First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

Predicting unplanned hospitalisations in older adults using routinely recorded general practice data.

BACKGROUND: Unplanned hospitalisations represent a hazardous event for older persons. Timely identification of high-risk individuals using a prediction tool may facilitate preventive interventions. AIM: To develop and validate an easy-to-use prediction model for unplanned hospitalisations in community-dwelling older adults using readily available data to allow rapid bedside assessment by general practitioners. DESIGN AND SETTING: Retrospective study using general practice electronic health records of 243,129 community-dwelling adults aged ≥65 years linked with national administrative data. METHODS: The dataset was geographically split into a development (58.7%) and validation (41.3%) sample to predict unplanned hospitalisations within 6 months. We evaluated the performance of three different models with increasingly smaller selections of candidate predictors (i.e. optimal, readily-available and easy-to-use model, respectively). We used logistic regression with backward selection for model development. The models were validated internally and externally. We assessed predictive performance by area under the curve (AUC) and calibration plots. RESULTS: In both samples, 7.6% had at least one unplanned hospitalisation within 6 months. The discriminative ability of the three models was comparable and remained stable after geographic validation. The easy-to-use model included age, sex, prior hospitalisations, pulmonary emphysema, heart failure and polypharmacy. Its discriminative ability after validation was AUC 0.72 [95% confidence interval: 0.72-0.71]. Calibration plots showed good calibration. CONCLUSION: Our models showed satisfactory predictive ability. Reducing the number of predictors and geographic validation did not impact predictive performance, demonstrating the robustness of the model. We developed an easy-to-use tool that may assist general practitioners in decision-making and targeted preventive interventions.

Costs of care trajectories of people with dementia compared with matched controls. Longitudinal analysis of linked health and administrative data.

OBJECTIVES: To provide insight into the health and social care costs during the disease trajectory in persons with dementia and the impact of institutionalization and death on healthcare costs compared with matched persons without dementia. METHODS: Electronic health record data from family physicians were linked with national administrative databases to estimate costs of primary care, medication, secondary care, mental care, home care and institutional care for people with dementia and matched persons from the year before the recorded dementia diagnosis until death or a maximum of 4 years after the diagnosis. RESULTS: Total mean health and social care costs among persons with dementia increased substantially during the disease trajectory, mainly due to institutional care costs. For people who remained living in the community, mean health and social care costs are higher for people with dementia than for those without dementia, while for those who are admitted to a long-term care facility, mean health and social care costs are higher for people without dementia than for those with dementia. CONCLUSIONS: The steep rise in health and social care costs across the dementia care trajectory is mainly due to increasing costs for institutional care. For those remaining in the community, home care costs and hospital care costs were the main cost drivers. Future research should adopt a societal perspective to investigate the influence of including social costs.

Lessons learned from the development of a national registry on dementia care and support based on linked national health and administrative data.

Introduction: This paper provides insight into the development of the Dutch Dementia Care and Support Registry and the lessons that can be learned from it. The aim of this Registry was to contribute to quality improvement in dementia care and support. Methods: This paper describes how the Registry was set up in four stages, reflecting the four FAIR principles: the selection of data sources (Findability); obtaining access to the selected data sources (Accessibility); data linkage (Interoperability); and the reuse of data (Reusability). Results: The linkage of 16 different data sources, including national routine health and administrative data appeared to be technically and legally feasible. The linked data in the Registry offers rich information about (the use of) care for persons with dementia across various healthcare settings, including but not limited to primary care, secondary care, long-term care and medication use, that cannot be obtained from single data sources. Conclusions: A key lesson learned is that in order to reuse the data for quality improvement in practice, it is essential to involve healthcare professionals in setting up the Registry and to guide them in the interpretation of the data.

Social Activity and Cognitive Decline in Older Residents of Long-Term Care Facilities: A Cohort Study.

Background: Cognitive decline is a major reason for dependence and resource use in long-term care. Objective: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities. Methods: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the interRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and health indicators. Results: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional. Conclusions: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents.

Self- reported and informal caregiver proxy-reported met needs in persons living with dementia are associated with lower health-related quality of life: a dyadic, cross-sectional study.

