Use of Red Blood Cell Phenotypes for Second Line Therapy Selection in Sickle Cell Disease

Abstract INTRODUCTION In sickle cell disease (SCD), abnormal red blood cells (RBCs) sickle upon deoxygenation due to polymerization of hemoglobin S (HbS). Sickle RBCs exhibit poor deformability and increased viscosity, density, and microvascular adhesion. These rheological properties can be measured using existing devices. An oxygen-gradient ektacytometer measures the deformability of sickle RBCs under normoxic (maximum elongation index, or EImax) and hypoxic conditions (minimum elongation index, or EImin), and the pO 2 level at which sickling beings (point of sickling, or PoS). Dense RBCs are measured using a commercially available hematology analyzer. The hematocrit-to-viscosity ratio (HVR), an oxygen delivery index, is calculated based on the viscosity as measured by a cone and plate viscometer. RBC adhesion in the microvasculature can be modeled using a laminin-lined microfluidics device. These rheological biomarkers correlate with clinical complications such as pain events and acute chest syndrome, and are modified by known, clinically effective therapies such as hydroxyurea (HU) and transfusion (TF). HU is the standard of care for most individuals with SCD and positively modifies EImin, EImax, PoS, HVR, adhesion, and %DRBC. Recently, new agents to treat SCD have emerged including voxelotor, crizanlizumab, and pyruvate kinase activators like etavopivat, which have more targeted effects. It is essential to pair the appropriate novel agent to the patient, addressing their most prominent RBC abnormality remaining after HU therapy. We hypothesize that there is significant variability of rheology biomarkers between individuals with SCD on standard of care therapy, and that the most severe aspects of their RBC pathophysiology can be identified and targeted by novel second line therapies for clinical optimization. METHODS We collected peripheral blood in EDTA under an IRB approved protocol from 312 pediatric patients with SCD ranging in age from 2 to 21 years, 70% on HU. Subjects on chronic TF therapy were excluded. We measured whole blood viscosity at 45s -1 shear and calculated the HVR. %DRBC and complete blood counts were obtained using an ADVIA hematology analyzer (Siemens) and EImin, EImax, and PoS obtained using oxygen gradient ektacytometry (Lorrca, RR Mechatronics). RBCs from 17 HbSS subjects were analyzed for adhesion index to a laminin-lined microfluidics device. Values were assembled for each biomarker into histograms to demonstrate distribution, and quartile ranked. Venn diagrams were constructed comparing overlap between top 25% most severe rheology biomarkers to demonstrate effectiveness of a targeted, precision medicine approach to adding second line therapies to individuals with SCD. RESULTS Distribution of biomarkers in a typical pediatric SCD population in a US academic center are shown in Figure 1. High PoS, adhesion index, %DRBC, and low EImin and EImax, low HVR, are associated with disease severity and clinical complications in SCD; biomarker values were stratified from high to low severity association. The most severe quartile subjects from each biomarker were compared, and percentage of overlap noted (Figure 2). CONCLUSION Our rheologic assessment of a large pediatric cohort heavily treated with HU indicates a broad distribution of RBC phenotypes. Even on HU, patients exhibited loss of deformability, sickling, adhesion, or RBC density abnormalities, with little overlap of unrelated biomarkers associated with disease severity in an individual, i.e. the individuals with very high PoS did not have low HVR (16% of highest severity quartile subjects in common), compared to related biomarkers PoS and EImin or EImax (48% of highest severity quartile subjects in common). Only four subjects, all on HU, were in the quartile associated with highest severity for all biomarkers. Given the lack of overlapping pathology between different red cell abnormalities, selection of the appropriate agent should be straightforward. With three new FDA approved therapies for SCD and novel therapies in clinical trials, it is possible to choose the appropriate second agent to be added to HU based on individual patient RBC phenotype according to the principles of precision medicine. Future goals include CLIA certification for novel devices like the oxygen gradient ektacytometer and adhesive microfluidics at major academic SCD centers and use of these biomarkers in routine patient care. Figure 1 Figure 1. Disclosures Rab: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Lam: Sanguina, Inc.: Current holder of individual stocks in a privately-held company. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sheehan: Beam Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Novartis: Research Funding.

