Pharmacodynamic Effects of AG-946, a Highly Potent Next-Generation Activator of Pyruvate Kinase, in Ex Vivo Treatment of Red Blood Cells from Sickle Cell Disease Patients

Abstract Background: Sickle cell disease (SCD) is a monogenetic red blood disorder that is characterized by hemolytic anemia and vaso-occlusive crises. Among the many factors that contribute to disease pathophysiology is stiffening and sickling of red blood cells (RBC), which is the direct result of the formation of abnormal hemoglobin S. Sickling is one of the core factors that cause vaso-occlusion and sickling is modulated by glycolytic intermediates such as 2,3-diphosphoglycerate (2,3-DPG) and ATP. Previously we showed that red blood cell pyruvate kinase (PKR), the key regulatory enzyme of glycolysis, is impaired in SCD and that ex vivo treatment with mitapivat, an allosteric activator of PKR, increased enzymatic activity and thermostability, reduced 2,3-DPG levels, decreased p50, and subsequently reduced sickling (Rab et al, Blood 2021). Currently, mitapivat is in phase 1 and phase 2 trials for SCD (#NCT04000165 and EudraCT#2019-003438). Aims: Recently, AG-946, a next-generation activator of PKR has been developed. Here we investigate the pharmacodynamic effects of AG-946 in ex vivo treatment of RBC from SCD patients in comparison with mitapivat. Methods: Buffy coat depleted whole blood obtained from five patients with SCD was incubated for 20-24 hrs in absence or presence of mitapivat (100 mM) or AG-946 (1 mM, 5 mM, 50 mM). After ex vivo treatment, enzymatic activities of PKR and PK-thermostability was measured. Glycolytic intermediates ATP and 2,3-DPG were measured using LC-MS/MS. Hemoglobin oxygen affinity (p50) was measured with the Hemox Analyzer. RBC sickling was analyzed with the oxygenscan, a newly developed method that characterizes individual sickling behavior by oxygen gradient ektacytometry. Individual tendency to sickle is reflected by Point-of-Sickling (PoS) that indicates the specific pO 2 at which RBCs start to sickle during deoxygenation under shear stress. Results: PKR activity was increased compared to vehicle (DMSO) to a similar extent in presence of both mitapivat and AG-946 (Figure 1A). In addition, PKR thermostability was significantly increased compared to vehicle (mean 22%, SD 6%) in samples treated with mitapivat 100 mM (mean 78%, SD 11%), as well as AG-946 5 mM (mean 66%, SD 23%), and AG-946 50 mM (mean 95%, SD 17%, Figure 1B). The glycolytic intermediate 2,3-DPG decreased after incubation with both mitapivat and AG-946 (Figure 1C), which was further illustrated by the improved ATP/2,3-DPG ratio (Figure 1D). In line with these latter results p50 decreased significantly after incubation with mitapivat 100 mM (mean 95%, SD 2%), as well as AG-946 1 mM (mean 96%, SD 2%), AG-946 5 mM (mean 94%, SD 2%), and AG-946 50 mM (mean 95%, SD 3%, Figure 1E). The improved metabolic status and p50 was accompanied by a decreased PoS compared to vehicle in RBCs treated with mitapivat or AG-946, indicating reduced RBC sickling tendency in vitro (Figure 1F). Conclusion: Ex vivo treatment of SCD RBCs with the next-generation PKR activator AG-946 activates and stabilizes PK, decreases 2,3-DPG levels, improves the ATP/2,3-DPG ratio, improves p50 and lowers the PoS. These beneficial effects are similar to ex vivo treatment with mitapivat but, importantly, are obtained at much lower concentrations. Therefore, AG-946 may be a potent activator of PKR in SCD. Taken together, these results are the first in an ex vivo model to demonstrate that the next-generation PK activator AG-946 has a similar favorable pharmacodynamic profile to mitapivat with enhanced PK-stabilizing properties and, hence, represents a potential novel therapeutic option in addition to mitapivat for the treatment of SCD and other hemolytic anemias. Figure 1 Figure 1. Disclosures Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Van Dijk: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kung: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Van Beers: Pfizer: Research Funding; RR Mechatronics: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dang: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options 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.

