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PurposeMethodsResultsConclusionIbrutinib is an irreversible Bruton’s tyrosine kinase inhibitor that disrupts B-cell receptor signalling. It is licensed for treatment of low-grade B-cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma and lymphoplasmacytic lymphoma. A few case reports in the literature suggest that uveitis may be a side effect of ibrutinib treatment. A strong association between ibrutinib and uveitis is yet to be established in significant numbers.The study is a retrospective case series, reporting cases of uveitis associated with ibrutinib from two tertiary centres in the United Kingdom: Liverpool University Hospitals NHS Foundation Trust and University Hospitals of Leicester NHS Trust.The study reports eight cases presenting over a four year period, with mean age of 66.8 years. Onset of uveitis was between 9 and 48 (median 14) months from commencing ibrutinib, categorising it as a Type D or delayed drug reaction. Cases included unilateral and bilateral; anterior, intermediate, posterior and panuveitis. There was an association with cystoid macular oedema or disc swelling. Severity varied from mild, to severe and vision threatening. Presenting visual acuity ranged from 6/9 to 6/60. In all eight cases, uveitis resolved after ibrutinib cessation. In two cases, reintroducing ibrutinib caused uveitis recurrence.Our case series provides evidence suggestive of a connection between ibrutinib and development of uveitis. Ibrutinib related uveitis appears to be more common than previously recognised. Ibrutinib cessation, if appropriate, appears to be the definitive management. Patients with ibrutinib-related uveitis benefit from multidisciplinary management involving communication between ophthalmologist and haemato-oncologist. [ABSTRACT FROM AUTHOR]

• The update covers the approval of time-limited ibrutinib–venetoclax in first line and new data on MRD-driven treatment. • It also covers the approval of the BTKi zanubrutinib in both treatment-naive and relapsed or refractory CLL. • Additional evidence on the time-limited combination of venetoclax plus an anti-CD20 antibody in the first line are included. • Options for later-line treatments based on the type of prior lines of treatment are also included. • Recommendations are based on available scientific data and the authors' collective expert opinion. [ABSTRACT FROM AUTHOR]

Background: Ibrutinib is a Bruton's tyrosine kinase inhibitor indicated for the first-line treatment and relapse of chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinemia (WM) and mantle cell lymphoma (MCL). This study aimed to describe the characteristics of CLL patients treated with ibrutinib and its effectiveness, safety, and treatment pattern in real life. Methods: All patients covered by the general health scheme (approximately 80% of the French population) with a first ibrutinib dispensation from August 1, 2017 (date of reimbursement in France) to December 31, 2020, were identified in the French National Health Insurance database (SNDS). An algorithm was developed to identify the disease (CLL, MCL or WM) for which ibrutinib was prescribed. This article focused on CLL patients. The time to next treatment (TTNT) was plotted using Kaplan‒Meier curves. Results: During this period, 6,083 patients initiated ibrutinib, among whom 2,771 (45.6%) patients had CLL (mean age of 74 years; 61% of men). At ibrutinib initiation, 46.6% of patients had a cardiovascular comorbidity. Most patients (91.7%) were not hospitalized during the exposure period for one of the cardiovascular or bleeding events studied. Hospitalizations were more frequent in patients with a cardiovascular comorbidity (5.9% versus 11.0%, p-value < 0.0001) and aged over 70 (5.9% versus 9.4%, p-value < 0.0001). The median TTNT was not reached. Conclusion: This is one of the largest cohorts of ibrutinib-treated patients in the world. The profile of CLL patients treated with ibrutinib was in accordance with the marketing authorization and reimbursement. This study confirmed effectiveness and safety data. [ABSTRACT FROM AUTHOR]

Summary Real‐world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi‐based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi‐based regimens in 1 L (1/2019–9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT‐D), and time off‐treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow‐up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT‐D was not reached for VenO; however, more VenO‐ versus BTKi‐treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off‐treatment was 11.3 vs. 4.3 months. In this real‐world study, VenO was associated with better effectiveness outcomes than BTKi‐based regimens in 1 L CLL. [ABSTRACT FROM AUTHOR]

Background: Immunocompromised hosts (ICH) experience more breakthrough infections and worse clinical outcomes following infection with COVID-19 than immunocompetent people. Prophylactic monoclonal antibody therapies can be challenging to access, and escape variants emerge rapidly. Immunity conferred through vaccination remains a central prevention strategy for COVID-19. COVID-19 vaccines do not elicit optimal immunity in ICH but boosting, through additional doses of vaccine improves humoral and cellular immune responses. This trial aims to assess the immunogenicity and safety of different COVID-19 vaccine booster strategies against SARS-CoV-2 for ICH in Australia. Methods: Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC) is an adaptive randomised trial of one or two additional doses of COVID-19 vaccines 3 months apart in people living with HIV, solid organ transplant (SOT) recipients, or those who have haematological malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma or multiple myeloma). Key eligibility criteria include having received 3 to 7 doses of Australian Therapeutic Goods Administration (TGA)-approved COVID-19 vaccines at least 3 months earlier, and having not received SARS-CoV-2-specific monoclonal antibodies in the 3 months prior to receiving the study vaccine. The primary outcome is the geometric mean concentration of anti-spike SARS-CoV-2 immunoglobulin G (IgG) 28 days after the final dose of the study vaccine. Key secondary outcomes include anti-spike SARS-CoV-2 IgG titres and the proportion of people seroconverting 6 and 12 months after study vaccines, local and systemic reactions in the 7 days after vaccination, adverse events of special interest, COVID-19 infection, mortality and quality of life. Discussion: This study will enhance the understanding of COVID-19 vaccine responses in ICH, and enable the development of safe, and optimised vaccine schedules in people with HIV, SOT, or haematological malignancy. Trial registration: ClinicalTrials.gov NCT05556720. Registered on 23rd August 2022. [ABSTRACT FROM AUTHOR]

Population‐based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age‐standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow‐up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0–35.3) and 4.6 (95% CI: 3.1–6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve. [ABSTRACT FROM AUTHOR]

Abstract Background Immunocompromised hosts (ICH) experience more breakthrough infections and worse clinical outcomes following infection with COVID-19 than immunocompetent people. Prophylactic monoclonal antibody therapies can be challenging to access, and escape variants emerge rapidly. Immunity conferred through vaccination remains a central prevention strategy for COVID-19. COVID-19 vaccines do not elicit optimal immunity in ICH but boosting, through additional doses of vaccine improves humoral and cellular immune responses. This trial aims to assess the immunogenicity and safety of different COVID-19 vaccine booster strategies against SARS-CoV-2 for ICH in Australia. Methods Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC) is an adaptive randomised trial of one or two additional doses of COVID-19 vaccines 3 months apart in people living with HIV, solid organ transplant (SOT) recipients, or those who have haematological malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma or multiple myeloma). Key eligibility criteria include having received 3 to 7 doses of Australian Therapeutic Goods Administration (TGA)-approved COVID-19 vaccines at least 3 months earlier, and having not received SARS-CoV-2-specific monoclonal antibodies in the 3 months prior to receiving the study vaccine. The primary outcome is the geometric mean concentration of anti-spike SARS-CoV-2 immunoglobulin G (IgG) 28 days after the final dose of the study vaccine. Key secondary outcomes include anti-spike SARS-CoV-2 IgG titres and the proportion of people seroconverting 6 and 12 months after study vaccines, local and systemic reactions in the 7 days after vaccination, adverse events of special interest, COVID-19 infection, mortality and quality of life. Discussion This study will enhance the understanding of COVID-19 vaccine responses in ICH, and enable the development of safe, and optimised vaccine schedules in people with HIV, SOT, or haematological malignancy. Trial registration ClinicalTrials.gov NCT05556720. Registered on 23rd August 2022.

