February 2022, 31 patients with SCD (age 22.5 [12-34] years) had been infused with exa-cel (follow-up 9.6 [2.0-32.3] months), of whom 6 (19.4%) were between the ages of 12 and <18 years and 29 (93.5%) had the βs/βs genotype. In the 2-year period before screening, patients experienced 3.9 (2.0-9.5) severe VOCs per year. After exa-cel infusion, all patients engrafted neutrophils and platelets with a median time of 27 and 32 days, respectively. All patients were VOC-free at the time of the data cut (duration of follow-up 2.0-32.3 months after exa-cel infusion; Figure). Median time from exa-cel infusion to last RBC transfusion was 19 (11-52) days. The mean proportion of HbF was >20% by Month 3, with mean total Hb levels >11 g/dL on and after Month 3. All 11 patients who have at least 12 months of follow-up after exa-cel infusion have maintained HbF levels >20% while experiencing no VOCs. At Month 6, the mean proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells was 86.6% and 76.0%, respectively. These proportions remained stable in all patients who had ≥1 year of follow-up (Figure). There were no patients who had serious AEs considered related to exa-cel. There were no deaths, discontinuations, or malignancies. Conclusions: Exa-cel infusion led to the elimination of VOCs in all patients with SCD, with associated clinically meaningful increases in HbF and total Hb that were maintained over time. Proportions of CRISPR/Cas9-edited BCL11A alleles have remained stable after ≥1 year, indicating that long-term HSCs were successfully edited. The safety profile was generally consistent with that of busulfan myeloablation and autologous transplant. Exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for SCD. Figure. Clinical data for patients with SCD (N=31) infused with exa-cel. Patients were VOC-free after exa-cel infusion. Time (months) since exa-cel infusion is indicated by the dark blue bar. Inset depicts the percentage of BCL11A-edited alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells of patients with SCD infused with exa-cel over time. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Induction of Fetal Hemoglobin and Reduction of Clinical Manifestations in Patients with Severe Sickle Cell Disease Treated with Shmir-Based Lentiviral Gene Therapy for Post-Transcriptional Gene Editing of BCL11A: Updated Results from Pilot and Feasibility Trial

