scholarly journals Profile of Pain Medication Use in Hemophilia and Hemarthrosis: An Analysis of a Pharmacy Claims Database

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3189-3189
Author(s):  
Kim Mauer ◽  
Travis Helm ◽  
Tyler W. Buckner ◽  
Corey Macgregor ◽  
Judith A. Boice ◽  
...  
Keyword(s):  
Joint Pain ◽  
Stock Options ◽  
Hemophilia A ◽  
Bleeding Disorders ◽  
Advisory Committees ◽  
Cross Sectional ◽  
Pharmacy Claims ◽  
Pain Medications ◽  
Outpatient Prescriptions ◽  
Privately Held

Abstract Introduction: Chronic joint pain associated with bleeding disorders (particularly Hemophilia A and Hemophilia B) is well characterized. The most common treatments reported by patients with bleeding disorders include acetaminophen, traditional nonsteroidal anti-inflammatory drugs (tNSAIDs; cyclooxygenase 1/2 inhibitors, COX-1/2), COX-2 selective NSAIDs, and opioids (Witkop, et al. Haemophilia . 2017;23:556). Up to 50% of patients have reported opioid use to manage both acute and chronic pain(Witkop, et al. Haemophilia . 2017;23:556). The aim of this study was to compare and analyze different types of prescription pain medications in patients with a diagnosis of hemophilia A, B, and hemarthrosis using a pharmacy claims database. Methods: A cross-sectional analysis was conducted on a retrospective cohort of patients with bleeding disorders receiving pain medications in the Truven Health MarketScan Commercial Claims and Encounters database, for which IRB approval was not required. Index encounters were reported from April 1, 2017 to March 30, 2018, with one year of follow up. Patients were outpatients, inpatients, or both. Patient-level demographics were not collected. Results: Unique patients totaling 876 received 5,702 prescriptions. Patient diagnosis codes included Hemophilia A (D66), Hemophilia B (D67), and hemarthrosis (M362), each of which contributed 79.2%, 11.9%, and 8.8%, respectively, to the total prescriptions. Outpatient prescriptions comprised 81.0% of total prescriptions. Scheduled prescriptions comprised 70.8% of all prescriptions, 81.7% of inpatient prescriptions, and 68.2% of outpatient prescriptions (see Table). Schedule II drugs comprised 82.6% and 77.3% of all scheduled inpatient and outpatient prescriptions, respectively (see Table). Schedule IV prescriptions were the next most common, followed by schedule III. Prescription NSAIDs were more common in the outpatient than in the inpatient setting (see Table). Among NSAIDs, celecoxib comprised approximately half of the outpatient NSAID prescriptions and 15.1% of all outpatient prescriptions. Discussion: Regardless of setting, schedule II drugs are the most common form of pain management prescription in patients with hemophilia or hemarthrosis. Prescriptions for scheduled medications appear similar to what might be inferred in previous studies of patient reported use (Witkop, et al. Haemophilia . 2017;23:556). Consistent with self-reports (Witkop, et al. Haemophilia . 2017;23:556), hydrocodone or oxycodone with acetaminophen were confirmed to be the most frequently prescribed schedule II opioids. tNSAIDs, such as those reported in this analysis share gastrointestinal (GI) bleeding risk which may be heightened in persons with hemophilia compared with those who have no bleeding disorders. Celecoxib represents approximately 50% of outpatient NSAID prescriptions in this analysis despite data showing its clinically significant GI event risk is similar to both ibuprofen and naproxen (Nissen, et al. N Engl J Med. 2016:2519). Over-the counter acetaminophen is commonly used to treat chronic joint pain in hemophilia (Witkop, et al. Haemophilia. 2017;23:556) presumably to avoid GI bleeding, yet is reported to be less efficacious than celecoxib (Rodriguez-Merchan, et al. Blood Rev. 2018: 116). The broad use of opioids with their attendant risk of misuse, addiction, and diversion; as well as tNSAIDs, with their attendant GI risks, underscores the limited pain management options available for persons with hemophilia. This cross-sectional prescription claims data analysis highlights the need to identify and develop alternate forms of chronic pain medications for this population who have unique unmet needs (Humphries, et al. Haemophilia. 2015:41). Figure 1 Figure 1. Disclosures Helm: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Buckner: Genetech: Honoraria; Spark: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria; CSL Behring: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; uniQure: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria. Macgregor: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boice: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cerasoli: RX Medical Dynamics LLC: Consultancy, Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Khan: Rx Medical Dynamics, LLC: Current Employment. Argoff: Tremeau Pharmaceuticals,Inc: Consultancy.

scholarly journals A Novel Methodology for Building Longitudinal, Patient-Centric Real World Datasets in Hemophilia A

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 594-594
Author(s):  
Mark W Skinner ◽  
Gillian Hanson ◽  
Tao Xu ◽  
Richard Ofori-Asenso ◽  
Richard H. Ko ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
Advisory Board ◽  
Real World Data ◽  
Advisory Committees ◽  
Patient Reported ◽  
Privately Held

