SCD-related Events Research Articles

Hematopoietic Cell Transplant compared with Standard Care in Adolescents and Young Adults with Sickle Cell Disease.

Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2-years after biologic assignment to a Donor or No Donor (SOC) Arm based on the availability of an HLA-matched sibling or unrelated donor (BMTCTN 1503; NCT02766465). A donor search was commenced after eligibility confirmation. The primary endpoint was the comparison of survival 2 years after biologic assignment between treatment arms. Power calculations required 60 participants on the Donor Arm and 140 on the No Donor Arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives compared changes in SCD-related events, functional outcomes, and organ function. Data were analyzed by the intent-to-treat principle. A total of 113 participants were enrolled, 28 on the Donor and 85 on the No Donor Arm The 2-year probabilities of survival were 89% and 93%, on the Donor and No Donor Arms, respectively. Vaso-occlusive pain (VOC) was less frequent on the Donor Arm in the second year after biologic assignment (p < 0.001). On PROMIS-57 surveys there was decreased fatigue (p=0.003) and an increased ability to participate in social roles and activities (p=0.003) on the Donor Arm 2-years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the Donor Arm led to improvements in VOC, fatigue, and social function.

Distinct Phenotypic Groups and Related Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes. This retrospective study analyzed 1231 consecutive patients with HCM from 2 tertiary hospitals. We performed latent class analysis to categorize patients into phenotypic groups. Three distinct phenotypic groups were identified using latent class analysis. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular events, 133 all-cause mortality events, and 70 noncardiovascular mortality events were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 versus 2 versus 3: 0.8% versus 8.2% versus 4.0%, respectively, P<0.001), and cardiovascular events were more frequent in Groups 2 and 3 compared with Group 1. All-cause and noncardiovascular mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance. This study identified 3 distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.

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

Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥12years with ≥4 vaso-occlusive events (VOEs) in the past 24months. We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses. Patients treated with lovo-cel were predicted to survive 23.84years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs. Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.

Antinuclear and Specific Autoantibodies Predict Autoimmune Disease in Sickle Cell Patients: A Longitudinal Cohort Study

Introduction: Sickle cell disease (SCD), the most frequent genetic disorder, can be associated with systemic autoimmune diseases (ADs). High levels of antinuclear antibodies (ANA) are commonly described in SCD, as alloimmunization after blood transfusion. However, the specificity and the prognostic value of ANA have not been fully determined. We aimed to evaluate the association of ANA with AD development during long-term follow-up in SCD patients. Our secondary goal was to assess mortality and serious SCD-related events in this population. Patients and methods: We conducted a single-center longitudinal cohort study on 66 adult SCD patients with ANA titers ≥1/320 at baseline followed over a 13 year-period. Patients known to have an AD (n=9) were excluded from the risk analysis. Results: During follow-up, 13 out of 57 patients (23%) developed AD. Patients with ANA titers ≥1/1280 had a 3-fold increased risk of developing AD (RR 3.4[1.4;8.6]) and a 9-fold increased risk in the presence of specific autoantibodies (anti-DNA, anti-ENA, RF or ACPA) (RR 9.0[3.7;23]) with a positive (PPV) and negative predictive value (NPV) of 90%. When these two immunological features were associated, specificity and PPV reached 100%, with a NPV of 84%. There was no significant difference in the occurrence of serious SCD-related events or mortality rate according to AD. Conclusions: Sickle cell patients with high level of antinuclear antibodies and specific autoantibodies are at high risk of developing AD. The occurrence of AD does not seem to have a significant impact on the course and severity of SCD.

Cardiac MRI to Predict Sudden Cardiac Death Risk in Dilated Cardiomyopathy.