Background Induction of fetal hemoglobin (HbF) by repressing BCL11A could reduce or eliminate sickle cell disease (SCD) clinical manifestations. The BCH-BB694 lentiviral vector (LVV) encodes a shRNA targeting BCL11A embedded in a microRNA scaffold (shmiR) allowing erythroid-specific knockdown to induce γ-globin expression and concomitantly and coordinately repress β-sickle globin expression (Brendel et al. JCI 2016). The safety and efficacy of gene therapy (GT) with BCH-BB694-transduced autologous CD34+ cells in patients with SCD is being investigated in a pilot and feasibility trial (NCT03282656), which has now completed enrollment of all 10 planned patients. Preliminary data in the first 6 patients described robust HbF induction and a favorable safety profile (Esrick et al. NEJM 2021). Additional follow-up data including all ten pilot trial patients is discussed here with longest follow-up now > 4 years. Methods Patients with severe SCD were screened for eligibility. Autologous CD34+ cells were collected via apheresis after plerixafor mobilization (Esrick and Manis et al. Blood Adv 2018) and then transduced ex vivo with the BCH-BB694 shmiR LVV. Gene modified cells were infused into subjects who had received myeloablative busulfan conditioning. Patients were monitored for adverse events (AEs), hemoglobin (Hb), HbF fraction, percent F cells, hemolysis markers, and SCD clinical manifestations. Results Ten patients (7-25 years of age at enrollment) received GT, with median follow-up of 30.5 (2-50) months. There were no Grade 3 or 4 AEs associated with mobilization, collection or infusion. Median product VCN, % transduced cells, and CD34+ cell dose in the 10 patients were 3.5 (1.8-6.9) copies/diploid genome (c/dg), 96% (62-100%), and 5.7 (3.6-8.8) x 106 CD34+ cells/kg, respectively. Engraftment of neutrophils occurred on day 22 (18-30) and of platelets on day 32 (25-62). One patient (patient 10) has low post-GT peripheral VCN, HbF, and percent F cells; most recently 0.23 c/dg, 11.2%, and 37.3% respectively. Although improved, this was considered a GT failure and the patient has been started on new SCD-directed therapies due to ongoing SCD clinical manifestations. Subsequent data described here exclude patient 10. At the most recent study visit, the 7 untransfused patients with follow up > 6 months had mean total Hb of 10.5 (8.8-12.2) g/dL, HbF/(F+S) of 30.3% (21.4 - 42.4%), percent F cells of 70.6% (58.8-79.8%), and HbF per F cell of 12 (10.1-14.4) pg (Table 1). The lowest Hb response was seen in patient 11 who has 2-gene deletion alpha thalassemia in combination with SCD. Five patients with follow-up > 6 months (patients 4, 6, 8, 9, and 11) had frequent severe vaso-occlusive events (ACS, priapism, or pain requiring inpatient or ED opioids) as indication for eligibility, with a median of 6 (3-13) events (Table 2). From 6 months after GT through present, these 5 patients have had a median of 1 (0-1) event. Three patients with follow-up > 6 months (patients 2, 3, and 7) were on chronic transfusion regimens pre-GT. Patient 3 has continued chronic transfusions due to pre-existing moyamoya with goal of maintaining HbS at pre-GT levels. Patients 2 and 7 have received no post-GT transfusions. Patients 2, 3, and 7 have had no SCD clinical events. Mean lactate dehydrogenase and absolute reticulocyte count at last study visit were 346 (215-389) U/L and 241 (200-360) 109/L, respectively, indicating decreased but persistent mild hemolysis in all patients. There have been no instances of graft failure, replication competent lentivirus detection, or clonal dominance in any patient. Six patients with ≥2 years post GT have had bone marrow biopsies at the 2 year timepoint without evidence of myelodysplasia. Targeted sequencing of ~95 genes frequently mutated in hematologic malignancies has been performed on peripheral blood samples every 6 months since early 2021 in patients with ≥6 months from GT. One patient had a pathogenic mutation detected in the DNMT3A gene, which was present in a stored pre-GT sample and has been present at a stable VAF <4% at 6, 9, and 12 months post-GT. Summary Post-transcriptional gene editing of BCL11A appears safe with stable induction of broadly distributed HbF and significant mitigation of VOE events in severe SCD in all but one treated patient. Based on the results of this pilot study, a phase 2, multi-institutional trial is now open for enrollment using the same vector and approach (NCT05353647). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction

Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization. Prior to infusion, participants received myeloablative busulfan. Primary endpoints are to evaluate engraftment, long-term safety, and efficacy of HbF expression. Results: As of the data cut-off (July 8, 2022), 2 participants had received OTQ923, with follow-ups of 9 months (mos) and 3 mos, respectively. Here, we present initial clinical data from these 2 participants; additional data will be presented at the meeting. Both participants were homozygous for the sickle mutation. Participant 1 is a 22-year-old male with a history of silent cerebral infarcts, ACS, and priapism. At study entry, he was receiving chronic transfusions. He received 2.8x106 CD34+ cells/kg of OTQ923 (2 combined manufacturing batches). Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea. He received 5.99x106 CD34+ cells/kg of OTQ923 (3 combined manufacturing batches). Time to neutrophil engraftment (the first of 3 consecutive days of absolute neutrophil count above 500 cells/mL after cell infusion) was 26 and 20 days for Participants 1 and 2, respectively. No OTQ923-related adverse events (AEs) were reported in either participant. All observed AEs were consistent with busulfan conditioning. Participants received RBC transfusions around conditioning and have received none after engraftment. For Participant 1, HbF level increased in the 6 mos after infusion and was stable at data cut-off (22.1% HbF at 9 mos after infusion). Induction of HbF was pancellular, with an F-cell percentage around 91% at 6 mos after infusion (Fig. 1A). Participant 2 had achieved an HbF level of 15.9% at 3 mos after infusion, the latest evaluable timepoint at data cut-off. Neither participant had any SCD-related VOEs after infusion of the cellular product. The proportion of edited alleles in the peripheral blood of Participant 1 was maintained at over 60% until Mo 6, which was the last evaluable timepoint (Fig. 1B). The indels were diverse, except for a predominant, large 5 kb deletion arising from simultaneous double-stranded DNA cleavage at HBG1 and HBG2 on-target sites, similar to previous reports. Conclusion: Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation. Taken together, these data suggest that this approach is safe and offers a potentially curative option for patients with severe SCD. Using cryopreserved, CD34+ cells as a starting material offers the advantage of centralizing manufacturing, scaling up the process to allow for improved patient access around the globe. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Heterogeneity of the long-term economic burden of severe sickle cell disease: a 5-year longitudinal analysis