OBJECTIVE: This study examined the dyadic association of self and informal caregiver proxy-reported met needs in persons living with dementia on the health-related quality of life (HRQOL). METHODS: A total of 237 persons with dementia and their caregivers were included from a previous observational study. HRQOL was assessed by the EuroQol-5D and the number of met needs by the Camberwell Assessment of Needs for the Elderly. The Actor-Partner Interdependence Model framework was used to analyze the effect of an individual's self or proxy-reported met needs on their own HRQOL (actor effects), and an individual's self or proxy-reported met needs on the other dyad member's HRQOL (partner effects). RESULTS: The number of self-reported met needs by persons living with dementia was negatively associated with their own HRQOL (actor effect b = -0.200, p < 0.001), and the HRQOL of informal caregivers (partner effect b = -0.114, p = 0.001). The number of proxy-reported met needs by informal caregivers was negatively associated with their own HRQOL (actor effect b = -0.105, p < 0.001) but not the person living with dementia's HRQOL (-0.025, p = 0.375). CONCLUSION: Study findings suggest that both self-reported and informal caregiver proxy-reported met needs in persons living with dementia should be considered in research and practice because they have different implications for each dyad members' HRQOL.

The prevalence of non-pharmacological interventions in older homecare recipients: an overview from six European countries.

PURPOSE: Non-pharmacological interventions (NPIs) play an important role in the management of older people receiving homecare. However, little is known about how often specific NPIs are being used and to what extent usage varies between countries. The aim of the current study was to investigate the prevalence of NPIs in older homecare recipients in six European countries. METHODS: This is a cross-sectional study of older homecare recipients (65+) using baseline data from the longitudinal cohort study 'Identifying best practices for care-dependent elderly by Benchmarking Costs and outcomes of community care' (IBenC). The analyzed NPIs are based on the interRAI Home Care instrument, a comprehensive geriatric assessment instrument. The prevalence of 24 NPIs was analyzed in Belgium, Germany, Finland, Iceland, Italy and the Netherlands. NPIs from seven groups were considered: psychosocial interventions, physical activity, regular care interventions, special therapies, preventive measures, special aids and environmental interventions. RESULTS: A total of 2884 homecare recipients were included. The mean age at baseline was 82.9 years and of all participants, 66.9% were female. The intervention with the highest prevalence in the study sample was 'emergency assistance available' (74%). Two other highly prevalent interventions were 'physical activity' (69%) and 'home nurse' (62%). Large differences between countries in the use of NPIs were observed and included, for example, 'going outside' (range 7-82%), 'home health aids' (range 12-93%), and 'physician visit' (range 24-94%). CONCLUSIONS: The use of NPIs varied considerably between homecare users in different European countries. It is important to better understand the barriers and facilitators of use of these potentially beneficial interventions in order to design successful uptake strategies.

Immunogenicity of the 13-Valent Pneumococcal Conjugated Vaccine Followed by the 23-Valent Polysaccharide Vaccine in Chronic Lymphocytic Leukemia.

Patients with Chronic Lymphocytic Leukemia (CLL) have a 29- to 36-fold increased risk of invasive pneumococcal disease (IPD) compared to healthy adults. Therefore, most guidelines recommend vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by the 23-valent polysaccharide vaccine (PPSV23). Because both CLL as well as immunosuppressive treatment have been identified as major determinants of immunogenicity, we aimed to assess the vaccination schedule in untreated and treated CLL patients. We quantified pneumococcal IgG concentrations against five serotypes shared across both vaccines, and against four serotypes unique to PPSV23, before and eight weeks after vaccination. In this retrospective cohort study, we included 143 CLL patients, either treated (n = 38) or naive to treatment (n = 105). While antibody concentrations increased significantly after vaccination, the overall serologic response was low (10.5%), defined as a ≥4-fold antibody increase against ≥70% of the measured serotypes, and significantly influenced by treatment status and prior lymphocyte number. The serologic protection rate, defined as an antibody concentration of ≥1.3 µg/mL for ≥70% of serotypes, was 13% in untreated and 3% in treated CLL patients. Future research should focus on vaccine regimens with a higher immunogenic potential, such as multi-dose schedules with higher-valent T cell dependent conjugated vaccines.

