ALBERT

Description: Background and purpose: There are no currently approved treatments for the vaso-occlusive crises (VOC) associated with sickle cell disease (SCD). In addition to causing pain, vaso-occlusion and the resulting hypoxia cause a reduction in overall life expectancy and increase chronic morbidity. Sevuparin is a novel, non-anticoagulant, low-molecular weight heparin analogue, with a preclinical multi-modal activity profile against VOC relevant targets (i.e. P- and L-selectin, thrombospondin, Von Willebrand factor, fibronectin). Due to its low risk for bleeding side effects, sevuparin can be dosed at levels that were previously unattainable with heparinoids. The present study evaluated whether sevuparin could shorten the time with VOC in hospitalized SCD patients compared to placebo. Patients and methods: This phase II, global, multicenter, randomized, double-blind, placebo-controlled and parallel group clinical trial enrolled patients aged 12 to 50 with a diagnosis of SCD (HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia). The study recruited patients across 22 sites in 8 countries (Netherlands, Belgium, Turkey, Oman, Bahrain, Lebanon, Saudi Arabia, and Jamaica). Patients with VOC received sevuparin or placebo (1:1) along with standard of care (SoC) therapy with a requirement for parenteral opioid use. The primary endpoint was time to VOC resolution, measured as the time from IMP start until resolution by fulfilment of the two following criteria: a) freedom from parenteral opioid use (8 ± 2 hours), b) readiness for discharge as judged by the patient or physician (whichever occurred first). In addition to assessing safety, main secondary efficacy measures were related to pain and opioid use. The sample size of 120 VOC resolution events was determined based on an assumed between-arm hazard ratio of 0.60. Results: Overall, 147 subjects were randomized (144 dosed) to sevuparin, n=71 (69); or placebo n=76 (75). The median age of subjects entering the study was 22 years with 72% adults and 62,5 % males. Treatment groups were generally balanced with respect to demographic and baseline characteristics. Sevuparin, infused continuously at 18 mg/kg/day, did not confer any benefit over placebo in the primary endpoint of time to VOC resolution (ITT Cox proportional HR 0.89 (95% CI 0.61-1.30; p = 0.554; Figure 1a), which was also reflected by the secondary endpoint analyses (exemplified in Figure 1b). Most AEs were mild to moderate and transient. The number of SAEs was slightly higher in the placebo group (21/17 [22.4%]; one fatal case with hyperhemolytic crisis) than in the sevuparin group (16/15 [22.1%]). The most commonly reported treatment emergent AEs (TEAEs) are displayed in Table 1. No clinically meaningful differences, imbalances or trends were apparent in TEAEs, laboratory parameters, vital signs, physical examination and ECG data across treatment groups. Conclusions: In this study, one of the largest VOC studies run to date, sevuparin failed to show an improvement of the VOC resolution time and associated measures (pain, opioid use, etc) in patients hospitalized with acute VOC. These results were surprising given both the promise from preclinical models and the clinical efficacy seen with selectin inhibition. It is possible that once full-blown, an acute VOC cannot be limited by sevuparin's mode of action (MoA). The understanding of sevuparin's MoA combined with this negative result may contribute to the notions of VOC causative factors and help inform future therapeutics targeting the VOC. The study is also important given its size and the high patient representation from the eastern Mediterranean and Middle Eastern regions, where SCD is of high prevalence. The comparison of this data with the available data from other VOC studies will be important in helping understand both regional and genetic differences in treatment practices and response to therapeutics. In conclusion, the present study showed that sevuparin treatment was not effective in acute VOC. However, sevuparin's promising safety profile and broad MoA including p-selectin inhibition, may warrant further exploration in the prodromal setting, especially given that sevuparin may be dosed by the patient at home in a convenient, subcutaneous format. Acknowledgements: Modus is grateful for the contributions from Ergomed, the Arabian Gulf University, the study sites, as well as to the patients for participating in this study. Disclosures Al-Khabori: Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria. Abboud:CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Inati:Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kristensen:Modus Therapeutics: Employment. Donnelly:Modus Therapeutics: Employment. Ohd:Modus Therapeutics: Employment.

Description: Introduction Sickle cell disease (SCD) is a severe, inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crisis (VOC) and progressive organ damage, resulting in poor quality of life and reduced life expectancy. Improvements in supportive care, use of (exchange) blood transfusions and hydroxyurea have resulted in better survival in SCD children. Nevertheless, SCD related organ damage continues during adult life, resulting in increased morbidity and mortality. Allogeneic stem cell transplantation is currently the only curative treatment option for SCD. In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab + 3 Gy total body irradiation (TBI)) using peripheral blood stem cells has shown promising results in adult SCD patients. In patients treated with this regimen the SCD phenotype resolved with only mild transplantation-related complications, but no reports of graft-versus-host disease (GvHD). However, a large part of these patients did not reach complete donor chimerism and graft failure rates of 8-13% have been reported with this regimen (Hsieh et al. JAMA, 2014; Saraf et al. Biol Blood Marrow Transplant, 2016). Adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism and reduce risk of graft failure. In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI conditioning on donor chimerism and graft failure in patients receiving MSD allogeneic stem cell transplantation for SCD. Methods Adult SCD patients with complications refractory to standard care who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day -10, aiming for HbS