Background Sickle cell disease (SCD) is a lifelong burdensome disorder of heterogenic expression. This study investigated the longer-term economic burden of severe presentation of SCD. As SCD treatment landscapes evolve toward curative intent gene therapies, understanding how SCD-associated costs may change over the patient lifetime will be important for medical decision-making. Methods Patients with severe presentation of SCD (presence of acute vaso-occlusive events [VOEs] or history of stroke and/or other disease-related sequelae), were identified within the MarketScan Commercial and Medicare Supplemental and Multi-state Medicaid Databases from 1/1/2010 to 12/31/2018. The first SCD claim served as the index date and patients were followed over a 5-year post-period. Clinical characteristics and healthcare resource utilization and costs were assessed over follow-up for eligible cohorts of commercial and Medicaid patients with severe SCD presentation and age-based subgroups (<18, 18–30, and ≥31). Results A total of 4,487 patients, primarily insured via Medicaid (79.2%), qualified for the analysis. Patients evidenced persistent VOEs over follow-up; prevalence of most comorbidities increased with age. Mean total healthcare costs over the 5-year follow-up were $275,143 (SD± $406,770) and $362,728 (SD± $620,189) in the commercial and Medicaid samples, respectively. Disease severity, assessed by the number of VOEs and utilization of inpatient and emergency services, peaked in the 18–30 year group in both samples. These groups also evidenced the highest mean healthcare costs over the 5-year follow-up at $344,776 (SD± $434,521) and $671,321 (SD± $938,764) in the commercial and Medicaid samples respectively. Conclusion Results indicate high clinical need and economic burden among patients with severe presentation of SCD. These findings not only highlight the need for improved therapeutic options to limit or prevent disease progression, but also start to provide insight on lifetime costs of SCD that will be needed in the evaluation of emerging curative intent therapies.

CLINICAL AND GENETIC FACTORS ASSOCIATED WITH OSTEONECROSIS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS: CASE-CONTROL STUDY

