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Overall survival with momelotinib vs. best available therapy in patients with ruxolitinib-experienced myelofibrosis: a matching-adjusted indirect comparison
The Janus kinase (JAK) inhibitor ruxolitinib is a standard first-line therapy for patients with symptomatic and/or intermediate- to high-risk myelofibrosis (MF). However, the majority of patients discontinue ruxolitinib within 5 years of initiation, mainly due to lack or loss of response and/or therapy-related cytopenias. Additional treatments are needed to improve long-term outcomes, including overall survival (OS). Momelotinib, a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated benefits in reducing anemia and improving symptoms and spleen size in 3 phase 3 trials of patients with intermediate- to high-risk MF (SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM). These studies also provide data on patients who received momelotinib after discontinuing ruxolitinib. In the absence of long-term head-to-head comparisons of momelotinib and other treatments after discontinuation of ruxolitinib, the present study compared OS in patients with ruxolitinib-experienced MF from the momelotinib phase 3 trials vs. those treated with best available therapy (BAT) after ruxolitinib from the RUX-MF retrospective real-world study. The comparison was performed using an unanchored matching-adjusted indirect comparison (MAIC). Additionally, an MAIC of OS was conducted in an anemic subgroup (hemoglobin < 10 g/dL). After adjustment for cross-trial differences, the MAIC results showed a favorable trend for momelotinib vs. BAT, both in the overall population and in the anemic subgroup, with hazard ratios < 1 across all analytical scenarios and all population-matching models with an effective sample size of ≥ 20. This study is a key addition to current evidence surrounding OS post ruxolitinib and highlights the benefit of momelotinib in this setting.
Journal Article
Say it loud : great speeches on civil rights and African American identity
Collects the text and audio recordings of famous African American political speeches, by individuals ranging from Malcolm X and Martin Luther King, Jr. to Condoleezza Rice and Barack Obama.
Book
Adolescence as the Context for Understanding Young Mothers’ Engagement with Health Promotion: A Phenomenological Exploration
Background: The current social construction of young mothers is generally negative, pointing to a lack of engagement with universal services and poor outcomes for their infants and children. However, qualitative studies offer an alternative, more positive construct of young motherhood. Understanding the context of young motherhood can improve the relevance and efficacy of health promotion directed to this group of high-risk mothers. Aim: To explore the lived experience of young women transitioning to motherhood to better understand their experiences and perspective; and what influences their engagement with health promotion aimed to support safer parenting practices and whether their behaviour changes over time with exposure to parenting health promotion. Method: Longitudinal Interpretative Phenomenological Analysis (IPA) was used with five first-time mothers identified with characteristics known to influence poorer outcomes for infants and children such as low educational achievement and economic disadvantage. Participants aged 16 to 19 years were recruited antenatally. Serial in-depth interviews were conducted at three time points during the ante- and post-natal periods. Interviews were transcribed and data were analysed inductively following the prescribed method of double hermeneutic analysis for IPA. Finding: Three themes were identified from the full study: Transition, Information, and Fractured application; the focus of this paper is Transition. Transition revealed that becoming mothers impacted key adolescent developmental tasks; their identity and relationships were significantly affected, both positively and negatively and adolescent brain development influenced behaviour and decision making capability. Adolescence influenced how these young mothers engaged with and interpreted parenting health promotion messages. Conclusions: Young mothers in this study operate within the context of adolescence. Adolescence impacts participants’ decision making activity and early parenting behaviours which informs the debate on why young mothers may fail to reduce risks for their infants. This insight can contribute to the development of more effective health promotion/educational strategies, and support professionals to better engage with this high-risk group to improve early parenting behaviour and subsequently improve outcomes for their infants and children.
Journal Article
Free all along : the Robert Penn Warren civil rights interviews
\"A collection of previously unpublished interviews with key figures of the black freedom struggle by Pulitzer Prize-winning author Robert Penn Warren\"-- Provided by publisher.
Book
Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis?
Background Systematic explorations of language abilities in patients with amyotrophic lateral sclerosis (ALS) are lacking in the context of wider cognitive change. Methodology Neuropsychological assessment data were obtained from 51 patients with ALS and 35 healthy controls matched for age, gender and IQ. Composite scores were derived for the domains of language and executive functioning. Domain impairment was defined as a composite score ≤5th centile relative to the control mean. Cognitive impairment was also classified using recently published consensus criteria. Results The patients with ALS were impaired on language and executive composite scores. Language domain impairment was found in 43% of patients with ALS, and executive domain impairment in 31%. Standardised language and executive composite scores correlated in the ALS group (r=0.68, p<0.001). Multiple regression analyses indicated that scores on the executive composite accounted for 44% of the variance in language composite scores. Conclusions Language impairments are at least as prevalent as executive dysfunction in ALS. While the two domains are strongly associated, executive dysfunction does not fully account for the profile of language impairments observed, further highlighting the heterogeneity of cognitive impairment in non-demented patients with ALS.
