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Emelie C Rotbain,1– 5 Klaus Rostgaard,3,5 Michael A Andersen,2,3 Caspar Da Cunha-Bang,2 Carsten U Niemann,2 Henrik Frederiksen,1,4,6 Henrik Hjalgrim2,3,5,7 1Department of Hematology, Odense University Hospital, Odense, Denmark; 2Department of Hematology, Rigshospitalet, Denmark; 3Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Danish Cancer Society Research Center, Hematology Research Group, Copenhagen, Denmark; 6Academy of Geriatric Cancer Research (AGECARE), Odense University Hospital, Odense, Denmark; 7Department of Clinical Medicine, Copenhagen University, Copenhagen, DenmarkCorrespondence: Emelie C RotbainDepartment of Hematology, Odense University Hospital, Kløvervænget 6, Odense, DK-5000, DenmarkTel +45 5369 0201Email erot0006@regionh.dkPurpose: Age-related comorbidity is highly prevalent in chronic lymphocytic leukemia (CLL). The purpose of this study was to provide information on current patterns of healthcare utilization in CLL.Patients and Methods: We used data from Danish nation-wide registers to study healthcare utilization the year before and the year after CLL diagnosis and in relation to first-line treatment. Patients diagnosed with CLL between 1997 and 2018 were included and stratified on number of comorbidities, presence of specific comorbidities, and fitness status, respectively. Healthcare utilization was studied in terms of hospital admissions, in-hospital bed days, out-patient visits, emergency room visits, and prescription drugs. Odds ratios with 95% confidence intervals were calculated using multivariable logistic regression analyses adjusting for age, sex, and calendar year.Results: The study comprised 9170 patients with CLL with a median age of 71 years, of whom 35% had ≥ 1 comorbidity. Healthcare utilization increased markedly upon CLL diagnosis both in patients with and without comorbidities. During the year after CLL diagnosis, 39% were hospitalized, 16% visited an emergency room, 88% visited an out-patient clinic, and 93% received prescription drugs. Both individual comorbidities and the total number of comorbidities were associated with increased healthcare utilization of all types, except for contacts to hematological departments.Conclusion: Our results suggest that CLL diagnosis may unveil incipient diseases and aggravate comorbidities and thereby have considerably wider health implications than those directly related to CLL. These findings may be used by clinicians and decisions makers to guide planning of multidisciplinary care for cancer patients.Keywords: chronic lymphocytic leukemia, hematology, epidemiology, real-world data

Jelena Jelicic,1 Thomas Stauffer Larsen,1,2 Henrik Frederiksen,1,2 Bosko Andjelic,3 Milos Maksimovic,4 Zoran Bukumiric5 1Department of Hematology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Haematology, Blackpool Victoria Hospital, Lancashire Haematology Centre, Blackpool, UK; 4Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark; 5Department of Statistics, Faculty of Medicine, University of Belgrade, Belgrade, SerbiaCorrespondence: Thomas Stauffer LarsenDepartment of Hematology, Odense University Hospital, Odense, DenmarkTel +45 2145 0236Fax +45 6541 3035Email Thomas.Stauffer.Larsen@rsyd.dkBackground and Aim: Based on advances in the diagnosis, classification, and management of diffuse large B-cell lymphoma (DLBCL), a number of new prognostic models have been proposed. The aim of this study was to review and compare different prognostic models of DLBCL based on the statistical methods used to evaluate the performance of each model, as well as to analyze the possible limitations of the methods.Methods and Results: A literature search identified 46 articles that proposed 55 different prognostic models for DLBCL by combining different clinical, laboratory, and other parameters of prognostic significance. In addition, six studies used nomograms, which avoid risk categorization, to create prognostic models. Only a minority of studies assessed discrimination and/or calibration to compare existing models built upon different statistical methods in the process of development of a new prognostic model. All models based on nomograms reported the c-index as a measure of discrimination. There was no uniform evaluation of the performance in other prognostic models. We compared these models of DLBCL by calculating differences and ratios of 3-year overall survival probabilities between the high- and the low-risk groups. We found that the highest and lowest ratio between low- and high-risk groups was 6 and 1.31, respectively, while the difference between these groups was 18.9% and 100%, respectively. However, these studies had limited duration of follow-up and the number of patients ranged from 71 to 335.Conclusion: There is no universal statistical instrument that could facilitate a comparison of prognostic models in DLBCL. However, when developing a prognostic model, it is recommended to report its discrimination and calibration in order to facilitate comparisons between different models. Furthermore, prognostic models based on nomograms are becoming more appealing owing to individualized disease-related risk estimations. However, they have not been validated yet in other study populations.Keywords: diffuse large B-cell lymphoma, discrimination, calibration, prognosis, models, nomograms