Abstract Background: There are limited real-world data (RWD) available on the unmet needs of people with mild or moderate hemophilia A (PwHA). This population accounts for 40-52% of all PwHA, including nearly all women with hemophilia A (HA), and is under-represented in scientific literature (Michele, et al. Haemophilia 2014; Benson, et al. Blood Transfus 2018; Peyvandi, et al. Haemophilia 2019). Available claims data from payer databases are confined to billing codes, and lack key information on outcomes and disease characterization (e.g. severity, treatment response.) (Tyree, et al. Am J Med Qual 2006). Registry datasets can require resource-intensive data entry and potentially miss key information about care received at outside facilities, at home, or after patients switch providers (Gliklich, et al. Registries for Evaluating Patient Outcomes: A User's Guide. 2014). To address these data gaps, we developed a novel, patient-centered approach to create a longitudinal healthcare database from individuals with mild and moderate HA in the United States. This study assessed the feasibility of this approach, which integrates medical record data collected during routine clinical care along with patient-reported outcomes (PROs) to provide needed insights into this under-represented population. Methods: Recruitment began in June 2020 via a broad strategy of social media outreach, healthcare provider partnerships, and patient advocacy groups. Eligibility was confined to mild or moderate PwHA, confirmed via physician report within provider notes in combination with baseline factor VIII levels (>5-50% mild, 1-5% moderate.) This study received research ethics board approval and abides by the guiding principles of the Declaration of Helsinki. PwHA enrolled via an online record management platform, PicnicHealth. After signing authorization forms for collection of their electronic health records (EHR) and informed consent to share their de-identified data for research, participants were prompted to enter information on their care providers. Records were gathered from all providers, across any facility, retrospectively as records were available. (Figure 1) All records obtained were made available to the participants via a medical timeline. Records were translated to text via optical character recognition with human review. Data elements from structured text as well as disease-specific elements from narrative text were captured using natural language processing and supervised machine learning. All elements, including visit metadata, conditions, measurements, drugs, and procedures were mapped to standardized medical ontologies and reviewed by a team of nurses. (Table 1) Quality control was assessed via inter-abstractor agreement on outputs with physician review. Patient-reported bleed, treatment, and pain data were collected via online questionnaire for a subset of PwHA, with participants prompted to enter data every 2 weeks. Abstracted EHR data was linked to PRO responses in a de-identified dataset. Cohort and abstraction characteristics were summarized descriptively. Results: From June 1, 2020 to June 30, 2021, 104 PwHA met eligibility criteria for enrollment (65 [62.5%] mild; 39 [37.5%] moderate). Participants saw providers across 34 states in the US, 22.1% (23/104) were female, and 20.6% (14/68) of those with known race/ethnicity status were from minority groups. Records were gathered from a median of six care sites and 16 providers per participant. A median of 50 (IQR [21-93]) clinical documents from 11 years were processed for each PwHA. (Table 2) Inter-abstractor agreement to assess abstraction quality averaged 95.9% for condition, 99.5% for drug name, and 95.4% for drug start date. As of June 2021, the average PRO response rate was 90.3% (150/166 of all requests) and continues prospectively. Conclusions: The patient-centric data collection methods implemented in this study provide a novel approach to build longitudinal real-world data sets. Technology-enabled data abstraction showed consistent high quality when processing the heterogeneous clinical records across disparate providers and care sites, and direct engagement with patients complements potential gaps in the clinical record. Additionally, this approach provides needed data on groups under-represented in RWD and traditional PwHA cohorts, including those with mild and moderate disease and women with HA. Figure 1 Figure 1. Disclosures Skinner: ICER: Membership on an entity's Board of Directors or advisory committees; Spark (DMC): Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Pfizer (DMC): Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; uniQure: Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Freeline: Research Funding; BioMarin: Honoraria, Research Funding; IPA Ltd.: Current holder of individual stocks in a privately-held company; National Hemophilia Foundation: Consultancy; Institute for Policy Advancement Ltd: Current Employment; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Xu: F. Hoffmann-La Roche AG: Current Employment. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Witkop: Roche Advisory Panel: Consultancy; National Hemophilia Foundation: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

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

Blood ◽  
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.

scholarly journals Emicizumab Outcomes in Hemophilia A Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 347-347
Author(s):  
Man-Chiu Poon ◽  
Adrienne Lee ◽  
Federico Germini ◽  
Arun Keepanasseril ◽  
Quazi Ibrahim ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Patient Reported Outcomes ◽  
Hemophilia A ◽  
Severe Disease ◽  
Mild Disease ◽  
Patient Reported ◽  
Privately Held ◽  
Mcmaster University

