The cost-effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis. We evaluated, the cost-effectiveness of pegcetacoplan, a novel proximal C3 inhibitor, versus ravulizumab in patients with PNH and hemoglobin levels <10.5 g/dl despite eculizumab treatment in the UK healthcare and social services setting. Materials & methods: A Markov cohort framework model, based on the data from the pivotal trial of pegcetacoplan (PEGASUS/NCT03500549), evaluated lifetime costs and outcomes. Patients transitioned through 3 PNH hemoglobin level/red blood cell transfusion health states. Results: Pegcetacoplan provides lower lifetime costs/greater quality-adjusted life years (£6,409,166/14.694QALYs, respectively) versus ravulizumab (£6,660,676/12.942QALYs). Conclusion: Pegcetacoplan is associated with enhanced anemia control, greater QALYs and reduced healthcare costs versus ravulizumab in the UK healthcare and social services setting.

Examining the impact of haemophilia treatment on health-related quality of life.

INTRODUCTION: Haemophilia has substantial SD effects on health-related quality of life (HRQoL), particularly for people with severe haemophilia. How certain aspects of haemophilia influence HRQoL is not well understood. AIM: To develop predictive models of variables influencing HRQoL in people with severe haemophilia A or B. METHODS: We used data from 514 participants with haemophilia A or B who provided EQ-5D-3L responses in the 2015 CHESS study. Treatment was categorized as always been on-demand (POD), previously on prophylaxis and moved to on-demand regimen (SOD), on prophylaxis from diagnosis (PX), and prophylaxis, previously on-demand (PXOD). Target joints were defined as 'locations of chronic synovitis' as reported by the treating physician. Regression models were evaluated to assess the impact of demographic and clinical covariates on HRQoL scores. RESULTS: Significant covariates were generally consistent across models, with number of target joints, number of hospital admissions, and any haemophilia treatment regimen other than PX all independently negatively impacting estimated EQ-5D score. Higher level of treatment adherence (high vs. low/medium) and use of a prophylaxis treatment regimen had positive effects on estimated EQ-5D scores. Target joints were associated with a 0.04 decrement in EQ-5D score, and high versus low/medium adherence was associated with a 0.06 increment. PXOD, POD, and SOD treatment regimens were associated with decrements in predicted scores of 0.07, 0.09, and 0.08, respectively, versus PX. CONCLUSION: This study provides a model to estimate the impact of haemophilia interventions on HRQoL, to help assess the relative impact on patient-centric outcomes for this lifelong condition.

A proposed comprehensive classification of tuberculosis disease severity in children.

BACKGROUND: Tuberculosis (TB) in children has conventionally been classified as pulmonary TB (PTB) and extrapulmonary TB (EPTB) disease, including disseminated TB (TB meningitis and miliary disease). There is no existing approach that comprehensively characterizes the spectrum and severity of pediatric TB. This limits accurate classification of patients and comparison across cohorts. AIMS: To develop a classification of pediatric TB that reflects the spectrum and severity of clinical disease better than currently available approaches. METHODS: We propose a framework for the standard classification of TB disease severity in children. From a literature search, the following sources of information were used: clinical data, bacteriologic, histopathologic, and imaging data (including information from chest radiography, computerized tomography, and bronchoscopy). Each individual disease entity was systematically considered. Based on the extent and the presence of complications, each entity was then classified as "severe" or "nonsevere." As an initial application, we compared the proposed classification with the convention (PTB, EPTB) in a cohort of HIV-infected and -uninfected infants with culture-confirmed TB. Agreement between the 2 systems was poor. CONCLUSIONS: The proposed comprehensive disease classification system may more accurately reflect the clinical TB disease spectrum in children, is relevant to clinical management, and may be valuable to inform research on diagnostic tools and TB treatment strategies in children. Prospective studies are required to evaluate this approach in representative pediatric populations, correlating TB disease severity with diagnostic yield, treatment response, and application in existing and novel treatment strategies.

Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia.

Many biologic markers are associated with poor prognosis in chronic lymphocytic leukemia (CLL), but their mechanistic role remains unclear. Bax is an essential proapoptotic protein and decreased levels in malignant cells lead to resistance to apoptosis. Using a Bax degradation activity (BDA) assay, CLL cells were found to show variable Bax instability. However, BDA did not correlate with Bax protein levels: BDA positive and negative cases had high and low baseline Bax levels. BDA positive cases showed a marked accumulation of poor prognostic markers-unmutated immunoglobulin heavy chain variable genes, ZAP-70/CD38 positivity, 11q22/17p13 deletion, and short lymphocyte doubling time. Patients with BDA positive cells had a shorter median overall survival (OS; 126 months vs not reached, P = .011) and time to first treatment (16 vs 156 months, P = .029) than BDA negative cases. Dual BDA and ZAP-70 positivity had a median OS of 84 months (P = .012). The BDA assay measures the intrinsic ubiquitin/proteasome activity of CLL cells and dynamic changes in Bax protein levels over time. Mechanistically, Bax instability may represent a final common pathway for disparate prognostic markers, as well as being itself an indicator of poor prognosis.