Initial Results from a Cohort in a Phase 2a Study (GBT440-007) Evaluating Adolescents with Sickle Cell Disease Treated with Multiple Doses of GBT440, a HbS Polymerization Inhibitor

Abstract Background: Sickle cell disease (SCD) is a genetic disorder in which deoxygenation produces polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing significant end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis) and other clinical complications that are under-recognized, under-treated, and associated with early death. GBT440 is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, thereby inhibiting hemoglobin polymerization. GBT440-007 is a Phase 2a study designed to assess the safety, pharmacokinetics (PK) and efficacy of GBT440 in pediatric SCD patients (HbSS or HbSβ0 thalassemia). This abstract reports the first evaluation of multiple doses of GBT440 in adolescents (12 to 17 years) with SCD. Methods: This ongoing study is being conducted in 2 parts, Part A: single dose of GBT440 at 600 mg in pediatric patients (6 to 11 years) and adolescents (12 to 17 years) and Part B: multiple doses of GBT440 at 2 dose levels, 900 mg/d and 1500 mg/d for 24 weeks in adolescents (approximately 12 patients at each dose). Part A PK data in adolescents was previously reported. The primary objective of Part B is to assess the effect of GBT440 on anemia. Secondary objectives include effect on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial Doppler ultrasound (TCD), daily SCD symptoms using a patient-reported outcome (PRO) measure and safety. The PRO Sickle Cell Disease Severity Measure (SCDSM) was developed following FDA guidance as a clinical outcomes assessment. Results: Enrollment in Part B of the 900 mg cohort is complete. As of 21July2017, 13 patients (7 females) have received GBT440 for up to 12 weeks. The median age was 13 years (range 12 to 17 years) and median weight 52 kg (range 30 to 96 kg); 92% were on hydroxyurea (HU); 38% had 2 or more painful crises (range 2 to 8) in the year prior to enrollment. Data for measures of hemolysis and TCD are available for 4 patients who received GBT440 for 12 weeks; all were receiving HU at study entry. Three of the 4 patients achieved hemoglobin (Hb) response of > 1 g/dl increase (Figure 1); one patient had a smaller Hb increase with documented non-adherence with study medication and associated lower GBT440 exposures. Clinical measures of hemolysis improved concordantly; median reduction in reticulocytes and indirect bilirubin were 34% and 27% respectively, consistent with previously reported results of GBT440 in adults with SCD. Preliminary data following multiple doses of GBT440 suggest that the PK in adolescents were similar to those observed in adults with SCD. Baseline TCD velocity ranged from 89 to 150 cm/s in 13 patients. One patient at 12 weeks had a decline in TCD velocity from baseline of 22 cm/s, and 3 patients showed small reductions. Empirical distribution functions of the SCDSM questionnaires indicate total symptom scores (TSS) trended lower post dose in comparison to screening (Figure 2). All treatment-related adverse events (AEs) were Grade 1 or 2 and there were no treatment- related serious adverse events or no drug discontinuations due to AEs. The most common treatment emergent AEs were Grade 1 nausea and diarrhea reported in 2 patients. Data for all 13 patients treated with GBT440 for a minimum of 12 weeks will be presented at the conference. Conclusions: Based on preliminary results, treatment with GBT440 at 900 mg has been well tolerated in all 13 adolescents. Data from 4 adolescents at 12 weeks show a marked improvement in Hb and reduction in clinical measures of hemolysis. Importantly, hematologic improvements are seen in patients already maximally managed with hydroxyurea. TCD and PRO data suggest that TCD velocity (i.e. risk of stroke) and clinical symptoms may improve with GBT440 treatment. Overall, these results are consistent with in vivo inhibition of HbS polymerization by GBT440 and support the ongoing clinical evaluation of GBT440 as a potential disease-modifying therapy for SCD in an ongoing pivotal Phase 3 study. Figure Figure. Disclosures Hoppe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Inati: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Piccone: Novartis Pharmaceuticals: Honoraria. Fong: Global Blood Therapeutics: Employment, Equity Ownership. Balaratnam: Global Blood Therapeutics: Employment, Equity Ownership. Dixon: Global Blood Therapeutics: Employment, Equity Ownership. Tonda: Global Blood Therapeutics: Employment, Equity Ownership. Washington: Global Blood Therapeutics: Employment, Equity Ownership. Yaron: Global Blood Therapeutics: Employment, Equity Ownership. Lehrer: Global Blood Therapeutics, Inc.: Employment, Equity Ownership.

