Combination therapy with ruxolitinib and pegylated interferon alfa-2a in newly diagnosed patients with polycythemia vera.

ABSTRACT: We report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography-verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13.

Relationship between reasons for intermittent missing patient-reported outcomes data and missing data mechanisms.

PURPOSE: Non-response (NR) to patient-reported outcome (PRO) questionnaires may cause bias if not handled appropriately. Collecting reasons for NR is recommended, but how reasons for NR are related to missing data mechanisms remains unexplored. We aimed to explore this relationship for intermittent NRs. METHODS: Patients with multiple myeloma completed validated PRO questionnaires at enrolment and 12 follow-up time-points. NR was defined as non-completion of a follow-up assessment within seven days, which triggered contact with the patient, recording the reason for missingness and an invitation to complete the questionnaire (denoted "salvage response"). Mean differences between salvage and previous on-time scores were estimated for groups defined by reasons for NR using linear regression with clustered standard errors. Statistically significant mean differences larger than minimal important difference thresholds were interpreted as "missing not at random" (MNAR) mechanism (i.e. assumed to be related to declining health), and the remainder interpreted as aligned with "missing completely at random" (MCAR) mechanism (i.e. assumed unrelated to changes in health). RESULTS: Most (7228/7534 (96%)) follow-up questionnaires were completed; 11% (802/7534) were salvage responses. Mean salvage scores were compared to previous on-time scores by reason: those due to hospital admission, mental or physical reasons were worse in 10/22 PRO domains; those due to technical difficulties/procedural errors were no different in 21/22 PRO domains; and those due to overlooked/forgotten or other/unspecified reasons were no different in any domains. CONCLUSION: Intermittent NRs due to hospital admission, mental or physical reasons were aligned with MNAR mechanism for nearly half of PRO domains, while intermittent NRs due to technical difficulties/procedural errors or other/unspecified reasons generally were aligned with MCAR mechanism.

Maternal thyroid function in early pregnancy and offspring school performance and neurodevelopmental disorders.

CONTEXT: Thyroid hormones are critical for neural development, and during the first trimester of pregnancy the fetus relies fully on maternal thyroid hormone production. OBJECTIVE: To investigate the associations between maternal thyroid hormone levels in the first trimester with the child's school performance, risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). METHODS: From the Copenhagen Primary Care Laboratory Pregnancy Database information on first trimester TSH and fT4 measurements in mothers of children born in 2000-2014 were linked with information on the child's standardized test scores in school, ADHD (patient record diagnoses and medication) and ASD (patient record diagnoses) until end of 2018. Associations of TSH and fT4 with the outcomes were individually assessed by linear mixed models and Cox regression models. The analyses were stratified by preexisting maternal thyroid disorders. RESULTS: TSH measurements were available for 17,909 mother-child dyads. Among those with children born in 2000-2009, 6,126 had a standardized school test score and were analyzed for the association between maternal thyroid hormone levels and child's school performance, and no support for an association was found. The association between thyroid hormone levels and child's risk of ADHD and ASD were analyzed for the 17,909 dyads and with no support for an association between thyroid hormone levels and these neurodevelopmental disorders. Stratification by preexisting maternal thyroid disorders did not affect the results. CONCLUSIONS: We found no evidence for associations between first trimester maternal thyroid hormone levels and child's school performance, or risk of ADHD or ASD.

The Copenhagen Primary Care Laboratory (CopLab) Database.

Background: The Copenhagen General Practice Laboratory (CGPL) was founded in 1922 to provide paraclinical analyses to the primary health-care sector in Copenhagen. At the end of 2015, CGPL was closed and the CopLab database was established to make CGPL data available for research. Methods: We isolated tests performed at the CGPL with clinically relevant test results. The database was linked to national registers containing health, social, and demographic information. Results are presented with descriptive statistics showing counts, percentages, medians, and interquartile ranges (IQR). Results: The CopLab database includes 1,373,643 unique individuals from primary care with test results from laboratory analyses of blood/urine/semen as well as cardiac and lung function tests collected by CGPL from greater Copenhagen from 2000 to 2015. The CopLab database holds nearly all test results requested by general practitioners throughout years 2000 to 2015 for residents in the greater Copenhagen area. The median age of the individuals was 51 years and 59.7% were females. Each individual has a median of 4 requisitions. More than 1 million participants are currently alive and living in Denmark and may be followed in national registries such as the Danish National Patient Registry, Laboratory Database, National Prescription Database etc.

