Absence of CALR Mutations in Idiopathic Erythrocytosis Patients with Low Serum Erythropoietin Levels

International audienc

AKT/mTORC2 inhibition activates FOXO1 function in CLL cells reducing B cell receptor-mediated survival

Purpose: To determine whether inhibition of mechanistic target of rapamycin (mTOR) kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL). Experimental Design: Stratification of mTOR activity was carried out in primary CLL patient samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib. Results: Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1T37/46 and decreased p70S6 kinase activity, suggesting that dual mTORC1/2 inhibitors may exhibit improved response in poor prognostic CLL compared with rapalogs. AZD8055 treatment of primary CLL cells significantly reduced CLL survival in vitro compared with rapamycin, preferentially targeting poor prognostic subsets and overcoming BCR-mediated survival advantages. Furthermore, AZD8055, and clinical analog AZD2014, significantly reduced CLL tumor load in mice. AKT substrate FOXO1, while overexpressed in CLL cells of poor prognostic patients in LN biopsies, peripheral CLL cells, and mouse-derived CLL-like cells, appeared to be inactive. AZD8055 treatment partially reversed FOXO1 inactivation downstream of BCR crosslinking, significantly inhibiting FOXO1T24 phosphorylation in an mTORC2-AKT-dependent manner, to promote FOXO1 nuclear localization, activity and FOXO1-mediated gene regulation. FOXO1 activity was further significantly enhanced on combining AZD8055 with ibrutinib. Conclusions: Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations

The impact of next generation sequencing technologies on haematological research - A review

AbstractNext-generation sequencing (NGS) technologies have begun to revolutionize the field of haematological malignancies through the assessment of a patient's genetic makeup with a minimal cost. Significant discoveries have already provided a unique insight into disease initiation, risk stratification and therapeutic intervention. Sequencing analysis will likely form part of the routine diagnostic testing in the future. However, a number of important issues need to be addressed for that to become a reality with regard to result interpretation, laboratory workflow, data storage and ethical issues. In this review we summarize the contribution that NGS has already made to the field of haematological malignancies. Finally, we discuss the challenges that NGS technologies will bring in relation to data storage, ethical and legal issues and laboratory validation. Despite these challenges, we predict that high-throughput DNA sequencing will redefine haematological malignancies based on individualized genomic analysis

Cost Effectiveness of Therapies for Atrial Fibrillation: A Review

Atrial fibrillation is the most common supraventricular tachyarrhythmia encountered in clinical practice, affecting over 5% of persons over the age of 65 years. A common pathophysiological mechanism for arrhythmia development is atrial distention and fibrosis induced by hypertension, coronary artery disease or ventricular dysfunction. Less frequently, atrial fibrillation is caused by mitral stenosis or other provocative factors such as thyrotoxicosis, pericarditis or alcohol intoxication. Depending on the extent of associated cardiovascular disease, atrial fibrillation may produce haemodynamic compromise, or symptoms such as palpitations, fatigue, chest pain or dyspnoea. Arrhythmia-induced atrial stasis can precipitate clot formation and the potential for subsequent thromboembolism. Comprehensive management of atrial fibrillation requires a multifaceted approach directed at controlling symptoms, protecting the patient from ischaemic stroke or peripheral embolism and possible conversion to or maintenance of sinus rhythm. Numerous randomised trials have demonstrated the efficacy of warfarin - and less so aspirin (acetylsalicylic acid) - in reducing the risk of embolic events. Furthermore, therapeutic strategies exist that can favourably modify symptoms by restoring and maintaining sinus rhythm with cardioversion and antiarrhythmic prophylaxis. However, the risks and benefits of various treatments is highly dependent on patient-specific features, emphasising the need for an individualised approach. This article reviews the findings of cost-effectiveness studies published over the past decade that have evaluated different components of treatment strategies for atrial fibrillation. These studies demonstrate the economic attractiveness of acute management options, long term warfarin prophylaxis, telemetry-guided initiation of antiarrhythmic therapy, approaches to restore and maintain sinus rhythm, and the potential role of transoesophageal echocardiographic screening for atrial thrombus prior to pharmacological or electrical cardioversion. Further, we discuss the merits and limitations of the cost-effectiveness analyses in the context of overall treatment strategies. Finally, we identify areas that will require additional research to achieve the goal of effective and economically efficient management of atrial fibrillation.Amiodarone, Antiarrhythmics, Antithrombotics, Aspirin, Atrial fibrillation, Cardiac pacing, Cost analysis, Pharmacoeconomics, Warfarin