Abstract In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients.

Abstract Pharmacotherapy options for chronic lymphocytic leukaemia (CLL) have expanded significantly in recent years. These options include chemotherapy, chemoimmunotherapy and signalling pathway inhibitors. A notable shift in the treatment landscape began with the widespread adoption of ibrutinib in 2016. This analysis of claims data focuses on understanding how the use of novel therapies has evolved in clinical practice over the past decade in Germany. Anonymized claims data (2010–2022) from German statutory health insurance was used, covering patient demographics, treatments, and prescriptions. The study population included patients with two confirmed CLL diagnoses. Treatment patterns were analysed, and survival outcomes were compared using time‐to‐event analyses. In the analysed cohort of 2983 incident CLL patients, 1041 started first‐line therapy between 2011 and 2022, with a median duration of 18 months from diagnosis to the first prescription. Chemoimmunotherapy, the predominant 1L therapy until 2019, decreased significantly, while targeted therapy usage increased from 3% in 2015 to 77% in 2022. Targeted therapies became dominant in patients receiving treatment for relapsed or refractory disease after 2016. Median treatment durations were: 122 days for chemo, 176 days for chemo‐immuno, and 373 days for targeted therapy. The overall survival for patients diagnosed in or after 2016 was significantly better (hazard ratio 0.56, 95% confidence interval, 0.44–0.69)). The adoption of targeted therapies like ibrutinib and venetoclax has transformed CLL treatment in Germany, leading to improved patient outcomes. Additionally, we demonstrate successful adherence to evolving clinical guidelines.

Summary Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild‐type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients. [ABSTRACT FROM AUTHOR]