Therapeutic drug monitoring of imatinib - how far are we in the leukemia setting?

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML. AREAS COVERED: This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias. EXPERT OPINION: TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.

Management of dyslipidaemia in individuals with severe mental illness: a population-based study in the Greater Copenhagen Area.

Background: Severe mental illness (SMI) is associated with increased cardiovascular risk. Dyslipidaemia is a potentially modifiable risk factor, which may be inadequately managed in patients with SMI. Objectives: To assess management of dyslipidaemia in patients with SMI versus healthy controls (HCs) in 2005 and 2015. Design and methods: Using Danish registers, we identified adult patients with SMI in the Greater Copenhagen Area (schizophrenia spectrum disorders or bipolar disorder) with ⩾1 general practitioner contact in the year before 2005 and 2015, respectively, and HCs without SMI matched on age and gender (1:5). Outcomes were lipid-profile measurements, presence of dyslipidaemia and redemption of lipid-lowering pharmacotherapy. Differences in outcomes between patients with SMI and controls were measured with multivariable logistic regression. Results: We identified 7217 patients with SMI in 2005 and 9939 in 2015. After 10 years, patients went from having lower odds of lipid measurements to having higher odds of lipid measurements compared with HCs [odds ratio (OR)2005 0.70 (99% confidence interval (CI) 0.63-0.78) versus OR2015 1.34 (99% CI 1.24-1.44); p2005versus2015 < 0.01]. Patients had higher odds of dyslipidaemia during both years [OR2005 1.43 (99% CI 1.10-1.85) and OR2015 1.23 (99% CI 1.08-1.41)]. Patients went from having lower odds of receiving lipid-lowering pharmacotherapy to having higher odds of receiving lipid-lowering pharmacotherapy [OR2005 0.77 (99% CI 0.66-0.89) versus OR2015 1.37 (99% CI 1.24-1.51); p2005versus2015 < 0.01]. However, among persons at high cardiovascular risk, patients had lower odds of receiving lipid-lowering pharmacotherapy during both years, including subsets with previous acute coronary syndrome [OR2005 0.30 (99% CI 0.15-0.59) and OR2015 0.44 (99% CI 0.24-0.83)] and ischaemic stroke or transient ischaemic attack (TIA) [OR2005 0.43 (99% CI 0.26-0.69) and OR 2015 0.61 (99% CI 0.41-0.89)]. Conclusion: These results imply an increased general awareness of managing dyslipidaemia among patients with SMI in the primary prophylaxis of cardiovascular disease. However, secondary prevention with lipid-lowering drugs in patients with SMI at high cardiovascular risk may be lacking.

Labor market affiliation of patients with myeloproliferative neoplasms: a population-based matched cohort study.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS: The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.

Risk of atrial fibrillation in individuals with dysglycemia and diabetes.

OBJECTIVE: Diabetes is a risk factor for atrial fibrillation (AF), and increases the risk of thromboembolic events in persons with AF. However, the link between the two conditions is not fully elucidated. Few studies have investigated the association of dysglycemia and incident AF. We investigated the risk of incident AF and prognosis according to diabetes status. RESEARCH DESIGN AND METHODS: The Copenhagen Primary Care Laboratory Database was merged with data on medical prescriptions, in- and outpatient contacts and vital status. The risk of AF according to diabetes status was investigated by use of Cox regression models. RESULTS: Of 354.807 individuals with a hemoglobin A1c (HbA1c) measurement, 28.541 (8 %) had known diabetes, 13.038 (4 %) had new onset diabetes and 27.754 (8 %) had prediabetes (HbA1c 42-47 mmol/mol). Persons with dysglycemia (HbA1c > 42 mmol/mol) and diabetes were older, more were men, they had lower level of education and were more likely to be living alone. We observed a gradual increase in risk of developing AF from HbA1c levels of 40 to 60 mmol/mol. In adjusted analyses we found a stepwise increase in hazard of AF from normoglycemia over prediabetes to persons with diabetes (no diabetes: 1.00 [ref.]; prediabetes: 1.12 [1.08-1.16]; new-onset diabetes: 1.16 [1.10-1.22]; known diabetes: 1.15 [1.11-1.20]). Persons with known diabetes had a significant higher hazard of stroke, cardiovascular and all-cause mortality. CONCLUSION: Increasing levels of HbA1c were associated with an increased hazard of developing AF. Persons with new onset of diabetes and those with known diabetes had similar hazard of developing AF, however persons with known diabetes had a significant higher hazard of stroke, cardiovascular- and all-cause mortality.