Dennis Lund Hansen,1,2 Sören Möller,1,3 Kjeld Andersen,1,4 David Gaist,1,5 Henrik Frederiksen1,2 1Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3OPEN, Odense University Hospital, Odense, Denmark; 4Department of Psychiatry, Odense, Region of Southern Denmark, Odense, Denmark; 5Neurology Research Unit, Department of Neurology, Odense University Hospital, Odense, DenmarkCorrespondence: Dennis Lund Hansen Email dlh@dadlnet.dkBackground: Acquired hemolytic disorders—autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), paroxysmal nocturnal hemoglobinuria (PNH), drug-induced hemolysis (DIHA), and acquired hemolysis not otherwise specified (AHNOS)—are considered rare. Despite their potentially major health implications, data regarding their incidence and prevalence are scarce.Methods: To fill this gap we collected data regarding all patients with acquired hemolytic disorder diagnoses in 1977– 2016 from the Danish National Patient Register. These data were linked with vital and migration status information from the Danish Civil Registration System. From these data combined with annual demographic data for the background population, we calculated age- and sex-specific incidence rates and prevalence proportions of acquired hemolytic disorders for specified time periods.Results: Our analysis included 5868 patients with acquired hemolytic disorders (2715 with AIHA, 112 CAD, 397 DIHA, 116 PNH, and 2154 AHNOS). The incidence rates per 100 000 person-years in 1980– 1993 and 2008– 2016 were 0.81 and 1.77 for AIHA, 0.31 and 0.12 for DIHA, and 0.04 and 0.08 for PNH, respectively. The 2008– 2016 CAD incidence rate was 0.18/100 000 person-years, CAD diagnosis code was not defined before 1994. All incidence rates increased with age. The prevalence proportion per 100 000 persons in 1980 and 2015 was 2.52 and 17.01 for AIHA, 0.80 and 1.50 for DIHA, and 0.18 and 1.04 for PNH. CAD prevalence in 2015 was 1.04/100 000 persons.Conclusion: Acquired hemolytic anemia incidence rates and prevalence proportions with the exception of DIHA are markedly increasing.Keywords: autoimmune hemolytic anemia, cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemia, incidence, prevalence

Dennis Lund Hansen,1,2 Andreas Glenthøj,3 Sören Möller,1,4 Bart J Biemond,5 Kjeld Andersen,1,6 David Gaist,1,7 Jesper Petersen,3 Henrik Frederiksen1,2 1Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Hematology, Center for Hemoglobinopathies, Herlev and Gentofte Hospital, Herlev, Denmark; 4OPEN, Odense University Hospital, Odense, Denmark; 5Department of Hematology, Amsterdam University Medical Centre’s, Amsterdam, Netherlands; 6Department of Mental Health - Odense, Region of Southern Denmark, Odense, Denmark; 7Neurology Research Unit, Department of Neurology, Odense University Hospital, Odense, DenmarkCorrespondence: Dennis Lund Hansen Email dlh@dadlnet.dkBackground: Congenital red blood cell (RBC) disorders, such as hemoglobinopathies, are frequent worldwide but with large geographical variation. Growing migration has increased the number of patients with RBC disorders in formerly low prevalence countries, eg, Denmark. However, accurate prevalences are unknown.Methods: Patients with a registered diagnosis of congenital hemolysis in the Danish National Patient Register between 1977 and 2016 were linked to a national laboratory database of RBC disorders and the Danish civil registration system. We calculate annual age- and sex-specific prevalences of the congenital hemolytic disorders from 2000 to 2016.Results: Prevalences of all subtypes of congenital hemolytic disorders increased during the study period. The prevalence of hereditary spherocytosis increased 1.73 times between 2000 and 2015, from 10.2/105 persons to 17.7/105 persons. Alpha thalassemia trait had a prevalence of 0.5/105 persons in 2000, but increased 41 times to 19.2/105 persons in 2015. Beta thalassemia minor increased eightfold from 4.5/105 persons in 2000 to 34.9/105 persons in 2015. Likewise, sickle cell trait increased 11 times from 0.7/105 persons in 2000 to 8.1/105 persons in 2015, whereas sickle cell disease increased from 0.5/105 persons to 2.7/105 persons in 2015, a fivefold increase.Conclusion: The prevalence of congenital RBC disorders in Denmark is increasing. The hemoglobinopathy traits now have prevalences as high as hereditary spherocytosis. These estimates of congenital hemolytic disorders in Denmark emphasize that inborn hemoglobin disorders are a public health concern, even in some formerly low prevalence countries.Keywords: hemolytic anemia, thalassemia, sickle cell disease, hereditary spherocytosis, hemoglobinopathies, sickle cell anemia