Sickle cell disease (SCD) includes a group of hereditary disorders characterized by mutations on the gene that codes hemoglobin (Hb). Patients with SCD are vulnerable to vascular occlusion within bone tissue, which may result in complications such as medullary infarction in the diaphysis and osteonecrosis (ON), which affects the epiphysis. Both processes may result in substantial morbidity and pain for the patients. This study aims to identify factors associated with the development of ON in patients with SCD. A nested case-control study of patients with SCD from six Brazilian blood centers, participating in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Brazil SCD Cohort was performed. A history of ON was abstracted from participants medical record using standardized definitions to define cases. Cases were matched to controls without ON in a 1:3 ratio matched by age, genotype and blood center using propensity score. A genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms (SNPs) associated with ON. There were 307 ON cases in the 2793 cohort participants (prevalence 11%) who were compared to 921 controls without ON. The most common locations of ON were the proximal femur (91.2%) and proximal humerus (7.7%). Variables independently associated with ON in a multivariable model included patients with more severe sickle cell disease (SS, Sβ0, severe Sβ+ or SD genotypes, OR 1.81, 95% CI 1.11; 2.95 compared to less severe genotypes SC/SB+), higher values of hemoglobin (OR 1.25, 1.12; 1.39), hospitalization by pain crisis (OR 1.44, 1.06; 1.94), chronic transfusion treatment (OR 1.53, 1.10; 2.11), acute chest syndrome (OR 1.46, 1.06; 2.00), sepsis/bacteremia (OR 1.67, 1.03; 2.70) and osteomyelitis (OR 1.72, 1.05; 2.80). Increased indirect bilirubin and stroke were associated with a lower chance of developing ON (OR 0.81, 0.71; 0.93 for indirect bilirubin and OR 0.42, 0.24; 0.72 for stroke). The GWAS suggested an association of ON with the gene doublesex and mab-3 related transcription factor 2 (DMRT2) (p < 5 × 10−8). SCD is the most common monogenic disorder in Brazil and is associated with multisystem complications. Orthopedic complications represent 31.0% of these manifestations, with ON being the most common non-infectious joint complication. Knowing the risk factors that precede ON may help to diagnose and treat it early in order to improve the quality of life of patients. The few studies carried out in the Brazilian population on the occurrence of ON in SCD patients had small sample sizes. A higher chance of having ON was associated with patients with higher hemoglobin levels, more hospitalizations for pain crises and acute chest syndrome. Also the relationship of treatment with chronic transfusion, sepsis/bacteremia and osteomyelitis were associated with ON, which may indicate that the occurrence of this complication may be multifactorial or related to the severity of SCD. SNPs near DMRT2, a gene previously associated with skeletal disorders, rib malformation in a newborn and transition of endochondral bone formation, showed an altered risk for ON.

Clinical Presentations and Predictors of Severe Sickle Cell Disease among Patients Who Attended Muhimbili National Hospital Dar-Es Salaam, Tanzania: A Retrospective Study

Inherited hemoglobinopathies led by Sickle Cell Disease (SCD) are key contributors to the anaemia burden in Sub-Saharan Africa (SSA). In Tanzania, an estimated six out of one thousand newborns are born with SCD, making Tanzania the fourth country with the highest burden of SCD patients in the world and the third in Africa after Nigeria and the Democratic Republic of Congo (DRC) (Nigeria 85,000, Democratic Republic of Congo 42,000 and Tanzania 11,000).

Allogeneic Bone Marrow Transplantation from Haplomatched Sibling Donor in a Pediatric Patient with Sickle Cell Disease with Multiple Painful Crises: An Experience

Bone marrow transplantation is the only cure for sickle cell disease but this curative therapy unfortunately lead to complication and several times death. Bone marrow transplantation indicated only for sickle cell patients with severe sickle cell disease who have complications including strokes, acute chest syndrome, recurrent pain crisis and exchange transfusions, nephropathy retinopathy, osteonecrosis of multiple joints and priapism. All sickle cell patients are not eligible for bone marrow transplantation due to associated toxicity [1]. Transplant is performed when benefit outweighs the risk. There has been much development and improvement in the bone marrow transplant since the first transplant done in 1984. This technique includes using chemotherapy for conditioning to remove the recipients cells and replacing it with donor cells free of sickling. Main problem limiting the transplant to all patients include getting a matched donor, risk associated with the procedure; including graft vs. host disease and cost. Hematopoietic stem cell transplant is safest when a matched donor is available. Even with this, there is still risk of graft rejection and chronic graft verses host disease. The unrelated cord blood stem cell transplant and haploidentical stem cell have been found to be less successful due to an increase in graft vs. host disease. Bone marrow transplantation has helped in improving the quality of life of the patient by eliminating the repeated hospital admission [2].

Hematopoietic Stem Cell Transplantation Stabilizes Cerebral Vasculopathy in High-Risk Pediatric Sickle Cell Disease Patients: Evidence From a Referral Transplant Center.