Cognitive Change Among Nursing Home Residents: CogRisk-NH Scale Development to Predict Decline.

OBJECTIVES: Examine cognitive changes over time among nursing home residents and develop a risk model for identifying predictors of cognitive decline. DESIGN: Using secondary analysis design with Minimum Data Set data, cognitive status was based on the Cognitive Performance Scale (CPS). SETTING AND PARTICIPANTS: Baseline and 7 quarterly follow-up analyses of US and Canadian interRAI data (N = 1,257,832) were completed. METHODS: Logistic regression analyses identified predictors of decline to form the CogRisk-NH scale. RESULTS: At baseline, about 15% of residents were cognitively intact (CPS = 0), and 11.2% borderline intact (CPS = 1). The remaining more intact, with mild impairment (CPS = 2), included 15.0%. Approximately 59% residents fell into CPS categories 3 to 6 (moderate to severe impairment). Over time, increasing proportions of residents declined: 17.1% at 6 months, 21.6% at 9 months, and 34.0% at 21 months. Baseline CPS score was a strong predictor of decline. Categories 0 to 2 had 3-month decline rates in midteens, and categories 3 to 5 had an average decline rate about 9%. Consequently, a 2-submodel construction was employed-one for CPS categories 0 to 2 and the other for categories 3 to 5. Both models were integrated into a 6-category risk scale (CogRisk-NH). CogRisk-NH scale score distribution had 15.9% in category 1, 26.84% in category 2, and 36.7% in category 3. Three higher-risk categories (ie, 4-6) represented 20.6% of residents. Mean decline rates at the 3-month assessment ranged from 4.4% to 28.3%. Over time, differentiation among risk categories continued: 6.9% to 38.4.% at 6 months, 11.0% to 51.0% at 1 year, and 16.2% to 61.4% at 21 months, providing internal validation of the prediction model. CONCLUSIONS AND IMPLICATIONS: Cognitive decline rates were higher among residents in less-impaired CPS categories. CogRisk-NH scale differentiates those with low likelihood of decline from those with moderate likelihood and, finally, much higher likelihood of decline. Knowledge of resident risk for cognitive decline enables allocation of resources targeting amenable factors and potential interventions to mitigate continuing decline.

Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL.

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

Diseases, Health-Related Problems, and the Incidence of Malnutrition in Long-Term Care Facilities.

Certain diseases and malnutrition are known to co-occur in residents of long-term care facilities (LTCF). We assessed which diseases and health-related problems are associated with malnutrition at admission or with incident malnutrition during stays and how different definitions of malnutrition affect these associations. Data of Dutch LTCF residents were obtained from the InterRAI-LTCF instrument (2005-2020). We analyzed the association of diseases (diabetes, cancer, pressure ulcers, neurological, musculoskeletal, psychiatric, cardiac, infectious and pulmonary diseases) and health-related problems (aspiration, fever, peripheral edema, aphasia, pain, supervised/assisted eating, balance, psychiatric, GI tract, sleep, dental and locomotion problems) with malnutrition (recent weight loss (WL), low age-specific BMI (BMI), and ESPEN 2015 definition (ESPEN)) at admission (n = 3713), as well as with incident malnutrition during stay (n = 3836, median follow-up ~1 year). Malnutrition prevalence at admission ranged from 8.8% (WL) to 27.4% (BMI); incident malnutrition during stay ranged from 8.9% (ESPEN) to 13.8% (WL). At admission, most diseases (except cardiometabolic diseases) and health-related problems were associated with higher prevalence of malnutrition based on either criterion, but strongest with WL. This was also seen in the prospective analysis, but relationships were less strong compared to the cross-sectional analysis. A considerable number of diseases and health-related problems are associated with an increased prevalence of malnutrition at admission and incident malnutrition during stays in LTCFs. At admission, low BMI is a good indicator of malnutrition; during stays, we advise use of WL.

Psychological Resilience in Older Residents of Long-Term Care Facilities: Occurrence and Associated Factors.