Background Arising in blood and lymph-forming tissues, haematological malignancies (leukaemias, lymphomas and myelomas) are the fifth most common group of cancers. Around 60% are currently incurable and follow a chronic, remitting–relapsing pathway often initially managed by ‘watch & wait’. This involves hospital-based monitoring, followed by treatment if the cancer progresses (which not all do) and then further observation, in a process that may continually repeat. New treatments are constantly emerging, survival is improving and prevalence is rising, but population-based data documenting entire care pathway are sparse. Hence, empirically-based incidence and prevalence estimates about various treatment states (watch and wait, first-line treatment, observation, second-line treatment, etc.) and patterns of healthcare activity are lacking. Likewise, despite complex trajectories, anxiety-provoking watch and wait, and therapies that impede quality of life and incur marked healthcare costs, evidence about patient preferences for information sharing and treatment decisions is scant. Objectives Primary – to generate high-quality, evidence-based information about the care pathways of the general population of patients with chronic haematological malignancies. Secondary – to produce information resources suitable for testing in routine National Health Service practice. Design Population-based cohort of ≈ 8000 patients with chronic haematological malignancies, incorporating five nested work packages, each with its own individual design: (1) exploration of patient experiences: information and treatment decisions; (2) population-based analyses; (3) health economics; (4) development of information resources to support decision-making; and (5) patient well-being and decision-making survey. Setting This programme is predicated on the infrastructure of the United Kingdom’s Haematological Malignancy Research Network (www.hmrn.org); which provides ‘real-world’, robust, generalisable data to inform research and clinical practice, nationally and internationally. Set in Yorkshire and Humberside, the Haematological Malignancy Research Network’s catchment population of ≈ 4 million has a comparable sex, age, urban/rural, and area-based deprivation (Index of Multiple Deprivation, income domain) distribution to the United Kingdom as a whole; and in terms of ethnic diversity the region is centrally ranked, with around 80% of residents identifying as White British, 9% as Asian and 2% as black. Within the Haematological Malignancy Research Network, clinical practice adheres to national guidelines, and all patients with blood cancers are centrally diagnosed (≈ 2500 each year), tracked through their treatment pathways and linked to national databases (deaths, cancer registrations and Hospital Episode Statistics). Linked to the same national databases, the Haematological Malignancy Research Network also contains an age- and sex-matched general-population cohort. Participants Patients aged ≥ 18 years, resident in the study region, and diagnosed with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Methods Core Haematological Malignancy Research Network data were used to compare the hospital activity of patients with chronic lymphocytic leukaemia, follicular lymphoma and myeloma with that of the general population. Following additional linkages to genetic and clinical data, follicular lymphoma prognostic factors were examined. Two self-administered questionnaires addressing (1) quality of life and well-being and (2) decision-making were iteratively developed, piloted and deployed. Linkage to quality of life, clinical information and Hospital Episode Statistics enabled economic (myeloma) model development. In-depth interviews were conducted with 35 patients (10 alongside relatives). Results Trajectories of ≈ 8000 patients were mapped, and patient-pathway visualisations summarising individual and aggregate information were developed. As expected, patients with chronic blood cancers experienced higher levels of hospital activity than their general population counterparts, the largest effects being for myeloma. Following survey deployment, 3153 patients were recruited across 14 hospitals, 1282 with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Over half of the questionnaires were completed by patients on watch and wait; the remainder were completed during treatment or post-chemotherapy monitoring. Information gathered, coupled with in-depth interviews, demonstrated patients’ marked anxiety and fluctuating preferences for information sharing and decision-making, contingent on complex, inter-related factors. In turn, prognostic and microsimulation economic models were used to predict individual-level trajectories across multiple treatment lines, examining associated overall survival, costs and quality-adjusted life-years. Limitations Survey mapping to individual care pathways could not be completed because the COVID-19 pandemic delayed clinical data collection. Patients who attended clinics and participated in the survey were more likely than non-attenders to have had first-line chemotherapy, be slightly younger and live in more affluent areas. Conclusions This programme collated high-quality, population-based evidence. Previously lacking, this, coupled with new findings on preferences for information sharing and treatment decisions, provides the foundation for future research. Future work The translation of information accrued into resources suitable for testing in routine NHS practice is key. In this regard, COVID-19 has changed the communication landscape. The visualisations developed by this programme require further refinement/testing using participatory co-design with stakeholder groups. Underpinned by a suitable protocol applied within a single multidisciplinary team setting, prior to further evaluation within/outside the region, such outputs require testing in a cluster-randomised trial. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0613-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 5. See the NIHR Funding and Awards website for further award information. Plain language summary Around half of all blood cancers (leukaemias, lymphomas and myeloma) are chronic and incurable. Management often involves ‘watch and wait’, which begins with hospital-based monitoring and is followed by treatment if the cancer progresses. This typically leads to further observation and treatment in an ongoing process over time. Patients often experience anxiety and distress about not being treated at diagnosis and also because of uncertainty about ‘if’ and ‘when’ chemotherapy might be needed. Information is critical if patients are to (1) understand what may happen to them in the future and (2) be involved treatment decisions. However, evidence about the care pathways most patients follow is lacking. This programme was designed to fill this gap, tracking all patients with chronic blood cancers through their care pathways. We collected information about diagnosis, treatment and outcome on approximately 8000 patients. These data were used to develop models that could be used to examine outcomes and costs. When compared with the general population, patients with blood cancer were confirmed to have more healthcare activity (e.g. hospital appointments and admissions). Computer programs were developed to electronically generate visual care-pathway ‘maps’ that revealed key similarities and differences between patient groups. Two questionnaires exploring quality of life and involvement in treatment decisions were developed and completed by 3153 patients in 14 hospitals. Thirty-five patients were interviewed about their preferences for information sharing and decision-making; needs were found to differ between patients and over time, and treatment recommendations from clinical staff were generally preferred. Emotional difficulties associated with uncertain trajectories were also clearly described. Yielding new information about the pathways of patients with chronic haematological malignancies, findings from this programme can be built on to improve future care. Final information resources could not be developed or tested in practice due to COVID-19, which continues to impact how health care is delivered. Scientific summary Background Population-based data are required to inform aetiological hypotheses, plan healthcare services and monitor the impact of therapeutic change in the general patient population. This need for data is particularly pertinent in fast-moving areas such as haemato-oncology, where treatments change rapidly and ‘gold-standard’ randomised controlled trials are absent or restricted to specific subgroups (often younger patients with fewer comorbidities), to specific time points (commonly first-line treatment) or by factors such as socioeconomic status, gender or ethnicity. Arising in blood and lymph-forming tissues, haematological malignancies (leukaemias, lymphomas and myelomas) are, collectively, the fifth most common cancer. With diverse aetiologies, treatments and outcomes, more than 100 subtypes are currently recognised by the World Health Organization. Although the incidence of these cancers is stable in high-income countries such as the UK, prevalence is increasing due to population ageing and the development of new multifaceted regimens (e.g. chemotherapies, radiotherapy, stem cell transplants, novel targeted agents). However, around 60% of blood cancers remain incurable, with management often beginning with regular hospital-based monitoring, known as ‘watch & wait’ (W&W). While some patients may never need treatment, others often experience a remitting–relapsing care pathway, requiring treatment at progression interspersed with further monitoring. As with many chronic conditions, there are often uncertainties regarding how individual trajectories will progress, and variations are evident in the need for (and response to) treatment; the most effective regimen; the time when treatment is required (if ever); and the impact of treatment (and non-treatment) on quality of life. Despite such complex trajectories, many of which are associated with anxiety-provoking W&W, and therapies that impede quality of life and incur marked healthcare costs, empirically-based incidence and prevalence estimates relating to treatment states (W&W, first-line treatment, second-line treatment, etc.) are lacking, and granular population-based evidence to guide treatment decisions is sparse. Importantly, new data-gathering measures to redress this deficit have been introduced in the UK but are presently insufficiently mature to guide decisions, and the rapidly evolving nature of haemato-oncology means that generic sources may never be adequate for assessing particular therapies and their impact on individuals. Furthermore, most health economic models have been developed to reflect specific (often static) decision problems, despite effective clinical management being dynamic, involving treatment, monitoring and therapy switching, and depending on treatment response and disease evolution. To summarise, there is a dearth of accessible, reliable information to guide clinicians and patients about treatment and associated healthcare activities, physical health (e.g. disruption to daily life), psychosocial well-being, quality of life and life expectancy. This situation, which is particularly difficult for patients who face uncertain pathways and unresolved anxiety about the future, is compounded by the fact that little is known about preferences for information sharing and the desire to engage in treatment decisions. Objectives This programme sought to address the deficits described above, the premise being that the provision of personalised evidence-based information at key decision points would facilitate treatment decisions, support clinical practice and improve patient experiences. The objectives were as follows: primary – to generate high-quality, longitudinal, real-world information about the care pathways of the general population of patients with chronic haematological malignancies, incorporating data on healthcare costs, and patient preferences for information sharing and engagement in treatment decisions secondary – to produce accessible information resources suitable for testing in routine NHS practice. Design This was a population-based cohort of ≈ 8000 patients with chronic haematological malignancies, incorporating 5 distinct, but inter-related, nested work packages with individual designs, including longitudinal studies, cross-sectional surveys, data linkage and qualitative investigation of patient experiences, as follows: in-depth exploration of patient experiences: information and decision-making population-based analyses health economics development of information resources to support decision-making patient well-being and decision-making survey. Setting This programme is predicated on the established expertise and infrastructure of the UK’s Haematological Malignancy Research Network (HMRN; www.hmrn.org), which was initiated in 2004 to provide robust, generalisable data to inform research and clinical practice. Set in Yorkshire and Humberside, HMRN’s population of ≈ 4 million people has a comparable sex, age, urban/rural and area-based deprivation (Index of Multiple Deprivation, income domain) distribution to that of the UK. Within HMRN, clinical practice adheres to national guidelines, and all patients are centrally diagnosed (≈ 2500 each year), tracked through their care pathways and linked to nationwide health administrative databases (deaths, cancer registrations and Hospital Episode Statistics). HMRN also contains a general-population cohort linked to the same nationwide administrative databases as the patient cohort. HMRN has ethics approval (Leeds West Research Ethics Committee 04/Q1205/69) and Section 251 support [NHS Act 2006: Patient Information and Advisory Group 1-05(h)2007], which provides the legal basis for data collection/linkage. Research building on HMRN’s infrastructure requires supplementary approvals, granted for this programme by the London, City and East Committee (Research Ethics Committee 16/LO/0740). Participants Participants were patients aged ≥ 18 years resident in the study area and diagnosed with one of the three commonest chronic haematological malignancies: chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Patient public involvement and engagement Patient and public involvement and engagement is integral to HMRN, and lay individuals are routinely involved in all research activities via the Patient Partnership, which was established in 2009 and is overseen by a Partnership Committee comprising patients, relatives/carers and researchers. The Partnership includes several hundred people who have agreed to further contact for research purposes, including directing HMRN’s activities and participating in surveys and individual/group discussions. HMRN also benefits from a group that act as a ‘sounding board’, ensuring that all our research is patient-centred and relevant. Patients and relatives were involved in the current programme as applicants and participants. Discussions preceding our application identified issues for investigation, based on patient experiences. Information was considered an area requiring improvement because of widespread concern about W&W and the anxiety and distress that this was said to instil due to uncertainty about ‘if’ and ‘when’ treatment may be required, and its likely impact. Such stories underpinned this programme, alongside our ability (via HMRN) to provide information, mapped to pathways. Changes to programme Following piloting, the survey instrument was split and the content expanded. Questionnaire 1 focused on quality of life and was to be completed pre appointment, and questionnaire 2 targeted treatment decisions and was to be completed post appointment. The number of in-depth interviews was finalised at 35 as the purposeful sampling strategy identified ‘information-rich’ sources and high-quality data. Finally, the secondary objective was curtailed by the COVID-19 pandemic (see Conclusions). Results Patient characteristics and treatment pathways With a median diagnostic age of 71 years, chronic lymphocytic leukaemia and myeloma occur more frequently in men than in women. By contrast, with a younger median age of 65.5 years, follicular lymphoma has a slight preponderance among female patients. First-line management varied markedly by subtype; 84.7% of chronic lymphocytic leukaemia patients were monitored via W&W, compared with 40.9% with follicular lymphoma and 20.2% with myeloma. Furthermore, with a 5-year relative survival of 47.7%, patients with myeloma fared less well than those with chronic lymphocytic leukaemia (5-year relative survival 84.1%) or follicular lymphoma (5-year relative survival 88.1%). To quantify/visualise the data, two software applications were developed. First, a tree-based approach aggregated patients into pathway subgroups, beginning with the initial management or event (chemotherapy, observation or death) and ending with the last. Diversity by cancer subtype was clearly evident: among those diagnosed between 2004 and 2010 who were initially managed by W&W, 40.6% (419/1031) with chronic lymphocytic leukaemia, 38.4% (93/242) with follicular lymphoma and 26.5% (90/339) with myeloma were still on W&W at the end of follow-up (5–11 years later). Second, a patient pathway generator was developed in-house from a Data-Driven Documents (D3) JavaScript library (https://d3js.org/), followed by an iterative graphical restructuring algorithm that displayed visualisations of entire pathways that included all diagnoses, investigations, treatments/responses and hospital activity in real time (generation < 1 second). Population-based analysis and prognostic model Facilitating the identification of patients requiring alternative treatment strategies and separating those at high-risk of disease progression and/or transformation from those who are not is important for clinicians and patients. With a view to incorporating genetic data into conventional prognostic models and the future development of novel targeted treatments, we examined the mutational data of patients newly diagnosed with follicular lymphoma. The molecular investigations undertaken determined that aberrant somatic hypermutations played a leading role in the genetic substructure of follicular lymphoma, with a small number of key genetic mutations, including STAT6, having a marked impact on prognosis. These clusters have implications both for understanding pathogenesis and for potential future treatment strategies. However, separation of follicular lymphoma according to mutational status despite being linked to apparent underlying mechanistic differences provides only limited prognostic information in conventionally treated patients. Hospital activity patterns Patients often question the difference their disease, or treatment, is likely to have on their survival, future healthcare needs and quality of life. As expected, inpatient and outpatient Hospital Episode Statistics activity post diagnosis was considerably higher among patients with chronic haematological malignancies than in the general population, the largest differences being for myeloma. For all three diagnoses, hospital activity peaks around the time of diagnosis, outpatient activity remaining high but levelling around 12 months after diagnosis, and inpatient activity around 8 months post diagnosis for chronic lymphocytic leukaemia and 36 months for follicular lymphoma. Health economics A microsimulation model was developed for myeloma to reflect multiple lines of treatment, post-treatment surveillance and overall survival. The model was used to predict long-term costs, and quality-adjusted life-years to enable future assessment of the expected impact of new treatments and policies. Input parameters were estimated by analysing individual-level time-to-event data (to represent patients’ trajectories), the EuroQol-5 Dimensions, five-level version (to derive quality-adjusted life-years), and HMRN treatment data (to model treatment sequences). Healthcare costs were estimated from Hospital Episode Statistics, based on national tariffs. The model is flexible enough to incorporate evidence from other sources, including clinical trials. Results were based on 2687 patients with myeloma, diagnosed 2004–15 and followed up until December 2017. Patient survey Two questionnaires for use in haemato-oncology outpatient clinics were developed in-house and piloted: questionnaire 1 (health-related quality of life) was to be completed before the clinic appointment, and questionnaire 2 (treatment decisions) was to be completed after. The survey was successfully implemented in all 14 HMRN hospitals, 2016–8, with 3153 patients participating, 1282 with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Providing information across the pathway, over half of patients completed questionnaires while on W&W; the remainder either received chemotherapy or were monitored post treatment. Survey distribution and data collection were found to be simple and effective, and patients said that they appreciated the opportunity to ‘give back’ via taking part in research. Patient preferences for information sharing and engagement in treatment decisions Interviews were conducted with 35 patients who had experienced varying treatment pathways, and 10 relatives. A large, rich data set generated multifaceted findings. The unpredictable nature of chronic haematological malignancies was confirmed, as were the challenges of coping with uncertain pathways. This caused prolonged anxiety, which could be more distressing than any physical symptoms and difficult to resolve because of infrequent clinic visits and an absence of definitive information. Preferences for information (timing, content, depth and format) varied markedly, both between patients and across individual pathways over time. Regarding treatment decisions, most interviewees said that they preferred a discussion about options, but did not wish, or felt ill-equipped, to make choices themselves. Finally, individual access to a support network (e.g. family, friends or clinical staff) was found to impact positively on experiences and preferences. Conclusions Enhancing understanding about the pathways of the general population of patients with chronic haematological malignancies, this programme has accrued an abundance of new evidence. Data collection instruments have been developed, pathway visualisation programmes have been written, and detailed quantitative and qualitative information, to an extent not previously captured, are now available. We have demonstrated that it is possible to distribute questionnaires and collect longitudinal data in hospital settings, and assemble, summarise and visualise longitudinal pathways, including data on diagnostics, prognostics, treatments, transformations/progressions, hospital episodes, outcomes and costs. Regarding health economics, we have shown the utility of using longitudinal data to estimate how many patients are on each treatment line, post treatment after each line, receiving palliative care, and so on, thereby facilitating cost calculations and resource planning. Such models could potentially be used by commissioners and healthcare managers to simulate the impact of novel policies, treatments and pathway changes prior to their introduction. The marked, ongoing anxiety experienced by some patients due to uncertain pathways suggests that benefits could be accrued from increased awareness about the extent and impact of this, alongside interventions to counteract such difficulties. Addressing varied preferences for information (content, depth, format and timing) would require a broad range and depth of material (from a basic overview to detailed options), complexity (from simple terminology to more complicated graphs) and methods for sharing (verbal, written or electronic), thereby enabling patients to access what they want to know, when they want to know it. As most (but not all) people reported a preference for clinicians to make treatment recommendations, this should also be considered. Changing preferences means that strategies for patient engagement with information-sharing and treatment decisions may need to be tailored to individual needs over time, assessed by routine clinician monitoring. Clinicians might also explore the social infrastructure and support network available to patients, so that they are aware of gaps that could be addressed. Based on several thousand patients, and exceeding any evidence previously generated, this programme collated, assessed and successfully mapped high-quality evidence-based information about the pathways of the general population of patients with chronic haematological malignancies. Previously lacking, these data, coupled with new evidence on preferences for information-sharing and treatment decisions garnered directly from patients, provide the foundation to improve clinical practice. Unfortunately, the final part of the programme could not be completed due to the COVID-19 pandemic; hence, the key future priority is the translation of the data accrued into accessible information resources suitable for testing in routine NHS practice. These would need to be responsive to both the rapidly changing haemato-oncology landscape and the varying needs of clinicians and patients at different points on the pathway. Building on the foundations of the present programme, future research, in collaboration with clinicians and patients, could include: co-refinement of electronic visualisations for use in multidisciplinary team settings co-design of resources for use in clinician–patient consultations development of cluster randomised trial protocols to test resources developed in (1) and (2) across a single multidisciplinary team area using the data collection instruments developed, prior to further evaluation within/outside the region. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0613-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 5. See the NIHR Funding and Awards website for further award information.