Description: While allogeneic hematopoietic stem cell transplantation (alloHSCT) has extensively been studied in patients with AML

Description: Abstract 1542 Poster Board I-565 Introduction Sickle cell disease (SCD) is characterized by increased oxidative stress playing an important role in the pathophysiology of hemolysis, vascular occlusion and organ damage in sickle cell patients. Sickle erythrocytes are both an important source and target of reactive oxygen species (ROS). Levels of both total and reduced form of glutathione (GSH), a major intracellular anti-oxidant, have been demonstrated to be decreased in sickle erythrocytes, despite the increased de novo synthesis of GSH in these cells. The mechanism leading to this depletion of intracellular glutathione in sickle erythrocytes is not known yet. After reaction with ROS, GSH is oxidized into its oxidized form (GSSG) and can be transported actively out of the erythrocyte. We questioned whether, during episodes of increased oxidative stress, GSSG efflux in sickle erythrocytes is higher than in normal erythrocytes. Materials and methods Erythrocytes of 10 homozygous sickle cell patients and 9 race-matched healthy controls were stimulated with 2,3-dimethoxy-l,4-naphthoquinone (DMNQ), which induces intracellular ROS generation, and hydrogen peroxide (H2O2) to stimulate GSH consumption. Intra- and extracellular levels of GSH and GSSG were measured at baseline and after 210 minutes of DMNQ and H2O2 stimulation. Results While both intra- and extracellular GSSG levels (μM) at baseline were comparable in sickle and control erythrocytes (14.5(11.5–22.7) vs. 14.3(11.6–16.3) and 0.05(0.00–0.19) vs. 0.07(0.00–0.20) respectively), GSSG levels were significantly higher in sickle erythrocytes after 210 minutes DMNQ stimulation (intracellular: 74.4(52.9–93.1) vs. 45.3(40.8–66.7),P=0.005; extracellular: 23.3(18.2–37.3) vs. 13.2(11.1–14.6),P=0.001) which suggests an increased generation of GSSG intracellularly and a resulting elevated efflux to the extracellular environment. These observations were confirmed with H2O2 stimulation of erythrocytes, showing that, while comparable at baseline, the GSSG levels were higher in sickle erythrocytes after 210 minutes stimulation (intracellular: 26.1(22.8–30.1) vs. 17.5(14.2–20.1),P=0.043; extracellular: 6.9(2.3–16.6) vs.1.2(0.6–1.6),P=0.008). In contrast to the control erythrocytes, where intracellular GSH levels remained unchanged, GSH levels decreased significantly in sickle erythrocytes during DMNQ stimulation, suggesting a limited anti-oxidative reserve capacity in SCD. Conclusion GSSG efflux in sickle erythrocytes is increased and results in net loss of intracellular glutathione, rendering sickle erythrocytes more susceptible to oxidative damage. The higher rate of GSH consumption during an episode of oxidative exacerbation in sickle erythrocytes suggests a reduced anti-oxidative reserve capacity in SCD. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Blood transfusions are an important treatment modality for patients with either acute or chronic onset anemia such as trauma, sickle cell disease, and hematological malignancies. Transfusion poses a risk for alloimmunization, which may lead to potentially lethal transfusion reactions. A promising strategy to prevent alloimmunization is extensive matching on blood groups, yet this is a costly procedure and should be reserved for patients at highest risk for alloimmunization. Identification of genetic variants that increase the risk for alloimmunization might help to identify high-risk patients and could be used as a screening tool for patients receiving multiple transfusions. Objectives: To summarize all available evidence on genetic risk factors for alloimmunization after blood transfusion. Design: Systematic review with meta-analysis of observational studies. Studies were only included in the meta-analysis if polymorphisms were tested at least 3 times, and if ethnic background of the population and the control populations were comparable between studies. Data sources: The online databases Embase, MEDLINE and the Cochrane Library were search for relevant articles with search terms: 1) transfusion, 2) alloimmunization 3) genetics. The search was last updated March 2018. Eligibility criteria: 1) Primary study that assessed the association of genetic polymorphisms with transfusion related alloimmunization, 2) a human population, 3) studies with at least 50 patients, 4) full text availability. Data extraction: Two reviewers independently screened articles for eligibility, extracted data using a standardized data extraction form. Extracted data included study setting, study population, participant demographics, baseline characteristics, study methodology, comparisons and outcome, and risk of bias. Primary outcome measure: Alloimmunization after one or more blood transfusions. Risk of bias assessment: The quality of the included studies was assessed by the Q-genie tool for genetic association studies. Results: A total of 2045 cases and 24084 controls were derived from 18 genetic case-control studies that were included in this systematic review. Most commonly studied disease group was sickle cell disease (SCD) (8 studies). Three studies included patients with different diseases and seven studies did not report the underlying disease. Eleven studies identified the association of HLA polymorphisms with alloimmunization and 8 studies focused on non-HLA variants. Overall quality of the included studies was moderate (11 studies), 2 studies were of high quality, and 5 studies were ranked as poor. HLA-DRB1*04 (Odds Ratio 7.16, 95%CI 3.87-13.22, P

