scholarly journals Assessment of TRM-201 (Rofecoxib) Efficacy and Safety for Chronic Pain in Hemophilic Arthropathy: The Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy (RESET-HA), a Randomized, Double-Blind Placebo-Controlled Phase III Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4243-4243
Author(s):  
Judith A. Boice ◽  
Tyler W. Buckner ◽  
Stacy E. Croteau ◽  
Nathaniel Katz ◽  
Robert F. Sidonio ◽  
...  
Keyword(s):  
Pain Management ◽  
Platelet Function ◽  
Stock Options ◽  
Research Funding ◽  
Rescue Medication ◽  
Package Insert ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Hemophilic Arthropathy ◽  
Privately Held

Abstract Background: Intra-articular bleeding (hemarthrosis) accounts for 80-90% (Roosendaal, et. al. Semin Thromb Hemost . 2003;29:37) of all bleeds and more than 90% of serious bleeding events in patients with severe hemophilia (Valentino. J Thromb Haemost . 2010;8:1895). Recurrent hemarthroses result in progressive joint damage and the development of hemophilic arthropathy (HA) in up to 50% of adults with hemophilia (Forsyth, et al. Haemophilia . 2014;20:44). Acetaminophen is commonly prescribed for pain due to HA yet has limited efficacy at therapeutic doses (Rodriguez-Merchan. Blood Rev. 2018;32:116). Traditional non-steroidal anti-inflammatory drugs (tNSAIDs) inhibit platelet function and cause gastrointestinal (GI) complications including bleeding, both of which can be harmful in patients with hemophilia (Rodriguez-Merchan. Blood Rev. 2018;32:116; Brooks, et al. Rheumatology . 1999;38(8):779). Opioids are prescribed in over 60% of patients with HA(Witkop, et al. Haemophilia. 2012;18:e115) despite dependence, potential for abuse, and an increased risk of falls and other opioid-related injury (Rodriguez-Merchan. Blood Rev. 2018;32:116). Given an unmet need in pain management for HA, alternate approaches are needed. TRM-201 (rofecoxib) is a cyclooxygenase-2 (COX-2) selective NSAID with no impact on platelet function and a lower GI risk than tNSAIDs (Vioxx (rofecoxib) package insert. Merck & Co. I, ed. Whitehouse Station, NJ, 2004). The RESET-HA study is designed to evaluate the efficacy and safety of rofecoxib for HA pain management. Methods/Design: RESET-HA is a multi-national, randomized, double-blind study to evaluate the efficacy and safety of rofecoxib in hemophilia A or B patients with diagnosed HA, aged 12 to 75 years and is based on a previous pilot study (Tsoukas, et al. Blood, 2006;107:1785). Patients must have a history of joint bleeding, and chronic symptomatic pain in one or more joint(s) on 20 of the 30 days prior to screening. Exclusion criteria include use of opioids for greater than 4 days/week, or opioid transdermal patches in the 30 days prior to screening, history of GI perforation, ulcer or bleeding, peptic ulcer disease and major cardiac ischemic symptoms or events. Randomized patients (n=80 per arm) are washed out of analgesics prior to daily administration of TRM-201 (17.5 mg/day) or placebo for 12 weeks (Part I) during which acetaminophen (Stage-1) and acetaminophen plus codeine (Stage-2) are available as rescue medication (where available and acceptable to the patient and study doctor). The patient assessment of hemophilic arthropathy pain, a 0- to 10-point numeric rating scale validated for the assessment of pain across many disease states, is recorded daily. The primary endpoint is the placebo adjusted change from baseline in weekly average of patient assessment of daily HA pain score at Week 12. Key secondary endpoints include patient assessments using the PROMIS physical function instrument and pain interference from the Brief Pain Inventory. Sleep disturbance is also measured using the PROMIS instrument. The study explores the efficacy of rofecoxib on the number of suspected joint bleeds and on the amount of rescue medication used. Following Part I, all study patients (regardless of original randomization arm) receive rofecoxib 17.5 mg once daily for up to 12 additional months (Part II). During Part II of the study, only acetaminophen will be provided as rescue medication. Discussion: The RESET-HA study is intended to evaluate the efficacy and safety of TRM-201 in patients with HA and is the first Phase III trial ever conducted to assess a treatment for HA pain. Pain management in HA requires analgesic anti-inflammatory treatment that does not exacerbate bleeding. Rofecoxib has been shown to have no effect on platelet function, even at supratherapeutic doses(Vioxx (rofecoxib) package insert. Merck & Co. Whitehouse Station, NJ, 2004), a decreased risk of GI side effects, including GI bleeding compared with tNSAIDs, and no greater cardiovascular risk than equipotent doses of COX-2 selective and tNSAIDs (U.S. Food and Drug Administration. J Pain Palliat Care Pharmacother. 2005;19:83). TRM-201 is anticipated to provide analgesic efficacy, with an acceptable tolerability and safety profile, and could become a new treatment option that may possibly facilitate the avoidance of opioid use in patients with HA. (NCT04684511) Disclosures 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. Buckner: Novo Nordisk: Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria; Genetech: Honoraria; Spark: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; uniQure: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Croteau: Tremeau Pharmaceuticals,Inc: Consultancy. Katz: Tremeau Pharmaceuticals,Inc: Consultancy. Sidonio: Takeda: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Guardian Therapeutics: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy; Biomarin: Consultancy; Pfizer: Consultancy; Genentech: Consultancy, Research Funding. Bolognese: Tremeau Pharmaceuticals,Inc: Consultancy. Garfield: 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. Corrigon: 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. Walsh: Genentech: Consultancy; Biomarin: Consultancy; Takeda: Consultancy; Novo Nordisk: Consultancy; Tremeau: Consultancy.