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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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A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-148370 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3109-3109

Author(s):

Joanna Howard ◽

Kevin H.M. Kuo ◽

Abdulafeez Oluyadi ◽

Hui Shao ◽

Susan Morris ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Phase 2 ◽

Phase 3 ◽

Advisory Committees ◽

Double Blind ◽

Hb Concentration ◽

To Receive ◽

2,3 Dpg

Abstract Background: Sickle cell disease (SCD) is a life-threatening, hereditary hemoglobin (Hb) disorder characterized by chronic hemolytic anemia, pain, end-organ damage, and poor quality of life. The key pathology is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP. Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis. SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an investigational, first-in-class, oral, small-molecule allosteric activator of the RBC-specific form of pyruvate kinase (PKR), a key enzyme in glycolysis. Activation of wild-type PKR decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD. Data from the Phase 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, and was associated with a dose-dependent increase in ATP and decrease in 2,3-DPG, in addition to improvements in anemia and hemolytic markers. Based on these results, a Phase 2/3 study investigating the safety and efficacy of mitapivat in patients (pts) with SCD is planned. Methods: This Phase 2/3, double-blind, randomized, placebo-controlled, multicenter study aims to evaluate the efficacy and safety of mitapivat in pts with SCD. Eligible: pts ≥ 16 years of age with documented SCD (HbSS, HbSC, HbSβ 0/HbSβ + thalassemia, other SCD variants), 2-10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and an Hb level of 5.5-10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥ 90 days before starting study drug. Not eligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving treatment with SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation. In the double-blind Phase 2 part of the study, 69 pts will be randomized (1:1:1) to receive 50 mg mitapivat, 100 mg mitapivat, or placebo BID for 12 weeks. The primary objective of the Phase 2 part of the study is to determine the recommended Phase 3 dose of mitapivat by evaluating anemia and safety vs placebo via the following endpoints: Hb response, defined as a ≥ 1.0 g/dL increase in average Hb concentration over Weeks 10-12 compared with baseline; and type, severity, and relationship of adverse events (AEs) and serious AEs (SAEs). In the double-blind Phase 3 part of the study, 198 pts who did not participate in the Phase 2 study will be randomized (2:1) to receive the selected Phase 3 dose of mitapivat or placebo, BID, for 52 weeks, stratified by the number of SCPCs in the prior year (< 5, ≥ 5) and by HU use. The primary objectives of the Phase 3 study are to determine the effect of mitapivat vs placebo on anemia in pts with SCD, measured by Hb response, defined as a ≥ 1.0 g/dL increase in average Hb concentration over Weeks 24-52 compared with baseline, and to determine the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include change over Weeks 24-52 compared with baseline in the following: average Hb concentration, indirect bilirubin, percent reticulocyte, and Patient-Reported Outcomes Measurement Information System ® (PROMIS) fatigue 13a Short Form scores; annualized frequency of hospitalizations for SCPC. Other secondary objectives include evaluation of effect on additional markers of hemolysis and erythropoiesis, additional clinical efficacy measures related to SCPC, additional patient-reported measures of fatigue and pain, physical activity, safety, and pharmacokinetics/pharmacodynamics of mitapivat. Pts who complete the double-blind period of either the Phase 2 or Phase 3 part of the study will be eligible to receive mitapivat for an additional 216 weeks in the open-label extension period. Results: Not yet available Conclusion: This Phase 2/3 study will investigate the efficacy and safety of the pyruvate kinase activator mitapivat in pts ≥ 16 years of age with SCD and enrollment will begin in 2021. Figure 1 Figure 1. Disclosures Howard: Resonance Health: Honoraria; Novartis: Consultancy, Honoraria; Bluebird Bio: Research Funding; Forma Therapeutics: Consultancy; Agios Pharmaceuticals: Consultancy; Novo Nordisk: Consultancy; Global Blood Therapeutics: Consultancy; Imara: Consultancy, Honoraria. Kuo: Bluebird Bio: Consultancy; Apellis: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Oluyadi: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Shao: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Morris: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Zaidi: Agios Pharmaceuticals: Current Employment. Van Beers: RR Mechatronics: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