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Efficacy and Safety of 1500 mg Voxelotor in a Phase 2a Study (GBT440-007) in Adolescents with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-117510 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 509-509 ◽

Cited By ~ 1

Author(s):

Clark Brown ◽

Carolyn Hoppe ◽

Adlette Inati ◽

Miguel R. Abboud ◽

Winfred Wang ◽

...

Keyword(s):

Sickle Cell Disease ◽

Adverse Events ◽

Flow Velocity ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Genetic Disorder ◽

Cell Disease ◽

Advisory Committees ◽

Clinical Measures

Abstract Background: Sickle cell disease (SCD) is a genetic disorder caused by a mutated hemoglobin S (HbS) that polymerizes in the deoxygenated state and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion, and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis), and other clinical complications that are underrecognized, undertreated, and associated with early death. Voxelotor is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby inhibiting Hb polymerization. GBT440-007 is a phase 2a study designed to assess the safety, pharmacokinetics (PK), and efficacy of voxelotor in pediatric patients with SCD (HbSS or HbSβ0 thalassemia). Methods: This ongoing study is evaluating multiple doses of voxelotor at 2 dose levels, 900 mg/day and 1500 mg/day, for 24 weeks in adolescents aged 12 to 17 years. The primary objective is to assess the effect of voxelotor on anemia. Secondary objectives include the effects on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial doppler ultrasound (TCD), and safety. Results: Results for adolescents treated with 900 mg/day have been previously reported. As of June 18, 2018, partial data are available for 13 patients (9 females and 4 males). The median age was 14 years (range, 12-17 years) and median weight was 47 kg (range, 31-72 kg). All participants were on hydroxyurea (HU), and 46% had 2 or more painful crises (range, 2-15) in the year prior to enrollment. The median baseline TCD flow velocity was 112 cm/s (range, 92-177 cm/s), and all were less than 135 cm/s at baseline except for 1 with a baseline of 177 cm/s. Data for measures of hemolysis and TCD are available for 5 adolescents who received voxelotor for 12 weeks. The median increase in Hb was 1.0 g/dL at 12 weeks (Table). Median reductions in reticulocytes and indirect bilirubin were 29% and 18%, respectively (Table), consistent with previously reported results of voxelotor in adults with SCD. Preliminary data suggest linear PK up to 1500 mg, the highest dose evaluated. The adolescent with a baseline conditional TCD (177 cm/s of the bifurcation of the internal carotid artery) on background HU at the maximum tolerated dose (29 mg/kg) had a reduction in TCD flow velocity of 20 cm/s with a concordant increase in Hb of 1.7 g/dL at week 24 with voxelotor compared to baseline and a decrease in reticulocytes from 16.45% to 10.4% (Figure). TCD flow velocities in all other arterial segments showed an overall decline at week 24. All treatment-related adverse events were grade 1 or 2, and there were no treatment-related serious adverse events. Data for all adolescents treated with voxelotor 1500 mg/day for up to 24 weeks will be presented at the conference. Conclusions: Preliminary results indicate that voxelotor at 1500 mg/day was well tolerated. Data from 5 adolescents at 12 weeks show a marked improvement in Hb and reductions in clinical measures of hemolysis. Importantly, hematologic improvements are seen in adolescents already managed at the maximally tolerated dose of HU. Compared to previously reported data at 900 mg/day, this indicates a dose-dependent improvement in hemolytic anemia. One adolescent with conditional TCD, despite background HU, achieved normalized TCD flow velocity after voxelotor therapy. Overall, these results are consistent with in vivo inhibition of HbS polymerization by voxelotor and support the ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adolescents with SCD. Disclosures Brown: Global Blood Therapeutics: Consultancy, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Astra Zeneca: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Woods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees. Hsu:Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy. Piccone:Novartis: Consultancy. Fong:Global Blood Therapeutics: Employment. Dixon:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Washington:Global Blood Therapeutics: Employment. Lehrer-Graiwer:Global Blood Therapeutics: Employment.