OBJECTIVES: The researchers aimed to (1) explore the occurrence of psychological resilience in the face of a major life stressor and conflict in older residents of long-term care facilities (LTCFs), and (2) identify factors associated with resilience in this population. DESIGN: Longitudinal cohort study using the Dutch InterRAI-LTCF cohort. SETTING AND PARTICIPANTS: Older residents (≥60 years old) of 21 LTCFs in the Netherlands. METHODS: The researchers selected 2 samples of residents who had at least 2 assessments surrounding (1) an incident major life stressor, or (2) incident conflict with other resident or staff. A resilient outcome was operationalized as not having clinically meaningful mood symptoms at the post-stressor assessment and equal or fewer mood symptoms at the post-stressor relative to the pre-stressor assessment. The researchers used 2 resilience outcomes per stressor: 1 based on observer-reported mood symptoms and 1 based on self-reported mood symptoms. The most important factors from among 21 potential resilience factors for each of the 4 operationalizations of resilience were identified using a backward selection procedure with 2-level generalized estimating equations analyses. RESULTS: Forty-eight percent and 50% of residents were resilient in the face of a major life stressor, based on observer-reported (n = 248) and self-reported (n = 211) mood, respectively. In the face of conflict, 26% and 51% of the residents demonstrated resilience, based on the observer-reported (n = 246) and self-reported (n = 183) mood, respectively. Better cognitive functioning, a strong and supportive relationship with family, participation in social activities, and better self-reported health were most strongly associated with resilience in the face of a major life stressor. Better communicative functioning, absence of psychiatric diagnoses, a strong and supportive relationship with family, not being lonely, social engagement, and not reminiscing about life were most strongly associated with resilience in the face of conflict. CONCLUSIONS AND IMPLICATIONS: Factors with a social aspect appear to be particularly important to psychological resilience in older LTCF residents, and provide a potential target for intervention in the LTCF setting.

Prediction models for the prediction of unplanned hospital admissions in community-dwelling older adults: A systematic review.

BACKGROUND: Identification of community-dwelling older adults at risk of unplanned hospitalizations is of importance to facilitate preventive interventions. Our objective was to review and appraise the methodological quality and predictive performance of prediction models for predicting unplanned hospitalizations in community-dwelling older adults. METHODS AND FINDINGS: We searched MEDLINE, EMBASE and CINAHL from August 2013 to January 2021. Additionally, we checked references of the identified articles for the inclusion of relevant publications and added studies from two previous reviews that fulfilled the eligibility criteria. We included prospective and retrospective studies with any follow-up period that recruited adults aged 65 and over and developed a prediction model predicting unplanned hospitalizations. We included models with at least one (internal or external) validation cohort. The models had to be intended to be used in a primary care setting. Two authors independently assessed studies for inclusion and undertook data extraction following recommendations of the CHARMS checklist, while quality assessment was performed using the PROBAST tool. A total of 19 studies met the inclusion criteria. Prediction horizon ranged from 4.5 months to 4 years. Most frequently included variables were specific medical diagnoses (n = 11), previous hospital admission (n = 11), age (n = 11), and sex or gender (n = 8). Predictive performance in terms of area under the curve ranged from 0.61 to 0.78. Models developed to predict potentially preventable hospitalizations tended to have better predictive performance than models predicting hospitalizations in general. Overall, risk of bias was high, predominantly in the analysis domain. CONCLUSIONS: Models developed to predict preventable hospitalizations tended to have better predictive performance than models to predict all-cause hospitalizations. There is however substantial room for improvement on the reporting and analysis of studies. We recommend better adherence to the TRIPOD guidelines.

The Effects of the 2020 COVID-19 Lockdown on Mood, Behavior, and Social and Cognitive Functioning in Older Long-Term Care Residents.