Journal Article
Anemia in Myelofibrosis: A Focus on Proactive Management and the Role of Momelotinib
Background: Anemia is a common and progressive clinical manifestation of myelofibrosis that may occur as part of the disease pathogenesis as well as due to the myelosuppressive effects of some treatments, with a substantial impact on quality of life, prognosis, and healthcare resource utilization. Despite these burdens, anemia management has traditionally been a secondary priority to spleen and symptom control, due in part to the limitations of available therapeutic approaches. With the initial regulatory approvals of momelotinib, a Janus kinase 1 (JAK1), JAK2, and activin A receptor type 1 inhibitor that provides anemia-related benefits in addition to addressing splenomegaly and symptoms, re-evaluation of anemia as an early and prominent treatment consideration is warranted. Methods: In this review, we discuss the journey of patients with myelofibrosis and anemia across various severities and clinical scenarios. Results: Summarized are traditional approaches to anemia management and the clinical trial efficacy and safety data that support momelotinib as an option in each setting from mild to severe anemia, including in the context of co-occurring thrombocytopenia. Conclusions: With the availability of momelotinib and other emerging therapies directed at anemia control, early treatment of anemia to avoid progression and support improvement in eligible patients with myelofibrosis should be a primary consideration.
Journal Article
Association Between Transfusion Status, Hemoglobin Levels, and Patient‐Reported Outcomes in Myelofibrosis: A Post Hoc Clinical Trial Analysis
Background Quality of life and symptom burden of patients with myelofibrosis are well recognized and compounded in those with anemia; however, the effects of transfusion burden or anemia severity on quality of life have not been comprehensively characterized. This post hoc descriptive analysis explored the association between transfusion status or hemoglobin improvement and patient‐reported outcomes (PROs). Methods The analysis used pooled populations across treatment arms from 3 clinical trials (SIMPLIFY‐1, SIMPLIFY‐2, MOMENTUM); sample sizes for each PRO measure were dependent on the trials in which they were administered. Results At both baseline and week 24, transfusion independence was associated with umerically greater mean SF‐36v2 and EORTC QLQ‐C30 scores than transfusion dependence; in the subgroup that was transfusion dependent at baseline, those who achieved transfusion independence at week 24 had greater PRO improvements than those who remained reliant on transfusions. Regardless of transfusion status, patients who achieved a hemoglobin improvement ≥ 1, ≥ 1.5, or ≥ 2 g/dL from baseline also had clinically meaningful improvements in quality of life (assessed via mean EQ‐5D‐5L or SF‐36v2 scores) and symptoms (assessed via PGIC or MPN‐SAF/MFSAF Total Symptom Score) at week 24 compared with those who did not. Conclusions Collectively, these results provide preliminary insights into the associations of transfusion status and anemia severity with quality of life in myelofibrosis; as current PRO measures do not directly evaluate the relationship between symptoms such as fatigue and anemia, development of new measures to more comprehensively capture the patient experience for those with anemia in myelofibrosis may be warranted. Trial Registration NCT01969838, NCT02101268, NCT04173494
Journal Article
Momelotinib: Mechanism of action, clinical, and translational science
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.
Journal Article
Executive dysfunction predicts social cognition impairment in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor system with recognised extra-motor and cognitive involvement. This cross-sectional study examined ALS patients’ performance on measures requiring social inference, and determined the relationship between such changes and variations in mood, behaviour, personality, empathy and executive function. Fifty-five ALS patients and 49 healthy controls were compared on tasks measuring social cognition and executive function. ALS patients also completed measures examining mood, behaviour and personality. Regression analyses explored the contribution of executive function, mood, behaviour and personality to social cognition scores within the ALS sample. A between-group MANOVA revealed that, the ALS group was impaired relative to controls on two composite scores for social cognition and executive function. Patients also performed worse on individual tests of executive function measuring cognitive flexibility, response inhibition and concept formation, and on individual aspects of social cognition assessing the attribution of emotional and mental states. Regression analyses indicated that ALS-related executive dysfunction was the main predictor of social cognition performance, above and beyond demographic variables, behaviour, mood and personality. On at least some aspects of social cognition, impaired performance in ALS appears to be secondary to executive dysfunction. The profile of cognitive impairment in ALS supports a cognitive continuum between ALS and frontotemporal dementia.
Journal Article