Background: Most of the predictive tools put up to prognosticate treatment outcomes in patients with chronic lymphocytic leukaemia (CLL) are not easily available and affordable in our resource-constrained environment. Aim: The aim of this study was to evaluate the impact of staging and some tumour bulk on treatment outcomes of persons with CLL, Enugu, Nigeria. Patients and Methods: This is a 10-year review of the CLL data from the haemato-oncology unit of a Nigerian tertiary hospital to evaluate the impact of staging and tumour bulk indicators. Data were retrieved from the case notes of 102 patients with CLL receiving care at the facility. Data of interest include basic demographic variables, clinical features including spleen size and disease staging and blood counts. Statistical analysis was done using SPSS version 22. Results: The median absolute lymphocyte count (ALC) was 108.05 (confidence interval [CI] = 50.8–201.3, interquartile range [IQR] = 124.4) ×109/L, and duration of survival for the study cohort was 5.5 (CI = 3.5–31.9, IQR = 27) months. Majority (69, 79.3%) were in Stage C. The Binet stage showed a significant association with the ALC (r = 0.338; P = 0.002) but not with spleen size (r = 0.198; P = 0.056). The duration of survival only showed a significant inverse relationship with the ALC (r = 0.35, P = 0.006) but with neither the Binet stage (r = 0.103, P = 0.431) nor spleen size (r = 0.184, P = 0.116). Conclusion: In CLL patients, ALC at presentation correlates with the duration of survival. We recommend that the ALC at presentation be used as a prognostic marker in our clime.