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Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease

Blood ◽

10.1182/blood.v130.suppl_1.990.990 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 990-990

Author(s):

John F Tisdale ◽

Francis J. Pierciey ◽

Rammurti Kamble ◽

Julie Kanter ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Ex Vivo ◽

Cell Disease ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Abstract Background Patients with severe sickle cell disease (SCD) may benefit from β-globin gene transfer into autologous hematopoietic stem cells (HSC). Successful HBB gene transfer requires vector-mediated transduction of primitive HSCs. Steady-state bone marrow (BM) is the default HSC source in patients with SCD. Normal human BM contains up to 30% CD34+CD19+ pro-B cells and other lineage-committed cell types (CD34dim) that will not contribute to improved long-term erythropoiesis via gene therapy; these cells mobilize at low rates. CD34+ cell yields from BM harvest (BMH) are typically lower than those after mobilization and peripheral blood (PB) apheresis; multiple rounds of BMH may be required to obtain adequate cell doses for autologous gene therapy (GT) protocols. As G-CSF can cause life-threatening SCD complications and is contraindicated, plerixafor, a CXCR4 receptor antagonist, may accomplish HSC mobilization without the neutrophil or endothelial activation that elicit vaso-occlusion. We modified the protocol for the HGB-206 phase 1 study of LentiGlobin GT in severe SCD (NCT02140554) to assess HSC mobilization with plerixafor alone, followed by apheresis and transduction of mobilized cells. We also characterized BM-derived and plerixafor-mobilized HSC populations from patients with SCD. Methods HGB-206 is a phase 1 study of LentiGlobin Drug Product (DP), which contains autologous HSCs transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector, in patients with severe SCD (defined as a history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s). Patients in group B receive 240 µg/kg plerixafor followed 4-6 hours later by apheresis, processing ~3 total blood volumes to collect backup HSCs. If < 1.5 x 106 CD34+ cells are collected, patients undergo a second day of apheresis. Cells collected in excess of those required for backup in case of graft failure are transduced with BB305 lentiviral vector for exploratory analyses. Group B patients then proceed to BMH to obtain cells for clinical DP manufacture. Group C will receive DP manufactured from mobilized PB. Mass cytometry (CyTOF) was used to analyze ex vivo cultured CD34+ cells with over 35 cell surface markers. Results To date, 3 patients have undergone plerixafor mobilization. Patients had a transient 1.5- to 3-fold increase in peak white blood cell and absolute neutrophil levels after plerixafor. Peak absolute CD34+ cell counts in PB were 170, 58, and 160 x 106 CD34+ cells/liter. A total of 15.3, 5.6, and 9.0 x 106 CD34+ cells/kg were collected in a single day of apheresis, and no subsequent apheresis or mobilization was required. In the same study, a mean of 5.0 (range 0.3-10.8) x 106 CD34+ cells/kg were collected per BMH (N=21). The mobilization and apheresis procedures had an acceptable toxicity profile. No dose-limiting toxicities were observed after plerixafor dosing. One patient had a single VOC approximately 48 hours after receiving plerixafor; this patient also experienced VOCs of similar severity after BMH. In contrast, after 21 BMHs in 9 patients, 18 ≥ grade 3 AEs were reported in 6 patients, primarily pain. Ex vivo cultured CD34+ cells isolated from BMH consisted of an average of 41.0% (17.3%-50.7%) CD34dim cells, with 16%-50% of the CD34dim cells expressing lymphoid markers. In contrast, ex vivo cultured CD34+ cells isolated from plerixafor mobilized PB contained an average of 8.2% (1.5-19.5%) CD34dim cells. Similar drug product vector copy numbers were obtained after research-scale transduction of CD34+ cells from marrow and PB from the same patient. Conclusion Initial results suggest that obtaining adequate doses of CD34+ cells from plerixafor-mobilized PB of patients with SCD may be safe and feasible, without the life-threatening complications associated with G-CSF, and with fewer, less invasive procedures compared with BMH. PB-derived CD34+ cells may contain lower proportions of lineage-committed CD34+ cells than BM-derived cells from patients with SCD. Cells collected by BMH and PB mobilization/apheresis appear to have an equivalent transduction efficiency. Together these results indicate that it may be possible to use plerixafor-only mobilization in clinical studies of autologous HSC GT in SCD. Results of mobilization, apheresis, and DP manufacturing at clinical scale for additional patients will be available for presentation. Disclosures Pierciey: bluebird bio: Employment. Kanter: American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancillo: Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; GBT: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski: Novartis: Research Funding; Bluebird Bio: Research Funding; Apopharma: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson: Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding. Shestopalov: bluebird bio: Employment, Equity Ownership. Bonner: bluebird bio: Employment, Equity Ownership. Joseney-Antoine: bluebird bio: Employment, Equity Ownership. Asmal: bluebird bio: Employment, Equity Ownership. Walters: bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; Sangamo Therapeutics: Consultancy; AllCells, Inc: Other: Medical Director.