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A Longitudinal Study to Identify and Assess Adhesion Indices during Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-120311 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1097-1097

Author(s):

Jennell White ◽

Xiufeng Gao ◽

Ke Liu ◽

Michael U. Callaghan ◽

Patrick C. Hines

Keyword(s):

Steady State ◽

Longitudinal Study ◽

Board Of Directors ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Blood Samples ◽

Equity Ownership ◽

Adhesion Index ◽

At Home

Abstract Sickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive complications (VOCs); however, there are no objective measures for VOC as a clinical endpoint. Vaso-occlusion results from processes that reduce blood flow in the microvasculature, including red cell stickiness and erythrocyte sickling. These processes lead to pain, chronic organ damage, and decreased life expectancy. The decision to seek medical contact varies amongst patients. When VOCs are managed at home valuable information remains unknown. We designed a longitudinal, observational study to capture adhesion data at home and in a hospital setting. The objective of this study was to determine whether a standardized, flow-based adhesion bioassay is capable of identifying VOCs occurring in SCD patients with varying degrees of medical contact. SCD patients (n=33) were evaluated over a 6-month period. Blood samples were collected every 3 weeks; when patients report a VOC corresponding blood samples are collected and steady state samples are resumed. During 6 months of evaluation, longitudinal measures of pain and clinical laboratory and biomarker samples from SCD patients (+/- hydroxyurea therapy) in steady state to VOC were studied. Blood samples were collected in sodium citrate from SCD subjects at steady state and during VOCs. Blood samples were perfused through VCAM-1-coated microchannels at standard physiologic flow conditions (1dyne/cm2, 1.67Hz). An adhesion index was established by quantifying adherent cells within a standard viewing area (cells/mm2), and could be obtained within 6-9 min. Adhesion indices varied from sample-to-sample at baseline (n=289; mean = 355 ± 235; median = 297 cells/mm2) and during VOC (n=59, mean=416±233, median=390). Repeated measures of adhesion over 6 months reveals significant intra-patient associations with C-reactive protein (CRP, n=335, r=0.16; p=0.006), lactose dehydrogenase (LDH, n=336, r=0.12; p=0.032), white blood cells (WBC, n=341, r=0.13; p=0.019), and reticulocyte percent (n=336, r=0.37, p<0.0001). The results also show significant inter-patient (n=35) correlations with CRP (r=0.34, p=0.047), fetal hemoglobin (HbF, r=-0.61, p=0.0001), reticulocyte percent (r=0.63, p<0.0001), reticulocyte (r=0.77, p<0.0001), and uric acid (r=0.37, p=0.028). At-home VOC adhesion indices (n=33; mean=482±255) were significantly higher than both ER-based VOC (n=8; mean=322± 153; p=0.031) and hospital-based VOC (n=18, mean=336±182; p=0.018) adhesion indices. The difference between at home VOC adhesion indices and baseline adhesion indices approached significance (482 ± 255 vs 355 ± 235, p=0.088). This study represents the largest longitudinal study of adhesion indices using a standardized clinical assay. These data confirm the normal range and longitudinal variability of SCD adhesion indices at baseline and during VOC. Adhesion increased during patient-reported VOCs in a subpopulation of individuals with SCD, suggesting there may be a subphenotype who are more predisposed to adhesion-mediated VOCs. At-home VOCs are likely higher because ER-VOC indices are influenced by fluid boluses, blood transfusions, or anti-inflammatory therapy. Further studies are underway to determine if a clinical adhesion index can effectively monitor response to SCD-modifying therapies and prospectively predict disease progression. Disclosures White: functional fluidics: Equity Ownership. Gao:Functional Fluidics: Equity Ownership. Liu:Functional Fluidics: Equity Ownership. Callaghan:Bioverativ: Honoraria; Alnylam Pharmaceuticals: Equity Ownership; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria; Sancilio Pharmaceuticals Company: Employment; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hema Pharmaceuticals: Honoraria; Grifols: Honoraria; Pfizer: Employment, Honoraria, Research Funding; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Employment; Global Blood Therepeutics: Employment. Hines:functional fluidics: Equity Ownership.