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Lee C-H, Wu Y-Y, Huang T-C, Lin C, Zou Y-F, Cheng J-C, Chen P-H, Jhou H-J, Ho C-L. Maintenance therapy for chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews 2024, Issue 1. Art. No.: CD013474. DOI: 10.1002/14651858.CD013474.pub2

The last ten years have seen a number of changes (better understanding of the biology of the disease, characterization of sub-populations at risk, development of oral therapies) which made a tremendous impact in the management of patients with chronic lymphocytic leukemia (CLL). Currently, Bruton tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 inhibitor (BCL2i) vénétoclax are standard 1st-line and relapse treatments, as monotherapy or in combination. However, optimal treatment sequences (continuous or fixed-duration) and combinations have yet to be defined. In this review, we will focus on the management of relapsed patients. We will discuss the important elements to be considered when choosing treatment and, more generally, the strategy of treatment lines. Recent advances in this disease represent significant progress and raise new questions about how available drugs should be used and how we can continue to improve the treatment of CLL. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia (CLL) is a clonal B‐cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B‐cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower‐risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases. [ABSTRACT FROM AUTHOR]

Summary: Large‐scale next‐generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome‐wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p− alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long‐term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis. [ABSTRACT FROM AUTHOR]

Background: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. Objectives: This study aimed to determine IFI incidence and risk factors in ibrutinibtreated patients in real-life settings. Methods: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients =18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. Results: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). Conclusions: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups. [ABSTRACT FROM AUTHOR]

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next‐generation sequencing (NGS)‐based studies have identified frequent low‐burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low‐burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS‐based mutation analysis in a 'real‐world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high‐burden mutations, while 52% were low‐burden TP53 mutations. Low‐burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low‐burden TP53 mutation. Patients harbouring low‐burden TP53 mutations had significantly lower time to first treatment compared to patients with wild‐type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low‐burden TP53 mutations. By demonstrating that patients with sole low‐burden TP53 variants represent more than one‐third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting. [ABSTRACT FROM AUTHOR]

Background: Most of the predictive tools put up to prognosticate treatment outcomes in patients with chronic lymphocytic leukaemia (CLL) are not easily available and affordable in our resource-constrained environment. Aim: The aim of this study was to evaluate the impact of staging and some tumour bulk on treatment outcomes of persons with CLL, Enugu, Nigeria. Patients and Methods: This is a 10-year review of the CLL data from the haemato-oncology unit of a Nigerian tertiary hospital to evaluate the impact of staging and tumour bulk indicators. Data were retrieved from the case notes of 102 patients with CLL receiving care at the facility. Data of interest include basic demographic variables, clinical features including spleen size and disease staging and blood counts. Statistical analysis was done using SPSS version 22. Results: The median absolute lymphocyte count (ALC) was 108.05 (confidence interval [CI] = 50.8–201.3, interquartile range [IQR] = 124.4) ×109/L, and duration of survival for the study cohort was 5.5 (CI = 3.5–31.9, IQR = 27) months. Majority (69, 79.3%) were in Stage C. The Binet stage showed a significant association with the ALC (r = 0.338; P = 0.002) but not with spleen size (r = 0.198; P = 0.056). The duration of survival only showed a significant inverse relationship with the ALC (r = 0.35, P = 0.006) but with neither the Binet stage (r = 0.103, P = 0.431) nor spleen size (r = 0.184, P = 0.116). Conclusion: In CLL patients, ALC at presentation correlates with the duration of survival. We recommend that the ALC at presentation be used as a prognostic marker in our clime. [ABSTRACT FROM AUTHOR]