Abstract Background: The Canadian Hemophilia Bleeding Disorders Registry (CBDR) is a clinical database including data from all Canadian Hemophilia Treatment Centers (HTCs) to assist in the management of hemophilia and other bleeding disorders. The CBDR launched on July 1, 2015 and integrates the data entry platform for patients, myCBDR, allowing direct entry of treatments, bleeding events, and other patient reported outcomes (PRO) data. Health Canada approved emicizumab in August 2018 for the treatment of persons with hemophilia A (PwHA) with factor (F)VIII inhibitors, and for PwHA without FVIII inhibitors in 2019, enabling some patients without FVIII inhibitors to be provided compassionate access beginning November 2019. Our aim for this analysis was to use the CBDR data to describe the demographics of the emicizumab-treated PwHA population and assess its effectiveness, safety, treatment patterns, and the impact on disease burden. Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once up to December 31, 2020. Disease severity is defined by the level of endogenous clotting FVIII activity. Effectiveness outcomes include number of patients (%) with zero treated bleeds, joint bleeds, and spontaneous bleeds; annualized bleeding rates (ABR) for any bleeds and treated bleeds; Hemophilia Joint Health Score (HJHS); Patient Reported Outcomes Burdens and Experiences (PROBE); and EQ-5D-5L index and visual analog scale (VAS). ABRs were calculated as (total number of bleeds/duration of follow-up [days])*365.25. All analyses were performed based on the observed values, without imputation. This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki. Results: 73 PwHA who received emicizumab at least once up to December 31, 2020 were identified. Demographic characteristics, severity, inhibitor status, and treatments are described in Table 1. Median (IQR) age for the entire cohort was 19.7 (10.0, 40.6) years with 45.2% ≤18 years. There were 64 PwHA with severe disease, 7 with moderate disease and 2 with mild disease; both cases with mild disease had current FVIII inhibitors. 49 PwHA had current FVIII inhibitors, 12 had a history of FVIII inhibitors, and 12 had no FVIII inhibitors. 5/73 (6.8%) received immune tolerance induction (ITI) treatment while on emicizumab. Two cases of rash (allergic or acute reactions) were reported (2/73, 2.7%) of which one (reported 6 days after administration) was possibly related to emicizumab according to the reporting HTC. No thromboembolisms or thrombotic microangiopathies were observed. Median ABR (IQR) for the entire study population was 0.0 (0, 0) and 59/73 (80.8%) had no recorded bleeds. In the 14/73 (19.2%) with recorded bleeds, median ABR (IQR) was 2 (1, 3); 8 of those 14 had joint bleeds and 7 had spontaneous bleeds. HJHS was recorded for 23, PROBE Score for 9, EQ-5D-5L for 9 and EQ-5D-5L VAS for 4 PwHA (Table 2). Conclusions: The Canadian population treated with emicizumab had severe disease and current or historical FVIII inhibitors. The bleed outcomes are consistent with earlier publications, showing 80.8% had no recorded bleeds. The CBDR will allow for longitudinal follow-up of this patient population. Our results can inform healthcare practitioners and regulatory authorities on the real-world safety and effectiveness outcomes of emicizumab in PwHA with and without FVIII inhibitors. Figure 1 Figure 1. Disclosures Poon: Roche: Honoraria; Pfizer: Honoraria; Novo Nordisk: Honoraria; Bioverativ/Sanofi: Honoraria; CSL-Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; University of Calgary: Current Employment; Takeda: Honoraria. Lee: Roche: Honoraria; Pfizer: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; CSL Behring: Honoraria; Biovertiv/Sanofi: Honoraria, Research Funding; Bayer: Research Funding, Speakers Bureau; Takeda: Honoraria. Keepanasseril: McMaster University: Current Employment; NovoNordisk Canada: Consultancy. Ibrahim: McMaster University: Current Employment. Nissen: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company; Novartis: Consultancy; Actelion: Consultancy. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Santos: F. Hoffmann-La Roche Ltd.: Current Employment; Roche: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Baxter: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Takeda: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Iorio: McMaster University: Current Employment; Bayer (funding to the institution): Research Funding; BioMarin (funding to the institution): Research Funding; NovoNordisk (funding to the institution): Research Funding; Octapharma (funding to the institution): Research Funding; Pfizer (funding to the institution): Research Funding; Roche (funding to the institution): Research Funding; Sanofi (funding to the institution): Research Funding; Sobi (funding to the institution): Research Funding; Takeda (funding to the institution): Research Funding.

scholarly journals Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1345-1345
Author(s):  
Peter Trask ◽  
Jaisson Bortolini ◽  
Shinya Rai ◽  
Antonio Salar ◽  
Miguel Canales ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Stock Options ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Time Savings ◽  
Low Levels ◽  
Grade 3 ◽  
Privately Held