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.

Eliglustat, an Investigational Oral Therapy for Gaucher Disease Type 1: Phase 2 Results After 4 Years of Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1038-1038
Author(s):  
M. Judith Peterschmitt ◽  
Elena Lukina ◽  
Nora Watman ◽  
Marta Dragosky ◽  
Gregory M Pastores ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Trough Level ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Therapeutic Goals ◽  
Gaucher Disease Type 1

Abstract Abstract 1038 Introduction: In Gaucher disease type 1 (GD1), genetically caused deficiency of the enzyme acid β-glucosidase results in undegraded glucosylceramide to accumulate in tissue macrophages (Gaucher cells), resulting in multisystemic manifestations that include thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. A variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores et al., Semin Hematol. 2004;41[suppl 5]:4–14). Eliglustat, a potent and specific inhibitor of glucosylceramide synthase, is under late-stage development as an oral substrate reduction therapy for GD1. Objective: To report long-term efficacy and safety results. Methods: This ongoing, open-label, uncontrolled, multicenter Phase 2 clinical trial enrolled 26 adult patients with GD1 who were not on treatment for the previous 12 months and who had splenomegaly with thrombocytopenia and/or anemia. Patients received 50 mg or 100 mg eliglustat twice daily depending on the plasma trough level. Efficacy outcomes were assessed periodically and included changes from baseline in hemoglobin, platelets, spleen and liver volumes, skeletal manifestations, disease-related biomarker levels, and achievement of therapeutic goals. Results: Nineteen patients completed 4 years of eliglustat treatment; no patient discontinued in the last 2 years. After 4 years of treatment, mean hemoglobin level and platelet count increased by 2.3±1.5 g/dL (from 11.3±1.5 g/dL to 13.6±1.2 g/dL) and 95% (from 68,700±21,200/mm3 to 125,400±51,100/mm3), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (from 17.3±9.5 to 6.1±3.4 MN) and 28% (from 1.7±0.4 MN to 1.2±0.3 MN), respectively. All patients met at least 3 of 4 long-term therapeutic goals (spleen, 100% of patients; liver, 94%; hemoglobin, 100%; platelets, 50%). Baseline platelet count was not found to be a predictive factor of response to treatment. However, a strong linear, statistically significant correlation was found between the mean plasma trough level of eliglustat and the platelet response in patients after 4 years of treatment with eliglustat (r=0.731, P=0.0004). Median chitotriosidase and CCL-18 each decreased by 82%; plasma GL-1 and GM3 normalized. Mean lumbar spine bone mineral density increased by 0.7 Z-score (from −1.2±0.9 to −0.5±1.1) and by 0.8 T-score (from −1.6±1.1 to −0.88±1.3). The greatest increases in lumbar spine T-scores occurred in patients with osteoporosis at baseline. Femur dark marrow, which is believed to reflect Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Eliglustat was well-tolerated. Most adverse events (AEs) were mild and unrelated to treatment. Ten drug-related AEs, all mild, occurred in 8 patients. No new serious AEs were reported in any patient between 3 and 4 years of treatment. Discussion: Eliglustat continues to show promising efficacy and safety, with clinically meaningful improvements across several disease parameters. Results from two controlled Phase 3 studies in untreated and enzyme replacement therapy maintenance patients will be available in 2013. Disclosures: Peterschmitt: Genzyme: Employment. Lukina:Genzyme: Honoraria, Research Funding. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Arreguin:Genzyme: Research Funding. Rosenbaum:Pfizer: Study Investigator Other. Zimran:Protalix Biotherapeutics: Consultancy; Protalix Biotherapeutics: stock options, stock options Other; Protalix Biotherapeutics: Scientific Advisory Board, Scientific Advisory Board Other; Genzyme: Research Funding; Shire HGT: Honoraria; Actelion: Honoraria; Pfizer: Honoraria. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment.

