RESUMO
Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Here, we evaluated the safety and tolerability of multiple ascending doses of mitapivat in adults with SCD with no recent blood transfusions or changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled; 1 subject was withdrawn shortly after starting the study. Sixteen subjects completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily [BID]) for 2 weeks each; following a protocol amendment, the dose was escalated to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels, with the most common treatment-emergent adverse events (AEs) being insomnia, headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive crises (VOCs), non-VOC-related shoulder pain, and a preexisting pulmonary embolism. Two VOCs occurred during drug taper and were possibly drug related; no other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin response of a ≥1 g/dL increase compared with baseline. Mean reductions in hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP were also observed. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165.
Assuntos
Anemia Falciforme , Piruvato Quinase , Adulto , Humanos , Ácido Pirúvico , 2,3-Difosfoglicerato , Anemia Falciforme/tratamento farmacológico , Hemoglobinas , Trifosfato de AdenosinaAssuntos
Anemia Falciforme/epidemiologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Hospedeiro Imunocomprometido , Pneumonia Viral/complicações , Anemia Falciforme/terapia , Anemia Falciforme/virologia , COVID-19 , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Gerenciamento Clínico , Humanos , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , SARS-CoV-2RESUMO
PURPOSE OF REVIEW: Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in cancer patients. A significant proportion of cancer-associated VTE occurs in the ambulatory setting and is associated with poorer outcomes and reduced survival. Risk for VTE is influenced by patient, cancer and treatment-specific factors. RECENT FINDINGS: Recent studies have identified biomarkers associated with increased VTE risk in malignancy, including leukocyte and platelet counts, tissue factor, prothrombin split products, D-dimer, P-selectin, factor VIII and C-reactive protein. Recent and ongoing clinical trials have focused on VTE prophylaxis with low-molecular weight heparins in high-risk cancer outpatients, particularly those with pancreatic cancer. These studies have yielded encouraging preliminary results but whether thromboprophylaxis provides significant benefit to unselected cancer outpatients remains unclear. SUMMARY: A risk stratification model incorporating known risk factors and biomarkers can identify those patients at highest risk. This review focuses on emerging data regarding risk assessment and benefit of thromboprophylaxis in patients with cancer.
Assuntos
Fibrinolíticos/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Biomarcadores/sangue , Humanos , Medição de Risco , Fatores de Risco , Tromboembolia Venosa/sangueRESUMO
IMPORTANCE: Regional variation in opioid use may be attenuated when pharmaceutical-sponsored trials include care that is often standardized by protocols. Understanding such variation is important for global trials that sometimes include time to opioid use as an end point. OBJECTIVE: To identify whether regional and country-level variation in opioid use exists among prostate cancer clinical trials across the world. DESIGN, SETTING, AND PARTICIPANTS: International phase 3 randomized clinical trials with patients with metastatic prostate cancer and initiation from January 1, 2008, or later were identified through internal databases of the US Food and Drug Administration. Data of patients in the intention-to-treat population from each trial were pooled. Descriptive and regression analyses of the collected data were conducted from September 2018 to February 2019. EXPOSURES: Cancer therapy. MAIN OUTCOMES AND MEASURES: Opioid use data were from concomitant medications reported in the database for each trial. Logistic regression models, descriptive statistics, and χ2 tests were used to compare opioid use across world regions while adjusting for patient age, presence of visceral disease, bony disease, and baseline Eastern Cooperative Oncology Group Performance Status score and pain score. RESULTS: In total, 9670 patients (mean [SD] age of 69.2 [8.3] years) from 8 prostate cancer clinical trials in 46 countries were included. Patients in Eastern Europe (adjusted odds ratio [AOR], 0.19; 95% CI, 0.16-0.22) and Asia (AOR, 0.31; 95% CI, 0.25-0.38) were less likely to use opioids compared with patients in North America. These findings held even when the analysis was restricted to patients who reported moderate to high pain levels at baseline (Eastern Europe: AOR, 0.16 [95% CI, 0.12-0.22]; Asia: AOR, 0.47 [95% CI, 0.29-0.79]). Within North America, rates of opioid use were similar between the United States and Canada (AOR, 1.13; 95% CI, 0.93-1.37). CONCLUSIONS AND RELEVANCE: This study found that, despite the clinical trial setting, opioid use appeared to vary by world regions, suggesting that this variability should be considered in international clinical trials.
RESUMO
The impact of venous thromboembolism (VTE) in the cancer population remains substantial despite significant advances in detecting and treating thrombotic events. While there is extensive literature regarding predictors of first VTE event in cancer patients as well as a validated predictive score, less data exist regarding recurrent VTE in cancer cohorts and associated predictive variables. A similar paucity of data in regard to bleeding events in cancer patients receiving anticoagulation has been observed. This review article will highlight clinical risk factors as well as predictive biomarkers associated with recurrent VTE and bleeding in cancer patients receiving therapeutic anticoagulation. Predictive risk assessment models for cancer-associated recurrent VTE and bleeding are also discussed.
Assuntos
Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular , Humanos , Recidiva , Fatores de Risco , Tromboembolia Venosa/complicações , Tromboembolia Venosa/prevenção & controleRESUMO
Pancreatic cancer is known to be associated with VTE, but contemporary rates of incidental and symptomatic VTE events and their association with mortality are incompletely understood. We conducted a retrospective cohort study of consecutive pancreatic adenocarcinoma patients at the University of Rochester from 2006-2009. Data were analysed using a Cox model with time-dependent covariates. A total of 1,151 radiologic exams of 135 patients were included. Forty-seven patients (34.8%) experienced VTE including 12 pulmonary emboli (PE), 28 deep-vein thromboses (DVTs) and 47 visceral vein events. Incidental events comprised 33.3% of PEs, 21.4% of DVTs and 100% of visceral VTE. Median (95% CI) conditional survival beyond three months was 233 (162-322) more days for those without VTE, which was significantly greater than 12 (3-60) days for those with DVT as first event (p<0.0001) and 87 (14-322) days with visceral first events (p=0.022). In multivariate analysis, DVT (HR 25, 95% CI 10-63, p <0.0001), PE (HR 8.9, 95% CI 2.5-31.7, p = 0.007) and incidental visceral events (HR 2.6, 95% CI 1.6-4.2, p =0.0001) were all associated with mortality, though anticoagulants reduced these risks by 70% (26-88%, p = 0.009). In conclusion, VTE occurs in over one-third of contemporary pancreatic cancer patients and, whether symptomatic or incidental, is strongly associated with worsened mortality. The role of anticoagulation in treating incidental or visceral VTE warrants further study.