Background Sudden cardiac death (SCD) is one of the leading causes of death in individuals with nonischemic dilated cardiomyopathy (DCM). However, the risk stratification of SCD events remains challenging in clinical practice. Purpose To determine whether myocardial tissue characterization with cardiac MRI could be used to predict SCD events and to explore a SCD stratification algorithm in nonischemic DCM. Materials and Methods In this prospective single-center study, adults with nonischemic DCM who underwent cardiac MRI between June 2012 and August 2020 were enrolled. SCD-related events included SCD, appropriate implantable cardioverter-defibrillator shock, and resuscitation after cardiac arrest. Competing risk regression analysis and Kaplan-Meier analysis were performed to identify the association of myocardial tissue characterization with outcomes. Results Among the 858 participants (mean age, 48 years; age range, 18-83 years; 603 men), 70 (8%) participants experienced SCD-related events during a median follow-up of 33.0 months. In multivariable competing risk analysis, late gadolinium enhancement (LGE) (hazard ratio [HR], 1.87; 95% CI: 1.07, 3.27; P = .03), native T1 (per 10-msec increase: HR, 1.07; 95% CI: 1.04, 1.11; P < .001), and extracellular volume fraction (per 3% increase: HR, 1.26; 95% CI: 1.11, 1.44; P < .001) were independent predictors of SCD-related events after adjustment of systolic blood pressure, atrial fibrillation, and left ventricular ejection fraction. An SCD risk stratification category was developed with a combination of native T1 and LGE. Participants with a native T1 value 4 or more SDs above the mean (1382 msec) had the highest annual SCD-related events rate of 9.3%, and participants with a native T1 value 2 SDs below the mean (1292 msec) and negative LGE had the lowest rate of 0.6%. This category showed good prediction ability (C statistic = 0.74) and could be used to discriminate SCD risk and competing heart failure risk. Conclusion Myocardial tissue characteristics derived from cardiac MRI were independent predictors of sudden cardiac death (SCD)-related events in individuals with nonischemic dilated cardiomyopathy and could be used to stratify participants according to different SCD risk categories. Clinical trial registration no. ChiCTR1800017058 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Sakuma in this issue.

Interim Safety and Efficacy Results from a Phase 1/2 Study of Zinc Finger Nuclease-Modified Autologous Hematopoietic Stem Cells for Sickle Cell Disease (PRECIZN-1)