A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib Compared to Ofatumumab in Patients with Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4171-4171 ◽  
Author(s):  
Paolo Ghia ◽  
Lydia Scarfo ◽  
Kumudu Pathiraja ◽  
Martha Derosier ◽  
Karen Small ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Median Survival ◽  
Stock Options ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Cdk Inhibitors ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Grade 3

Abstract Introduction: Abnormalities of cell cycle regulation have an important role in the pathogenesis of cancers. Cyclin dependent kinase (CDK) inhibitors have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. Dinaciclib (MK-7965/SCH 727965) is a novel, selective inhibitor of CDK1, CDK2, CDK5, and CDK9. Prior studies show that dinaciclib has anti-leukemic activity against CLL. The present study compared the efficacy and safety of dinaciclib with ofatumumab in patients with refractory CLL. Methods: This Phase 3 randomized, open-label, active-controlled, balanced, multi-site, group sequential confirmatory trial evaluated the progression-free survival (PFS; primary objective), overall response rate and overall survival (secondary objectives), and safety of dinaciclib vs. ofatumumab in patients with refractory CLL. Patients with a confirmed diagnosis of CLL (based on 2008 International Workshop on CLL criteria) and fludarabine or chemoimmunotherapy refractory disease were enrolled if they had no central nervous system involvement, prior allogenic bone marrow transplant or uncontrolled autoimmune anemia or thrombocytopenia. Patients previously treated with dinaciclib, ofatumumab, or other CDK inhibitors were excluded. In Cycle 1, dinaciclib was administered intravenously (IV) over 2 hours at doses of 7 mg/m2 on Day 1, 10 mg/m2 on Day 8 and 14 mg/m2 on Day 15. In Cycle 2 and thereafter, dinaciclib was dosed at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for a total of 12 cycles. Ofatumumab was administered IV once-weekly for 8 weeks starting in Cycle 1 on Day 1, followed by 9 monthly doses as follows: 300 mg in Cycle 1 on Day 1; 2000 mg in Cycle 1 on Days 8, 15, and 22, Cycle 2 Days 1, 8, 15, and 22, and 5 weeks later on Day 1 of Cycles 4-12. Efficacy results are from the intent to treat (ITT) population, and safety results are from the all-subjects-as-treated population. Results: In total, 44 patients were randomized (ITT) and 42 were treated (20 dinaciclib and 22 ofatumumab) due to early study termination not attributed to safety. At study entry, the median age was 62 years (range, 43-77), 32/42 (76.2%) patients were male, 26/42 (62.0%) were RAI stage III-IV, 24/42 (57.1%) had bulky disease, 40/42 (95.2%) were ECOG ≤ 1, the median number of prior therapies was 3 (range, 1-20), and 39/42 (92.9%) patients received prior fludarabine. Deletion 17p (del 17p) was present in 17/42 (38.6%) patients, 7 dinaciclib and 10 ofatumumab. Median follow-up (range) was 16.7 (0.4-26.1) months. In the dinaciclib and ofatumumab groups, respectively, 11 (55.0%) and 17 (70.8%) patients had PFS events, and median (95% CI) PFS was 59.7 (45.0, 92.1) and 25.7 (9.3, 40.7) weeks. Overall response (all partial responses) was recorded for 8 (40.0%) dinaciclib and 2 (8.3%) ofatumumab patients. Stable disease was achieved by 7 (35.0%) dinaciclib and 11 (45.8%) ofatumumab