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Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase R, in Subjects with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE)

Blood ◽

10.1182/blood-2021-150234 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2047-2047

Author(s):

Myrthe J. van Dijk ◽

Minke A.E. Rab ◽

Anita W. Rijneveld ◽

Erfan Nur ◽

Marije Bartels ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Health Research ◽

Research Funding ◽

Oxygen Affinity ◽

Dose Finding ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

2,3 Dpg

Abstract Background Sickle cell disease (SCD) is one of the most common and devastating inherited blood disorders characterized by a single nucleotide mutation in the beta-globin chain leading to the production of mutant hemoglobin S (HbS). HbS polymerizes upon deoxygenation causing red blood cells (RBC) to sickle which results in extremely painful episodes of vaso-occlusive crisis (VOC), severe hemolytic anemia, chronic multiorgan failure and a reduced life span. An important metabolic feature directly associated with RBC sickling is increased intracellular levels of the glycolytic intermediate 2,3-diphosphyglycerate (2,3-DPG) which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb). Pyruvate kinase R (PKR) is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, membrane integrity and deformability, and modulates 2,3-DPG levels. Mitapivat (AG-348) is an oral, small molecule allosteric activator of PKR and shows promise as an anti-sickling agent in addition to its effect in PK deficiency and thalassemia. The safety and efficacy of mitapivat in subjects with SCD was evaluated in the dose finding period of this ongoing phase 2 study. Methods The ESTIMATE study is a phase 2, open-label study in which subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+) with a baseline hemoglobin >6.1 g/dL and ≤11.1 g/dL, no chronic transfusion and adequate organ function were eligible. In the 8-week Dose Finding Period, initial dosing of mitapivat was 20 mg twice daily (BID). Subjects received a maximum of two sequential dose escalations of mitapivat (i.e. from 20 mg BID to 50 mg BID and 100 mg BID) depending on safety. The primary endpoints were safety, evaluated by frequency and severity of adverse events (AEs), and efficacy of mitapivat on RBC sickling. RBC sickling was evaluated by change in Point of Sickling (PoS), the pO2 at which sickling occurs as measured by oxygen gradient ektacytrometry on the Lorrca (RR Mechatronics). Secondary endpoints included changes in hematological parameters, levels of 2,3-DPG and ATP, Hb-oxygen affinity (p50) and surrogate markers of organ damage and mortality. Subjects who safely tolerated mitapivat and showed evidence of clinical improvement, were eligible to continue a 52-week follow-up period (Fixed Dose Extension Period). Results Six subjects have been enrolled as of September 2020 and completed the Dose Finding Period. All had homozygous HbSS except one patient who had HbS/β0-thalassemia. Baseline characteristics were: median age of 36 years (range 20-59 years), 4 (66.7%) were female and 5 (83.3%) were on stable-dose hydroxyurea. All subjects received dose escalation to a maximum dose of 100 mg BID. No serious adverse events (SAEs) occurred. Adverse events (AEs) were mild and often transient, with the most common treatment emergent AEs: transaminase increase (n=3 [50.0%], Grade 1), gastrointestinal disorders including dyspepsia, diarrhea and abdominal discomfort (n=3 [50.0%], Grade 1) and headache (n=2 [33.3%], Grade 1). One VOC occurred without hospital admission and did not require dose reduction or discontinuation. Table 1 summarizes the anti-sickling effect as well as the hematological and biochemical response to mitapivat treatment. Sickling occurred at lower pO2 levels in all 6 patients during the Dose Finding Period reflected by a significant decrease in treatment week 8 mean PoS compared to baseline. 5/6 subjects (83.3%) achieved a Hb increase of ≥1 g/dL during this period, which was accompanied by a decrease in hemolytic markers. Consistent with activation of PKR, 2,3-DPG levels decreased and ATP levels increased. Additional results including biomarker data will be presented. Conclusion Mitapivat demonstrated an adequate safety profile during the 8-week Dose Finding Period in patients with SCD. The data show promising efficacy in terms of a decrease in the pO2 at which RBCs start to sickle, as well as increase in Hb from baseline and a concomitant decrease in markers reflecting hemolysis. The observed changes in 2,3-DPG and ATP levels are consistent with the proposed mechanism of the drug. The study is ongoing and further data including follow-up data, patient-reported outcomes, PKR activity and thermostability will be reported at a later stage. Figure 1 Figure 1. Disclosures van Dijk: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Rijneveld: Servier: Research Funding; Amgen: Research Funding. Nur: Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Roche: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Novo Nordisk: Research Funding; OctaPharma: Research Funding; Pfizer: Research Funding; Shire/Takeda: Research Funding; Bayer: Research Funding. 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. Van Beers: Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding.