Introduction Sickle cell disease (SCD) is caused by pathologic variants in both alleles of the β-globin gene. Elevated fetal hemoglobin (HbF) levels inhibit sickle cell formation and ameliorate symptoms and improve survival in patients with SCD (Hebert, Am J Hematol, 2020;95:1235-45). BIVV003 is a novel therapeutic product comprising autologous CD34+ hematopoietic stem precursor cells (HSPC) modified ex vivo by zinc finger nucleases (ZFN) targeting specifically the BCL11A gene erythroid-specific enhancer (ESE) to increase endogenous HbF production in erythrocytes (RBC). Methods PRECIZN-1 (NCT03653247) is an ongoing first-in-human, open label, single arm, multi-center study evaluating safety and tolerability of BIVV003 (n=8; aged 18-40 years) with severe SCD. Eligible subjects underwent mobilization and apheresis with plerixafor 240 ug/kg/day for up to 3 days to collect autologous CD34+HSPCs for manufacturing of BIVV003. HSPCs were transfected ex vivo with ZFN mRNAs targeting the ESE region of the BCL11A locus to manufacture BIVV003. After myeloablative conditioning with busulfan 3.2 mg/kg/day intravenously (IV) for 4 days with dose adjustment based on pharmacokinetics, subjects received BIVV003 as a single minimum dose of 3× 106 CD34+ HSPC/kg IV. Subjects were monitored for stem cell engraftment and hematopoietic recovery, adverse events (AEs), clinical and laboratory hemolysis markers, total hemoglobin (Hb) and HbF, RBC containing HbF (F cells), and SCD-related events for up to 104 weeks post-BIVV003 infusion. Results As of the cutoff date of 03 May 2022, 4 subjects have received BIVV003 infusions up to 125 weeks of follow-up. A fifth subject was dosed with BIVV003 on 04 May 2022 and has engrafted. Among the 5 subjects, the male:female ratio is 3:2, the age range is 18-35 years, and 4 have genotype HbSS and 1 HbS-β0. No subject has required HSPC rescue; all subjects had hematopoietic reconstitution without requiring RBC or platelet transfusions for more than one month post-BIVV003 infusion. The average time to neutrophil and platelet engraftment was 23 days and 33 days, respectively. In bone marrow aspirates 26 weeks post-infusion, the frequency of cells containing indels at the BCL11A ESE target locus was in the range of 17.1-34.1%. No clonal dominance has been observed in bone marrow or peripheral blood cells. By Week 26, all 4 subjects reached a protective level of ≥ 10 pg HbF/F cell that inhibits HbS polymerization (Steinberg, Blood, 2014;123:481-485), and this level was sustained in 3 out of 4 subjects through the most recent assessment at Week 104, 78, and 52, respectively, along with F cell levels of 90% or higher. The change in total Hb from baseline (at screening) to the latest visit was -0.3-3.1 g/dL, and the HbF fraction increased to 12.2-41.2% (Figure 1). Three subjects have had no recurrence of severe vaso-occlusive crises (VOCs) post-infusion, compared to experiencing 6 to 22 severe VOCs in the 2 years pre-study. The one subject who did not sustain a HbF/F level ≥ 10 pg experienced 2 severe VOCs at 9 and 16 months post-infusion. The adverse events (AEs) reported were consistent with plerixafor mobilization and busulfan myeloablative conditioning. No AEs related to BIVV003 were reported. Conclusions The interim safety and efficacy results reported here confirm the potential therapeutic value of ZFN-mediated modification of the BCL11A ESE region and BIVV003 infusion to address current unmet needs of patients with SCD. BIVV003 has been well tolerated in the 5 subjects infused to date, with no AEs related to BIVV003. Three of the 4 subjects infused and with over 52 weeks of follow-up have had stable engraftment of ZFN-modified HSPCs resulting in sustained elevated HbF levels and absence of severe VOCs post-BIVV003 administration. A fifth subject received BIVV003 manufactured using an improved process that has shown in internal experiments to increase the number of ZFN-modified long-term progenitors in the drug product. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Promis Pediatric Profile Parent Proxy 25 with Clinical and Functional Outcomes in Pediatric Sickle Cell Disease Patients