Henrik Frederiksen,1–3 Szimonetta Szépligeti,1 Marie Bak,4 Waleed Ghanima,5,6 Hans Carl Hasselbalch,4 Christian Fynbo Christiansen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Haematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Department of Haematology, Zealand University Hospital, Roskilde, Denmark; 5Departments of Oncology, Medicine and Research, Østfold Hospital Trust, Kalnes, Norway; 6Department of Haematology, Institute of Clinical Medicine, University of Oslo, Oslo, NorwayCorrespondence: Henrik FrederiksenDepartment of Haematology, Odense University Hospital, Kloevervaenget 6, Entrance 93, 12th Floor, Odense C DK-5000, DenmarkEmail henrik.frederiksen@rsyd.dkBackground: Patients with chronic myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are at high risk of vascular complications. However, the magnitude of this is risk not well known and the possible effect of comorbidity is poorly understood.Aim: Our aim was to compare the risk of vascular diseases in patients with MPNs and matched comparisons from the general population and to study the effect modification of comorbidity.Methods: We followed 3087 patients with ET, 6076 with PV, 3719 with PMF or unspecified MPN, and age- and sex-matched general population comparisons to estimate the risks of cardiovascular diseases such as myocardial infarction and stroke. We computed 5-year cumulative incidences (risks) for vascular disease in patients with MPNs and comparisons as well as 1-year and 5-year risks, risk differences, and hazard ratios (HRs) for vascular diseases comparing rates in each group of patients with their comparison cohort by level of comorbidity based on the Charlson Comorbidity Index (CCI) [score of 0 (low comorbidity), of 1–2 (moderate comorbidity), and of >2 (severe comorbidity)], as well as other comorbid conditions.Results: The overall 5-year risk of vascular disease ranged from 0.5% to 7.7% in patients with MPNs, which was higher than the risk in the general population. In the same period, the adjusted HRs for vascular disease were 1.3 to 3.7 folds higher in patients with MPNs compared to the general population. An increase in CCI score was associated with an equally increased rate of most types of vascular diseases during the first 5 years of follow-up in both MPN and comparisons.Conclusion: Patients with MPNs have a higher risk of vascular diseases during the first 5 years than that of the general population; however, comorbidity modifies the rates similarly in MPN and in the general population.Keywords: myeloproliferative neoplasms, thrombosis, comorbidity, stroke, epidemiology

Henrik FrederiksenDepartment of Haematology, Odense University Hospital, Odense, DenmarkAbstract: Dehydrated hereditary stomatocytosis (DHSt) is a nonimmune congenital hemolytic disorder characterized by red blood cell (RBC) dehydration and lysis. It has been a recognized diagnostic entity for almost 50 years, and autosomal dominant inheritance has long been suspected, but it was not until 2011 that the first genetic alterations were identified. The current study reviews 73 articles published during 1971–2019 and focuses on clinical perspectives of the disease. All but one of the published clinical data in DHSt were either single case reports or case series. From these, it can be seen that patients with DHSt often have fully or partially compensated hemolysis with few symptoms. Despite this, iron overload is an almost universal finding even in patients without or with only sporadic blood transfusions, and this may lead to organ dysfunction. Other severe complications, such as thrombosis and perinatal fluid effusions unrelated to fetal hemoglobin concentration, may also occur. No specific treatment for symptomatic hemolysis exists, and splenectomy should be avoided as it seems to aggravate the risk of thrombosis. Recently, treatment with senicapoc has shown activity against RBC dehydration in vitro; however, it is not known if this translates into relevant clinical effects. In conclusion, despite recent advances in the understanding of pathophysiology in DHSt, options for clinical management have not improved. Entering data into international registries has the potential to fill gaps in knowledge and eventually care of these rare patients.Keywords: xerocytosis, hemolysis, iron overload, perinatal, thrombosis, review