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Edx-17: A Novel, Safe and Efficacious Treatment for Sickle Cell Disease

Blood ◽

10.1182/blood.v124.21.1357.1357 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1357-1357

Author(s):

Robert H. Broyles ◽

Sunil K. Joshi ◽

Carol D. Curtis ◽

Austin C. Roth ◽

Patrick A. Floyd ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Cell Disease ◽

Employment Equity ◽

Advisory Committees ◽

Erythroid Precursor ◽

Gamma Globin ◽

Equity Ownership

Abstract Gene regulation of developmental hemoglobin switching holds the potential for therapeutic relief from all symptoms associated with Sickle Cell Disease (SCD). Reactivation of fetal gamma-globin expression (HbF) can replace mutant betaS-globin (HbS) to produce functional hemoglobin tetramers and eliminate the hemoglobin polymerization that is characteristic of sickled red blood cells. We have discovered a protein that regulates this developmental switch, and have identified a compound that stimulates expression of this protein. EdX-17 promotes expression of the anti-stress factor ferritin heavy chain (FtH), which enters the nucleus of erythroid precursor cells and activates expression of fetal gamma-globin, producing HbF (PNAS 98:9145-50, 2001; Blood 108:790a, 2006). Mononuclear cells were isolated from SCD patient blood and matured in vitro to the advanced erythroblast stage using a 28-day, 2-phase culture system (Methods in Molecular Biology 482:127-40, 2009; Blood 119:6296-306, 2012). Treatment with EdX-17 for 24h resulted in a dose-responsive induction of gamma-globin gene expression and a concomitant dose-responsive increase in HbF was observed after 28 days in culture. These studies demonstrate that EdX-17 doses in the picomolar range are sufficient to significantly enhance HbF. Furthermore, EdX-17 treatment reconstitutes fetal hemoglobin (HbF) in transgenic betaYAC mice to levels above 25-30% - the range thought to be sufficient to ameliorate symptoms of SCD – with no detectable ill effects. In fact, mice treated with EdX-17 tend to have shinier coats, are more alert and stronger than age-matched, untreated mice. Development of this novel therapeutic is expected to ameliorate SCD symptoms, decrease pain and morbidity, increase life-span, greatly improve patient quality of life, and significantly reduce treatment costs. Supported in part by The Sickle Cell Cure Foundation, Inc., the Bill & Melinda Gates Foundation, and EpimedX, LLC. Disclosures Broyles: EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Roth:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Belegu:EpimedX, LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Chronic Kidney Disease Is Under-Screened in SCD and Mild Albuminuria Is Associated with a Drop in Hemoglobin: A Report from the Grndad Sickle Cell Registry

Blood ◽

10.1182/blood-2019-124933 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2284-2284

Author(s):