Abstract Background Pituitary apoplexy is a neurosurgical emergency and is a known yet rare complication of pituitary macroadenoma. Patients typically present with visual field defects, headache and altered sensorium. There are multiple risk factors for this complication and a thorough drug history is essential to exclude iatrogenic causes of disease. We present an extremely rare case of newly diagnosed pituitary insufficiency unveiled by ibrutinib therapy (a Bruton tyrosine kinase inhibitor). Furthermore, after initial withdrawal of ibrutinib because of the erroneous diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), its re-administration led to the development of classical pituitary apoplexy 4 months after treatment was restarted. Case presentation A male patient in his 60s with a background of chronic lymphocytic leukaemia (CLL) on ibrutinib and venetoclax presents with acute confusion and deranged electrolytes. He is found to be hyponatraemic and is diagnosed with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and treated with fluid restriction. He represents again 3 weeks later with hyponatraemia and further investigations reveal pituitary insufficiency and macroadenoma. He was restarted on ibrutinib and venetoclax at the time of discharge. Four months later, he presents with sudden retro-orbital headache associated with vomiting. Clinical findings include cranial nerve III, IV and XI palsy. Humphrey’s visual field examination revealed a left visual field index (VFI) of only 1% while the right was 64% with temporal hemianopia. Both pupils were mid-dilated and poorly reactive to light. MRI pituitary with contrast showed features of pituitary apoplexy and optic nerve compression. He was urgently referred to the neurosurgical team and underwent an emergency trans-sphenoidal hypophysectomy with circumferential excision of the macroadenoma. Post-operative recovery was uneventful with marked improvement in vision bilaterally. The patient was restarted on ibrutinib and venetoclax 2 weeks post-operatively. Approximately 1 year post-treatment, he remains in radiological, clinical and biochemical remission from CLL and all medications have been withdrawn. Conclusions This is a unique and rare case of pituitary macroadenoma apoplexy following the commencement of ibrutinib for CLL. Central nervous system haemorrhage is a rare side effect of ibrutinib due to its platelet dysfunction effects. A thorough assessment is required to assess the risks and benefits of using ibrutinib in patients with pituitary macroadenoma to avoid serious complications.

Background: Metabolic dependencies of chronic lymphocytic leukaemia (CLL) cells may represent new personalized treatment approaches in patients harbouring unfavourable features. Methods: Here, we used untargeted metabolomics and lipidomics analyses to isolate metabolomic features associated with aggressive CLL and poor survival outcomes. We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance. Results: Leukaemic B‐cell metabolomes indicated a significant perturbation in lipids, predominantly bio‐active sphingolipids. Expression of numerous enzyme‐encoding genes of sphingolipid biosynthesis pathways was significantly associated with shorter patient survival. Targeted metabolomics further exposed higher circulating levels of glucosylceramides (C16:0 GluCer) in CLL patients relative to healthy donors and an aggressive cancer biology. In multivariate analyses, C16:0 GluCer and sphinganine were independent prognostic markers and were inversely linked to treatment‐free survival. These two sphingolipid species function as antagonistic mediators, with sphinganine being pro‐apoptotic and GluCer being pro‐proliferative, tested in leukemic B‐CLL cell models. Blocking GluCer synthesis using ceramide glucosyltransferase inhibitors induced cell death and reduced the proliferative phenotype, which further sensitized a leukaemic B‐cell model to the anti‐leukaemics fludarabine and ibrutinib in vitro. Conclusions: Specific sphingolipids may serve as prognostic markers in CLL, and inhibiting enzymatic pathways involved in their biosynthesis has potential as a therapaeutic approach. [ABSTRACT FROM AUTHOR]

In Australia, over half of patients with relapsed/refractory chronic lymphocytic leukaemia treated with ibrutinib use concomitant proton pump inhibitors (PPIs). High gastric pH reduces the bioavailability of some Bruton tyrosine kinase inhibitors. There was no difference in duration on ibrutinib with or without concomitant PPI (unadjusted P = 0.61; adjusted hazard ratio: 1.23, 95% confidence interval: 0.75–2.02, P = 0.411). PPI use does not affect ibrutinib treatment persistence. [ABSTRACT FROM AUTHOR]

Though the chronic lymphocytic leukaemia (CLL) management options in India are still limited compared to the novel drug options in resource-rich settings, the availability of less costly generics and the government health insurance scheme has enabled many patients to access the newer drugs in India. The current study compared the cost-effectiveness and cost-utility of existing initial management options for the progression-free survival (PFS) time horizon from the patient's perspective. A two-health-state, PFS and progressive disease, Markov model was assumed for three regimens (generics): ibrutinib monotherapy, bendamustine-rituximab (B-R), and rituximab-chlorambucil (RClb) used as the frontline treatment of CLL patients in India. All costs, utilization of services, and consequences data during the PFS period were collected from interviewing patients during follow-up visits. The transition probability (TP) and average PFS information were obtained from landmark published studies. EQ-5D-5L questionnaires were utilized to assess the quality of life (QoL). Quality-adjusted life years (QALY) were measured during the PFS period. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were studied. Upon analysis, the entire monetary expense during the PFS time was ₹1581964 with ibrutinib, ₹171434 with B-R, and ₹91997 with RClb treatment arm. Pooled PFS and QALY gain was 10.33 and 8.28 years for ibrutinib, 4.08 and 3.53 years for the B-R regimen, and 1.33 and 1.23 years in RClb arms, respectively. Ibrutinib's ICER and ICUR were ₹214587.32 per PFS year gain and ₹282384.86 per QALY gain when assessed against the B-R regimen. Ibrutinib also performed better in ICER and ICUR against the RClb arm with ₹157014.29 per PFS year gain and ₹200413.6 per QALY gain. In conclusion, generic ibrutinib is a cost-effective initial line of management compared to other commonly used treatment regimes in resource-limited settings. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukaemia (CLL), immune dysregulation is common and can manifest as immune thrombocytopenia (ITP). Corticosteroids are the mainstay for front-line management of CLL-associated ITP. Therapy refractoriness represents a clinical challenge and is an indication to commence CLL-directed treatment, historically with anti-CD20 antibody-based chemoimmunotherapy. There is a small but growing body of evidence supporting the use of Bruton's tyrosine kinase (BTK) inhibitors in this setting, but not the B-cell lymphoma-2 inhibitor, venetoclax. Here, we describe two cases of refractory ITP in patients with CLL who successfully achieved and sustained complete remission with fixed-duration venetoclax monotherapy. Responses were rapid and durable and not explained by the concomitant use of an anti-CD20 antibody. This supports a dual role for single-agent venetoclax in managing active CLL and associated ITP as an alternative to BTK inhibitors and anti-CD20 monoclonals. [ABSTRACT FROM AUTHOR]