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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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Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Blood ◽

10.1182/blood-2021-154314 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Surbhi Shah ◽

Shuchi Gulati ◽

Ang Li ◽

Julie Fu ◽

Vaibhav Kumar ◽

...

Keyword(s):

Mechanical Ventilation ◽

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Tumor Board ◽

Bleeding Complications ◽

Advisory Committees ◽

Icu Admission ◽

Patients With Cancer ◽

Privately Held

Abstract Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

Blood ◽

10.1182/blood.v122.21.1496.1496 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1496-1496 ◽

Cited By ~ 3

Author(s):

Philipp D. Le Coutre ◽

Dong-Wook Kim ◽

Javier Pinilla-Ibarz ◽

Ronald Paquette ◽

Charles Chuah ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Peripheral Vascular ◽

Vascular Events ◽

Advisory Committees ◽

Dose Modification ◽

Advisory Boards ◽

Initial Onset ◽

Grade 3

Abstract Background Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below (Figure). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. ClinicalTrials.gov ID: NCT01207440 aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Ariad, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

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Dose Dependent Enhancement Of Neutrophil Recovery By Infusion Of Notch Ligand Ex Vivo Expanded Cord Blood Progenitors: Results Of a Multi-Center Phase I Trial

Blood ◽

10.1182/blood.v122.21.297.297 ◽

2013 ◽

Vol 122 (21) ◽

pp. 297-297 ◽

Cited By ~ 4

Author(s):