Elizabeth Williams ◽

Elizabeth Brown ◽

Deepa Manwani ◽

Payal Desai ◽

Joshua J. Field ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Sickle Cell Disease ◽

Kidney Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Cell Disease ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

The Globin Research Network for Data and Discovery (GRNDaD) is a combined effort, from 6 US clinical sites (Baltimore, Cleveland, Columbus OH, Milwaukee, Oakland, and The Bronx) that care for people with sickle cell disease (SCD), to improve care through shared data collection and review and quality improvement. Using a single IRB-Reliant protocol, we have assembled harmonized baseline and annual data on 758 adults with sickle cell disease (41.7% male and 58.3% female, mean age 35.5), collected on a REDCap server housed at Johns Hopkins. For this study, we reviewed adherence to the 2014 NHLBI Guidelines on the management of SCD -- which recommends annual screening for chronic kidney disease (CKD) by testing for albuminuria or proteinuria in anyone over the age of 10 with sickle cell disease. To evaluate whether subjects had an annual visit in any given year we used the recording of a well visit hemoglobin. Of the 758 adults in the study 411 had at least one year of follow up data marked as completed. Among these 411 adults there were 826 distinct observations. Of these 826 observations, 137 observations among 85 subjects did not have any hemoglobin lab drawn, suggesting that they did not have a well outpatient visit during that year. Amongst the observation years, where a well hemoglobin was performed, yearly screening for albuminuria occurred in 37.4% (258/689) of annual observations. There was an association between having screening for CKD and site of care (p<.0001), with some sites having adhered to guidelines in 34.2% of observation years and others having adhered 75.9% of years. There was no association between adherence and genotype or sex. Albuminuria was associated with a clinical phenotype. A multi-variable linear mixed effects model controlling for age and gender with a randomly varying intercept based on the subject, excluding chronically transfused subjects, and stratified by sickle cell anemia (HbSS or HbSB0, SCA) or variant genotypes was used. There was a significant association in those with SCA between the presence of albuminuria between 30 and 300, level (A2) and hemoglobin. Hemoglobin levels were, on average, 0.79 g/dL lower in those with albuminuria between 30-300 when compared to those with no albuminuria (A1, P=0.005). For those with SCA and albuminuria greater than 300 (A3), the sample size was small (n=28) and hemoglobin levels were 0.61 g/dl lower compared to those without albuminuria but this was not statistically significant (p=0.12). For those with variant compound heterozygous SCD and A2 albuminuria, hemoglobin levels were not statistically significantly different from those without albuminuria. However, high-grade albuminuria (A3) was associated with hemoglobin levels which were, on average, 1.86 g/dL lower than those in group A1 (P=0.004). Interestingly, the association between reduced hemoglobin and albuminuria was seen in both variant and SCA genotypes in the context of a preserved creatinine (<1.0 mg/dL). Using a multisite registry we demonstrate the need to develop strategies to assist providers and patients with adherence to guideline based recommendations for routine screening for chronic kidney disease in adults with SCD. The early association of albuminuria with worsening anemia, even in the absence of elevated creatinine levels, suggests an added urgency to screening. The causality of the association remains unclear but emphasizes the need for longitudinally followed cohorts that might help us understand the relationship between anemia and the development of CKD. Figure Disclosures Manwani: Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Desai:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Neumayr:La Jolla Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy; CTD Holdings: Consultancy; CDC: Research Funding; Celgene: Research Funding; Imara: Research Funding; NHLBI: Research Funding; Sangamo: Research Funding; HRSA: Research Funding; GBT: Research Funding; Emmaus: Consultancy; Apopharma: Consultancy; Sancillo: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Silarus: Research Funding; Terumo: Research Funding; PCORI: Research Funding; Doris Duke Foundation: Research Funding; Seattle Children's Research Grants: Research Funding. Clay:Novartis: Speakers Bureau. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Global Blood Therapeutics: Employment, Equity Ownership. Lanzkron:PCORI: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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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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A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Effects on In Vivo Markers of Platelet Activation and of Coagulation

Blood ◽

10.1182/blood.v118.21.1049.1049 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1049-1049

Author(s):

Joseph A. Jakubowski ◽

Chunmei Zhou ◽

David S. Small ◽

Kenneth J. Winters ◽

D. Richard Lachno ◽

...