patients. Median survival (95% CI) was 21.2 (16.6, NR) months with dinaciclib and 16.7 (2.3, 20.2) months with ofatumumab; 6 (30.0%) and 11 (45.8%) patients have died in each group, respectively. There were 2 treatment-related deaths in the dinaciclib arm (pneumonia and febrile neutropenia) and none in the ofatumumab arm. Median survival (95% CI) in the del 17p population was 21.2 (1.4, 21.2) months with dinaciclib and 5.4 (0.4, NR) months with ofatumumab. Overall, 17 (85.0%) dinaciclib and 13 (59.0%) ofatumumab patients had a grade 3-5 adverse event (AE). The most common grade ≥ 3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia, 7 (35.0%) vs. 2 (9.1%); thrombocytopenia, 4 (20.0%) vs. 2 (9.1%); decreased neutrophil count, 4 (20.0%) vs. 1 (4.5%); pneumonia, 1 (5.0%) vs. 3 (13.6%); sepsis, 1 (5.0%) vs. 3 (13.6%); and febrile neutropenia, 2 (10.0%) vs. 1 (4.5%). One dinaciclib patient developed tumor lysis syndrome that was deemed not treatment-related. Ten (50.0%) dinaciclib and 13 (54.2%) ofatumumab patients discontinued from the study for the following reasons: AE, 3 (15.0%) vs. 1 (4.2%); disease progression, 4 (20.0%) vs. 4 (16.7%); death, 1 (5.0%) vs. 5 (20.8%); and other/unknown, 2 (10.0%) vs. 4 (16.7%). Conclusion: The limited data from this study demonstrate potential anti-cancer activity and tolerability of dinaciclib compared with ofatumumab in patients with refractory CLL. Based on these results and given the distinct mechanism of action, combinations of dinaciclib with other novel therapies should be explored. Disclosures Ghia: Janssen: Consultancy; Acerta Pharma BV: Research Funding; Adaptive: Consultancy; Pharmacyclics: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding. Pathiraja:Merck & Co., Inc.: Employment, Other: stock/stock options. Derosier:Merck & Co., Inc.: Employment, Other: stock/stock options. Small:Merck & Co., Inc.: Employment, Other: stock/stock options.

scholarly journals Heterogeneity of Minimal/Measurable Residual Disease (MRD) Practices in Adult B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in the United States

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4478-4478
Author(s):  
Juliana E. Hidalgo-Lopez ◽  
Gail J. Roboz ◽  
Brent Wood ◽  
Michael Borowitz ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
United States ◽  
Bone Marrow ◽  
Best Practices ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Bone Marrow Sample ◽  
Sample Collection ◽  
Nccn Guidelines ◽  
Privately Held

Abstract Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These factors may impact the quality and reliability of MRD assessment. Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway. Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment. Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients. Figure 1 Figure 1. Disclosures Hidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.

scholarly journals Prevalence of Acute and Chronic Migraine Among Patients with Von Willebrand Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4245-4245
Author(s):  
Corey Macgregor ◽  
Travis Helm ◽  
Frank Cerasoli ◽  
Judith A. Boice ◽  
Robert F. Sidonio
Keyword(s):  
General Population ◽  
Chronic Migraine ◽  
Stock Options ◽  
Research Funding ◽  
Total Sample ◽  
Von Willebrand Disease ◽  
The Past ◽  
Age Of Diagnosis ◽  
Von Willebrand ◽  
Privately Held