Abstract Background: Patients with follicular lymphoma (FL) who are on initial treatment, report low levels of symptoms and a higher quality of life index in contrast to patients who have relapsed (Pettengell et al. Ann Oncol 2008). In the immunochemotherapy era, effective and safe treatments should create minimal treatment-related symptoms, regardless of the underlying patient characteristics. In the GALLIUM study (NCT01332968), patients treated with obinutuzumab (G)-chemotherapy followed by G maintenance reported low levels of symptoms (Davies et al. Ann Hematol 2020). Short duration infusions (SDI) of treatments for patients with untreated, advanced FL may yield substantial time savings for patients, and free up healthcare resources. The GAZELLE study (NCT03817853) is a prospective open label, multicenter, single arm, Phase IV study, which evaluated the safety of G administered as a 90-minute (min) SDI infusion from Cycle 2 (C2) onwards in patients with previously untreated advanced FL. G SDI appears to be safe, with no Grade 3 infusion-related reactions (IRRs) reported in C2, and only one Grade 3 IRR reported in subsequent cycles (Canales et al. ASCO 2021). In this analysis, we report symptom levels and provider preference during G SDI administration. Methods: During the first cycle, patients received the first three infusions of G (1000mg) administered at the standard infusion rate on Days 1, 8, and 15. Patients who did not experience any Grade ≥3 IRRs during the first cycle received G as a SDI from C2 onwards. The M.D. Anderson Symptom Inventory (MDASI: range 0 [not present) to 10 [worst]) was used to assess the severity of disease/treatment-related symptoms, and how symptoms interfere with aspects of the patient's daily living. It was completed on Day 1 of C1-6, at the end of induction, during maintenance, at the end of maintenance, and at the end of the study. Additional MDASI analyses were conducted based on patient risk groups (bulky disease, Ann Arbor staging, Eastern Cooperative Oncology Group performance score, B-symptoms, Follicular Lymphoma International Prognostic Index). At any time point after C4 Day 1, study investigators (physicians and nurses) completed an evaluation composed of questions addressing their site's experience with regards to time saved, convenience and infusion preference after administration of SDI and standard infusion of G, across all patients enrolled in the study. Results: 110/113 patients received at least one SDI of G, as per protocol. Median age was 62 years, (range: 28-86 years) and 62% of patients had stage IV FL, 51% presented with B-symptoms at baseline, 45% with bulky disease and 45% were classified as high-risk FLIPI. Median baseline MDASI severity and interference scores were 0 or 1 for most symptoms. Interference scores did not meaningfully change over the course of treatment. Median MDASI scores (baseline or change over treatment), also did not differ by risk subgroups. Over 60% of providers reported that SDI of G would save at least 2 hours in infusion time per visit, with >65% saying it was much more convenient versus regular infusion. SDI was preferred by >95% of providers for reasons attributed to time savings and patient comfort. Conclusions: Untreated, advanced FL patients had no or mild symptom severity and interference at baseline regardless of risk group. These low levels were maintained during G SDI administration. Additionally, SDI administration was preferred by providers for the time it saved, convenience, and comfort for patients, suggesting that G SDI administration can be a beneficial treatment option for untreated, advanced FL patients by minimizing patient treatment burden with no impact on health-related quality of life. Disclosures Trask: Genentech: Current Employment; Genentech/Roche: Current equity holder in publicly-traded company. Bortolini: Novartis: Speakers Bureau. Rai: Janssen Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau. Salar: Abbvie: Research Funding; Beigene: Consultancy; BMS/Celgene: Consultancy, Speakers Bureau; EusaPharma: Consultancy; Janssen: Consultancy, Speakers Bureau; Hospital del Mar: Current Employment. Canales: Eusa Pharma: Consultancy, Honoraria; iQone: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Sandoz: Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau. Klingbiel: F.Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Parreira: Hoffmann la Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Honoraria. Deraet: Hoffmann La Roche: Current Employment, Current holder of individual stocks in a privately-held company. Vorozheikina: IQVIA: Current Employment. Hübel: Celgene: Consultancy; Servier: Consultancy, Speakers Bureau; EUSA: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Buchholz: Scripps Health Care System: Current Employment; Roche (Navify software): Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nucleix LLC: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Ultimate Opinions in Medicine LLC: Honoraria; Empyrean medical systems: Membership on an entity's Board of Directors or advisory committees; Mirada: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Evaluation of the Safety of Emicizumab Prophylaxis in Persons with Hemophilia A: An Updated Summary of Thrombotic Events and Thrombotic Microangiopathies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3186-3186
Author(s):  
Monet Howard ◽  
Derrick McKinley ◽  
Fabian Sanabria ◽  
Richard H. Ko ◽  
Francis Nissen
Keyword(s):  
Risk Factors ◽  
Stock Options ◽  
Hemophilia A ◽  
Publicly Traded ◽  
Thrombotic Microangiopathies ◽  
Off Label ◽  
Coronary Syndrome ◽  
Patient Reported ◽  
Post Marketing ◽  
Privately Held