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Severe Acute Complications of Sickle Cell Disease in Two Expert Referral Centers (UK and Italy): Natural History Studies Highlight Ongoing Unmet Need for Effective Disease Modifying or Curative Therapies

Blood ◽

10.1182/blood-2021-151407 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3093-3093

Author(s):

Raffaella Colombatti ◽

Cynthia Sangarappillai ◽

Muriel Soriano ◽

Jonathan Bestwick ◽

Will Hann ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Real World ◽

Research Funding ◽

Standard Of Care ◽

Cell Disease ◽

Advisory Committees ◽

Treatment Groups ◽

Acute Complications

Abstract Background: Hydroxyurea (HU) and chronic transfusion therapy (CTT) are the only disease modifying therapies (DMTs) currently available as standard of care in the UK and Italy for patients with sickle cell disease (SCD), with hematopoietic stem cell transplant (HSCT) available to a small fraction of patients. Few registries capture long-term follow up of real-world outcomes among patients with SCD and there is a need for natural history studies demonstrating morbidity and mortality under existing standard of care. The East London Newborn Sickle Cohort Study (ELNSCS) at the Royal London Hospital and the Sickle Cell Disease Cohort (SCDC) at the University of Padova (UNIPD) collect biomarker and clinical data on patients followed comprehensively at two expert referral centers and provide an opportunity to understand SCD real-world outcomes. Here, we report severe acute complications under standard of care during years when HU and CTT were widely available and accepted. Methods: Inclusion of patients in the ELNSCS required being born in a designated region in London, diagnosed by newborn screening between 1983-2018 and, for this analysis, followed during 2015-2018. Inclusion in the SCDC required being followed, for this analysis, at the UNIPD during 2016-2019. Analyses were restricted to patients with β Sβ S, β Sβ 0, and, for ELNSCS, β Sβ +. Data were entered into clinical databases at each site and subsequently validated against institutional records. Severe vaso-occlusive events (VOEs) were defined as events requiring admission (inpatient, ED, or hematology day unit) for acute chest syndrome (ACS), acute painful crisis, acute hepatic/splenic sequestration, acute ischaemic stroke, dactylitis and priapism. Statistical analysis was aligned between both sites. Patients were categorized into three mutually exclusive treatment groups (HU, CTT, no treatment) according to treatment during study period. Results: One hundred seventy-two patients in the ELNSCS and 62 patients at UNIPD met study inclusion criteria in the four-year analysis period. HbSS genotype accounted for 161 (93.6%) of ELNSCS cohort and 58 (93.5%) of UNIPD cohort. Median age at study entry was 11.6 (range 0.2 - 31.4) years in the ELNSCS and 7.66 (range 0.12 - 19.96) years at UNIPD. Median age differed across treatment groups; HU group tended to be younger, while CTT group tended to be older. According to institutional standards of care, 47 (27.3%) patients from the ELNSCS and 50 (80.6%) from UNIPD received HU, 53 (30.8%) from the ELNSCS and 8 (12.9%) from UNIPD received CTT, and 72 (41.9%) from the ELNSCS and 4 (6.5%) from UNIPD received no treatment during the four year study period. Differences in treatment allocation reflect slightly different patient populations and approaches to care at the two centers. Severe VOEs persist among patients in all three treatment groups at both sites. Of those receiving HU, 83.0% from the ELNSCS and 68.0% at UNIPD had ≥1 severe VOE, including 21.3% from the ELNSCS and 44.0% at UNIPD experiencing ≥1 ACS event. The rate of severe VOEs in the HU group was 0.75 (range 0 - 39.5) per patient year from the ELNSCS and 0.49 (range 0 - 3.00) per patient year from UNIPD. HU dosing and adherence will be explored using data collected on hematologic parameters. In the ELNSCS, of those receiving CTT, 60.4% experienced ≥1 severe VOE (20.8% had ≥1 ACS event); of those receiving no therapy, 56.9% experienced ≥1 severe VOE (11.1% had ≥1 ACS event). At UNIPD, severe VOEs were observed in 62.5% of the CTT group and 50% of the no treatment group, though sample sizes were very small. C onclusions: Despite receiving expert care in accordance with local and international guidelines at two large academic centers, a significant sub-group of patients continue to experience severe VOEs. Results show that real-world usage of HU and CTT may not be optimized and, even if optimized, some patients may continue to experience severe acute complications including ACS. Both cohorts confirm that implementation of existing standard of care is insufficient to prevent significant morbidity in patients with SCD. Findings suggest the need to introduce DMT early in life to reduce and prevent acute complications and minimize disease progression. There is a persistent need for maximizing effective DMTs, as well as further developing curative therapies such as HSCT and gene therapy for both pediatric and adult patients. Figure 1 Figure 1. Disclosures Colombatti: Novartis: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBirdBio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chawla: BlueBirdBio: Current Employment. Puri-Sharma: BlueBirdBio: Current Employment. Walls: BlueBirdBio: Current Employment. Kommera: BlueBirdBio: Current Employment. Telfer: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; ApoPharma: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBirdBio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees.

