scholarly journals Investigating the Potential Impact of Dosing Tolerance to Facilitate Use of Nplate Self-Administration in Adult Patients with ITP

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4231-4231
Author(s):  
Florencio Serrano Castillo ◽  
Hossam A Saad ◽  
Kejia Wang ◽  
Alicia Zhang ◽  
Vincent Chow ◽  
...  
Keyword(s):  
Healthcare Provider ◽  
Maintenance Dose ◽  
Adult Patients ◽  
Target Range ◽  
Dose Titration ◽  
Self Administration ◽  
Publicly Traded ◽  
Platelet Counts ◽  
Stable Maintenance ◽  
The Impact

Abstract Background and Objective: Romiplostim, is a TPO agonist approved for the treatment for adult ITP. It follows a weight-based and platelet response-guided dose titration algorithm to maintain patients' platelet counts (PC) between 50 and 200x10 9/L, after which a maintenance dose is administered once weekly to keep platelet counts within the target range. While self-administration of romiplostim maintenance dose has been approved in EU for adult patients, in the US romiplostim is only approved for weekly administration by a healthcare provider (HCP) using an 0.01 mL graduation syringe to ensure dosing accuracy; a dose tolerance margin of romiplostim has never been investigated before. The following work explores the impact of dosing tolerance on PC to assess the feasibility of romiplostim self-administration in adult ITP patients. Methods: The analysis was based on a previously developed pharmacodynamic model of romiplostim in ITP patients (Perez-Ruixo et al, 2012, Gibiansky et al, 2021). Previous romiplostim clinical studies in patients with ITP were leveraged to develop an updated model of 475 ITP patients (>50 kg, weekly romiplostim total dose > 100 µg and between 1 and 10 µg/kg stable maintenance dose for at least 1 month, self-administration) and assess potential differences in PC between ITP patients who qualify for self-administration and the general adult ITP population. Comparison of observed and model predicted PC and romiplostim dose over time confirmed the adequacy of the model to assess the impact of varying dose tolerances on PC that may occur with self-administration. Under the proposed guidelines for romiplostim self-administration eligibility, an adult patient would self-administer up to 4 weekly stable maintenance doses of romiplostim between two platelet measurements 1 month apart. To evaluate the impact on PC over 1 month when patients self-administered all four weekly doses versus patients receiving the same prescribed dose by a healthcare provider, three dosing scenarios were considered: (1) exact titrated dose (no dose deviation), (2) titrated dose plus 0.03 mL or 15 µg of romiplostim, and (3) titrated dose minus 0.03 mL or 15 µg of romiplostim. To further characterize the number of ITP patients with clinically meaningful platelet deviations, the predicted number of virtual patients with a PC below 30 x10 9/L or above 400 x10 9/L were also summarized for each simulated scenario. Lastly, the simulated population was divided into four groups based on the magnitude of their prescribed dose and used to evaluate whether the prescribed romiplostim dose influences platelet excursion rates following the investigated dose scenarios. Results: Simulations suggest that 4 successive weekly doses of ± 0.03 mL (or ± 15 µg) the prescribed romiplostim dose is unlikely to cause a significant change in platelet excursion rates relative to continuous administration of the exact prescribed dose. No meaningful increase (0.1 - 0.4%) was observed in the predicted excursion rates across these thresholds for either the under- or overdosing scenarios (Figure 1). This results also show that while there is a slight trend between the magnitude of the prescribed dose and the fraction of subjects that experience a platelet excursion, it does not result in a meaningful increase (<4%) in platelet excursions in any of the evaluated subgroups. Specifically, we observed minimal changes in the fraction of patients with a platelet excursion outside the potentially clinically meaningful thresholds across all simulated dose groups and dosing scenarios (Table 1). The results from this analysis suggest that possible dosing variance expected from the self-administration of romiplostim by an eligible lay person (± 0.03 mL or 15 μg) with monthly PC evaluation will not lead to a significant increase in the rate of platelet count excursions for patients who achieve a stable romiplostim dose and meet the proposed eligibility criteria. Figure 1 Figure 1. Disclosures Serrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Wang: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Zhang: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