BackgroundSevere sickle cell disease (SCD) can present with different vaso-occlusive manifestations with cerebral vasculopathy (CV) as one of the most serious complications. Hematopoietic stem cell transplant (HSCT) is the ultimate therapy for this complication. The aim of this study was to assess the outcome and impact of HSCT on severe SCD patients with CV complications.MethodsTwenty-five consecutive transplants-naive pediatric SCD patients with CV complications underwent HSCT at our institution between 1993 and 2015, using bone marrow as stem cells source from fully match related donors were included. Neurologic evaluation was done both clinically and radiologically before transplantation and regularly following the HSCT.ResultsWith a median follow-up of 52.2 ± 5.8 months, the cumulative probability of overall survival (OS) at 3 years was 92.0% and event-free survival (EFS) was 88%. Significant neurologic improvements were observed in most of the patients clinically. Different neurologic complications were assessed. The neurologic manifestations before and after HSCT were hemiparesis (11, 1), seizures (13, 8), focal neurologic deficit (4, 2), loss of conscious (2, 1) headache (6, 1), and psychological symptoms (5, 2). Post-HSCT radiological imaging was done in 15 patients, which showed stabilization of CV among all.ConclusionsAllogeneic HSCT in patients with severe SCD presenting with CV complications including moyamoya vasculopathy showed favorable outcome with significant clinical neurologic improvement and stabilization of the disease. None of the patients with severe vasculopathy underwent neurological vascular by-pass surgery prior to HSCT.

S128: CONTINUOUS QUALITY IMPROVEMENT IN PAEDIATRIC SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) is characterised by severe episodic pain requiring prompt and effective analgesia. However, SCD patients frequently experience poor quality of care due to lack of awareness of the condition among non- specialist staff, pre-conceived biases and unfounded allegation of drug-seeking behaviour. Several reports and surveys using Patient Reported Experience Measure (PREM) tools indicate widespread prevalence of ineffective pain relief in emergency department(ED), poor access to psychological therapies and poor funding for service development. Aims: To use a validated PREM tool to survey patients or carers of sickle cell disease within the paediatric service of a Specialist Haemoglobinopathy Team. To use an established Continuous Quality Improvement (CQI) methodology (5-D’s-define, describe, design, deliver, digest) to ensure sustained improvement in patient- reported areas of service deficit. Methods: The PREM survey was conducted as part of a network- wide initiative in 2018. The survey responses were analysed and problem scores created for specialist care, emergency care, ward-based care, information and support. These problem areas were categorised into domains where further improvement action was needed. CQI tools were used to map the patient journey within Emergency Department (ED) when presenting with pain followed by thematic analysis to identify potential improvements in the patient journey. Results: The PREM survey analysis identified three domains for improvement: Domain A: To improve the effectiveness of pain relief and quality of empathic and informed care to paediatric sickle cell patients and their families in ED. We developed multi-disciplinary teaching videos with patient involvement and patient information material based on ED/pain/sickle staff feedback. Excellent engagement from all staff groups obtained. Patient involvement in ED teaching video was well received. Thematic analysis of ED process mapping highlighted need for sustained staff education and re-writing ED pain protocol to align with current practice. Pre-conceived biases were identified among staff with respect to attributing drug-seeking behaviour to patients during severe sickle cell pain. Domain B: To improve the information presented to children regarding SCD and the care services available in our trust We developed child friendly Information leaflets targeting primary school age and secondary school age readers Domain C: To improve the availability of, and access to, mental health services for paediatric SCD patients. We developed virtual parent support groups and psychological health screening for adolescent patients in clinics. We organised a ‘Tree of Life’ (ToL) patient empowerment workshop. The parent support groups were well attended. Plans are in place to continue ToL workshops and support groups on a regular basis. Future work: A rapid improvement workshop is being planned to engage a wider multi-disciplinary team to engender a culture of empathy in line with our trust values. Further input from workshop is expected to identify and implement sustainable goals. We plan to undertake a repeat PREM survey following the end of this CQI project to understand the impact and the implemented improvements.