Keyword(s):

Sickle Cell Disease ◽

Platelet Activation ◽

Sickle Cell ◽

Research Funding ◽

Blood Platelet ◽

Cell Disease ◽

Employment Equity ◽

Equity Ownership ◽

Adp Receptor

Abstract Abstract 1049 Introduction: Evidence suggests that platelets are activated in sickle cell disease (SCD) and this appears to increase further during painful crises caused by vascular occlusions from sickled red blood cells. Antiplatelet therapy may be useful in reducing the frequency and severity of acute pain episodes and reducing the risk of thrombotic complications. Prasugrel, an ADP receptor antagonist, irreversibly inhibits the P2Y12 ADP receptor, blocking ADP-stimulated platelet activation and aggregation and reducing downstream procoagulant activities. Here we present the first evaluation of prasugrel's effects on markers of in vivo platelet activation and of coagulation in subjects with SCD. Methods: Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Markers of platelet activation and coagulation included whole-blood platelet-monocyte and -neutrophil aggregates, and whole blood platelet-associated P-selectin and platelet CD40L, all measured by flow cytometry and presented as percent (%) of marker positive cells. Plasma soluble (s) P-selectin, CD40L, and plasma prothrombin fragment 1.2 (F1.2) were evaluated by ELISA. Results: Results from the biomarkers are presented in the table. Prior to prasugrel administration (baseline), subjects with SCD had significantly higher levels of the following biomarkers compared to healthy subjects: Platelet-monocyte aggregates, platelet-neutrophil aggregates, platelet CD40L, and plasma F1.2. In addition, subjects with SCD had numerically higher values of sCD40L, as well as platelet-associated and sP-selectin. Prasugrel treatment resulted in numerical decreases in levels of all biomarkers (with the exception of platelet-associated CD40L for control subjects), most notably in SCD subjects with elevated baseline levels. Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion: In this study, compared to healthy controls, baseline elevation of several platelet-activation and coagulation markers among adult subjects with SCD is consistent with that seen in previous studies of both children and adults with SCD. The decrease in platelet activation biomarkers following 12 days of prasugrel treatment in subjects with SCD suggests prasugrel interrupts SCD-related platelet activation in vivo and raises the possibility that prasugrel may modulate the frequency and/or severity of painful crises associated with SCD. These data support additional studies of the safety and efficacy of prasugrel in the treatment of vascular complications associated with SCD. Disclosures: Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding; GLSynthesis: Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Compnay: Employment, Equity Ownership.

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Crizanlizumab Therapy Is Associated with Lower Levels of Circulating Extracellular Vesicles in Sickle Cell Disease Patients

Blood ◽

10.1182/blood-2021-153377 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 955-955

Author(s):

Cristiane Maria de Souza ◽

Carolina Lanaro ◽

Irene Pereira dos Santos ◽

Oladele Olatunya ◽

Sara T Olalla Saad ◽

...

Keyword(s):

Endothelial Cells ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Extracellular Vesicles ◽