A Novel Canine Model of Immune Thrombocytopenia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3326-3326
Author(s):  
Dana N LeVine ◽  
Adam J Birkenheuer ◽  
Marjory B Brooks ◽  
Shila K Nordone ◽  
Dwight A Bellinger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Canine Model ◽  
Target Range ◽  
Dose Titration ◽  
Platelet Glycoprotein ◽  
Control Group ◽  
Large Animal ◽  
Isotype Control ◽  
Platelet Counts

Abstract Abstract 3326 Immune thrombocytopenia (ITP) is a relatively prevalent disease in dogs with significant morbidity and mortality. Canine ITP is clinically analogous to human ITP, with heterogeneity in bleeding manifestations in individuals with similar platelet counts. With a view to ultimately investigate this bleeding heterogeneity, we set out to develop a canine model of ITP. There are currently no existing large animal models of ITP. An induced canine ITP model would be representative of ITP without the confounding co-morbidities seen in clinical cases. Since spontaneous ITP occurs in both dogs and humans, the dog is an ideal translational model. We hypothesized that 2F9, a murine IgG2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP), would induce predictable dose-dependent thrombocytopenia (TCP) in healthy dogs. 2F9 had not been previously administered in vivo. We produced highly purified 2F9 and αYFA antibodies from the 2F9 hybridoma (gift of David Wilcox, Blood Research Institute, Wisconsin) and an isotype control murine anti-yellow fever antibody (αYFA) hybridoma. A dose titration (2 dogs) and a dose repeatability study (3 dogs) were performed in healthy adult research dogs by repeated intravenous infusion (≤ 6 doses) of 2F9 antibody until a target nadir of 5–30 × 103 platelets/μl was reached. Platelet counts were performed hourly until the platelet count reached the desired nadir range (t=0 hrs), after which complete blood counts were performed at 2, 4, 6, 8, 12, 24 hours, then q 24 hours for 10 days. The following were evaluated throughout the study: physical examination, buccal mucosal bleeding time (BMBT, baseline and t=0 only), serum cytokines and chemokines (INFγ, Interleukin (IL) 2, 6, 7, 8, 10, 15, 18, KC, IP-10, MCP-1, GM-CSF, TNFα; Milliplex CCYTOMAG-90K), fibrinogen, and D-dimers. Specificity of the 2F9 effect was confirmed by IV infusion of the isotype control (αYFA) to 3 dogs at the highest cumulative effective dose of 2F9 (167 μg/kg); all parameters were measured as above (t=0 hrs was one hour after αYFA dosing). Within 2 hours of a median cumulative 2F9 administration of 63 μg/kg (range 50.0–166.6 μg/kg), all dogs developed profound TCP (range 11–28 × 103/μl). Compared to the control group, platelet nadir was significantly lower (median (range): 6 (4–11) × 103/μl vs. 200 (179–209) × 103/μl; p= 0.036) and change in platelet count from baseline to nadir was significantly greater in the 2F9-treated group (median (range): 238 (179–325) × 103/μl vs. 4 (0–10) × 103/μl; p=0.036) (Fig 1); p-values were calculated using the exact Wilcoxon rank-sum test. Platelet nadir was in our target range and platelet count remained < 40 × 103/μl in all 2F9-treated dogs for 24 hours. Dosing was predictable: in each dog, after an initial dose of 50 μg/kg 2F9, the second dose needed to reach the target nadir could be accurately calculated from the initial platelet decrease. 2F9-treated dogs developed a range of clinical bleeding from none to petechiae, ecchymoses, melena, and hematuria. At t=0 hrs, BMBT increased 3–8 fold in treated dogs, compared to < 2 fold in control dogs. Dogs had no changes in vital signs or demeanor and did not require any transfusion support. The model does not appear pro-thrombotic as fibrinogen and D-dimers were similar over time in 2F9-treated vs. control dogs. 2F9 infusion also generated negligible systemic inflammation, as assessed by white blood cell count and serum cytokine measurement. Unexpectedly, however, serum IL8 tracked faithfully with platelet count, demonstrating that platelets are a major source of serum IL8 in dogs (Fig 2). Although α granules are known to contain IL8, platelets have not been previously described as a significant serum IL8 source. Since IL8 is an important neutrophil chemokine, our finding may illuminate a novel mechanism of platelet-neutrophil cross-talk. In summary, we have developed a novel large animal ITP model that is highly representative of the spontaneous disease. Like naturally-occurring ITP, dogs demonstrate bleeding heterogeneity despite similar platelet counts (data not shown). We expect our model to lead to further insights into bleeding mechanisms in ITP. Ultimately, understanding what factors predispose certain patients to bleed will allow us to exploit these factors therapeutically as novel ITP treatments. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Burden of Paroxysmal Nocturnal Hemoglobinuria Among Patients Receiving C5 Inhibitors in the United States