Colleen Delaney ◽

Filippo Milano ◽

Ian Nicoud ◽

Shelly Heimfeld ◽

Chatchada Karanes ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Ex Vivo ◽

Chronic Gvhd ◽

Advisory Committees ◽

Neutrophil Recovery ◽

Cd34 Cells ◽

Primary Graft Failure

Abstract Introduction There is a strong clinical need to overcome the increased early non relapse mortality (NRM) associated with delayed neutrophil recovery following cord blood transplant (CBT). Therefore we established a methodology using Notch ligand (Delta1) as a strategy for increasing the absolute number of marrow repopulating CB hematopoietic stem/progenitor cells (HSPC). We previously reported preliminary results of the first 10 patients in 2010 demonstrating the ability of Notch-expanded CB HSPC to provide rapid myeloid recovery post-CBT.1 Herein we present the updated results on 23 patients accrued to this trial aimed at assessment of efficacy as well as the feasibility of overnight shipment of the expanded cell product to three outside institutions. Methods Between July 2006 and March 2013, 23 patients with hematologic malignancies were enrolled in this prospective multi-center Phase I trial coordinated by the Fred Hutchinson Cancer Research Center in which one CB unit was ex vivo expanded prior to infusion. Conditioning consisted of Fludarabine (75mg/m2), Cyclophosphamide (120mg/kg) and TBI (13.2 Gy) over 8 days. On day 0, the unmanipulated CB unit was infused first followed 4 hours later by infusion of the freshly harvested expanded CB cells. Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine and MMF beginning on day -3. All CB grafts were 4-6/6 HLA-matched (A/B antigen level, DRB1 allele level) to the recipient. Engraftment, NRM, relapse and GVHD were calculated using cumulative incidence rates to accommodate competing risks. Overall survival was analyzed using Kaplan-Meier estimates. Results Patient diagnosis was AML (n=16), ALL (n=5) and biphenotypic leukemia (n=2). Nine patients (39%) were ≥CR2 and 5 were MRD+ at the time of transplant. Median age was 28 years (range, 4-43) and weight 70 kg (range, 16-91) with a median follow-up of 614 days (range, 271-2443). 22 patients received the expanded graft with one product not meeting release criteria. The cell doses infused were significantly higher in the expanded CB graft: 2.7 (1.5-6.3) vs 6.9 (0.4-27.6) x107 TNC/kg, p<0.0008; 0.15 (0.02-0.57) vs 7.7 (0.62-49.5) x106 CD34/kg, p<0.0001. HLA-matching and ABO incompatibility of the expanded and unmanipulated products were similar. The incidence of neutrophil recovery was 95% (95% CI, 71-100) at a median of 13 days (range, 6-41 days) among the 22 patients receiving expanded CB cells which is significantly faster than that observed in 40 recipients of two unmanipulated units otherwise treated identically at a median time of 25 days (range, 14 to 45; p<0.0001). The incidence of platelet recovery (>20 x 10^9/L) was 77% (CI 95%: 53- 89) by day 100 at a median of 38 days (range, 19 – 134). There was one case of primary graft failure. Importantly, rate of neutrophil recovery correlated with CD34+ cell dose/kg with 8 out of 11 patients receiving greater than 8x106 CD34+cells/kg achieved an ANC ≥ 500/µl within 10 days. 21 patients were evaluable for in vivo persistence of the expanded cells. Ten (48%) demonstrated in vivo persistence beyond one month post infusion. The expanded cell graft was persistent at day 180 in 7 patients, and in those that survived to one year, dominance of the expanded cell graft persisted in one patient. The incidences of grade II-IV and III-IV acute GVHD was 77% (95% CI, 53-89) and 18% (95% CI, 5-36%), respectively; mild chronic GVHD was observed in 4 patients and severe chronic GVHD in one. Probability of OS was 62% (95% CI, 37-79%) at 4 years. Notably, the cumulative incidence of NRM at day 100 was 8% (95% CI, 14-24%) and at 4 years was 32% (95% CI, 8-40%). Nine patients died at a median time of 216 days (range, 31-1578 days) with respiratory failure/infection the most common cause (n=6). There were two relapses at day 156 and 365 post-transplant, with one death due to relapse. Secondary malignancy and primary graft failure were the other 2 causes of death. Conclusions Infusion of Notch-expanded CB progenitors is safe and effective, significantly reducing the time to neutrophil recovery and risks of NRM during the first 100 days. An advantage for infusion of higher numbers of CD34+ cells/kg further demonstrates the need to develop methods that reproducibly provide even greater expansion of repopulating cells than currently achieved to improve efficacy and potentially cost effectiveness. 1. Delaney C, et al, Nat Med. 2010 Feb;16(2):232-6. Disclosures: Delaney: Novartis: DSMB, DSMB Other; Biolife: Membership on an entity’s Board of Directors or advisory committees; medac: Research Funding. Wagner:Novartis: Research Funding; cord use: Membership on an entity’s Board of Directors or advisory committees.

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Blockade of PD-1 in Combination with Dendritic Cell/Myeloma Fusion Cell Vaccination Following Autologous Stem Cell Transplantation Is Well Tolerated, Induces Anti-Tumor Immunity and May Lead to Eradication of Measureable Disease

Blood ◽

10.1182/blood.v126.23.4218.4218 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4218-4218 ◽

Cited By ~ 7

Author(s):

Jacalyn Rosenblatt ◽

Irit Avivi ◽

Noam Binyamini ◽

Lynne Uhl ◽

Poorvi Somaiya ◽

...