Erzsébet Horváth-Puhó,1 Marit M Suttorp,2 Henrik Frederiksen,1,3 Tiny Hoekstra,2 Olaf M Dekkers,1,2 Lars Pedersen,1 Suzanne C Cannegieter,2 Friedo W Dekker,2 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Haematology, Odense University Hospital, Odense, Denmark Introduction: Erythropoiesis-stimulating agent (ESA) treatment has been associated with an increased risk of venous thromboembolism (VTE) in patients with solid tumors and with an increased risk of cardiovascular events in patients with chronic kidney disease. The ESA-related risk in patients with hematological neoplasms remains unclear. We, therefore, aimed to assess the ESA-related risk of VTE, myocardial infarction (MI), and stroke in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). Materials and methods: We conducted a population-based cohort study in Denmark, using medical databases to identify 2,114 MDS patients and 3,105 MM patients diagnosed in 2004–2013. Incidence rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE, MI, and stroke associated with ESA treatment were computed. HRs were calculated in time-dependent Cox regression and adjusted for age, sex, MDS prognosis group, comorbidities, and treatments. Results: Incidence rates per 1,000 person-years for VTE, MI, and stroke were 10.8, 8.2, and 16.0 in MDS patients, and 21.9, 10.2 and 9.9 in MM patients without ESA treatment, respectively. MDS patients with ESA treatment had a 1.6-fold increased risk of MI (HR 1.60 [95% CI 0.90–2.86]) and an almost twofold increased risk of stroke (HR 1.94 [95% CI 1.28–2.94]). Adjusted HR for VTE was 1.04 (95% CI 0.57–1.89) compared with MDS patients without ESAs. In MM patients with ESAs compared with patients without ESAs, HRs were 1.41 (95% CI 0.96–2.08) for VTE, 1.23 (95% CI 0.68–2.20) for MI, and 1.63 (95% CI 0.96–2.77) for stroke. Conclusion: ESA use was associated with stroke in MDS patients. Among MM patients, ESA treatment was associated with a higher risk of all cardiovascular events, although all CIs included equivalence. Keywords: cohort study, epidemiology, erythropoietin, multiple myeloma, myelodysplastic syndromes, myocardial infarction, stroke, pulmonary embolism, venous thrombosis

Caspar da Cunha-Bang,1 Christian Hartmann Geisler,2 Lisbeth Enggaard,3 Christian Bjørn Poulsen,4 Peter de Nully Brown,2 Henrik Frederiksen,5 Olav Jonas Bergmann,6 Elisa Jacobsen Pulczynski,7 Robert Schou Pedersen,8 Linda Højberg Nielsen,9 Ilse Christiansen,10 Carsten Utoft Niemann2 1Department of Internal Medicine, Roskilde Hospital, Roskilde, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3Department of Hematology, Herlev Hospital, Herlev, Denmark; 4Department of Hematology, Roskilde Hospital, Roskilde, Denmark; 5Department of Hematology, Odense University Hospital, Odense, Denmark; 6Department of Hematology, Vejle Hospital, Vejle, Denmark; 7Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 8Department of Hematology, Holstebro Hospital, Holstebro, Denmark; 9Department of Hematology, Esbjerg Hospital, Esbjerg, Denmark; 10Department of Hematology, Aalborg University Hospital, Aalborg, Denmark 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. Keywords: CLL, population based, epidemiology, targeted treatment, survival, comorbidity

Dennis Lund Hansen,1 Ulrik Malthe Overgaard,2 Lars Pedersen,3 Henrik Frederiksen1,3 1Department of Haematology, Odense University Hospital, Odense, 2Department of Haematology, Herlev Hospital, Herlev, 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Purpose: The nationwide public health registers in Denmark provide a unique opportunity for evaluation of disease-associated morbidity if the positive predictive values (PPVs) of the primary diagnosis are known. The aim of this study was to evaluate the predictive values of hemolytic anemias registered in the Danish National Patient Register. Patients and methods: All patients with a first-ever diagnosis of hemolytic anemia from either specialist outpatient clinic contact or inpatient admission at Odense University Hospital from January 1994 through December 2011 were considered for inclusion. Patients with mechanical reason for hemolysis such as an artificial heart valve, and patients with vitamin-B12 or folic acid deficiency were excluded. Results: We identified 412 eligible patients: 249 with a congenital hemolytic anemia diagnosis and 163 with acquired hemolytic anemia diagnosis. In all, hemolysis was confirmed in 359 patients, yielding an overall PPV of 87.1% (95% confidence interval [CI]: 83.5%–90.2%). A diagnosis could be established in 392 patients of whom 355 patients had a hemolytic diagnosis. Diagnosis was confirmed in 197 of the 249 patients with congenital hemolytic anemia, yielding a PPV of 79.1% (95% CI: 73.5%–84.0%). Diagnosis of acquired hemolytic anemia could be confirmed in 136 of the 163 patients, resulting in a PPV of 83.4% (95% CI: 76.8%–88.8%). For hemoglobinopathy PPV was 84.1% (95% CI: 77.4%–89.4%), for hereditary spherocytosis PPV was 80.6% (95% CI: 69.5%–88.9%), and for autoimmune hemolytic anemia PPV was 78.4% (95% CI: 70.4%–85.0%). Conclusion: The PPV of hemolytic anemias was moderately high. The PPVs were comparable in the three main categories of overall hemolysis, and congenital and acquired hemolytic anemia. Keywords: ICD-10 coding, diagnosis validation, hemoglobinopathy, spherocytosis, epidemiology, congenital hemolytic anemia, acquired hemolytic anemia