Background: Patient reported outcomes (PROs) can be critical in allowing the clinical team to understand patients' perspectives on their quality of life (QoL) and functioning. PROs can serve as a basis for fostering shared decision making and individualized care. Patients with sickle cell disease (SCD) often experience a high symptom burden and PROs can be an important tool for improving patients' health. In the case of pediatric patients, guardian proxy reports may give additional insight since children may be too young to complete assessments themselves. Additionally, guardian perceptions can influence healthcare-related decision making. Understanding the relationships between guardian-reported PROs with clinical outcomes, such as healthcare utilization, and functional impairment may provide a valuable tool for shaping clinical decisions. Here, we examine the relationships between the six domains of QoL using the parent proxy version of the Patient Reported Outcome Measurement System (PROMIS), healthcare utilization and functional limitations in children with SCD. Methods: Pediatric patients and their guardians between the ages of 5 and 18 were approached while attending outpatient appointments at Children's Hospital of Richmond Comprehensive Sickle Cell Clinic. Children who were ill or in pain were excluded from enrollment during that visit. Consented guardians (n=43) completed a demographic questionnaire that included questions on recent healthcare utilization followed by the PROMIS Parent Proxy Pediatric Profile-25 with short forms assessing depression and sadness, pain interference, fatigue, anxiety and fear, mobility, and peer relations during the prior seven days. Outcome variables of interest included emergency department (ED) utilization and hospitalizations in the previous six months; acute SCD-related events in the prior year (acute chest syndrome, right upper quadrant syndrome, skeletal and joint issues, hand/foot issues, CNS involvement, acute anemia, sepsis, priapism), missed school days/planned activities due to SCD pain in the prior 30 days as well as academic performance. Counts and percentages were used to describe characteristics of children and guardians; t-tests were used to examine the relationship between domains of the PROMIS and outcome variables of interest. Specifically, we dichotomized all outcomes of interest, and then examined the means and 95% confidence intervals of the dichotomized groups for each of the PROMIS domains. Results: Demographic characteristics of both guardians and children are described in Table 1. Thirty five percent of participants had a hospitalization and 44% had an ED visit in the previous six months, 33% had an acute SCD event in the prior year, 62% reported one or more missed days of school/activities and 38% reported grades lower than a B. Healthcare utilization (ED visit and hospitalization) and acute medical events were all significantly associated with higher levels of proxy-reported pain interference, fatigue, and anxiety/fear; ED visits was also associated with higher levels of proxy-reported depression and sadness (Table 2). Missed days of school were associated with greater proxy-reported pain interference and decreased mobility while none of the domains were associated with grades achieved. Conclusions: Despite being administered during non-sick visits, multiple PROMIS Parent Proxy Pediatric Profile-25 domains that assessed QoL in the past seven days were associated with previous healthcare utilization in the past six months, acute medical events in the past year and missed school days in the past month. PROs can provide valuable information to clinicians, suggesting both the importance of addressing QoL outcomes for patients with recent healthcare events and the usefulness of guardian responses. The association of these PROs with clinical outcomes suggests that the PROMIS may be used prospectively to help identify and prevent further disease-related impairment and healthcare use. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Insights from cardiopulmonary exercise testing in pediatric patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is characterized by extremely varied phenotypic expression ranging from asymptomatic to heart failure (HF) to sudden cardiac death (SCD). Although children with HCM are considered in the highest risk spectrum, the most common recommendations on pharmacological and non-pharmacological treatment (i.e. drugs, ICD, septal reduction procedures, inclusion in cardiac transplantation list) are often disregarded or too much postponed in this setting and strong evidence-based risk prediction models are missing. A systematic cardiopulmonary exercise test (CPET) assessment might be helpful to disclose an unsuspected functional limitation. Purpose The aim of our multicenter retrospective study was to investigate possible clinical insights, in terms of functional and prognostic assessment, coming from a full CPET assessment in a cohort of pediatric HCM outpatients aged less than 18 years old. Methods Sixty consecutive pediatric HCM outpatients aged &amp;lt;18 years-old were enrolled, each of them undergoing a full clinical assessment including a CPET; a group of 60 healthy subjects served as controls. An unique composite end-point of HF-related and SCD or SCD-equivalent events was also explored. During a median follow-up of 53 months, a total of 13 HF- and 7 SCD-related first events were collected. Results An impaired exercise capacity, consisting on peak VO2 values &amp;lt;80% of the predicted, has been found in the 78% of the study sample (n. 47 patients). Despite most of the HCM patients were classified in NYHA I functional class, most of them (n. 33, 73%) showed a reduced exercise capacity, the percentage of impaired exercise capacity raising in the NYHA II group (n. 14 patients, 93%). Respect to the control Group, the HCM patients showed a significantly poorer functional status in terms of maximum workload achieved, peak VO2 (regardless the adopted correction), circulatory power and VE/VCO2 slope values (Figure 1, panel A). HCM patients who experience adverse events during the follow-up (Event Group) showed the worst CPET profile (Figure 1, panel B). The composite end-point occurred more frequently in patients with the worst CPETs' profiles. At the univariate analysis, peak VO2% was the variable with the strongest association with adverse events at follow-up (C-index=0.72, p=0.025) and a cut-off value equal to 60% was the most accurate in identifying those patients at the highest risk (Figure 2). Conclusions Our findings support the role of CPET analysis as an insightful approach in the young HCM clinical management. In a group of young asymptomatic or slightly symptomatic HCM patients, the CPET allowed us to estimate accurately their functional capacity and to disclose a portion of un-recognized exercise impairment. Our data argue in favor of a possible role of some CPET-derived variables in the early identification of those young HCM patients at highest risk of HCM related events. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed By Newborn Screening: A Real-World Nation-Wide Study in France

