Risk of dementia among older patients with lymphoma: A Danish nationwide matched cohort study.

INTRODUCTION: Treatment of lymphoma can be associated with cognitive challenges, and some patients may fear development of dementia as long-term complication. Studies report a lower risk of dementia after cancer. Some believe this difference to be a protective mechanism of cancer, others believe it to be driven by bias. The risk of developing dementia after lymphoma has not been investigated in a population-based setting. The aim of this study was to identify the risk of being diagnosed with dementia after lymphoma treatment. MATERIALS AND METHODS: This Danish nationwide matched cohort study included patients aged ≥65 years with a first-time diagnosis of a non-central nervous system lymphoma between 2005 and 2018 in complete remission after treatment with chemotherapy. Patients diagnosed with dementia or treated with dementia medication before lymphoma diagnosis were excluded. Each patient was matched 1:5 on sex, year of birth, and a modified Charlson comorbidity index. Patients and matched comparators were followed from the corresponding patient's date of complete remission. The risk of developing dementia was calculated using cause-specific hazard ratios (HR), and the cumulative risk was estimated by Aalen-Johansen with death as the competing risk. RESULTS: A total of 3,244 patients and 16,220 matched comparators were included in the study. There was no difference in risk of all-cause dementia among patients with lymphoma compared to matched comparators with cause-specific HR of 0.85 (95% confidence interval [CI]: 0.70;1.04). The risk of both Alzheimer's disease and non-Alzheimer's dementia was equal among patients and comparators: HR 0.89 (95% CI: 0.66;1.21) and 0.82 (95% CI: 0.63;1.07), respectively. Stratified by lymphoma subtype, age, or year of diagnosis, the risk of all-cause dementia remained equal among patients and matched comparators. The cumulative risk of all-cause dementia was significantly lower among patients with lymphoma compared to matched comparators (Gray's test p < 0.001), probably reflecting higher mortality in patients with lymphoma. DISCUSSION: The risk of all-cause dementia, Alzheimer's disease, and non-Alzheimer's dementia was equal among older patients with lymphoma compared to matched comparators. Our data suggests that risk of developing dementia is not changed after lymphoma treatment.

Prognostic indices in diffuse large B-cell lymphoma: a population-based comparison and validation study of multiple models.

Currently, the International Prognostic Index (IPI) is the most used and reported model for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). IPI-like variations have been proposed, but only a few have been validated in different populations (e.g., revised IPI (R-IPI), National Comprehensive Cancer Network IPI (NCCN-IPI)). We aimed to validate and compare different IPI-like variations to identify the model with the highest predictive accuracy for survival in newly diagnosed DLBCL patients. We included 5126 DLBCL patients treated with immunochemotherapy with available data required by 13 different prognostic models. All models could predict survival, but NCCN-IPI consistently provided high levels of accuracy. Moreover, we found similar 5-year overall survivals in the high-risk group (33.4%) compared to the original validation study of NCCN-IPI. Additionally, only one model incorporating albumin performed similarly well but did not outperform NCCN-IPI regarding discrimination (c-index 0.693). Poor fit, discrimination, and calibration were observed in models with only three risk groups and without age as a risk factor. In this extensive retrospective registry-based study comparing 13 prognostic models, we suggest that NCCN-IPI should be reported as the reference model along with IPI in newly diagnosed DLBCL patients until more accurate validated prognostic models for DLBCL become available.

Work Disability and Return to Work After Lymphoma: A Danish Nationwide Cohort Study.