Abstract Background: The prevalence of migraine in the general population is approximately 18% in females and 6% in males (Lipton, et. al. Headache 2001;41:646). Among migraineurs, 7-8% experience chronic migraines (CM) (Adams AM, et. al. Cephalalgia 2015;35:563). Von Willebrand factor (VWF), secreted from endothelial cells, is reported to be elevated in migraineurs and in particular during the course of migraine, although its role is unclear (Cesar, et. al. Acta Neurol Scand 1995;91:412; Tietjen, et. al. Neurology 2001;57:334; Tietjen, et. al. Cephalalgia 2018;38:511). Patients with Von Willebrand Disease (VWD) have low levels of or a defective form of VWF, which has led some to hypothesize a lower prevalence of migraine in the VWD population. Conversely, a retrospective case control study found that migraine in VWD patients (n=197) was 6 times more prevalent when compared with age- and sex-match healthy controls (n=197) (18% vs. 3%, respectively)(Hassan, et. al. Intl Journal of Hem, Blood Diseases and Disorders 2014;2:23-5). The current investigation was performed to further explore the relationship between migraine and VWD. Methods: A cross-sectional study was conducted in March 2021 using the InCrowd digital survey tool in which patients with self-reported diagnosis of VWD were invited to participate. The study included 75 VWD patients ≥18 years of age. Survey questions detailed VWD sub-type, gender, clinical diagnosis of migraine, medical specialty diagnosing migraine, migraine treatments, and age of diagnosis. The Lipton Identify Chronic Migraine (ID-CM) tool was used within the survey to identify patients who had experienced chronic migraine(Lipton, et al. Cephalalgia. 2016;36:203). Criteria for designation of chronic migraine from the ID-CM was either the combination of Frequency of Migraine and Symptoms or the combination of Use of Medication and Activity Avoidance. Results: The gender distribution of the 75 participants was 83% female and 17% male. The sub-type of VWD diagnosed was: Type 1 (57%), Type 2 (28%), Type 3 (15%). Fifty-seven percent (57%) of all VWD patients reported being diagnosed with migraine. Rates did not vary significantly by VWD sub-type. Diagnosed migraine was only slightly more common in females (60%, n=62) compared with males (46%, n=7). Average age of diagnosis was 22 years with a median of 17 years (n=43). Two clear clusters defined the age of diagnosis with migraine. The first was between ages 10 and 20 (n=24, 56% of total sample reporting age) and the second was approximately age 30 [28-32] (n=8, 19% of total sample reporting age). Migraine diagnosis was established by primary care physicians (44%), neurologists (44%) hematologists (9%), and headache specialists (2%). Only 4% of surveyed patients met the ID-CM criteria for chronic migraine, yet 71% of patients met the criteria for migraine symptoms. Chronic migraine diagnosis using the ID-CM tool requires a combination of headache frequency (at least half of the past 30 or 90 days), multiple migraine symptoms (present >rarely in the past 30 days), medication use for headache as well as interference with activities (≥10 of the past 30 days) and a headache that either interfered with plans or caused worry for making plans (>rarely in the past 30 days). Frequency of migraine was mentioned by 11% of patients and symptoms by 71%, medication use by 31%, activity limitation by 15%, and changing plans by 25%. Conclusions: This survey illustrates that migraine is significantly more common in people with VWD than in the general population, regardless of VWD sub-type. However, the age-associated incidence pattern follows a similar bimodal distribution as observed in the general population(Victor, et al. Cephalalgia. 2010;30:1065). Notably, the prevalence of diagnosed migraine in VWD males approaches the prevalence in VWD females and exceeds that of females in the general population (Lipton RB, et. al. Headache 2001;41:646). These results suggest a distinct etiology of VWD that makes affected patients more susceptible to migraine. Notably, migraine treatment options may be more limited for these patients, given that traditional NSAIDs are commonly used for fast-acting migraine relief, but their antiplatelet effects and potential for gastrointestinal bleeding make them undesirable in VWD. Further investigation of both the etiology and treatment for VWD migraine is warranted. Disclosures 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. 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. 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. 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. Sidonio: Novo Nordisk: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Biomarin: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

scholarly journals Pre-Clinical Characterization of a Novel Fusion Protein (AT-03), with Pan-Amyloid Binding and Removal