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The Effect of Crizanlizumab Plus Standard of Care (SoC) Versus Soc Alone on Renal Function in Patients with Sickle Cell Disease and Chronic Kidney Disease: A Randomized, Multicenter, Open-Label, Phase II Study (STEADFAST)

Blood ◽

10.1182/blood-2019-124823 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1018-1018

Author(s):

Kenneth I. Ataga ◽

Santosh L. Saraf ◽

Vimal K. Derebail ◽

Claire C. Sharpe ◽

Adlette Inati ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Ace Inhibitors ◽

Research Funding ◽

Standard Of Care ◽

Creatinine Ratio ◽

Cell Disease ◽

Advisory Committees

Background: Sickle cell disease (SCD) is an inherited genetic disorder that results in the formation of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, deforming erythrocytes and leading to chronic hemolysis, anemia and vaso-occlusion. Sickle cell nephropathy (SCN) is the term used to describe the renal complications of SCD. Renal vaso-occlusion and hemolysis contribute to the manifestations of SCN which include hyperfiltration and progressive renal impairment. Chronic kidney disease (CKD) is diagnosed if abnormalities in kidney structure or function are present for >3 months. The prevalence of CKD in patients with SCD increases with age, and ~12% of patients progress to end-stage renal disease (Gosmanova et al. J Investig Med 2014; Powars et al. Medicine 2005). There are no treatments approved for CKD caused by SCD. Standard of care (SoC) typically consists of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and/or hydroxyurea (HU). Evidence for the clinical effectiveness of ARBs and ACE inhibitors has been generated mainly from trials in other causes of kidney disease or short-term studies in SCD. P-selectin contributes to vaso-occlusion by mediating adhesion of sickled erythrocytes and leukocytes to the endothelium. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin with high affinity and specificity. In SUSTAIN, crizanlizumab significantly reduced the median annual rate of vaso-occlusive crises compared with placebo (Ataga et al. N Engl J Med 2017). Preclinical data show P-selectin expression in the kidneys and upregulation in response to renal ischemia-reperfusion injury (Singbartl et al. FASEB J 2000; Zizzi et al. J Pediatr Surg 1997). Crizanlizumab may have a beneficial effect in patients with SCD and CKD by blocking P-selectin-mediated multicellular adhesion, reducing the effects of vaso-occlusion in the renal vasculature and slowing the decline in renal function. The aim of the STEADFAST study is to determine if crizanlizumab can slow the progression of CKD due to SCD (EUDRACT no. 2018-003608-38). Methods: Approximately 170 patients aged ≥16 years with CKD due to SCD will be enrolled. Eligible patients will have HbSS or HbSβ0-thalassemia genotypes, an estimated glomerular filtration rate (eGFR) ≥45 to ≤120 mL/min/1.73 m2, an albumin-to-creatinine ratio (ACR) ≥100 to <2000 mg/g and be receiving