Vertex Pharmaceuticals

Chimeric antigen receptor (CAR) T cell therapy is being used to target a range of pediatric cancers. Starting materials are critical for successful CAR T cell manufacturing, most often obtained via autologous mononuclear cell (auto-MNC) apheresis. While apheresis strategies are established for patients with B cell acute lymphoblastic leukemia (B-ALL), these approaches are not standardized and there are limited data on how these practices apply across other disease groups. Here, we report our experience with apheresis for CAR T cell production across various pediatric cancer diagnoses. We performed a single-center retrospective analysis of auto-MNC apheresis events. Parameters for apheresis suitability included peripheral blood absolute lymphocyte count (ALC) ≥300 cells/µL and CD3+ ≥150 cells/µL. Meeting apheresis goal was defined as postprocessing yield within 90% of target (2 × 109 total nucleated cells [TNC] and 1 × 109 CD3+ cells). Multi-day collections were considered single apheresis events. Baseline and collection characteristics were compared across disease groups, and univariable and multivariable logistic regression models were applied to explore the associations between baseline factors and successful apheresis collection, adjusting for baseline covariates. We evaluated 151 auto-MNC apheresis collections from 138 unique patients diagnosed with ALL (n = 80), AML (n = 23), lymphoma (n = 2), solid tumor (n = 16), or brain tumor (n = 17). The median age at time of apheresis collection was 11.7 years (range 1.4-23.5), and the median amount of blood processed was 1.9 (range 0.8-8.2) total blood volumes (TBV), with no statistically significant difference in TBV processed between disease groups (P = 0.218). Overall, 87% of patients met both total nucleated cell (TNC) and CD3+ goals, with no statistically significant differences across disease groups in univariate or multivariate analyses. Collection efficiency was not impacted by burden of peripheral blasts among patients with leukemia. In multivariate analysis, increasing age was associated with increased odds of successful apheresis (OR: 1.17, 95% CI: 1.06-1.32), while odds of successful collection decreased with increasing baseline white blood cell count (OR: 0.92, 95% CI: 0.81-0.99). Subsequent CAR T cell manufacturing was successful in 127 of 129 procedures (98.4%). We report that auto-MNC apheresis collection criteria can be applied across an array of pediatric oncologic indications, resulting in highly successful apheresis and subsequent manufacturing campaigns without significant differences between disease groups. Age and baseline WBC count may influence successful apheresis, but overall low failure rates limit current risk factor analysis.

Anemia presents a challenge in the management of myelofibrosis (MF). This symptom may be present at diagnosis or develop soon after, and around half of patients with MF require red blood cell transfusions within the first year. Progression to being transfusion dependent (TD) negatively affects prognosis and quality of life. This retrospective cohort study examined treatment sequencing from MF diagnosis, and overall survival (OS) and healthcare resource utilization (HCRU) from diagnosis and by transfusion status in newly diagnosed patients with MF in Germany. Data from 2010 to 2022 were collected from the AOK PLUS statutory health insurance fund database. Transfusion status was determined during a 180-day landmark period following first anemia treatment; patients were transfusion independent (TI) if they had received no transfusion, TD if they received ≥ 3 transfusions within 12 weeks, and transfusion requiring (TR) if they received transfusions but did not meet TD criteria during the landmark period. Of 555 patients assessed for treatment sequencing, only 41.8% received MF therapies (Janus kinase [JAK] inhibitors, peginterferon alpha-2a, immunomodulators, hydroxycarbamide, allogeneic hematopoietic stem cell transplantation), while 69.0% received anemia-directed interventions (59.8% being blood transfusions). Among patients receiving treatment for anemia (n = 233), transfusion need was associated with shorter median OS (TD: 14.9, TR: 33.3, and TI: 74.3 months after the landmark period) and higher HCRU burden. This study documented high clinical and economic burden of anemia in patients with MF within Germany, particularly among TD patients, highlighting the need for novel treatments providing better prevention of anemia in MF.

The current cystic fibrosis (CF) care era, while hugely welcome, raises new challenges, particularly the need for more sensitive pulmonary outcome measures. Seeking further optimisation, we previously developed a Short extension to multiple breath washout measure (MBWShX) which captures previously overlooked, under-ventilated lung units but lacks regional information. Functional lung MRI addresses this limitation. We hypothesised these measures would be more sensitive to change in tracking CF lung disease than usual clinical respiratory function tests. Forty-six people with (pw)CF, median age 15 (range 6-55) years were recruited to a single-centre study. While clinically stable, pwCF performed OE-MRI, MBW+/-ShX and spirometry at baseline and at 6 monthly intervals over 18 months of follow-up. A subgroup of pwCF (n=20) and age-matched healthy controls (HC, n=20) performed two repeatability visits within 6 weeks. OE-MRI/MBWShX were well tolerated, differentiated HC and CF groups, and were repeatable with negligible differences between two visits <6 weeks apart. OE-MRI/MBWShX parameters worsened at 12 months (p<0.05) and 18 months (p<0.01). In contrast, conventional measures of pulmonary function (FEV1+ LCI2.5) did not change significantly. OE-MRI/MBWShX are novel, sensitive tools to track progression of abnormalities in lung structure/function. Such progression may not be detected by conventional outcome measures. CF transmembrane conductance regulator (CFTR) modulators have been transformative for many pwCF and generally lead to substantial improvements in lung health. Stable FEV1 over longer time periods and, during mucoactive treatment withdrawal, may give false reassurance. OE-MRI/MBWShX reveal the likely less welcome reality that lung-disease progresses despite CFTR modulators. These measures could be considered in future studies when enhanced sensitivity is required.