Keyword(s):

Stem Cell ◽

Dendritic Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Ex Vivo ◽

Advisory Committees ◽

Post Transplant ◽

Fusion Cell ◽

Equity Ownership

Abstract Autologous stem cell transplantation (ASCT) for multiple myeloma (MM) offers a unique setting to incorporate immunotherapy in an effort to target residual disease. Our group has developed a cancer vaccine in which dendritic cells (DCs) are fused to autologous tumor cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response. A fundamental challenge to developing a more effective tumor vaccine is overcoming the immunosuppressive milieu by which tumor cells evade host immunity. Up-regulation of the PD-1/PDL1 pathway represents a key element contributing to tumor-mediated tolerance, and potentially muting response to vaccination. We are conducting a clinical trial in which patients with MM are treated with an anti-PD1 antibody (Pidilizumab, MDV9300) in combination with a dendritic cell/myeloma fusion cell vaccine following autologous transplantation. 22 patients have been treated with post-transplant immunotherapy. Mean age was 64. MM cells were isolated from bone marrow and were identified by expression of CD38 or CD138. Mean tumor cell yield was 118x106 cells. Adherent mononuclear cells were isolated from leukapheresis collections and cultured with GM-CSF and IL-4 for 5-7 days, then exposed to TNFα for 48-72 hours to generate mature DCs. DCs expressed co-stimulatory (mean CD86 75%) and maturation markers (mean CD83 50%). DC and MM cells were co-cultured with PEG and fusion cells were quantified by determining the percentage of cells that co-express unique DC and myeloma antigens. Mean fusion efficiency was 41% and the mean cell dose generated was 4 x 106 fusion cells. Mean viability of the DC, myeloma, and fusion preparations was 92%, 89%, and 85%, respectively. As a measure of their potency as antigen presenting cells, DC/MM fusions potently stimulate allogeneic T cell proliferation ex-vivo (Mean stimulation index of 1.9, 9.2 and 7.1 for tumor, DC and DC/myeloma fusions respectively, n=21) Post-transplant immunotherapy was initiated after recovery from transplant-related toxicities. Median time from transplant to initiation of post-transplant immunotherapy was 80 days. Patients received 3 doses of Pidilizumab at 6-week intervals. DC/myeloma fusion cells vaccination is administered 1 week before each dose of Pidilizumab. To date, 22 patients have completed vaccinations and Pidilizumab. Adverse events judged to be potentially treatment related included grade 1-2 diarrhea, arthralgias, myalgias, fatigue, headache, nausea, chills, transaminitis, cytopenia, elevated TSH, and vaccine site reactions. A significant increase in circulatingtumor reactive lymphocytes was noted following post-transplant immunotherapy, as determined by T cell expressionof IFN-γ by CD8 cells following ex-vivo co-culture withautologous myeloma cell lysate. Mean percentage of tumor reactiveCD8 cells increased from 1.8% post-transplant to a peak of 9.16% following immunotherapy. In the post-transplant period, regulatory T cells fell to minimal levels and remained low throughout the period of immunotherapy. 6 patients achieved a best response of VGPR, 6 patients have achieved a nCR/CR, including 3 who converted to CR following immunotherapy. Median PFS from transplant is 19 months with ongoing follow up. In summary, DC/MM fusion cell vaccination in conjunction with PD1 blockade following ASCT was well tolerated, potently induced anti-tumor immunity, and in a subset of patients, resulted in the eradication of post-transplant measurable disease. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Anderson:Celgene: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership. Rowe:BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BioLineRx Ltd.: Consultancy. Kufe:Genus Oncology: Consultancy, Equity Ownership.

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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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Efficacy and Safety of Voxelotor in Adolescents and Adults with Sickle Cell Disease: HOPE Trial 72-Week Analysis

Blood ◽

10.1182/blood-2020-140553 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-19

Author(s):