SoC (which includes HU, ACE inhibitors and/or ARBs) for SCD and/or CKD. Patients must have been receiving SoC for ≥6 months and plan to continue at the same dose and schedule until study end. Exclusion criteria include history of stem cell transplant, chronic red blood cell transfusion therapy, acute kidney injury (AKI) within 3 months of study entry, and patients undergoing hemodialysis. Patients will be randomized to receive crizanlizumab 5.0 mg/kg plus SoC or SoC alone. Patients in the combination arm will receive crizanlizumab 5.0 mg/kg by IV infusion over 30 minutes on day 1 of week 1, followed by a second dose 2 weeks later, after which it will be administered every 4 weeks. The total treatment period is 12 months. Primary endpoint: proportion of patients with a ≥30% decrease from baseline in ACR at 12 months, based on the intent-to-treat population. A logistic regression model including treatment effects and stratification factors will be utilized and the test (based on the log-odds ratio estimated by the model) will be carried out at the 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from baseline to 3, 6, 9, and 12 months, proportion of patients with ≥30% decrease in ACR at 6 months, proportion of patients with ≥20% improvement of protein-to-creatinine ratio (PCR) at 12 months, percentage change in eGFR from baseline to 3, 6, 9, and 12 months, and the proportion of patients with progression of CKD (based on decline in eGFR category accompanied by a ≥25% drop in eGFR from baseline) from baseline to 12 months. Exploratory endpoints include improvement in renal and cardiac biomarkers at 3, 6, 9, and 12 months and tricuspid regurgitation velocity (TRV) <2.5 m/s at 12 months among patients with abnormal TRV at baseline. Conclusion: CKD is a common complication of SCD. The STEADFAST study will evaluate whether crizanlizumab, in combination with SoC, can reduce albuminuria and slow CKD progression, thus providing evidence of a reno-protective effect of crizanlizumab. Figure Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Saraf:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Derebail:RTI: Honoraria; Novartis: Consultancy; Retrophin: Consultancy. Sharpe:Novartis: Consultancy. Inati: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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Lebensburger:Pfizer: Research Funding; Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Zhang:Novartis: Employment. Bartolucci:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Outcome of Lower Risk Non Del 5q MDS after Failure of Erythropoiesis Stimulating Agents (ESA), and Impact of Post-ESA Treatment on Survival: A Retrospective European Study

Blood ◽

10.1182/blood.v126.23.1665.1665 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1665-1665 ◽

Cited By ~ 1

Author(s):

Sophie Park ◽

Jean-François Hamel ◽

Andrea Toma ◽

Charikleia Kelaidi ◽

Maria Campelo Diez ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Cooperative Groups ◽