Abstract Background: Emicizumab is indicated for routine prophylaxis in persons with congenital hemophilia A (PwcHA) with/without factor (F)VIII inhibitors in >100 and >80 countries, respectively. Emicizumab has been used by >11,400 persons across the globe (data cut-off 15 May 2021). The pivotal HAVEN 1-4 trials established the efficacy and safety of emicizumab prophylaxis; however, the HAVEN 1 trial identified an increased risk of thrombotic events (TEs) and thrombotic microangiopathies (TMAs) when used in conjunction with >100 U/kg/24 hours activated prothrombin complex concentrate (aPCC) for ≥24 hours (Oldenburg, et al. New Engl J Med 2017). Here we report an updated safety evaluation of emicizumab prophylaxis focusing on TEs and TMAs. Methods: All individual safety reports for emicizumab from clinical trials, registries, expanded access programs, compassionate use and the post-marketing setting were collated with a cut-off date of 15 May 2021 and analyzed for TEs and TMAs. Number of TEs/TMAs, clinical factors (indication, age, FVIII inhibitor status, comorbidities) and drug factors (co-exposure to medications affecting coagulation) are presented in aggregate. Individual case reports (cases) were reviewed to exclude non-TEs and any duplicate reports. TEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA) search strategy: 'Embolic and Thrombotic Events' Standardized Medical Query ([SMQ] Wide) and Preferred Term 'Acute Coronary Syndrome'. TMAs were defined as hemolytic uremic syndrome, microangiopathic hemolytic anemia, microangiopathy, thrombotic microangiopathy and thrombotic thrombocytopenic purpura. Results: In total, 52 cases (56 events) meeting the search criteria were identified on the Roche Global Safety Database as of 15 May 2021 (Figure). After review, 39 cases were reported in PwcHA and 10 cases were determined to be off-label (acquired hemophilia A, n=7; or unknown indication, n=3). Two additional cases were determined to be duplicates. One case of 'hemiparesis' was identified through SMQ review, but did not fit the clinical definition of a true TE. Six cases occurred with concomitant aPCC use, of which four were TMAs. In total, 33 cases were not associated with concomitant aPCC use, and these comprised 37 TEs and no TMAs in PwcHA. No new TEs or TMAs associated with aPCC were reported since the last update (Lee, et al. Haemophilia 2020). For the 37 TEs reported in PwcHA and not associated with aPCC, the median age (range) at time of event was 49 years (0.42-84) and the median (range) emicizumab treatment duration at time of event was 330 days (0-1076). In total, 36 (97.3%) TEs were medically confirmed and one (2.7%) was patient reported. Seventeen (45.9%) TEs occurred in PwcHA with FVIII inhibitors. Seven (18.9%) TEs were associated with central venous access devices (CVADs), of which four were reported to be resolving/recovering at last report. All except for two (with limited information) non-aPCC associated TEs in PwcHA were associated with ≥1 cardiovascular (CV) risk factors (e.g. previous myocardial infarction, ischemic heart disease, coronary artery disease, hypertension, hyperlipidemia, smoking, advanced age) or other risk factors for thrombosis (e.g. sepsis/bacteremia, device use, coinciding injury, hepatitis C). Of the non-aPCC and non-CVAD associated events reported, six (20.0%) TEs led to the discontinuation of emicizumab. Across all non-aPCC associated events, an evaluation of latency or duration of treatment did not reveal any patterns or trends. In total, four TEs were fatal: two myocardial infarctions, both in medically complex patients; and two disseminated intravascular coagulation events in patients >70 years of age with pneumonia. Where reported, 20/31 (64.5%) TEs were recovered/resolving at the time of this analysis, with the majority of these cases reporting no change to emicizumab prophylaxis as a result of the event. Conclusions: The reporting rate for TEs without concomitant aPCC remains low as exposure increases. Notably, all cases with adequate information available were associated with CV risk factors and/or risk factors for thrombosis. All TMAs were associated with concomitant use of aPCC. This post-marketing analysis does not support TEs and TMAs without concomitant aPCC as an identified risk for PwcHA receiving emicizumab prophylaxis. The risk-benefit profile of emicizumab remains unchanged. Figure 1 Figure 1. Disclosures Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McKinley: Pro Unlimited: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: The enclosed analysis of the Roche Hemlibra internal database was produced by submitted safety reports, including reports of off-label use. These data will be discussed in aggregate, and not individually described.

scholarly journals SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2009-2009
Author(s):  
John B. Porter ◽  
Alison Scrimgeour ◽  
Alberto Martinez ◽  
Leo James ◽  
Manuela Aleku ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Serum Iron ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Beta Thalassemia ◽  
Advisory Committees ◽  
Treatment Groups ◽  
The Mean ◽  
Privately Held