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1207-1207
Author(s):  
Christophe Sirac ◽  
Arnaud Jaccard ◽  
Roussine Codo ◽  
Sebastien Bender ◽  
Gemma Martinez-Rivas ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Stock Options ◽  
Research Funding ◽  
Specific Binding ◽  
The Body ◽  
Al Amyloidosis ◽  
Patent Holder ◽  
Single Chain ◽  
Amyloid Deposits ◽  
Privately Held

Abstract Background: Amyloidosis is characterized by extracellular deposition of protein fibrils that can involve any organ or tissue in the body. It is a severe, progressive and often lethal disorder. There are approximately seventeen different systemic amyloid diseases, each associated with the deposition of a specific precursor protein. Toxic amyloid deposits result in significant organ dysfunction and increased morbidity and mortality. Reduction and removal of tissue amyloid deposits could restore organ function, improve quality of life and increase life expectancy for patients. We have developed and characterized a fusion protein consisting of serum amyloid protein (SAP) linked to a single chain human IgG1 Fc domain, designated AT-03. SAP is a pentameric serum protein that is ubiquitously associated with amyloid deposits. The high affinity and specificity for amyloid resulted in the use of radio-iodinated SAP as an imaging agent for the non-invasive detection of systemic amyloid. The SAP domain of the fusion protein targets the amyloid deposits delivering Fc domains to stimulate amyloid removal via macrophage mediated phagocytosis. Methods: Binding of AT-03 to ATTR and AL fibrils and extracts was assessed by ELISA. Ex vivo phagocytosis of amyloid substrates was studied using activated human THP-1 cells. The biodistribution of AT-03 in murine models of AA, AApoA2 and AL amyloidosis was evaluated immunohistochemically or by SPECT imaging and microautoradiography. Clearance of AA amyloidosis in response to AT-03 therapy was accessed in a mouse model using histological scoring of amyloid burden. Results: AT-03 bound amyloid AL and ATTR substrates with sub nanomolar EC50 values. Systemic administration of AT-03 resulted in specific binding to diverse forms of amyloid in the heart, kidney, liver and/or spleen in multiple animal models. Opsonization of amyloid deposits with AT-03 in vitro resulted in a dose dependent phagocytosis by activated THP-1 cells. A single IV dose of AT-03 resulted in significant reduction of splenic AA amyloid within 14 days post-injection. Conclusions: We have developed a novel fusion protein with sub nanomolar pan amyloid reactivity that specifically binds diverse forms of amyloid in multiple organs and tissues in vivo and can effectuate amyloid removal. The data indicates that AT-03 may serve as a novel therapeutic for the removal of systemic amyloid deposits of diverse types. AT-03 is currently being developed for clinical evaluation. Disclosures Sirac: Attralus, Inc: Patents & Royalties, Research Funding. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy. Bell: Attralus Inc: Current Employment. Guthrie: Attralus Inc: Current Employment. Selvarajah: Attralus Inc: Current Employment. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder. Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding.

scholarly journals A Comparison of Clinical Outcomes from Updated Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3543-3543
Author(s):  
M. Lia Palomba ◽  
Paola Ghione ◽  
Anik R. Patel ◽  
Kevin Deighton ◽  
Caron Jacobson ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Clinical Outcomes ◽  
Odds Ratio ◽  
Stock Options ◽  
Research Funding ◽  
External Control ◽  
Control Cohort ◽  
Publicly Traded ◽  
Free Survival ◽  
Privately Held