Second Line ◽

Advisory Committees ◽

Primary Resistance ◽

Investigational Drugs ◽

Significant Difference ◽

Very High

Abstract Background : Most non-del 5q lower risk MDS patients (pts) are first treated with ESA, with about 50% (generally transient) responses, and second line treatments (TX) including hypomethylating agent (HMA), Lenalidomide (LEN) and investigational drugs are then often proposed, but their effect on overall survival (OS) is unknown. In a previous work on 253 such pts, we found worse OS with early failure to ESA, i.e. primary resistance (RES) or relapse (REL) < 6 months after ESA onset (Kelaidi, Leukemia, 2013), but only few pts had received, after ESA failure, TX other than RBC transfusions. In the present study, we gathered non-del 5q lower risk MDS treated with ESA from several EU MDS cooperative groups, and analyzed their outcome after ESA failure, and the effect of second line TX on survival. Methods : 1611 IPSS low and int-1 (lower risk) non del 5q MDS pts included in the French (GFM), Italian (FISM), Spanish (GESMD), Greek, Düsseldorf and Munich registries between 1997 and 2014, and treated by ESA were studied. Survival was assessed from failure of ESA (i.e. from primary failure evaluated after 12 to 24 weeks of ESA treatment, or from relapse after a response). Progression at ESA failure was defined upon progression to a higher IPSS-R class at ESA failure as compared with ESA onset. Results : At ESA onset, the 1611 pts were reclassified by IPSS-R in 16% very low, 54% low, 13% int, 6% high, 1% very high and 10% ND. HI-E (using IWG 2006 criteria) to ESA treatment was 66.9%, and the median duration of response was 15 months. The cohort of 1038 pts with ESA failure included 521 RES and 517 REL. Median OS was 4.2 years in REL and 3.7 years in RES pts (p=0.56), and no significant difference was seen, even after restricting the analysis to very low and low IPSS-R pts (p=0.81), or when analyzing "early" vs "late" failures, with cut-off points at 6 or 12 months, as we previously reported (Kelaidi, Leukemia, 2013). 336 (32%) pts received second line treatment (TX2) other than RBC transfusions, including HMA in 88 pts, LEN in 169 pts, and other TX (OT) in 79 pts (including 11 chemotherapy, 17 thalidomide, 11 immunosuppressors (ATG, cyclosporine), or investigational drugs), with response rates of 46%, 39% and 33% respectively (p=0.4). 87 pts had a third line TX (mostly a new drug, but also 7 pts who received HMA after LEN, and 33 pts LEN after HMA). Pts treated with LEN as TX2 were younger (median age 70 vs 75 for BSC, and 70 for HMA p<10-4), had more RARS (67% vs 28% for BSC and 27% for HMA, p<10-4), while pts treated with HMA as TX2 had more RAEB-1 (34% vs 10% for BSC and 12% for LEN, p<10-4) and more high and very high IPSS-R at onset of TX2 (48% vs 4.6% for BSC and 3.1% for LEN, p<10-4). Median OS for pts receiving BSC, LEN, HMA and OT as TX 2 was 4.3y, 3.7y (HR 1.1 [0.81-1.50] p=0.5), 2.1y (HR 1.59 [1.12-2.72], p=0.01) and 2.2y (HR1.17 [0.81-1.68], p=0.41) respectively (Figure). However, in a multivariate analysis adjusted on age, gender, and IPSS-R progression at ESA failure, OS difference became not significant. Analysis of AML progression in the different TX2 groups is currently being finalized. C onclusion: In this large multicenter retrospective cohort of non-del 5q lower risk MDS pts having failed ESA treatment, OS from failure was similar in RES and REL pts, contrary to our previous smaller experience. About 1/3 of the pts received second line treatments other than RBC transfusion, mainly LEN or HMA. However, none of those treatments was able to improve OS compared to BSC. Newer treatments are required in this situation, possibly including allogeneic SCT in younger pts. Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidomide in non del 5q MDS. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wattel:PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Genes Influencing the Development and Severity of Chronic ITP Identified through Whole Exome Sequencing

Blood ◽

10.1182/blood.v126.23.73.73 ◽

2015 ◽

Vol 126 (23) ◽

pp. 73-73 ◽

Cited By ~ 3

Author(s):

Jenny M. Despotovic ◽

Linda M. Polfus ◽

Jonathan M. Flanagan ◽

Carolyn M. Bennett ◽

Michele P Lambert ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Chronic Itp ◽