Background: The goals of newborn screening programs (NBS) for sickle cell disease (SCD) are to reduce early mortality and morbidity, by introducing preventive measures like penicillin prophylaxis, pneumococcal vaccines and Transcranial Doppler (TCD) screening. The main objective of this study (NCT 03119922) was to assess on a national scale and during the first 5 years residual risks of death, overt stroke and bacterial meningitis/septicemia resulting from current TCD and pneumococcal prophylactic utilization in SCD children diagnosed at birth. An additional objective was to determine the frequency of other main SCD-related events and the use of disease-modifying or curative therapy. Methods: Using the national NBS database between 2006-2010, data was collected in 2014/2015 from the patients' medical files up to the age of 5 years, and included age at first prescription of penicillin, occurrence of death/overt stroke/bacterial meningitis and septicemia, age at first transfusion (TF), use of pneumococcal vaccines/chronic transfusion program/hydroxyurea (HU)/hematopoietic stem cell transplantation (HSCT) and TCD results. Results: Out of 1792 eligible subjects, 152 (8%) were lost to follow-up. A total of 1620 patients with available follow-up data across 69 centers constituted the EVADREP cohort. Of them, 71.8% had SS or S beta°-thalassemia (SB°) while 20.3% had SC /S Beta+-thalassemia (SB+) disease, and 59.6% resided in Paris area. Overall mortality rate for all patients was 0.23/100 person-years during the 5 first years of life and probability of survival at 5 years was 98.9% (95%CI: 98.2-99.3), with 18 deaths during the study period, 12 related to SCD (11 patients SS or SB°). The probability of overt stroke at 5 years was 1.1% all in SS/SB° patients. DTC was performed in 56% and 81% of patients before 2 and 3 years of age, respectively. The probability of abnormal TCD at 5 years was 10.4%. A total of 26 patients had a severe infection (meningitis or septicemia), lethal in 8 cases and caused by a pneumococcal strain in 8 cases. More than 99% of patients were prescribed prophylactic penicillin, started at a median age of 2.2 months of life. Full pneumococcal vaccination (at least 4 PCV and one P23) was performed in only 47.4% before 3 years but the probability of receiving P23 was 90% at 5 years. At 3 years, 42.9% of the EVADREP cohort had experienced a first VOE and the probability of survival without VOE was 62.4% [60.0-64.8] at 5 years. When pooling all SCD-related events (death, stroke, severe infection, VOE, acute anemia, as well as abnormal DTC, pneumonia and/or ACS and transfusion), 58.6% of children had experienced at least one event at 3 years. The probability of survival without SCD-related events at 5 years was 10.7% [0.9-12.6] for SS/SB° patients and 46.3% (41.5-51) for SC/SB+. In sharp contrast, HU was prescribed in 13.7% and HSCT performed in 9 patients only. Vaccination and DTC coverage, use of TF program and HU were significantly higher in larger centers. Summary/Conclusion: Current residual risks of severe complications and mortality rates on a national scale are similar to those observed in SCD expert center cohorts, presumably as a result of good TCD and vaccination coverage and an easy access to health care in France. Further improvement could be achieved with better referral to centers of expertise. The burden of disease is still high and increased use of disease modifying or curative therapy should benefit more children in the future. Disclosures Brousse: Add medica: Consultancy; bluebird bio: Consultancy. Bernaudin:BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France.

This study’s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006–2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

Long-term outcome of conservative and invasive treatment in patients with hypertrophic obstructive cardiomyopathy