Description: Abstract 2661 Background: Patients with sickle cell disease (SCD) develop accumulating organ damage throughout their lives as result of chronic hemolytic anemia and ongoing microvascular vaso-occlusion. Chronic organ damage has been related to significant morbidity and increased mortality. Previous studies have shown significant increased foetal and maternal complications in patients with SCD. It is unclear whether the presence of chronic organ damage is related to pregnancy complications in these patients. Therefore, we determined the relation between chronic organ damage and pregnancy complications in women with SCD. Methods: We performed a retrospective analysis of pregnancy complications in all women known with SCD (defined as HbSS, HbS-β°, HbSC and HbSβ+) in a teaching hospital in the Netherlands. Pregnancy complications consisted of: hypertension, (pre)eclampsia, still birth, preterm birth, dysmaturity, urinary tract infection, perinatal mortality, maternal mortality, painful crisis and acute chest syndrome (ACS). In all patients vaso-occlusion related organ damage (pain rate 〉1 crises/year, ACS, avascular osteonecrosis and retinopathy) as well as hemolysis related organ damage (microalbuminuria, renal failure, pulmonary hypertension, chronic leg ulcers, stroke and cholelithiasis) was assessed. The patients were divided in a severe (HbSS/HbSβ°) and a mild genotype group (HbSC/HbSβ+). Chronic organ damage and the history of previous sickle cell-related complications were related to pregnancy complications, birth weight and laboratory tests. We adjusted for multiple pregnancies with the generalized estimated equations (GEE) model. Results: All 97 female patients known with SCD in our hospital were systematically evaluated for organ damage and sickle cell related complications. Thirty-six patients had not been pregnant at time of evaluation, medical information about their pregnancy was missing for 7 women and 6 women were only known with an elective abortion. Fifty-five pregnancies in 48 women with SCD (18 HbSS, 4 HbSβ0, 21 HbSC and 5 HbSβ+) were evaluated for pregnancy complications. Hemolysis related organ damage was present in 17/22 (77%) of the patients with a severe genotype and 7/32 (22%) patients with a mild genotype (p

Description: Introduction The occurrence of organ damage in sickle cell disease (SCD) is a crucial determinant for both medical treatment and prognosis. In a previous study, we systematically analyzed the prevalence of SCD related organ damage and complications in adult sickle cell patients in a tertiary teaching hospital in the Netherlands. We now describe a seven-year follow-up of this patient cohort, to provide an insight into the course of the various forms of organ damage and SCD related complications. Methods At baseline in 2006, 110 adult patients visiting the outpatient clinic of our hospital were enrolled. All enrolled patients from the primary analysis were included for follow-up. Patients were screened for sickle cell related manifestations during visits to the outpatient clinic biannually. Various forms of sickle cell related organ damage and complications (presence of microalbuminuria, renal failure, pulmonary hypertension retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome, stroke, priapism and admissions for painful crises) were routinely screened according to international guidelines. Patients with genotype HbSS/HbSβ0 and HbSC/HbSβ+were grouped for further analysis. Results Of all originally included patients (N=110), nine were lost to follow-up (N=9). The mean age of the current study cohort is 37 years (IQR 27-46). Overall, 59 patients (58%) developed a new form of organ damage or new complication since baseline analysis, including eight patients who deceased (7 due to a sickle cell disease related death). In the HbSS/HbSβ0 genotype group (N=60) we found an increase in the percentage of patients who have had an Acute Chest Syndrome (29% to 47%) or have been diagnosed with avascular osteonecrosis (15% to 24%), retinopathy (23% to 34%) or pulmonary hypertension (31% to 48%). In the HbSC/HbSβ+ (N=35) group we found an increase in the occurrence of avascular osteonecrosis (9% to 14%), retinopathy (59 % to 70%) and pulmonary hypertension (9% to 19%). Furthermore, the use of hydroxycarbamide increased in both genotype groups and the frequency of admissions for painful crises remained stable for both genotype groups. Conclusion In the past period of seven years 58% of the patients in a previously well descript cohort of adult SCD patients developed a new sickle cell related complication. For some forms of organ damage or complications a substantial increase occurred dependent of a patient’s genotype. Disclosures: No relevant conflicts of interest to declare.

Description: The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.