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
David Dingli ◽  
Joana E. Matos ◽  
Kerri Lehrhaupt ◽  
Sangeeta Krishnan ◽  
Sujata P. Sarda ◽  
...  
Keyword(s):  
United States ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Burden Of Illness ◽  
Thrombotic Event ◽  
The United States ◽  
Adult Patients ◽  
Red Blood Cell Transfusion ◽  
Publicly Traded ◽  
Clinical Measures ◽  
The Impact

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by chronic complement-mediated hemolysis. Treatment with the C5 inhibitor eculizumab has resulted in a reduction in intravascular hemolysis (IVH) and improvements in morbidity and mortality. However, in a single-center cohort of patients with PNH receiving treatment with eculizumab, 72% remained anemic and 36% continued to require transfusions due to ongoing IVH and extravascular hemolysis (McKinley CE, et al.Blood. 2017;130(Suppl 1):3471; Risitano AM, et al.Front Immunol. 2019;10:1157). This study aims to describe the burden of illness in patients with PNH currently being treated with C5 inhibitors (eculizumab and ravulizumab). Overall, the study aims to understand the clinical and hematological outcomes associated with burden of illness in about 150 patients with PNH globally. In these preliminary analyses, the impact of PNH on hematologic and clinical measures is assessed from patients in the United States. METHODS A cross-sectional survey was administered to adult patients ≥18 years of age in the United States with a self-reported diagnosis of PNH, recruited through a patient advocacy group. Inclusion criteria to complete the secure online survey included current treatment with either eculizumab or ravulizumab, informed consent, and agreement to adverse event reporting. This study was initiated in July 2020 and is ongoing. Results presented herein are preliminary. Impact of PNH on hematologic and clinical measures will be assessed using the following variables: diagnosis levels; and any patient history of blood transfusions, thrombotic events, renal impairment, fatigue, and other PNH-associated symptoms as well as dosing frequency and treatment patterns. For these preliminary analyses, descriptive statistics will be reported for patients who have completed the survey. RESULTS As of August 6, 2020, 58 adult patients with a median age of 52 years (range, 21-88) completed the survey, among which 78% were female. Current medications included eculizumab (n = 20 [34.5%]) or ravulizumab (n = 38 [65.5%]), as well as concurrent anticoagulants (n = 9 [15.5%]) and/or anti-thrombotics (n = 2 [3%]). Most patients initiated treatment with eculizumab (n = 20 [100%]) or with ravulizumab (n = 34 [90%]) ≥3 months before. Median (interquartile range) last known hemoglobin level for patients on eculizumab and ravulizumab was 9.3 g/dL (8.0-11.1) and 10.1 g/dL (8.9-11.5), respectively. Overall, 45 (82%) patients reported hemoglobin values &lt;12 g/dL (eculizumab: 90%; ravulizumab: 78%). Forty (69%) patients reported having ≥1 red blood cell transfusion at any point during their disease. Within the previous 12 months, 53% and 26% of eculizumab- and ravulizumab-treated patients, respectively, had ≥1 transfusion, and 12% and 17% were unsure. Among those patients who had ever received ≥1 transfusion, 6% and 13% had &gt;4 transfusions in the previous 12 months for eculizumab and ravulizumab, respectively. Seventeen patients (29%) reported ≥1 thrombotic event at any point during their disease. Seven patients reported thrombotic events over the previous 12 months; six were receiving ravulizumab. The majority (77%) of patients reported fatigue. Fatigue was reported by nearly 95% of eculizumab-treated patients and 68% of ravulizumab-treated patients. CONCLUSIONS Preliminary results from this burden of illness survey demonstrate that a majority of patients with PNH report remaining anemic, despite treatment with C5 inhibitors eculizumab and ravulizumab for a period of ≥3 months. Disclosures Dingli: Sanofi-Genzyme:Consultancy;Karyopharm Therapeutics:Research Funding;Bristol Myers Squibb:Research Funding;Millenium:Consultancy;Alexion:Consultancy;Apellis:Consultancy;Rigel:Consultancy;Janssen:Consultancy.Matos:Kantar:Current Employment.Lehrhaupt:Kantar:Current Employment.Krishnan:Apellis:Current Employment, Current equity holder in publicly-traded company.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