Abstract Background: In the pivotal ZUMA-5 (Z-5) trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in r/r FL patients, including those with high-risk disease such as patients who progressed within 24 months of initiating first-line chemoimmunotherapy (POD24). Aims: To compare clinical outcomes from updated 24-month Z-5 to a weighted sample from the international SCHOLAR-5 (S-5) external control cohort. Methods: The international S-5 cohort data were extracted for r/r FL patients from 7 institutions in 5 countries who initiated a third or higher (3L+) line of therapy (LOT) after July 2014. Data from the pivotal idelalisib DELTA trial was also included in the S-5 cohort. Z-5 trial eligibility criteria were applied to the S-5 cohort, with patients excluded or censored upon transformation. The S-5 and Z-5 cohorts were balanced for patient characteristics through propensity scoring on prespecified prognostic factors and standardized mortality ratio weighting. Characteristics with a standardized mean difference (SMD) <0.1 were deemed balanced. Overall response rate (ORR) was compared using odds ratio. Overall survival (OS), progression-free survival (PFS) and next treatment-free survival (NTFS) were evaluated using Kaplan-Meier analysis. Subgroup analysis was conducted on patients who initiated a fourth or higher (4L+) LOT. Results: 143 patients were identified in S-5, reducing to 85 patients after applying propensity score weights, versus 86 patients in Z-5. Median follow-up time for Z-5 and S-5 were 29.4 and 26.2 months respectively. Variables that were successfully balanced (SMD<0.1) included POD24, number of prior LOT, relapsed vs refractory, prior stem cell transplant, size of largest nodal mass, response to prior LOT, time since last therapy and age (Table 1). Despite weighting, the S-5 cohort had a higher proportion of ECOG 1 vs 0 (66.9% vs 40.7%) at baseline. In 3L+ patients, the ORR was 42/85 (49.9%) in S-5 compared to 81/86 (94.2%) in Z-5 for an odds ratio of 16.2 (95% confidence interval [CI]: 5.6-46.9). The median OS was not reached in Z-5 while median PFS was 39.6 months. In S-5 median OS and PFS were 59.8 months and 12.7 months, respectively (Table 2). The hazard ratios for OS and PFS were 0.52 (95%CI: 0.28-0.95) and 0.28 (0.17-0.45) (Figure 1). In sub-group analysis of 4L+ patients, which compared 60 patients from Z-5 to 59 patients from S-5, improvements in OS and PFS outcomes were more pronounced (Table 2). Summary/Conclusion: Compared to currently available therapies in r/r FL patients, axi-cel demonstrated a substantial and statistically significant improvement in meaningful clinical endpoints including ORR, PFS, NTFS and OS, highlighting the durable treatment effect of axi-cel. These findings suggest that axi-cel addresses an important unmet medical need for r/r FL patients. Figure 1 Figure 1. Disclosures Palomba: PCYC: Consultancy; BeiGene: Consultancy; Juno: Patents & Royalties; Pluto: Honoraria; Wolters Kluwer: Patents & Royalties; Kite: Consultancy; Notch: Honoraria, Other: Stock; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Priothera: Honoraria; Nektar: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; Rheos: Honoraria; WindMIL: Honoraria; Ceramedix: Honoraria; Novartis: Consultancy. Patel: Kite, A Gilead company: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Deighton: Delta Hat: Current Employment. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support. Nahas: Kite: Current Employment; Gilead: Current equity holder in publicly-traded company. Jung: Kite, a Gilead Company: Current Employment; Amgen, Kura, Gilead, and Turning Point: Current equity holder in publicly-traded company. Hatswell: Delta Hat: Current Employment. Kanters: RainCity Analytics: Current Employment. Limbrick-Oldfield: RainCity Analytics: Current Employment. Wade: Kite, A Gilead Company: Consultancy; Amgen: Consultancy; Allergan: Consultancy. Thornton Snider: Kite, a Gilead Company: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Gilead: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding. Gribben: Abbvie: Honoraria; AZ: Honoraria, Research Funding; BMS: Honoraria; Gilead/Kite: Honoraria; Janssen: Honoraria, Research Funding; Morphosys: Honoraria; Novartis: Honoraria; Takeda: Honoraria; TG Therapeutis: Honoraria. Radford: ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company; BMS: Honoraria. Bobillo: Gilead: Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau. Ghesquieres: Gilead Science: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy; Mundipharma: Consultancy, Honoraria; Janssen: Honoraria.

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 Tumor-Confirmed Follicular Lymphoma Mutations Are Detectable in Peripheral Blood Years Prior to Clinical Diagnosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 709-709
Author(s):  
Joseph G Schroers-Martin ◽  
Joanne Soo ◽  
Gabriel Brisou ◽  
Florian Scherer ◽  
David M. Kurtz ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Clinical Diagnosis ◽  
Peripheral Blood ◽  
Stock Options ◽  
Research Funding ◽  
Low Grade ◽  
Pet Ct ◽  
Significant Difference ◽  
Tumor Biopsies ◽  
Privately Held