OBJECTIVES: We aimed to explore the effects of the Dutch COVID-19 lockdown (March 20-May 25, 2020) on mood, behavior, and social and cognitive functioning of older residents of long-term care facilities (LTCFs) prospectively. DESIGN: Mixed methods: historically controlled longitudinal cohort study and focus groups. SETTING AND PARTICIPANTS: Residents of Dutch LTCFs. METHODS: Residents who were assessed during and prior to the lockdown were compared to residents of the same wards with 2 assessments prior to the lockdown. We used mixed models and generalized estimating equation analyses to explore differences in changes in mood, withdrawal and aggressive behavior, loneliness and conflict, and cognition and delirium. We also explored whether the effect of the lockdown differed for different subgroups. In 2 online focus groups, LTCF care professionals, ranging from care staff to physicians, reflected on their experiences of the effect of the lockdown and the cohort study results. RESULTS: The lockdown group of 298 residents was compared to the control group of 625 residents. Self-reported mood symptoms showed a slightly greater increase during the lockdown. During the first half of the lockdown, the level of conflict with other residents decreased whereas it increased in the control group. The subgroup with moderate-severe cognitive impairment showed a decrease in withdrawal during the lockdown, whereas the group with no-mild cognitive impairment showed a statistically nonsignificant relative increase. Professionals described great individual variation in the effects of the lockdown on residents. Facilities attempted to preserve the experienced positive effects, for example, by promoting tranquility in shared rooms and continuing to organize individualized ward-based activities. CONCLUSIONS AND IMPLICATIONS: We did not find clinically relevant negative effects of the lockdown on mood, behavior, and social and cognitive functioning in older residents of LTCFs at the group level. Possibly, staff mitigated the negative effects at the group level. Meanwhile, they learned lessons that they continue to apply to enhance resident well-being.

Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group.

Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.

The Association Between Possible Stressors and Mood Outcomes in Older Residents of Long-Term Care Facilities.

Introduction: Resilience incorporates the presence of a positive response to some type of stressor. To properly explore resilience, it is important to systematically identify relevant stressors. We aimed to identify (combinations of) stressors with the strongest relationship with observer-reported and self-reported mood outcomes in older residents of long-term care facilities (LTCFs) in The Netherlands. Materials and Methods: We included 4,499 older (≥60) residents of 40 LTCFs who participated in the Dutch InterRAI-LTCF cohort between 2005 and 2018. The association of possible stressors (single stressors, number of stressors, and combinations of two stressors) in this population with observer-reported (Depression Rating Scale) and self-reported mood outcomes was analyzed using multilevel tobit models and logistic regressions. Results: Major life stressor ["experiences that (threatened to) disrupt(ed) a person's daily routine and imposed some degree of readjustment"] and conflict with other care recipients and/or staff were most strongly associated with both mood outcomes. Furthermore, conflict was a particularly prevalent stressor (24%). Falls, fractures, and hospital visits were more weakly or not associated at all. Overall, the associations were similar for the mood outcomes based on observer-report and self-report, although there were some differences. Multiple stressors were more strongly associated with both mood outcomes than one stressor. Conclusion: Major life stressor and conflict emerged as important stressors for resilience research within the psychological domain in LTCF residents. Further (longitudinal) research is necessary to determine the directionality and relevance of the strong association of conflict with mood for LTCF practice.

Occurrence and Timing of Advance Care Planning in Persons With Dementia in General Practice: Analysis of Linked Electronic Health Records and Administrative Data.

Background: Advance care planning (ACP) is a process of communication in which patients and family caregivers discuss preferences for future care with the healthcare team. For persons with dementia, it is crucial to timely engage in ACP. Therefore, we study ACP in dementia using electronic health record data. This study aims to determine how often ACP conversations are recorded, analyze time from dementia diagnosis until the first recorded conversation and time from the first recorded conversation to death, and analyze which factors are associated with the timing of ACP. Methods: Electronic records of 15,493 persons with dementia in Dutch general practice between 2008 and 2016 were linked to national administrative databases. ACP conversations and indicators of health deficits to determine frailty were obtained from electronic records coded with the International Classification of Primary Care. Socio-demographic characteristics were derived from the national population registry managed by Statistics Netherlands. Date of death was derived from the Personal Records Database (2008-2018). Results: ACP was recorded as such as 22 (95% CI, 20-23) first conversations per 1,000 person-years of follow-up. The hazard ratio (HR) for the first conversation increased every year after dementia diagnosis, from 0.01 in the first year to 0.07 in the 7th and 8th year after diagnosis. Median time from a first conversation to death was 2.57 years (95% CI, 2.31-2.82). Migrant status [non-Western vs. Western (HR 0.31, 95% CI, 0.15-0.65)] was significantly associated with a longer time from dementia diagnosis to the first conversation. Being pre-frail (HR 2.06, 95% CI, 1.58-2.69) or frail (HR 1.40, 95% CI, 1.13-1.73) vs. non-frail was significantly associated with a shorter time from dementia diagnosis to the first ACP conversation. Conclusion: ACP conversations in Dutch general practice were rare for persons with dementia, or was rarely recorded as such. In particular among persons with a non-Western migration background and those who are non-frail, it started long after diagnosis. We advise further research into public health and practical strategies to engage persons with dementia with a non-Western migration background and non-frail persons early in the disease trajectory in ACP.