Abstract Background Hepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers. Objectives The primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated. Methods Each subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo. Results Three cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed. Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively. Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57. The mean (±SD) percent transferrin saturation (TSAT) was reduced from baseline levels in all single dose administration groups with maximum decreases observed at day 29 but reductions still observed at day 57. (Table 1). The observed PK is consistent with the PK model based on preclinical data. Thus, whereas the effects of SLN124 on plasma hepcidin show clear increments across the dose range tested, the effect on lowering serum iron and transferrin saturation shows something of a plateau effect at the highest dose. In future studies in patients with raised baseline transferrin saturations, it will be of note to determine whether transferrin saturation continues to decrease at the highest SLN124 doses. Conclusion/summary In summary, SLN124, a GalNAc conjugated siRNA targeting TMPRSS6, effectively reduces serum iron levels and has the potential as a therapeutic for patients with alpha and beta-thalassemia, myelodysplastic syndromes, hereditary hemochromatosis and other related disorders. The effect on hepcidin levels at the end of study, day 57, suggest a prolonged duration of action. The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial (NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients withthalassemia and myelodysplastic syndromes. Figure 1 Figure 1. Disclosures Porter: bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scrimgeour: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Martinez: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. James: Silence Therapeutics: Consultancy. Aleku: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wilson: Silence Therapeutics: Consultancy. Muckenthaler: Silence Therapeutics: Research Funding. Schaeper: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Silence Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

scholarly journals Clofarabine-Based Chemotherapy for KMT2Ar Infantile Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3406-3406
Author(s):  
Tanja Andrea Gruber ◽  
Deqing Pei ◽  
John Kim Choi ◽  
Cheng Cheng ◽  
Elaine Coustan-Smith ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Stock Options ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Childhood All ◽  
Risk Patients ◽  
Severe Infections ◽  
Privately Held

Abstract Rearrangements in KMT2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event-free-survival (EFS) of 33.6-36.9%. In the context of the remarkable improvements in the treatment of childhood ALL, the dismal outcome of infantile KMT2Ar ALL and the lack of any significant progress for more than two decades are striking . The St. Jude Total Therapy 16 study (the most recently reported study of a program for childhood ALL that begun in 1962) yielded a 5-year EFS of 88.2% overall. Total 16 enrolled all subtypes of newly diagnosed pediatric ALL patients including infants, with intensity of treatment adapted to presenting clinical and genomic features, and early treatment response as determined by minimal/measurable residual disease (MRD). KMT2Ar infants were treated on an intensified high-risk arm and received clofarabine in combination with cyclophosphamide and etoposide (CCE) at two points during treatment: Induction days 22-25 and Reinduction I. Infants who lacked KMT2Ar and KMT2Ar patients who were one year of age or older received the same risk-directed treatment plan given to all other patients enrolled on study. A total of 28 patients with KMT2Ar were enrolled on Total 16; the 19 patients > 1 year of age received standard-risk therapy, and the 9 patients < 1 year of age received high-risk therapy on the infant arm with CCE. The probabilities of 5-year EFS and overall survival in KMT2Ar patients > 1 year of age and those < 1 year of age were 73.3% vs. 44.4% (p=0.071) and 84.2% vs. 55.6% (p=0.060), respectively. Six of the nine infants were MRD-positive on Induction day 15 prior to CCE (MRD-positive range, 0.012% to 13.7%; median, 2.13%) with MRD negative status (<0.01%) achieved post CCE in six of the eight patients with data (MRD was 0.011% and 0.07% in the remaining two patients). The trend towards superior outcomes in older KMT2Ar patients was not due to a lower incidence of relapse, as the 5-year cumulative incidence of relapse was 26.7% in patients > 1 year of age and 12.5% for those < 1 year of age (p=0.454). Five infants remain alive (four in CR1, one in CR2), while four expired in CR1. Three deaths were secondary to infection, including a multi-drug resistant soft tissue bacterial infection during Induction days 1-21, a respiratory syncytial virus pneumonia during Reinduction II, and a chronic parainfluenza 3 infection during Continuation weeks 70-101 that led to chronic pneumonitis and interstitial fibrosis. The fourth patient developed grade 5 pulmonary hypertension following induction, a complication potentially compounded by their presenting WBC count of 905 x 10 9/L and pulmonary leukostasis. A comparison of 3-year cumulative risk of selected major toxic effects of treatment revealed that high-risk infants had a lower incidence of asparaginase allergic reactions, osteonecrosis, hyperglycemia, and pancreatitis; in contrast, the incidence of fever and neutropenia, hepatic toxicity and seizures, was similar in high-risk patients regardless of age. Infants had a higher risk of thrombosis (46.7% vs. 23.1%, p<0.001) and of severe infection (70% vs. 19.7%, p<0.001). To further study the contribution of clofarabine to severe infections, we looked at the incidence in high-risk patients > 1 year of age that received one or more clofarabine-containing Reintensification chemotherapy cycles prior to hematopoietic stem cell transplant in first remission (CR1). This revealed a higher frequency of infections in infants, suggesting a greater susceptibility to this complication independent from clofarabine exposure (mean number of episodes, 2.39 vs. 1, p<0.001, Poisson regression modeling). In conclusion, treatment of infants with KMT2Ar ALL with chemotherapy including high-intensity clofarabine leads to a lower cumulative incidence of relapse but a higher risk of treatment-related mortality. Severe infections were a major cause of morbidity and mortality. Disclosures Gruber: Kura Oncology: Consultancy. Coustan-Smith: Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Current holder of individual stocks in a privately-held company; Medisix Therapeutics: Current holder of individual stocks in a privately-held company. Campana: Nkarta Therapeutics: Current holder of stock options in a privately-held company; Medisix Therapeutics: Current holder of stock options in a privately-held company; Juno: Other: patent licensing payments; Juno Therapeutics (a Bristol-Myers Squibb company),: Other: patents on methods for minimal residual disease detection.. Evans: St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

