Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL

On groups and initial segments in nonstandard models of Peano Arithmetic

This thesis concerns M-finite groups and a notion of discrete measure in models of Peano Arithmetic. First we look at a measure construction for arbitrary non-M-finite sets via suprema and infima of appropriate M-finite sets. The basic properties of the measures are covered, along with non-measurable sets and the use of end-extensions. Next we look at nonstandard finite permutations, introducing nonstandard symmetric and alternating groups. We show that the standard cut being strong is necessary and sufficient for coding of the cycle shape in the standard system to be equivalent to the cycle being contained within the external normal closure of the nonstandard symmetric group. Subsequently the normal subgroup structure of nonstandard symmetric and alternating groups is given as a result analogous to the result of Baer, Schreier and Ulam for infinite symmetric groups. The external structure of nonstandard cyclic groups of prime order is identified as that of infinite dimensional rational vector spaces and the normal subgroup structure of nonstandard projective special linear groups is given for models elementarily extending the standard model. Finally we discuss some applications of our measure to nonstandard finite groups

An updated perspective on immunoglobulin replacement in chronic lymphocytic leukaemia in the era of targeted therapies

Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton's tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of 'IgG quality' may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function. KEYWORDS C L L , h y p o g a m m a g l o b u l i n e m i a , I g r e p l a c e m e n t , i m m u n o m o d u l a t i o n , restoration immunity Frontiers in Oncolog

An updated perspective on immunoglobulin replacement in chronic lymphocytic leukaemia in the era of targeted therapies

Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton’s tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of ‘IgG quality’ may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu’s advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden

A self-contained wind speed, direction and location system for buoys and ships in the World Ocean Circulation Experiment

Knowledge of the absolute wind velocity near the surface of the ocean is a requirement of the World Ocean Circulation Experiment (WOCE) and other large programs directed towards understanding air-sea interactions and how ocean circulation and climate are interrelated. The measurement is made possible using IMET (Improved METeorology) modules, a next generation meteorological data acquisition system developed as part of the WOCE program. An IMET system consists of a set of intelligent modules for each measurement variable, with data being recorded on a computer, typically PC-based. The IMET wind module includes a propeller for wind speed, a vane and optical encoder for wind direction, a flux gate compass for the north reference, and microprocessor-based electronics for control and data formatting. The IMET Global Positioning System (GPS) module includes a five chanel GPS receiver and microprocessor based electronics for control and data formatting. These modules, as part of the complete measurement suite, result in a self-contained system that can make accurate measurements from research ships, drifting and moored buoys, and volunteer observing ships (VOS).Funding was provided by Grant No. OCE-8709614 from the National Science Foundation

Pirtobrutinib in Chronic Lymphocytic Leukemia: Navigating Resistance and the Personalisation of BTK-Targeted Therapy

Background/Objectives: Covalent Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) improve outcomes in advanced chronic lymphocytic leukemia (CLL) but resistance, largely driven by BTK C481 mutations, and adverse events limit long-term benefit. Noncovalent BTK inhibitors (e.g., pirtobrutinib) reversibly inhibit the BTK ATP-binding pocket independent of C481, potentially overcoming resistance and reducing toxicity. This review summarizes clinical evidence for pirtobrutinib in CLL. Methods: A PubMed search of articles through July 2025 was conducted, focusing on clinical trials of pirtobrutinib. We extracted efficacy, safety, and resistance data, emphasizing the BRUIN CLL-321 phase 3 trial and related studies. Results: Pirtobrutinib demonstrates activity against BTK resistance mutations with a favorable safety profile, partly due to high kinase selectivity. In BRUIN CLL-321, pirtobrutinib achieved an overall response rate (ORR) of 62% and a median progression-free survival (PFS) of 20 months in heavily pretreated patients, including those with resistance mutations. Yet, resistance mechanisms—such as alternative pathway activation and additional BTK mutations—emerge in a subset. Baseline genetic features, including BTK mutation status and cytogenetics, influence response durability and outcomes. Ongoing phase 3 trials comparing pirtobrutinib with covalent BTK inhibitors will clarify its potential as a first-line option and its integration into treatment algorithms. In relapsed/refractory CLL, noncovalent BTK inhibitors may be incorporated into personalized pathways, including bridging to CAR-T therapy, to optimize long-term disease control. Conclusions: Pirtobrutinib offers a promising strategy to address resistance and potentially improve durable disease control in CLL. Definitive trials will define its role relative to covalent BTK inhibitors and its utility across treatment lines within personalized, multimodal regimens

Chronic Lymphocytic Leukemia Care and Beyond: Navigating the Needs of Long-Term Survivors

Chronic lymphocytic leukemia (CLL) treatment has undergone a significant evolution with a shift from historical chemotherapeutic regimens to targeted therapies such as Bruton tyrosine kinase (BTK) and BCL-2 inhibitors. These advancements have been associated with a notable improvement in survival rates with a transformation of CLL into a chronic and manageable condition for most persons with this disease. However, as a consequence of improved outcomes, long-term CLL survivors now face emergent challenges which include a risk of infections, cardiovascular complications, and secondary malignancies. In this changed scenario, holistic models of care are essential to address emergent health risks. Such models of care for CLL patients require a multidisciplinary approach that integrates CLL treatment with the proactive management of frailty, comorbidities, and psychosocial well-being to enhance both survival and quality of life (QoL). CLL predominantly affects older persons, many of whom present with concurrent frailty and comorbidities that may complicate CLL treatment and impact QoL. Comprehensive geriatric assessments (GA) may play a critical role in the identification of persons at a heightened risk of treatment-related toxicity and may help guide rational therapy selection, particularly in very frail persons. In addition to the assessment of hematological responses, the prospective assessment of patient-reported outcomes (PROs) and frailty metrics may offer a more nuanced understanding of the global treatment benefits. A survivorship-focused care model is crucial to address the multifaceted needs of CLL patients with the extension of patient care into the broader domain of long-term health maintenance with associated improvements in QoL