The multidisciplinary approach to eosinophilia.

Eosinophilic granulocytes are normally present in low numbers in the bloodstream. Patients with an increased number of eosinophilic granulocytes in the differential count (eosinophilia) are common and can pose a clinical challenge because conditions with eosinophilia occur in all medical specialties. The diagnostic approach must be guided by a thorough medical history, supported by specific tests to guide individualized treatment. Neoplastic (primary) eosinophilia is identified by one of several unique acquired genetic causes. In contrast, reactive (secondary) eosinophilia is associated with a cytokine stimulus in a specific disease, while idiopathic eosinophilia is a diagnosis by exclusion. Rational treatment is disease-directed in secondary cases and has paved the way for targeted treatment against the driver in primary eosinophilia, whereas idiopathic cases are treated as needed by principles in eosinophilia originating from clonal drivers. The vast majority of patients are diagnosed with secondary eosinophilia and are managed by the relevant specialty-e.g., rheumatology, allergy, dermatology, gastroenterology, pulmonary medicine, hematology, or infectious disease. The overlap in symptoms and the risk of irreversible organ involvement in eosinophilia, irrespective of the cause, warrants that patients without a diagnostic clarification or who do not respond to adequate treatment should be referred to a multidisciplinary function anchored in a hematology department for evaluation. This review presents the pathophysiology, manifestations, differential diagnosis, diagnostic workup, and management of (adult) patients with eosinophilia. The purpose is to place eosinophilia in a clinical context, and therefore justify and inspire the establishment of a multidisciplinary team of experts from diagnostic and clinical specialties at the regional level to support the second opinion. The target patient population requires highly specialized laboratory analysis and therapy and occasionally has severe eosinophil-induced organ dysfunction. An added value of a centralized, clinical function is to serve as a platform for education and research to further improve the management of patients with eosinophilia. Primary and idiopathic eosinophilia are key topics in the review, which also address current research and discusses outstanding issues in the field.

Diabetes treatment for persons with severe mental illness: A registry-based cohort study to explore medication treatment differences for persons with type 2 diabetes with and without severe mental illness.

It has been argued that persons with severe mental illness (SMI) receive poorer treatment for somatic comorbidities. This study assesses the treatment rates of glucose-lowering and cardiovascular medications among persons with incident type 2 diabetes (T2D) and SMI compared to persons with T2D without SMI. We identified persons ≥30 years old with incident diabetes (HbA1c ≥ 48 mmol/mol and/or glucose ≥ 11.0 mmol/L) from 2001 through 2015 in the Copenhagen Primary Care Laboratory (CopLab) Database. The SMI group included persons with psychotic, affective, or personality disorders within five years preceding the T2D diagnosis. Using a Poisson regression model, we calculated the adjusted rate ratios (aRR) for the redemption of various glucose-lowering and cardiovascular medications up to ten years after T2D diagnosis. We identified 1,316 persons with T2D and SMI and 41,538 persons with T2D but no SMI. Despite similar glycemic control at diagnosis, persons with SMI redeemed a glucose-lowering medication more often than persons without SMI in the period 0.5-2 years after the T2D diagnosis; for example, the aRR was 1.05 (95% CI 1.00-1.11) in the period 1.5-2 years after the T2D diagnosis. This difference was mainly driven by metformin. In contrast, persons with SMI were less often treated with cardiovascular medications during the first 3 years after T2D diagnosis, e.g., in the period 1.5-2 years after T2D diagnosis, the aRR was 0.96 (95% CI 0.92-0.99). For people with SMI in addition to T2D, metformin is more likely to be used in the initial years after T2D diagnosis, while our results suggest potential room for improvement regarding the use of cardiovascular medications.