Line Therapy ◽

Whole Exome ◽

Phenotype Data

Abstract Background: Chronic immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by antibody mediated platelet destruction and impaired production. Sustained autoimmunity in chronic ITP appears to be due to generalized immune dysregulation including altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells (Treg). The cause of these abnormalities has not been fully elucidated and is likely multifactorial, but genetic factors may be involved in ITP pathogenesis. Improved understanding of genetic influences could lead to novel therapeutic approaches. Aim: To identify genetic variants that may be involved in chronic ITP susceptibility and severity. Methods: Whole exome sequencing (WES) was performed on 262 samples with robust phenotype data on children with chronic ITP from the North American Chronic ITP Registry (NACIR, n= 173) and the Platelet Disorders Center at the Weill-Cornell Medical Center (n=89). All but three patients were ≤19 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, 7% had other autoimmune disorders. Sequencing data for ITP cases of European American (EA) ancestry were compared to EA controls with platelets >150 x 109/L sequenced in the Atherosclerosis Risk in Communities (ARIC) Study (N=5664) to identify candidate genes associated with ITP susceptibility. Analyses filtered variants on a minor allele frequency (MAF) <0.01 as well as functionality of nonsynonymous, stop gain, splicing, stop loss, and indel variants. Both Fisher-Exact tests of single variants and Firth logistic regression for gene-based tests, accounting for an unequal proportion of cases compared to controls, were used. A Bonferroni corrected threshold based on 16,532 genes was calculated at 3.0x10-6. In a separate analysis, phenotype data for ITP cases were reviewed and cases stratified by disease severity according to second line treatment needed (Yes =139, No=113) and compared to ARIC EA controls with platelet count >150 x 109/L (N=5664). Results: Several damaging variants identified in genes involved in cellular immunity had a significantly increased frequency in the EA ITP cohort (Table). The most significant associations were detected in the IFNA17 gene, which is involved in TGF-β secretion and could affect number and function of the Treg compartment. IFNA17 rs9298814 (9:21227622 A>C) was identified in 26% of cases in the EA ITP cohort compared to <0.01% of EA controls, and other low frequency but presumed deleterious variants were also identified in IFNA17. IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene's functional relevance in the pathogenesis and pathophysiology of ITP. Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained variants with increased frequency in the EA ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy. Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP. Conclusion: Damaging variants in genes associated with cellular immunity have an increased frequency in children with chronic ITP compared to controls, providing further evidence for the role of T cell abnormalities in the pathophysiology of ITP. The IFNA17 and IFNLR1 genes maintained significance when the ITP cohort was stratified according to disease severity, and may be important candidate genes involved in immune regulation and sustained autoimmunity associated with chronic ITP. Table. Genes identified through WES analysis of children with chronic ITP. Gene Function Relevant to ITP Pathophysiology Minor Allele Count (MAC)Cases Controls p value EA Chronic ITP vs. EA ARIC (non-ITP) controls N=172 N=5664 IFNA17 Treg, TGF-β signaling 91 17 3.97x10-13 DGCR14 IL-17 induction 14 3 1.27x10-10 SMAD2 TGF-β signaling 1 0 5.62x10-22 CD83 Th17/Treg balance 2 3 1.67x10-6 EA Chronic ITP requiring Second Line Therapy vs. EA ARIC (non-ITP) controls N=139 N=5664 IFNLR1 Class II cytokine receptor 2 1 3.95x10-15 IFNA17 Treg, TGF-β signaling 75 17 3.40x10-7 REL T and B cell function, inflammation 2 0 1.39x10-14 Disclosures Off Label Use: Off-label use of CliniMACS purified CD34+ cells. Lambert:GSK: Consultancy; NovoNordisk: Honoraria; Hardin Kundla McKeon & Poletto: Consultancy. Recht:Baxalta: Research Funding; Kedrion: Consultancy. Bussel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; protalex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.3444.3444 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3444-3444 ◽

Cited By ~ 1

Author(s):

Yi L. Hwa ◽

Rahma Warsame ◽

Morie A. Gertz ◽

Francis K Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Practice Patterns ◽

Autologous Stem Cell Transplant ◽

Al Amyloidosis ◽

Cell Transplant ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.646.646 ◽

2016 ◽

Vol 128 (22) ◽

pp. 646-646 ◽

Cited By ~ 27

Author(s):

Efstathios Kastritis ◽

Xavier Leleu ◽

Bertrand Arnulf ◽

Elena Zamagni ◽

María Teresa Cibeira ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Cardiac Response ◽

Phase Iii ◽

Al Amyloidosis ◽

Advisory Committees ◽

Phase Iii Trial ◽

Hematologic Response ◽

Grade 3

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

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Off-Label Prescription of Hydroxycarbamide (Hydroxyurea, HU) for Severe Anemia: Preliminary Results from European Non-Interventional, Multicentric, Prospective Escort-HU Study

Blood ◽

10.1182/blood.v130.suppl_1.758.758 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 758-758

Author(s):

Mariane De Montalembert ◽

Gylna Loko ◽

Jerome Clouzeau ◽

Valentine Brousse ◽

Frederic Galacteros ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Expert Panel ◽