Sickle Cell ◽

Treated Group ◽

Clinical Severity ◽

Cell Disease ◽

Advisory Committees ◽

Activated Platelets

Abstract Extracellular vesicles (EVs) are submicron structures released in blood circulation by different cell types which have been found to be increased in sickle cell disease (SCD) and are associated with clinical complications. The most abundant EVs in SCD patients derive from platelets, endothelial cells, and red blood cells (RBCs) and EVs have been explored as biomarkers of clinical severity. Crizanlizumab is a monoclonal antibody against P-selectin, an adhesion molecule expressed in activated platelets and endothelial cells. P-selectin facilitates the formation of heterocellular aggregates and is implicated in the pathophysiology of vaso-occlusive episodes (VOEs) in SCD. This study aimed to investigate the circulating levels of EVs in patients with SCD on standard of care or treated with crizanlizumab. We collected peripheral blood samples from 20 adults with SCD (Non treated group: 7 patients on hydroxyurea treatment and 7 without it. Treated group: 6 patients undergoing treatment with crizanlizumab in combination with hydroxyurea). Patients received the last dose of crizanlizumab at least a month prior to the study. EVs were identified by lactadherin+calcein stain and quantified by flow cytometry to determine the immunophenotype of their parent cell (platelet, endothelial cell, and RBC, with CD41+; CD146+/CD45-; CD235+, respectively). EV quantification was calculated in number per ml of blood as previously described by our group (Olatunya et al., 2019). We found that patients on crizanlizumab had lower total circulating EV counts than patients not receiving the drug (62.670.000,00 ± 15.600.000,00 vs 13.100.000,00 ± 3.513.000,00/mL, respectively, p=0,0076). The difference was statistically significant in platelet-derived EVs levels (5.397.000,00 ± 953.875,00 vs 2.413.000,00 ± 745.165,00/mL, p=0,0169), but not in endothelium-derived or RBC-derived EVs (345714 ± 101817 vs 220000 ± 64291, and 2.189.000,00 ± 1.648.000,00 vs 1.013.000,00 ± 572775, respectively). Crizanlizumab therapy has been shown to reduce the incidence of VOEs in SCD. EVs have been recognized as bio-effectors involved in VOEs, contributing to a hypercoagulable state, chronic inflammation, and endothelial damage. Our findings show an association between the use of crizanlizumab and lower EV levels, particularly of the platelet-derived type. While the anti-P-selectin activity of crizanlizumab could be expected to help remove platelets from circulation, clinical studies have not reported a reduction in platelet counts in patients treated with crizanlizumab. Therefore, we speculate that crizanlizumab may decrease the release of EV by activated platelets, reduce platelet activation, or contribute to EV removal from circulation. Our findings suggest that crizanlizumab therapy may modulate EV levels in the plasma of SCD patients and provide, for the first time, data to support exploring the use of extracellular vesicles as biomarkers to monitor the clinical response to this drug in patients. Further studies on EV expression of P-selectin and how crizanlizumab interacts with EVs and platelets may help clarify this particular effect of this drug. Disclosures Benites: Novartis: Honoraria. Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa: Novartis: Consultancy.

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Sex Based Differences in Sickle Cell Disease

Blood ◽

10.1182/blood-2020-140896 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Mitchell Knisely ◽

Liliana Preiss ◽

Eleanor Stevenson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Categorical Variables ◽

Continuous Variables ◽

Cell Disease ◽

Advisory Committees ◽

Blood Institute ◽

National Heart Lung

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p <0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and <0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

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Central Venous Access Device (CVAD) Use and Complications in Sickle Cell Disease Patients from Medicaid and Commercially-Insured U.S. Populations

Blood ◽

10.1182/blood.v126.23.2057.2057 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2057-2057

Author(s):