Since 2018, important advancements in the medical care of people with cystic fibrosis, particularly the introduction and widespread use of highly effective cystic fibrosis transmembrane conductance regulator modulators, have contributed to the adult cystic fibrosis population growing substantially and has led to an increased need for tailored health-care approaches. Our study aimed to analyse the extent to which the clinical characteristics and treatment outcomes of adults with cystic fibrosis have evolved from 2014 to 2024. The European Cystic Fibrosis Society Patient Registry (ECFSPR), collects annual data for more than 55 000 people with cystic fibrosis. Longitudinal data from 20 countries in Europe with high patient coverage (>85%) from 2014 to 2024 were analysed, representing 80% of the whole ECFSPR cohort. Differences in annual cross-sectional estimates were assessed using regression models. Between 2014 and 2024, the number of adults with cystic fibrosis increased by 45·0%, from 50·9% to 60·5% of the total cystic fibrosis population. The number of adults older than 30 years nearly doubled. Among adults with cystic fibrosis who had not received a transplant, mean percent predicted FEV1 improved from 66·1% to 78·8% (p<0·0001), with most of the gain occurring after 2020. Chronic Pseudomonas aeruginosa infection declined significantly (p<0·0001), whereas mean BMI increased significantly (p<0·0001), halving the proportion of individuals who are underweight. Age-related complications, such as malignancy, increased, whereas cystic fibrosis-specific complications and insulin-treated diabetes declined. The largest improvements were observed in individuals with at least one variant responsive to elexacaftor-tezacaftor-ivacaftor (ETI). The uptake of ETI increased from 2% in 2019 to 71% in 2024, associated with improvements in health indicators. From 2014 to 2024, the adult cystic fibrosis population in Europe expanded substantially due to marked improvements in treatment, particularly following the availability of ETI triple therapy from 2018-19 onwards. The growing number of people with CF surviving to adulthood is consistent with substantial effects from improved care and cystic fibrosis transmembrane conductance regulator modulators, such as ETI, and highlight evolving care needs of people with cystic fibrosis. None.

Genome-wide association study (GWAS) summary statistics for training and individual-level cohorts for fine-tuning are essential for constructing predictive polygenic risk score (PRS) models. However, the relatively low representation of admixed populations in both GWAS summary statistics and individual-level datasets hinders the development of PRSs and equitable clinical translation for admixed populations. Prior work indicates that the most informative PRS model for a genetically homogeneous sample varies linearly in an ancestry continuum space. Guided by these observations, we introduce a genetic-distance-assisted PRS combination pipeline for diverse genetic ancestries (DiscoDivas) to interpolate a harmonized PRS for diverse, especially admixed, genetic ancestries. DiscoDivas leverages multiple PRS models fine-tuned within existing samples, which are mostly of single ancestry, and genetic distance. It provides a new approach to generate genetic-ancestry-specific PRSs when a suitably matched individual-level fine-tuning cohort is unavailable or underpowered. DiscoDivas treats genetic ancestry as a continuous variable and does not require shifting across different models when calculating PRSs for different ancestries. We generated PRSs with DiscoDivas and the current conventional method, i.e., fine-tuning multiple GWAS PRSs using the matched or similar genetic-ancestry samples. DiscoDivas generated a harmonized PRS, performing comparable to or better than the conventional approach, with the greatest advantage exhibited in admixed individuals.

Individuals carrying ultra-rare CFTR variants remain untreated with CFTR modulator therapies due to a lack of functional and clinical data supporting variant-specific responsiveness. This study aimed to functionally characterize two ultra-rare CFTR variants, p.Glu1104Lys (E1104K) and p.Leu999del (L999del), each found in trans with the minimal function variant G542X, and to evaluate their responsiveness to the triple-combination regimens elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and vanzacaftor/tezacaftor/ivacaftor (VAN/TEZ/IVA). Patient-derived intestinal organoids (PDIOs) of two people with cystic fibrosis (G542X/E1104K and G542X/L999del) were cultured from rectal biopsies and subjected to forskolin-induced swelling (FIS) assays. CFTR function was quantified by calculating the area under the curve after 60 minutes. Human nasal epithelial cells (HNECs) were obtained by nasal brushing, expanded under air-liquid interface conditions, and evaluated in Ussing chambers. CFTRinh-172-sensitive stimulated currents (ΔCFTRinh-172 ISC) were expressed as percentages of the mean response of healthy controls. Both PDIOs exhibited visible swelling under untreated conditions, indicating residual CFTR function. Following pretreatment with ELX/TEZ or VAN/TEZ, both showed marked pre-swelling limiting quantitative analysis to qualitative assessment. In HNECs, residual CFTR activity reached 15% and 13% of WT levels for E1104K and L999del, respectively. Upon modulator treatment, CFTR activity increased to 90% (ELX/TEZ) and 97% (VAN/TEZ) in E1104K, and to 46% and 56% in L999del. E1104K and L999del exhibit measurable residual CFTR function and in vitro responsiveness to two CFTRm triple-combination regimens. These findings support theranostic approaches to guide therapy in individuals with ultra-rare CFTR genotypes, while clinical use remains dependent on regulatory approval and individualized patient assessment.