Background: Pituitary apoplexy is a neurosurgical emergency and is a known yet rare complication of pituitary macroadenoma. Patients typically present with visual field defects, headache and altered sensorium. There are multiple risk factors for this complication and a thorough drug history is essential to exclude iatrogenic causes of disease. We present an extremely rare case of newly diagnosed pituitary insufficiency unveiled by ibrutinib therapy (a Bruton tyrosine kinase inhibitor). Furthermore, after initial withdrawal of ibrutinib because of the erroneous diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), its re-administration led to the development of classical pituitary apoplexy 4 months after treatment was restarted. Case presentation: A male patient in his 60s with a background of chronic lymphocytic leukaemia (CLL) on ibrutinib and venetoclax presents with acute confusion and deranged electrolytes. He is found to be hyponatraemic and is diagnosed with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and treated with fluid restriction. He represents again 3 weeks later with hyponatraemia and further investigations reveal pituitary insufficiency and macroadenoma. He was restarted on ibrutinib and venetoclax at the time of discharge. Four months later, he presents with sudden retro-orbital headache associated with vomiting. Clinical findings include cranial nerve III, IV and XI palsy. Humphrey's visual field examination revealed a left visual field index (VFI) of only 1% while the right was 64% with temporal hemianopia. Both pupils were mid-dilated and poorly reactive to light. MRI pituitary with contrast showed features of pituitary apoplexy and optic nerve compression. He was urgently referred to the neurosurgical team and underwent an emergency trans-sphenoidal hypophysectomy with circumferential excision of the macroadenoma. Post-operative recovery was uneventful with marked improvement in vision bilaterally. The patient was restarted on ibrutinib and venetoclax 2 weeks post-operatively. Approximately 1 year post-treatment, he remains in radiological, clinical and biochemical remission from CLL and all medications have been withdrawn. Conclusions: This is a unique and rare case of pituitary macroadenoma apoplexy following the commencement of ibrutinib for CLL. Central nervous system haemorrhage is a rare side effect of ibrutinib due to its platelet dysfunction effects. A thorough assessment is required to assess the risks and benefits of using ibrutinib in patients with pituitary macroadenoma to avoid serious complications. [ABSTRACT FROM AUTHOR]

Summary: Signalling events downstream the B‐cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down‐modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca++ after BCR stimulation, had less amount of full‐length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)‐unmutated poor‐prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable‐prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL. [ABSTRACT FROM AUTHOR]

In recent years, considerable progress has been made in the standard treatment for chronic lymphocytic leukaemia (CLL) due to the availability of new potent drugs. However, the majority of data on CLL were derived from Western populations, with limited studies and guidelines on the management of CLL from an Asian population perspective. This consensus guideline aims to understand treatment challenges and suggest appropriate management approaches for CLL in the Asian population and other countries with a similar socio-economic profile. The following recommendations are based on a consensus by experts and an extensive literature review and contribute towards uniform patient care in Asia. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder characterised by an accumulation of monoclonal B lymphocytes, with an increased risk of secondary cancers. The coexistence of CLL and chronic myeloid leukaemia (CML) is a rare phenomenon, with three main types being classified: CML preceding CLL, CLL preceding CML and simultaneous occurrence. The coexistence of these chronic leukaemias poses a complex clinical challenge, with the underlying mechanisms of their association remaining enigmatic. Here, we present a report of an elderly male with a long history of CLL, who was subsequently diagnosed with secondary CML.

Abstract TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next‐generation sequencing (NGS)‐based studies have identified frequent low‐burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low‐burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS‐based mutation analysis in a ‘real‐world’ cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high‐burden mutations, while 52% were low‐burden TP53 mutations. Low‐burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low‐burden TP53 mutation. Patients harbouring low‐burden TP53 mutations had significantly lower time to first treatment compared to patients with wild‐type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low‐burden TP53 mutations. By demonstrating that patients with sole low‐burden TP53 variants represent more than one‐third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Preventing or overcoming resistance to the Bcl‐2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti‐apoptotic Bcl‐2 members through signalling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non‐canonical NF‐κB activation and subsequent Bcl‐XL induction. Moreover, the T cell‐derived cytokines IL‐21 and IL‐4 differentially affect Bcl‐XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl‐XL is regulated in the context of JAK–STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL‐21/STAT3 signalling in the NF‐κB‐mediated expression of Bcl‐XL, whereas IL‐4/STAT6 further promoted the expression of Bcl‐XL. In comparison, Bfl‐1, another NF‐κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl‐XL transcription by binding to its promoter without disrupting the DNA‐binding activity of NF‐κB. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK–STAT signalling and NF‐κB, in which STAT3 inhibited canonical NF‐κB by accelerating nuclear export, and STAT6 promoted non‐canonical NF‐κB. Finally, NF‐κB inducing kinase (NIK) inhibition interrupted the NF‐κB/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL, thereby revealing new potential therapeutic targets.

Abstract Background Metabolic dependencies of chronic lymphocytic leukaemia (CLL) cells may represent new personalized treatment approaches in patients harbouring unfavourable features. Methods Here, we used untargeted metabolomics and lipidomics analyses to isolate metabolomic features associated with aggressive CLL and poor survival outcomes. We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance. Results Leukaemic B‐cell metabolomes indicated a significant perturbation in lipids, predominantly bio‐active sphingolipids. Expression of numerous enzyme‐encoding genes of sphingolipid biosynthesis pathways was significantly associated with shorter patient survival. Targeted metabolomics further exposed higher circulating levels of glucosylceramides (C16:0 GluCer) in CLL patients relative to healthy donors and an aggressive cancer biology. In multivariate analyses, C16:0 GluCer and sphinganine were independent prognostic markers and were inversely linked to treatment‐free survival. These two sphingolipid species function as antagonistic mediators, with sphinganine being pro‐apoptotic and GluCer being pro‐proliferative, tested in leukemic B‐CLL cell models. Blocking GluCer synthesis using ceramide glucosyltransferase inhibitors induced cell death and reduced the proliferative phenotype, which further sensitized a leukaemic B‐cell model to the anti‐leukaemics fludarabine and ibrutinib in vitro. Conclusions Specific sphingolipids may serve as prognostic markers in CLL, and inhibiting enzymatic pathways involved in their biosynthesis has potential as a therapaeutic approach.

Background: Chronic lymphocytic leukaemia (CLL) is an incurable disease; many people with the condition do not require active treatment and are monitored using a watch and wait approach. Aim: The aim of this study was to explore the experiences of people living with a diagnosis of CLL and on watch and wait. Methods: Using a descriptive qualitative approach, seven participants on the watch and wait approach were interviewed. Data analysis was guided by systematic text condensation. Findings: Participants reported anxiety, referring to 'wait and worry'. Their information needs were not met, and they resorted to seeking information on possible future treatments themselves. They also experienced feeling like an imposter because they were not receiving active treatment like other patients with cancer. Conclusions: A greater understanding of how information provision affects levels of anxiety and worry among people living with CLL on watch and wait is needed. In addition, clinical nurse specialists could deliver education on the watch and wait approach, supplemented by video-based educational materials developed by the haematology team. [ABSTRACT FROM AUTHOR]

Summary: We explored the relevance of genomic microarrays (GM) in the refinement of prognosis in newly diagnosed low‐risk chronic lymphocytic leukaemia (CLL) patients as defined by isolated del(13q) or no lesions by a standard 4 probe fluorescence in situ hybridization (FISH) analysis. Compared to FISH, additional lesions were detected by GM in 27 of the 119 patients (22.7%). The concordance rate between FISH and GM was 87.4%. Discordant results between cytogenetic banding analysis (CBA) and GM were observed in 45/119 cases (37.8%) and were mainly due to the intrinsic characteristics of each technique. The presence of additional lesions by GM was associated with age > 65 years (p = 0.047), advanced Binet stage (p = 0.001), CLL‐IPI score (p < 0.001), a complex karyotype (p = 0.004) and a worse time‐to‐first treatment in multivariate analysis (p = 0.009). Additional lesions by GM were also significantly associated with a worse time‐to‐first treatment in the subset of patients with wild‐type TP53 and mutated IGHV (p = 0.025). In CLL patients with low‐risk features, the presence of additional lesions identified by GM helps to identify a subset of patients with a worse outcome that could be proposed for a risk‐adapted follow‐up and for early treatment including targeted agents within clinical trials. [ABSTRACT FROM AUTHOR]