Nancy Maserejian ◽

Cortney Hayflinger ◽

Susan Eaton ◽

Catherine Madigan ◽

William E. Hobbs

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Central Venous Access ◽

Venous Access ◽

Treatment Burden ◽

Cell Disease ◽

Central Venous ◽

Employment Equity ◽

Equity Ownership ◽

The Mean

Abstract Central venous access devices (CVADs), such as tunneled central venous catheters (tCVADs) and peripherally inserted central catheters (PICCs), help provide essential care for some patients with sickle cell disease (SCD). CVADs facilitate administration of multiple intravenous (IV) medications and blood products, as well as blood draws for laboratory analysis. Understanding CVAD use and complications is particularly relevant for SCD patients because of their high risk of having insufficient peripheral IV access. Prior studies describing CVAD use and complications in SCD patients were limited by small sample sizes, typically including 15-20 SCD patients in a single treatment center. The resulting estimates for CVAD use and complications in SCD patients vary widely, are insufficient for development of evidence-based guidelines, and may not be representative of the treatment burden in the broader SCD population. The purpose of this study was to describe the frequency of CVAD use and CVAD-associated complications among SCD patients in a large US population sample. We used data from two large U.S. insurance claims databases from Truven Health MarketScan® Research to examine both Medicaid-insured and commercially-insured SCD patients. From January 2009 through December 2013, these databases encompassed over 14 million Medicaid-insured and over 116 million commercially-insured patients. SCD patients were defined as patients with at least two International Classification of Disease-9 (ICD-9) diagnosis codes for SCD (282.41-42, 282.6x) on separate dates in excess of sickle cell trait codes, or one ICD-9 code for an inpatient (emergency department or hospitalization) visit with sickle cell crisis. CVAD insertions were identified using relevant procedure codes for tCVADs or PICCs. We conducted two sets of analyses for each database: (1) per patient among those with at least one CVAD insertion, and (2) per CVAD insertion. We conducted descriptive analyses on the frequency of CVAD-related procedures (e.g., repair, replacement, removal of obstructive material, repositioning), complications, and infections, thromboses, or phlebitis. A total 17,119 Medicaid-insured SCD patients and 21,342 commercially-insured SCD patients were observed for an average of 3-4 years, during which 1,945 (11.4%) and 1,316 (6.2%) patients, respectively, had at least one CVAD insertion. Most SCD patients (80%) were aged >18 y at time of first CVAD insertion; 18% of adult Medicaid SCD patients had at least one CVAD inserted. The mean number of CVAD insertions per patient was 3.1 (Medicaid) and 2.4 (commercially-insured). In the per CVAD analysis, complication claims were frequent, including infection (31-37%), thrombosis (4-5%), and phlebitis/thrombophlebitis (12-15%). The mean time to removal of CVADs (duration) was 31-34 days (PICC lines) and 102 days (tCVADs). In the per patient analysis, 54.3% had infection claims, 24.3% had thrombosis claims, and 10.2% had phlebitis/thrombophlebitis claims in Medicaid (see Table and Figure; additional results to be provided, also stratified by age). Both tCVADs and PICCs were commonly used in SCD patients, particularly adults, with high occurrence of infection, thrombosis and phlebitis/thrombophlebitis, as well as repeated CVAD insertions. Determinants of CVAD use and complications warrant further investigation to inform practice standards. These findings from a large observational study indicate that device-related risks of administering IV treatments are limitations of IV treatment options and may add to SCD treatment burden. Table 1. Medicaid-Insured Commercially-Insured Any CVAD (Overall) PICC Only tCVAD Only Both PICC and tCVAD Any CVAD (Overall) PICC Only tCVAD Only Both PICC and tCVAD N (%) 1,945 681 (35.0%) 893 (45.9%) 371 (19.1%) 1,316 450 (34.2%) 664 (50.5%) 202 (15.3%) Age, mean (sd) y 30.0 (16.3) 34.2 (14.9) 26.9 (17.5) 30.1 (13.6) 32.6 (17.1) 34.1 (15.8) 31.3 (18.3) 33.2 (15.9) CVAD insertions per patient, mean (sd) 3.1 (3.9) 3.1 (3.9) 1.8 (1.3) 6.2 (5.8) 2.4 (2.3) 2.5 (2.6) 1.6 (1.0) 4.5 (2.9) CVAD insertions total 6,107 3,651 2,456 n/a 3,082 1,636 1,446 n/a Duration per CVAD, median days 44 31 102 n/a 53 34 102 n/a CVAD complications, % patients with CVAD Complication, general 28.8% 13.2% 31.8% 50.1% 22.3% 9.1% 25.9% 39.6% Removal of obstructive material 11.2% 3.8% 15.3% 14.6% 9.0% 2.4% 11.4% 15.3% Replacement 8.3% 3.7% 10.2% 12.4% 6.5% 3.8% 6.5% 12.9% Figure 1. Figure 1. Disclosures Maserejian: Biogen: Employment, Equity Ownership. Hayflinger:Biogen: Consultancy, Employment. Eaton:Biogen: Employment, Equity Ownership. Madigan:Biogen: Employment, Equity Ownership. Hobbs:Biogen: Employment, Equity Ownership.

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