scholarly journals Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110026
Author(s):  
Chinar R. Parikh ◽  
Jaya K. Ponnampalam ◽  
George Seligmann ◽  
Leda Coelewij ◽  
Ines Pineda-Torra ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Efficacy ◽  
Inflammatory Arthritis ◽  
Biologic Agents ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Biologic Drugs ◽  
Therapeutic Implications ◽  
The Impact ◽  
First Time

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications.

scholarly journals Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine—a meta-analysis

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e039358
Author(s):  
Suhairul Sazali ◽  
Salziyan Badrin ◽  
Mohd Noor Norhayati ◽  
Nur Suhaila Idris
Keyword(s):  
Random Effects ◽  
Coenzyme Q10 ◽  
Migraine Headache ◽  
Meta Analysis ◽  
Adult Patients ◽  
Control Group ◽  
Cochrane Central Register ◽  
Statistical Heterogeneity ◽  
Coq10 Supplementation ◽  
The Impact

ObjectiveTo determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.DesignSystematic review and meta-analysis.Data sourcesCochrane Central Register of Controlled Trials, CENTRAL, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Psychological Information Database (PsycINFO) from inception till December 2019.Study selectionAll randomised control trials comparing CoQ10 with placebo or used as an adjunct treatment included in this meta-analysis. Cross-over designs and controlled clinical trials were excluded.Data synthesisHeterogeneity at face value by comparing populations, settings, interventions and outcomes were measured and statistical heterogeneity was assessed by means of the I2 statistic. The treatment effect for dichotomous outcomes were using risk ratios and risk difference, and for continuous outcomes, mean differences (MDs) or standardised mean difference; both with 95% CIs were used. Subgroup analyses were carried out for dosage of CoQ10 and if CoQ10 combined with another supplementation. Sensitivity analysis was used to investigate the impact risk of bias for sequence generation and allocation concealment of included studies.ResultsSix studies with a total of 371 participants were included in the meta-analysis. There is no statistically significant reduction in severity of migraine headache with CoQ10 supplementation. CoQ10 supplementation reduced the duration of headache attacks compared with the control group (MD: −0.19; 95% CI: −0.27 to −0.11; random effects; I2 statistic=0%; p<0.00001). CoQ10 usage reduced the frequency of migraine headache compared with the control group (MD: −1.52; 95% CI: −2.40 to −0.65; random effects; I2 statistic=0%; p<0.001).ConclusionCoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack.PROSPERO registration numberCRD42019126127.

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