Summary: Undetectable measurable residual disease (MRD) is associated with favourable clinical outcomes in chronic lymphocytic leukaemia (CLL). While assessment is commonly performed using multiparameter flow cytometry (MFC), this approach is associated with limitations including user bias and expertise that may not be widely available. Implementation of unsupervised clustering algorithms in the laboratory can address these limitations and have not been previously reported in a systematic quantitative manner. We developed a computational pipeline to assess CLL MRD using FlowSOM. In the training step, a self‐organising map was generated with nodes representing the full breadth of normal immature and mature B cells along with disease immunophenotypes. This map was used to detect MRD in multiple validation cohorts containing a total of 456 samples. This included an evaluation of atypical CLL cases and samples collected from two different laboratories. Computational MRD showed high correlation with expert analysis (Pearson's r > 0.99 for typical CLL). Binary classification of typical CLL samples as either MRD positive or negative demonstrated high concordance (>98%). Interestingly, computational MRD detected disease in a small number of atypical CLL cases in which MRD was not detected by expert analysis. These results demonstrate the feasibility and value of automated MFC analysis in a diagnostic laboratory. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukaemia (CLL), immune dysregulation is common and can manifest as immune thrombocytopenia (ITP). Corticosteroids are the mainstay for front-line management of CLL-associated ITP. Therapy refractoriness represents a clinical challenge and is an indication to commence CLL-directed treatment, historically with anti-CD20 antibody-based chemoimmunotherapy. There is a small but growing body of evidence supporting the use of Bruton’s tyrosine kinase (BTK) inhibitors in this setting, but not the B-cell lymphoma-2 inhibitor, venetoclax. Here, we describe two cases of refractory ITP in patients with CLL who successfully achieved and sustained complete remission with fixed-duration venetoclax monotherapy. Responses were rapid and durable and not explained by the concomitant use of an anti-CD20 antibody. This supports a dual role for single-agent venetoclax in managing active CLL and associated ITP as an alternative to BTK inhibitors and anti-CD20 monoclonals.

Summary: This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp‐up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high‐risk patients, four occurred at 20 mg dose and three at the 6‐h time‐point. Inpatient versus outpatient TLS rates within the high‐risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high‐risk cohorts. These observations require confirmation in larger studies. [ABSTRACT FROM AUTHOR]

Summary: Idelalisib (idela), a phosphatidylinositol 3‐kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R‐idela) versus ibrutinib have been conducted. Therefore, we performed a real‐world retrospective analysis of patients with R/R CLL treated with R‐idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R‐idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression‐free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R‐idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R‐idela in patients with R/R CLL treated in routine practice. The R‐idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative. [ABSTRACT FROM AUTHOR]

Background: Alterations of plateletcrit and mean platelet volume (MPV) and pathogenesis of chronic lymphocytic leukaemia (CLL) have been linked to various inflammatory disorders. The prognostic impact of plateletcrit and MPV were evaluated. Methods: MPV and plateletcrit levels of both CLL and control group were compared and then in CLL patients, additional diseases, leukocyte count, platelet count, lactate dehydrogenase, Rai stage, progression-free and overall survival, mutations, if any, and chemotherapy, if any, were recorded. Then, the relationship between MPV and plateletcrit values and these parameters were evaluated in CLL patients. Results: Platelet and plateletcrit values were found to be significantly lower in CLL patients than the control group (p

Background: B-Cell Lymphoproliferative Disorders (B-LPDs) are a group of heterogenous disorders characterised by the accumulation of B-cells in peripheral blood, bone marrow, lymph nodes and spleen. They have a variable disease course and outcome and many share similar features making differential diagnosis challenging. Therefore, accurate diagnosis is fundamental in particular for determining treatment options. Immunophenotyping by flow cytometry plays a crucial role in the diagnosis of B-LPDs. However, overlapping immunophenotyping patterns exist and the use of novel monoclonal antibodies has become increasingly important in immunophenotyping analysis. More recently differential expression of CD200 has been reported in various B-LPDs and that CD200 may improve the differentiation between chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). In this study CD200 expression is evaluated in different B-LPDs.Methods: A total of 100 samples were collected and analysed by immunophenotyping flow cytometry over a period of 1 year (2017–2018), by a panel of monoclonal antibodies including CD200. The percentage of CD200 and its expression intensity was evaluated and compared between different groups of B-LPDs.Results: All of the 50 cases of CLL expressed CD200 with moderate to bright intensity, 6 MCL cases lacked the expression of CD200. Furthermore, all 5 cases of hairy cell leukaemia (HCL) expressed CD200. Out of all B-LPDs evaluated, CD200 expression in HCL cases was noted to be the brightest. The other 39 cases were not found to be B-LPDs.Conclusion: CD200 has an important role in differentiating CLL from MCL, HCL has a consistent bright expression of CD200. By adding CD200 to the combinations of markers in routine testing panel, Immunophenotyping by flow cytometry can be an effective tool in the diagnosis of B-LPDs especially in cases with atypical immunophenotyping pattern. Our result support that CD200 can be added to routine testing panel as it is useful in differentiating them.

Objective: To assess the spectrum and clinico-haematological profile of chronic lymphoproliferative disorders in patients presenting with lymphocytosis. Method: The cross-sectional, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data related to cases of bone marrow aspirate and trephine from January to November 2020. Patients for whom the bone marrow was done for lymphocytosis were studied for the presence of lymphoproliferative disorders, sub-types and patients’ characteristics. The diagnosis and classification were based on the World Health Organisation criteria for tumours of haematopoietic and lymphoid tissues. Data was analysed using SPSS 21. Results: Of the 3,334 bone marrow specimens tested, 103(3%) were related to lymphocytosis. Of these, 84(82%) were diagnosed with lymphoproliferative disorders, while diagnosis remained undetermined in 19(18%) cases. Male:female ratio was 3.6:1 and median age was 60 years (range: 21-85 years). Constitutional symptoms were found in 61(73%) patients. Median absolute lymphocyte count was 45x109/L (range: 5.3-480). All 84(100%) patients were classified as B-cell lymphoproliferative disorder. Chronic lymphocytic leukaemia was the most common form, 61(73%), and 31(51%) of them presented with advanced stage disease. Conclusion: A huge majority of patients presenting with lymphocytosis had underlying lymphoproliferative disorders of which B-cell chronic lymphocytic leukaemia was found to be the most common. Key Words: Lymphoproliferative disorder, Lymphocytosis, Chronic lymphocytic leukaemia, Bone marrow, Pakistan.