Background and objective: Treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM) can be either conservative or invasive (alcohol septal ablation (ASA) and myectomy). As there is no clear consensus on the long-term effects of these different strategies, the aim was to compare the long-term outcome in a large tertiary referral university hospital. Methods: We retrospectively included 106 HOCM patients. Twenty-nine (27.4%) patients were treated conservatively, 25 (23.6%) underwent ASA and 52 (49.0%) myectomy. Endpoints were all-cause mortality and sudden cardiac death (SCD)-related events (including SCD, aborted SCD and appropriate ICD shocks). Kaplan–Meier survival analysis and Cox proportional hazard regression models were used. Results: The mean follow-up period was 7.7 ± 4.9 years. Overall, there was no significant difference in survival between the three treatment strategies (p = 0.7). Annual rates of SCD-related events at 5 years and the complete follow-up period were significantly higher (p = 0.034) after conservative treatment (4.9%/year and 2.7%/year, respectively) compared to ASA (0.9%/year, 0.5%/year) and myectomy (1.0%/year, 0.6%/year). Independent predictors of SCD-related events were: conservative treatment (HR 10.66; 1.88–60.55), a known mutation (HR 9.36; 1.43–61.20), left ventricular wall thickness (LVWT) > 30 mm (HR 6.48; 1.05–39.92) and non-sustained VT (HR 16.82; 2.29–123.29). Invasive treatment resulted in a significant higher proportion of patients requiring pacing (p = 0.033). Conclusions: Long-term mortality rates for patients with HOCM are similarly low between treatment groups. However, conservative treatment was associated with SCD-related events, as were known mutations, increased LVWT and non-sustained VT. Invasive treatment was associated with a higher need for implantation of a pacemaker.

Impact Of Use Of a Disease-Specific Patient Portal On Transition Readiness and Quality Of Life In Adolescents With Sickle Cell Disease

IntroductionDisease-specific patient portals use technology to provide patients with easy access to health information and have been shown to promote healthy behaviors, encourage self-care, and assist with informed decision-making. Most of the available studies, however, have failed to examine the feasibility of patient portals with adolescent/young adult, vulnerable or underrepresented populations. As a first step toward enhancing patient access to medical information and better understanding how to engage adolescent/ young adult, diverse and vulnerable populations in using a patient portal, we designed and refined a disease-specific version of an existing patient portal (MyChart) for use with adolescents and young adults with sickle cell disease (SCD). We then piloted the patient portal with the goal of understanding the impact of the intervention on quality of life and transition readiness outcomes. We hypothesized that the patient portal would be rated as feasible, accurate and useful, and that use of the patient portal would be positively associated with transition readiness and increased quality of life. MethodsPatients were recruited from a Comprehensive Sickle Cell Center at an urban pediatric medical center in the Midwest through letters, at clinic visits and at SCD-related events. The current study reports data from a sample of participants who have been followed 6 months post-intervention. At each time point (Baseline, Post, 3, 6 Months Post-Intervention), participants completed a series of measures including the Pediatric Quality of Life Inventory (PedsQLTM) and an item asking about their readiness to transition to the adult healthcare system. The patient portal intervention consisted of four assignments to facilitate familiarity with the portal (e.g. graphing a test result). All participants completed these assignments over the 6-week intervention. ResultsAll participants in the study were African American (N=20; 60% male) with a mean age of 19.4 years (SD = 2.08). Ninety percent had HbSS (5% HbSC; 5% HbSB+Thal). At the post-intervention time point, the portal was rated as feasible (M = 3.3/5) and useful (M = 4.3/5). Data indicated that participants viewed/used the following portal features most often: 1) Lab results, 2) Medications, 3) Messaging, and 4) Appointment Review. Patients logged in an average of 6.59 times over six months (range: 0-39). Portal use was analyzed categorically as non-users (with zero independent logins after the intervention period) and users (with one or more independent logins after the intervention period). Sixty percent (n=12) of participants were users, whereas 40% were non-users. Portal patients reported increasing readiness to transition over the follow-up period (Post M = 2.3/5; 3-month M = 3/5; 6-month M = 3.6/5). Finally, a repeated measures ANOVA determined that Total PedsQLTM scores increased significantly over time, (F(3) = 2.98, p = .05). Post hoc tests using Bonferroni correction revealed the largest increase in Total PedsQL scores between the post-intervention and 3-month time points. Although this increase was not statistically significant, there was a significant correlation between transition readiness and Total PedsQL scores at the 3-month time point. DiscussionStudy results suggest that participants found the disease-specific patient portal easy to use and beneficial to their overall health management. Participants also showed improvements in quality of life across the post-intervention time period, suggesting that use of a patient portal may have served to bolster quality of life in this sample. Study participants further reported increased readiness to transition, which was positively associated with quality of life at 3 months post- intervention. Despite the small sample size, results of this study help to increase our understanding of the relationship between portal use and health and transition outcomes. This intervention shows promise in engaging SCD adolescent/ young adult patients in clinical care and disease management that can ultimately be evaluated in a larger multi-site study.This study was funded in part by NHLBI Grant#: 1K07HL108720-03 and the Cincinnati Children's Hospital Medical Center Place Outcomes Award. Disclosures:No relevant conflicts of interest to declare.