Purpose: Many patients diagnosed with lymphoma are of working age. Cancer patients are known to have a higher risk of sick leave and disability pension, but this has only been delineated for certain subtypes of lymphoma. Therefore, this study aimed at investigating the overall risk of disability pension for all lymphoma subtypes and at quantifying return to work for patients with lymphoma in work before diagnosis. Patients and Methods: Patients aged 18-60 years with lymphoma in complete remission (CR) diagnosed between 2000 and 2019 were included in the study. Using national registers, each patient was matched with five comparators from the general population with same sex, birth year, and level of Charlson Comorbidity Index. Risk of disability pension was calculated from 90 days after CR or end of treatment with competing events (death, retirement pension, early retirement pension, relapse for patients, or lymphoma diagnosis for comparators). Return to work for patients was calculated annually until 5 years after diagnosis for patients employed before diagnosis. Results: In total, 4072 patients and 20,360 comparators were included. There was a significant increased risk of disability pension for patients with all types of lymphoma compared to the general population (5-year risk difference: 5.3 (95% confidence interval (CI): 4.4;6.2)). Patients with non-Hodgkin lymphoma were more likely to get disability pension than patients with Hodgkin lymphoma (sex- and age-adjusted 10-year risk difference: 2.9 (95% CI: 0.3;5.5)). One year after diagnosis, 24.5% of the relapse-free patients were on sick leave. Return to work was highest 2 years after diagnosis (82.1%). Conclusion: Patients with lymphoma across all subtypes have a significantly higher risk of disability pension. Return to work peaks at 2 years after diagnosis.

Geographical and ecological analyses of multiple myeloma in Denmark: Identification of potential hotspot areas and impact of urbanisation.

BACKGROUND: The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures. METHODS: Patients diagnosed with MM in Denmark during 2005-2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age- and sex-standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios. RESULTS: In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas. CONCLUSION: The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors.

Risk of diabetes and the impact on preexisting diabetes in patients with lymphoma treated with steroid-containing immunochemotherapy.

First-line treatments for lymphomas often include high doses of prednisolone, but the risks of new-onset diabetes mellitus (DM) or worsening of preexisting DM following treatment with cyclic high dose corticosteroids is unknown. This cohort study matched non-Hodgkin lymphoma (NHL) patients treated with steroid-containing immunochemotherapy (ie, R-CHOP[-like] and R-CVP) between 2002 and 2015 to individuals from the Danish population to investigate the risks of new-onset DM. For patients with preexisting DM, the risks of insulin dependency and anthracycline-associated cardiovascular diseases (CVDs) were assessed. In total, 5672 NHL patients and 28 360 matched comparators were included. Time-varying incidence rate ratios (IRRs) showed increased risk of DM in the first year after treatment compared with matched comparators, with the highest IRR being 2.7. The absolute risks were higher among patients in the first 2 years, but the difference was clinically insignificant. NHL patients with preexisting DM had increased risks of insulin prescriptions with 0.5-, 5-, and 10-year cumulative risk differences of insulin treatment of 15.3, 11.8, and 6.0 percentage units as compared with the DM comparators. In a landmark analysis at 1 year, DM patients with lymphoma had decreased risks of insulin dependency compared with comparators. Time-varying IRRs showed a higher CVD risk for NHL patients with DM as compared with comparators in the first year after treatment. NHL patients treated with steroid-containing immunochemotherapy regimens have a clinically insignificant increased risk of DM in the first year following treatment, and patients with preexisting DM have a temporary increased risk of insulin prescriptions and CVD.

Mental health among patients with non-Hodgkin lymphoma: A Danish nationwide study of psychotropic drug use in 8750 patients and 43 750 matched comparators.