scholarly journals Usability and Performance Testing of Pointcheck™: A Noninvasive Neutropenia Screening Device for Chemotherapy Outpatients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4924-4924
Author(s):  
Ganimete Lamaj ◽  
Alberto Pablo-Trinidad ◽  
Ian Butterworth ◽  
Nolan Bell ◽  
Ryan Benasutti ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Stock Options ◽  
Diagnostic Performance ◽  
Severe Neutropenia ◽  
Primary Study ◽  
Advisory Committees ◽  
First Time ◽  
Privately Held

Abstract Introduction Every year, approximately 110,000 cancer patients treated with cytotoxic chemotherapy in the US endure at least one episode of febrile neutropenia (FN). Each FN episode will require an approximate 8-9-day admission costing $25,000 and may have associated mortality rates as high as 7% . Timely detection and awareness of severe neutropenia (i.e., Absolute Neutrophil Count (ANC) <500/µL) is key to managing FN. The current gold standard relies on blood draws and analysis is hence limited to the clinical setting. We have developed PointCheck™, a noninvasive, portable technology (Fig. 1-A) that can automatically monitor for severe neutropenia and enables prompt detection in the home- as described in Bourquard et al (2018) and Pablo-Trinidad et al (2019). Methods We conducted a multicenter study to evaluate the usability and diagnostic performance of PointCheck™ in a cohort of 26 participants. The primary study objectives were to assess device usability when operated by first-time users and to meet a priori specified diagnostic performance goals in achieving 92% sensitivity (true positive rate) and 80% specificity (true negative rate). Study coordinators read a short script providing the participants with information about how to use the device. In addition, participants watched a 1-minute tutorial video, were provided with a one-page user guide before attempting to take a measurement on their own following the on-screen Graphical User Interface instructions (Fig. 1-B). They did so autonomously to simulate home usage. Usability data was collected using a combination of methods, including the think-aloud technique, a short-answer qualitative questionnaire, and a standardized quantitative System Usability Survey (SUS)- a usability evaluation method widely used in UI/UX design comprising 10 questions. Participants were also given the opportunity to document their thoughts, feelings, and experience using the device in the form of an e-questionnaire containing 4 questions about their perceptions. Design and functionality issues were primarily identified by the research staff through observation of participants and documentation of missed or incorrectly completed steps. Participants also had their blood drawn for a comparison with their complete blood count (CBC) to assess diagnostic performance. PointCheck™ measurement results were compared with clinical standard CBC tests and assessed for accuracy in classifying subjects as severely neutropenic (<500/µL, grade IV neutropenia) or non-severely neutropenic (≥500/µL). Results Usability and diagnostic performance data was gathered from untrained cancer patients and healthy volunteers. We included patients with lymphoma and myeloma, among other tumor types, who visited either Boston Medical Center (BMC) and Hospital Universitario 12 de Octubre (H12O) for routine chemotherapy administration. The healthy volunteers were recruited at the Massachusetts Institute of Technology Clinical Research Center (MITCRC). The PointCheck™ device detected severe neutropenia with 92% sensitivity and 83% specificity in 24 subjects (Fig. 1-C). Two out of 26 subjects were flagged and excluded by the device Quality Control system. With respect to usability, we found that 80.8% of participants scored above 80.8 on the SUS scale across all sites, with a mean SUS score of 89.1 across all sites (Fig. 1-D). The most common user errors seen were incorrect placement of the finger, hand, and arm. Discussion We have shown that PointCheck™, a novel technology for non-invasive, home-based neutropenia detection, is accurate and easy to use by first-time users in a simulated home environment with a mean SUS score of 89.1, indicating above average perception of user experience and falling within the top 10% of systems as evaluated by the SUS scale. The technology accurately detects severe neutropenia in the cohort of patients presented here, which included liquid tumors, other cancer conditions, and healthy volunteers. These preliminary results show that PointCheck™ is a promising technology to aid in the detection of severe neutropenia in the home setting. These results need to be confirmed in a larger patient cohort with a final device design. Figure 1 Figure 1. Disclosures Lamaj: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Pablo-Trinidad: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Butterworth: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bell: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Benasutti: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Verdone: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company. Bourquard: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Sanchez-Ferro: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Castro-Gonzalez: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria.