Abstract Background: Mutations in chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 have been inferred as early events in follicular lymphoma (FL) by truncal status in mature tumors and persistence between diagnosis and relapse. We previously reported frequent detection of CREBBP lysine acetyltransferase (KAT) domain mutations in pre-diagnostic blood and tissue specimens from individuals later developing FL (Schroers-Martin et al, ASH Annual Meeting 2017). However, the limited availability of paired tumor biopsies has precluded confirmation of concordance between precursor lesions and subsequent clinical malignancy. Methods: The American Cancer Society (ACS) Cancer Prevention Study-II (CPS-II) LifeLink cohort collected screening blood or saliva samples from over 100,000 cancer-free American participants between 1998 and 2002. To evaluate detection of tumor-confirmed variants in pre-diagnostic specimens, we identified 29 FL patients with available FFPE tumor biopsy and screening sample (Fig A). The median age at screening was 71 years (range 56-83) with a median time to FL diagnosis of 56 months (TTD, range 6-139). Tumor biopsies were sequenced utilizing hybrid capture sequencing for commonly mutated lymphoma genes. DNA extracted from pre-diagnostic blood or saliva cell pellet specimens was sequenced utilizing error-corrected CAPP-Seq (Newman et al Nat Biotech 2016) to a median depth of 5204x. We sequenced to similar depths peripheral blood DNA from control cohorts of individuals with detectable t(14;18) but no subsequent lymphoma diagnosis (n=14) and healthy individuals without detectable t(14;18) by PCR (n=20). Results: Coding mutations were identified from all tumors with a mutational distribution similar to prior FL sequencing studies. Tumor-derived variants were detected in 7 of 29 paired pre-diagnostic specimens (24%) at a median TTD of 44 months (range 11-112 months, Fig B). The statistical significance of detection was assessed using a previously described approach based on Monte Carlo sampling (Newman et al Nat Biotech 2016) and the error distribution of affected loci in control cohorts. While an outlier case contained concordant TNFRSF14, FOXO1, and STAT6 mutations 90 months pre-diagnosis at an elevated allelic fraction (AF) of 1.8%, the mean AF of other detected precursor variants was 0.091%. Individuals with detected variants were not older (Fig C) nor significantly closer to clinical diagnosis (Fig D). The most frequently detected lesions were CREBBP (6/15 cases, 40%) and BCL2 (3/13, 23%) with one case demonstrating a fuller mutational profile including FOXO1 and ARID1A at 44 months before diagnosis. All detected precursor CREBBP variants localized to the KAT domain, reflecting prior observations in pre-diagnostic samples without confirmatory biopsy (Fig E). Of note, saliva cell pellets may contain 30% or more hematopoietic DNA (Kaur et al Chimerism 2012) and we detected tumor-confirmed variants in both saliva and blood screening specimens (Fig F) with no significant difference in AF (Fig G). In an illustrative independent case with available imaging, a patient undergoing radical prostatectomy was found to have involvement of a pelvic lymph node with in situ follicular neoplasia (ISFN). Staging PET/CT showed no evidence of FL (Fig H) and he was followed expectantly for 4 years without emergent disease. Eight years after surgery he presented with inguinal swelling and bilateral FDG-avid adenopathy on PET/CT. Excisional biopsy confirmed low grade FL and sequencing for M7-FLIPI revealed a CREBBP KAT domain variant. Retrospective sequencing of serial peripheral blood specimens from his initial surveillance showed detectable CREBBP R1446C at the earliest collected time point (AF range 0.019-0.046%) rising to AF 0.082% after clinical diagnosis. Conclusions: Precursor FL mutations are detectable in peripheral blood and saliva years prior to clinical diagnosis with a spectrum of variants enriched in CREBBP and BCL2 and concordant with subsequent FL tumors. Such lesions may assist in stratifying individuals at elevated risk of clinical malignancy, including after identification of pathologic precursors such as ISFN. Figure 1 Figure 1. Disclosures Kurtz: Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Roche: Consultancy; Genentech: Consultancy. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees. Diehn: Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy; Varian Medical Systems: Research Funding; Illumina: Research Funding; CiberMed: Current holder of stock options in a privately-held company, Patents & Royalties; Foresight Diagnostics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Roulland: BMS: Research Funding. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

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