Psychological distress following cancer diagnosis may lead to mental health complications including depression and anxiety. Non-Hodgkin lymphomas (NHLs) include indolent and aggressive subtypes for which treatment and prognosis differ widely. Incident use of psychotropic drugs (PDs-antidepressants, antipsychotics, and anxiolytics) and its correlation to lymphoma types can give insights into the psychological distress these patients endure. In this prospective matched cohort study, we used nationwide population-based registries to investigate the cumulative risk of PD use in NHL patients compared to a sex- and age-matched cohort from the Danish background population. In addition, contact patterns to psychiatric departments and incident intentional self-harm or completed suicide were explored. In total, 8750 NHL patients and 43 750 matched comparators were included (median age 68; male:female ratio 1.6). Median follow-up was 7.1 years. Two-year cumulative risk of PD use was higher in NHL patients (16.4%) as compared to the matched comparators (5.1%, p < .01); patients with aggressive NHL subtypes had the highest incidence. Prescription rates were higher in the first years after diagnosis but approached the rate of the matched population 5 years into survivorship in aggressive NHLs, whereas patients with indolent subtypes continued to be at higher risk. NHL patients had a slightly higher two-year risk of suicide/intentional self-harm (0.3%) as compared to the matched comparators (0.2%, p = .01). These results demonstrate that mental health complications among NHL patients are frequent. Routine assessment for symptoms of depression and anxiety should be consider as part of standard follow-up of NHL patients.

Patients in complete remission after R-CHOP(-like) therapy for diffuse large B-cell lymphoma have limited excess use of health care services in Denmark.

For most patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), R-CHOP immunochemotherapy leads to complete remission and 60-70% of patients remain progression-free after 5 years. Given a median age of 65, it is relevant to disentangle how DLBCL and DLBCL therapy influence health care use among the survivors. In this nationwide study, the health care use among Danish DLBCL patients diagnosed in 2007-2015, who achieved complete remission after R-CHOP(-like) therapy, was explored and compared to matched comparators from the Danish general population. The post-remission 5-year risk of hospitalization was significantly higher among DLBCL survivors (55%) compared to matched comparators (49%, P < 0.001). DLBCL survivors had on average 10.3 (9.3-11.3) inpatient bed days within 5 years of response evaluation, whereas matched comparators had 8.4 (7.9-8.8). The rate of outpatient visits was also significantly higher(excluding routine follow-up visits, incidence rate ratio, 1.3, P < 0.001), but translated into only a very small absolute difference of <1 outpatient visits within 5 years between DLBCL survivors (4.2 visits, 95% CI, 4.0-4.4) and matched comparators (3.8 visits, 95% CI, 3.7-3.9). In conclusion, DLBCL survivors have an increased incidence of hospital visits due to a wide range of conditions, but in absolute terms the excess use of health care services in DLBCL survivors was small.

Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib.

Ibrutinib has now been approved for treatment of chronic lymphocytic leukemia (CLL) in both front-line setting and as later-line treatment. However, knowledge about the outcomes and adverse events (AE) among patients at a population-based level is still limited. OBJECTIVES: To report outcomes and AEs in a population-based cohort treated with ibrutinib outside clinical trials. METHODS: We conducted a multicenter, retrospective cohort study including all patients with CLL treated with ibrutinib. RESULTS: In total, 205 patients were included of whom 39 (19%) were treatment-naïve. The median follow-up was 21.4 months (interquartile range (IQR), 11.9,32.8), the estimated overall survival at 12 months was 88.8% (95% confidence interval (CI); 84.3%, 93.3%), and the estimated progression-free survival at 12 months was 86.3% (95% CI; 81.3%, 91.2%). During follow-up, 200 (97.6%) patients had at least one AE and 100 (48.8%) patients had at least one grade ≥3 AE. Eighty-six patients (42.0%) discontinued ibrutinib, hereof 47 (54.7%) due to AEs and 19 (22.1%) had progression of CLL or Richter transformation. CONCLUSIONS: In our study, we find comparable, though slightly inferior, overall, and progression-free survival, and discontinuation due to toxicity was higher compared with clinical trials. Patient training and information may improve treatment adherence outside clinical trials.

Depth of neutrophil nadir after first cycle of R-CHOP predicts outcome in diffuse large B-cell lymphoma - a nationwide population-based cohort study.

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan-Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1-2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49-1.21) for grade 1-2, 1.18 (95% CI 0.82-1.71) for grade 3, and 1.33 (95% CI 1.02-1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1-2. Grade 1-2 neutropenia seemed to have superior outcome.

Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study.

Venous thromboembolism (VTE) is associated with inferior survival in cancer patients. The risk of VTE and its effect on survival in chronic lymphocytic leukemia (CLL) patients remains unclear. The present study investigated the impact of patient-related factors, CLL prognostic markers, and CLL treatment on the risk of VTE and assessed overall survival relative to VTE. All patients in the Danish National CLL Registry (2008-2015) were followed from the date of CLL diagnosis to death, VTE, emigration, or administrative censoring. Hazard ratios (HRs) were estimated using Cox models, and second primary cancers and anticoagulation treatment were included as time-varying exposures. During a median follow-up of 2.6 years, 92 VTEs occurred among 3609 CLL patients, corresponding to a total incidence rate of 8.2 VTEs per 1000 person-years (95% confidence interval [CI], 6.7-10.1). A history of VTE or second primary cancer was associated with HRs of VTE of 5.09 (95% CI, 2.82-9.17) and 3.72 (95% CI, 2.15-6.34), respectively, while ß2-microglobulin >4 mg/L, unmutated immunoglobulin HV and unfavorable cytogenetics had lower HRs. CLL patients with VTE had marginally higher mortality, which was most pronounced among patients <60 years of age (HR, 7.74; 95% CI, 2.12-28.29). Our findings suggest that markers of unfavorable CLL prognosis contribute to an increased risk of VTE; however, previous VTE or a second primary cancer is more strongly associated with the risk of VTE than any CLL-specific marker. Focusing attention on this preventable complication may improve survival in young CLL patients.

Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.

BACKGROUND: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. PATIENTS AND METHODS: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. RESULTS: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. CONCLUSION: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.

The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study.

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma.

The Danish National Acute Leukemia Registry.

AIM OF DATABASE: The main aim of the Danish National Acute Leukemia Registry (DNLR) was to obtain information about the epidemiology of the hematologic cancers acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). STUDY POPULATION: The registry was established in January 2000 by the Danish Acute Leukemia Group and has been expanded over the years. It includes adult AML patients diagnosed in Denmark since 2000, ALL patients diagnosed since 2005, and MDS patients diagnosed since 2010. The coverage of leukemia patients exceeds 99%, and the coverage of MDS patients is currently 90%. MAIN VARIABLES AND DESCRIPTIVE DATA: Approximately, 250 AML patients, 25 ALL patients, and 230 MDS patients are registered in the DNLR every year. In January 2015, the registry included detailed patient characteristics, disease characteristics, treatment characteristics, and outcome data on more than 3,500 AML, 300 ALL, and 1,100 MDS patients. Many of the included prognostic variables have been found to be of high quality including positive predictive values and completeness exceeding 90%. These variables have been used in prognostic observational studies in the last few years. To ensure this high coverage, completeness, and quality of data, linkage to the Danish Civil Registration System and the Danish National Registry of Patients, and several programmed data entry checks are used. CONCLUSION: The completeness and positive predictive values of the leukemia data have been found to be high. In recent years, the DNLR has shown to be an important high-quality resource for clinical prognostic research.

The Danish National Chronic Lymphocytic Leukemia Registry.

AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. STUDY POPULATION: All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data. MAIN VARIABLES: Predefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected. DESCRIPTIVE DATA: To ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National Patient Registry are performed. Data from the registry are published in an annual report summarizing the collected data, the overall survival for yearly cohorts, and the degree of data coverage. Per year approximately 450 new patients with CLL are registered in the registry, cumulative as of July 1, 2015, 3,082 patients have been registered. CONCLUSION: The Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark and offers a unique opportunity for population-based research.

The Danish National Multiple Myeloma Registry.

AIM: The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research. STUDY POPULATION: All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. MAIN VARIABLES: The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival. DESCRIPTIVE DATA: Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013-2014 by the Danish Myeloma Study Group showed >95% data correctness. CONCLUSION: The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research.