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial.

BACKGROUND: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. METHODS: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). FINDINGS: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. INTERPRETATION: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. FUNDING: F Hoffmann-La Roche.

Prevalence of Health Problems and Health-Care Use in Partners of People with Dementia: Longitudinal Analysis with Routinely Recorded Health and Administrative Data.

INTRODUCTION: This study aims to provide insight into the prevalence of health problems and the frequency of general practitioner (GP) contacts in cohabiting partners of persons with dementia, during the year prior to the dementia diagnosis and up to 3 years after the diagnosis. METHODS: Partners of persons with dementia and a matched control group of partners of persons without dementia were identified in the routinely recorded electronic health records of 451 Dutch general practices in 2008-2015. These data were used to examine the prevalence of the partners' health problems. Differences between these partners and comparison partners in the prevalence of 16 groups of health problems (diagnostic chapters) and in the frequency of GP contacts were examined using generalized estimating equation models. RESULTS: 1,711 partners of persons with dementia and 6,201 comparison partners were included in the analyses. Social problems, more specifically problems related to the illness and/or the loss of the partner, were significantly more prevalent in partners than in comparison partners across the years (p < 0.01), as were musculoskeletal problems (p < 0.01). Respiratory and psychological problems increased over time in partners and remained stable in comparison partners. Across the years, partners contacted their GP more often than comparison partners (p < 0.01). DISCUSSION/CONCLUSION: Having a cohabiting partner with dementia has consequences for caregiver's physical and psychosocial health. The specific health problems found in this study and the increase in GP contacts might be relevant indicators of overburdening in partners of persons with dementia.

Predicting unplanned hospital visits in older home care recipients: a cross-country external validation study.

BACKGROUND: Accurate identification of older persons at risk of unplanned hospital visits can facilitate preventive interventions. Several risk scores have been developed to identify older adults at risk of unplanned hospital visits. It is unclear whether risk scores developed in one country, perform as well in another. This study validates seven risk scores to predict unplanned hospital admissions and emergency department (ED) visits in older home care recipients from six countries. METHODS: We used the IBenC sample (n = 2446), a cohort of older home care recipients from six countries (Belgium, Finland, Germany, Iceland, Italy and The Netherlands) to validate four specific risk scores (DIVERT, CARS, EARLI and previous acute admissions) and three frailty indicators (CHESS, Fried Frailty Criteria and Frailty Index). Outcome measures were unplanned hospital admissions, ED visits or any unplanned hospital visits after 6 months. Missing data were handled by multiple imputation. Performance was determined by assessing calibration and discrimination (area under receiver operating characteristic curve (AUC)). RESULTS: Risk score performance varied across countries. In Iceland, for any unplanned hospital visits DIVERT and CARS reached a fair predictive value (AUC 0.74 [0.68-0.80] and AUC 0.74 [0.67-0.80]), respectively). In Finland, DIVERT had fair performance predicting ED visits (AUC 0.72 [0.67-0.77]) and any unplanned hospital visits (AUC 0.73 [0.67-0.77]). In other countries, AUCs did not exceed 0.70. CONCLUSIONS: Geographical validation of risk scores predicting unplanned hospital visits in home care recipients showed substantial variations of poor to fair performance across countries. Unplanned hospital visits seem considerably dependent on healthcare context. Therefore, risk scores should be validated regionally before applied to practice. Future studies should focus on identification of more discriminative predictors in order to develop more accurate risk scores.