A Phase 2 Clinical Study of HQK-1001 (2,2-dimethylbutyrate, sodium salt), a Fetal Hemoglobin Inducer, in Patients with Sickle Cell Disease

Abstract 1066▪▪This icon denotes a clinically relevant abstractFetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943).This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period. [Display omitted] Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events. Disclosures:Aiello:HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.

Mixed haematopoietic chimerism for sickle cell disease prevents intravascular haemolysis

Mixed haematopoietic chimerism for sickle cell disease prevents intravascular haemolysis

Effect of active prenatal management on pregnancy outcome in sickle cell disease in an African setting

AbstractSickle cell disease (SCD) is associated with an increased risk of medical complications during pregnancy. In sub-Saharan Africa, fetal and maternal mortality rates are particularly high. This study evaluated the effect of an active prenatal management program on pregnancy outcome in patients with SCD in an African setting. Pregnant women with SCD attending the National Teaching Hospital in Cotonou (The Republic of Benin, West Africa) were recruited before the 28th week of gestation. Management was based on providing information and education about SCD and improving nutritional status, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion. Maternal and fetal mortality rates and SCD-related morbidity were the principal variables assessed. One hundred and eight patients (42 SS and 66 SC) with 111 fetuses were included in the study. Thirteen fetal deaths (from 9 SS and 4 SC mothers) were recorded and 2 deaths of SC mothers. The maternal mortality rate of 1.8% was comparable with the overall maternal mortality rate for this maternity unit (1.2%). Few SCD-related events were recorded. Plasmodium falciparum malaria infection was the major cause of morbidity. Sixty-three patients (19 SS and 44 SC) successfully completed their pregnancy (58.3%) without requiring transfusion. Providing pregnant SCD patients with relevant medical care based on simple cost-effective approaches can have a positive impact on SCD-associated morbidity and mortality in an otherwise difficult setting in Africa.

Effect of active prenatal management on pregnancy outcome in sickle cell disease in an African setting

Sickle cell disease (SCD) is associated with an increased risk of medical complications during pregnancy. In sub-Saharan Africa, fetal and maternal mortality rates are particularly high. This study evaluated the effect of an active prenatal management program on pregnancy outcome in patients with SCD in an African setting. Pregnant women with SCD attending the National Teaching Hospital in Cotonou (The Republic of Benin, West Africa) were recruited before the 28th week of gestation. Management was based on providing information and education about SCD and improving nutritional status, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion. Maternal and fetal mortality rates and SCD-related morbidity were the principal variables assessed. One hundred and eight patients (42 SS and 66 SC) with 111 fetuses were included in the study. Thirteen fetal deaths (from 9 SS and 4 SC mothers) were recorded and 2 deaths of SC mothers. The maternal mortality rate of 1.8% was comparable with the overall maternal mortality rate for this maternity unit (1.2%). Few SCD-related events were recorded. Plasmodium falciparum malaria infection was the major cause of morbidity. Sixty-three patients (19 SS and 44 SC) successfully completed their pregnancy (58.3%) without requiring transfusion. Providing pregnant SCD patients with relevant medical care based on simple cost-effective approaches can have a positive impact on SCD-associated morbidity and mortality in an otherwise difficult setting in Africa. (Blood. 2000;96:1685-1689)