scholarly journals Assessing the Role of BCOR/BCORL1 and Other Historically Low-Frequency Somatic Mutations in Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4647-4647
Author(s):  
Taha Alrifai ◽  
Natasha Edwin ◽  
Dale L. Bixby ◽  
Adam John Hockenberry ◽  
Emmanuel Okeke ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Somatic Mutations ◽  
Clinical Investigation ◽  
Clinical Information ◽  
Advisory Committees ◽  
Cancer Types ◽  
Generation Sequencing ◽  
Privately Held

Abstract Background: Myelodysplastic syndromes (MDS) represent a heterogeneous group of malignancies that are characterized by aberrant hematopoiesis and consequently abnormal blood counts. Patients with MDS have an increased likelihood of developing acute myeloid leukemia (AML). Next generation sequencing (NGS) is currently being used to study the genetic landscapes of diverse cancer types in finer detail than has previously been possible, owing to its ease-of-use and widespread availability. Crucially, the accuracy and broad breadth of genomic coverage provided by NGS approaches may permit the study of mutations that are rare in MDS patients, yet well studied in AML or other cancer types. Based on the fact that much less is known about particular rare somatic mutations in MDS, we decided to investigate 6 genes. IDH1 and IDH2 are targetable in patients with AML. Mutations in JAK2 are found in high proportions in patients with myeloproliferative neoplasms (MPNs) or MDS/MPN overlap neoplasms. Finally, other mutations in genes such as BCOR, BCORL1, and MUTYH also occur in MDS patients with appreciable-but generally low-frequencies such that their overall impact on MDS patients is largely unknown. Methods: We utilized the Tempus LENS platform to retrospectively characterize 236 MDS patients who underwent genomic-testing with the Tempus|xT assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq; data accessed on 06/28/2021). The patient population was 28% female, with a median age of 71.6 years. Mutations identified included germline and/or somatic single nucleotide variants (though we only considered somatic variants in this study), insertions/deletions and copy number variations (gains defined as ≥8 copies). For a subset of patients processed at Rush University Medical Center (RUMC), we additionally performed a curated clinical investigation into laboratory variables, prognostic data, treatment history and outcomes data. Results: Within the Tempus MDS dataset, we observed a range of mutation frequencies. In total, 58 patients had mutations in at least one of either: JAK2, BCOR, IDH2, IDH1, BCORL1, and MUTYH. When comparing the observed frequencies against values that have previously been reported, mutations in these 6 genes occurred with higher frequency in our dataset while most other mutations were in accordance with the relative frequencies reported by other sources (Table 1). We observed the largest deviation from expectation for BCOR. Whereas prior reports list this mutation as occurring with a frequency of <5%, greater than 10% of the records we analyzed contained a mutation in either BCOR (n=24, 10.16%) or BCORL1 (n=6, 2.54%). Four records in the dataset had mutations in both BCOR and BCORL1; a total of 26 records (11%) thus contained mutations in one of these two genes. Of these 26 patients, 50% were female and the median age was 70 years. The most commonly observed co-mutations with BCOR/BCORL1 were-in order of frequency-RUNX1 (50%), ASXL1 (23%), DNMT3A (23%), SF3B1 (19%), and STAG2 (19%). Additional data were derived from detailed clinical investigation into a limited subset of 4 patients who were treated at RUMC and who had mutations in either BCOR or BCORL1. Revised International Prognostic Scoring System (IPSS-R) scores were: high/very high (2) and low (2). Three of the four patients displayed complex karyotypes and three of the four progressed to AML. Conclusions: We identified a higher frequency of BCOR/BCORL1 mutations among patients with MDS than has been previously reported. At the same time, most other mutation frequencies were in relative accordance with existing reports. We observed complex cytogenetic abnormalities in 75% of patients for which we had extensive clinical information. Our data suggest an association between BCOR/BCORL1 mutations and complex karyotypes, a finding that may establish a prognostic role of BCOR/BCORL1 and have potential therapeutic implications. This hypothesis is, however, subject to further investigation and will require larger sample sizes that are likely to become available with the rapidly increasing utilization of next generation sequencing techniques and availability of high-quality, curated clinical information. Figure 1 Figure 1. Disclosures Hockenberry: Tempus Labs, Inc: Current Employment, Current holder of stock options in a privately-held company. Okeke: Tempus Labs, Inc: Current Employment. Mahon: Tempus Labs, Inc: Current Employment. Hassane: Tempus Labs, Inc: Current Employment. Enschede: Tempus Labs, Inc: Current Employment, Current holder of stock options in a privately-held company. Shammo: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astra zeneca: Research Funding; CTI pharma: Research Funding; Stemline therapeutics: Research Funding; Kartos Pharma: Research Funding; Takeda: Consultancy, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Abbvie: Current holder of individual stocks in a privately-held company, Research Funding; Baxter: Current holder of stock options in a privately-held company; sanofi: Consultancy, Honoraria, Speakers Bureau; NS Pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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