Safety Data ◽

Incidence Rates ◽

Cell Disease ◽

Advisory Committees ◽

Off Label ◽

Preliminary Results ◽

The Mean

Abstract HU is licensed in Europe in the prevention of recurrent painful vaso-occlusive crises (VOC) including acute chest syndromes in adults, adolescents and children older than 2 years with sickle-cell disease (SCD). However, based on US and European expert panel recommendations (Yawn 2014, Habibi 2015) and results from placebo-controlled clinical trials, HU could be useful in SCD patients with severe anemia without VOC since it has been demonstrated to increase total Hb level (Wang 2011) and to decrease the need for blood transfusion. We hereby present preliminary results on effectiveness and safety data related to the prescription of HU for anemia from ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea), a multicentric, prospective, non-interventional European study designed to collect long-term safety data on HU in SCD population. Between January 2009 and June 2017, 1841 patients were enrolled from 63 centers in France, Germany, Greece and Italy, amongst which 126 patients (6.8%) were started on HU for anemia from 34 centers. Of these 126, 96 were HU-naive. These HU-naive patients treated for anemia ('anemic' subpopulation) were selected for analysis to evaluate effectiveness and safety of HU in this indication and compared with data in HU-naive patients treated for other SCD indications. Demographic data and Hb genotypes are displayed in Table 1. The mean age, distribution of gender, Hb genotype and the mean HU dose at initiation were comparable in the 'anemic' subpopulation and the 'non-anemic' HU-naive cohort. Not surprisingly, mean Hb level at initiation was markedly lower in the 'anemic' subpopulation (7.07 ± 0.88 g/dl) than in the 'non-anemic' HU-naive cohort (8.71 ± 1.51 g/dl), with a lower proportion of patients with history of VOC and SCD-related hospitalization prior to HU initiation. The mean HU dose after 6 months was comparable in both groups (15.6 ± 3.83 mg/kg/day and 15.4 ± 4.11 mg/kg/day, respectively). Variation of blood parameters are displayed in Table 2. Similarly to what has been observed previously, a dramatic rise in Hb concentration (> 2 g/dl) was observed. This increase was comparable in absolute value to the increase observed in non-anemic patients. An increase in HbF was observed in the "anemic" subpopulation, with a near 2-fold increase in %HbF, markedly in children. Changes in reticulocyte counts were inconclusive due to small number of patients in the dataset. Safety of HU in the population of patients treated for anemia was evaluated by comparing incidence rates of non-SCD related adverse events (AEs) in HU-naive patients treated for anemia with the 'non-anemic' HU-naive ESCORT-HU subpopulation (Table 3). With mean follow-up periods of 18.3 months in 'anemic' subpopulation and 34.2 months in 'non-anemic' HU-naive cohort, preliminary results showed no striking difference in the incidence rate of reported AEs (total and serious) between the two populations (112.5% vs 139.8%, respectively for incidence rate of total AEs), and in the distribution of AEs by System Organ Class (SOC), at least in SOC where the number of adverse events was large enough to allow for comparison between the groups. Similarly, when focusing on AE causally related to HU (as judged by the investigators), the most frequently reported toxicity in the 'anemic' population was myelosuppression (anemia, neutropenia thrombocytopenia, pancytopenia reported in 4 children, one event each), as in the 'non-anemic' HU-naive cohort, with comparable incidence rates. In conclusion, even though HU is not licensed in Europe in severe chronic anemia, European and US expert panel guidelines recommend treatment with HU in this indication. Data from ESCORT-HU observational study on a subset of SCD patients treated off label in this indication confirmed total Hb level increase while the safety profile of HU in this subpopulation did not differ significantly from the 'non-anemic' HU-naive population. Disclosures De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding. Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. Galacteros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽

10.1182/blood-2019-127966 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4838-4838

Author(s):

Sophia Delicou ◽

Michael D. Diamantidis ◽

Konstantinos Manganas ◽

Eftychios Eftychiadis ◽

Despoina Pantelidou ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Educational Status ◽

Current Treatment ◽

Advisory Committees ◽

Chi Square ◽

Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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