Jo Howard ◽

Kenneth I. Ataga ◽

R. Clark Brown ◽

Maureen Achebe ◽

Videlis Nduba ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

Board Of Directors ◽

Research Funding ◽

Efficacy And Safety ◽

Cell Disease ◽

Publicly Traded ◽

Advisory Committees ◽

Time Points ◽

Indirect Bilirubin ◽

Safety Signals

Background: Sickle cell disease (SCD) is a lifelong, inherited disorder characterized by mutations in the hemoglobin (Hb) subunit β gene that leads to the production of sickle hemoglobin (HbS). When HbS is deoxygenated, polymerization leads to red blood cell sickling and damage, resulting in hemolysis, chronic anemia, and episodic vaso-occlusive crises (VOCs). Patients with SCD are at an increased risk of developing long-term complications, including stroke, leg ulcers, and other end-organ damage. Lower Hb levels highly correlate with increased morbidity and early mortality in SCD. Voxelotor (Oxbryta®) is an oral, once-daily HbS polymerization inhibitor indicated for the treatment of SCD in adults and adolescent patients ≥12 years of age. The 24-week analysis of the HOPE trial demonstrated that treatment with voxelotor 1500 mg resulted in a significantly greater proportion of patients achieving a >1 g/dL Hb increase compared with placebo (51.1% vs 6.5%, P<0.001), which was associated with concordant improvements in hematological markers of hemolysis (indirect bilirubin and reticulocyte percentage). Here we report the evaluation of efficacy and safety of voxelotor 1500 mg at 72 weeks, the conclusion of the placebo-controlled HOPE trial. Methods: In the randomized, double-blinded, placebo-controlled, phase 3 HOPE trial, adults and adolescents (aged 12-65 years) with SCD were randomized to receive voxelotor (1500 mg or 900 mg) or placebo. Included patients had an Hb level of 5.5 to 10.5 g/dL at enrollment and 1 to 10 vaso-occlusive crises in the 12 months prior to screening. Concurrent hydroxyurea was allowed if the dose had been stable for ≥90 days at enrollment. Changes from baseline in Hb and hemolysis markers (absolute and percentage reticulocyte, indirect bilirubin levels, and lactate dehydrogenase levels) and safety were assessed at week 72. Results: 89% (95% CI, 82.4% to 95.4%) of patients receiving voxelotor 1500 mg achieved a Hb increase of >1 g/dL at 1 or more time points during the 72-week treatment period compared with 25% (95% CI, 16.2% to 33.8%) of those receiving placebo (P<0.001). The mean change in Hb from baseline at week 72 was 1.0 g/dL in patients treated with voxelotor 1500 mg compared with 0.0 g/dL in patients receiving placebo (Figure 1; P<0.001). Mean change from baseline to average Hb throughout the 72-week duration was 1.26 g/dL in patients treated with voxelotor 1500 mg. Consistent with the week 24 analysis, significant improvements in markers of hemolysis (assessed by difference in adjusted mean percent change versus placebo) were seen in indirect bilirubin (-26.6% [95% CI, -40.2% to -12.9%]) and reticulocyte percentage (-18.6% [95% CI, -33.9% to -3.3%]) in the voxelotor 1500 mg group relative to placebo, with favorable trends of reduction in other markers, such as absolute reticulocyte count (-5.8% [95% CI, -23.4% to 11.9%] and lactate dehydrogenase (-4.8% [95% CI, -13.8% to 4.1%]). The overall incidence rate of VOCs was numerically lower in the 1500 mg arm compared with placebo, but was not statistically significant. Rates of non-SCD and SCD-related treatment-emergent adverse events were similar between the treatment groups, with no new safety signals noted through week 72. Conclusions: Voxelotor 1500 mg resulted in durable improvements in Hb levels and markers of hemolysis out to 72 weeks of treatment, with approximately 90% of patients achieving an increase in Hb >1 g/dL at 1 or more time points during the study. Treatment with voxelotor remained well tolerated, with no new safety signals detected with longer-term follow-up. These results support the sustained and chronic use of voxelotor to reduce anemia and hemolysis, thereby potentially mitigating the associated morbidity and mortality of SCD. Disclosures Howard: Imara, Inc., Novartis, Resonance Health: Honoraria; Agios, Forma Therapeutics, Inc., Global Blood Therapeutics, Imara, Inc., Novo Nordisk, Novartis: Membership on an entity's Board of Directors or advisory committees. Ataga:Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire/Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Forma Therapeutics: Consultancy; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees. Achebe:Global Blood Therapeutics: Consultancy. Hassab:Global Blood Therapeutics: Research Funding. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tonda:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lehrer-Graiwer:Global Blood Therapeutics: Other: Former employee and former equity holder. Vichinsky:Pfizer: Research Funding; Agios: Research Funding; Global Blood Therapeutics: Consultancy.

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