Chronic kidney disease in primary care: risk of cardiovascular events, end stage kidney disease and death.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing globally. Early diagnosis in primary care may have a role in ensuring proper intervention. We aimed to determine the prevalence and outcome of CKD in primary care. METHODS: We performed an observational cohort study in primary care in Copenhagen (2001-2015). Outcomes were stroke, myocardial infarction (MI), heart failure (HF), peripheral artery disease (PAD), all-cause- and cardiovascular mortality. We combined individuals with normal kidney function and CKD stage 2 as reference. We conducted cause-specific Cox proportional regressions to calculate the hazard ratios for outcomes according to CKD group. We explored the associations between kidney function and the outcomes examined using eGFR as a continuous variable modelled with penalised splines. All models were adjusted for age, gender, diabetes, hypertension, existing CVD, heart failure, LDL cholesterol and use of antihypertensive treatment. RESULTS: We included 171,133 individuals with at least two eGFR measurements of which the majority (n = 157,002) had eGFR > 60 ml/min/1.73m2 at index date, and 0.05% were in CKD stage 5. Event rates were low in eGFR > 60 ml/min/1.73m2 but increased in those with higher stages of CKD. In adjusted analyses we observed an increase in hazard rates for every outcome with every increment in CKD stage. Compared to the reference group, individuals in CKD stage 4 had double the hazard rate of PAD, MI, cardiovascular and all-cause mortality. CONCLUSIONS: Our data from a large primary care cohort demonstrate an early increase in the risk of adverse outcomes already at CKD stage 3. This underlines the importance of studying early intervention in primary care.

Associations between education level, blood-lipid measurements and statin treatment in a Danish primary health care population from 2000 to 2018.

OBJECTIVE: To examine whether education level influences screening, monitoring, and treatment of hypercholesterolemia. DESIGN: Epidemiological cohort study. SETTING: Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre. SUBJECTS: Cholesterol blood test results ordered by general practitioners in Greater Copenhagen were retrieved from 2000-2018. Using the International Standard Classification of Education classification, the population was categorized by length of education in three groups (basic education; up to 10 years, intermediate education; 11-12 years, advanced education; 13 years or more). The database comprised 13,019,486 blood sample results from 653,903 patients. MAIN OUTCOME MEASURES: Frequency of lipid measurement, prevalence of statin treatment, age and comorbidity at treatment initiation, total cholesterol threshold for statin treatment initiation, and achievement of treatment goal. RESULTS: The basic education group was measured more frequently (1.46% absolute percentage difference of total population measured [95% CI 0.86%-2.05%] in 2000 and 9.67% [95% CI 9.20%-10.15%] in 2018) over the period compared to the intermediate education group. The advanced education group was younger when receiving first statin prescription (1.87 years younger [95% CI 1.02-2.72] in 2000 and 1.06 years younger [95% CI 0.54-1.58 in 2018) compared to the intermediate education group. All education groups reached the treatment goals equally well when statin treatment was initiated. CONCLUSION: Higher education was associated with earlier statin prescription, although the higher educated group was monitored less frequently. There was no difference in reaching treatment goal between the three education groups. These findings suggest patients with higher education level achieve an earlier dyslipidemia prevention intervention with an equally satisfying result compared to lower education patients.Key PointsLittle is known about the role of social inequality as a possible barrier for managing hypercholesterolemia in general practice.Increasing education level was associated to less frequent measurement and less frequent statin treatment.Patients with higher education level were younger, and less comorbidity at first statin prescription.Education level had no effect on frequency of statin treatment-initiated patients reaching the treatment goal was found.

Monocytosis in primary care and risk of haematological malignancies.

Monocytosis (≥0.5 × 109 /L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including other haematological malignancies. In the primary care sector, monocytosis is a relatively common finding, but its predictive value for haematological malignancy is unknown. We included 663 184 adult primary care patients from the greater Copenhagen area with one or more differential cell counts registered between 2000 and 2016 and followed them in the extensive nationwide Danish health data registers for 3 years after blood sampling. We used logistic regression to model the risk of haematological malignancy and death following monocytosis. Monocytosis was associated with an increased risk of all types of haematological malignancy with the greatest relative risk increase observed in CMML with an OR of 105.22 (95% confidence interval: 38.27-289.30). Sustained monocytosis (at least two requisitions in 3 months) further increased CMML risk, although the diagnosis was still very rare, that is, observed in only 0.1% of these individuals. Outside the haematological setting, the absolute risk of haematological malignancy associated with monocytosis is low and haematological malignancy should mainly be suspected when monocytosis is sustained or the clinical presentation raises suspicion of malignancy.

Biochemical profiling, pharmacological management and clinical outcomes in type 2 diabetes in Danish primary care from 2001 to 2015.

AIMS: Primary care plays an integral role in the management of type 2 diabetes (T2D). We investigated in a large group of individuals in this setting the biochemical profiles, pharmacological management and clinical outcomes as well as their changes over time. METHODS: This is a register-based study including relevant laboratory test results requested between 2000 and 2015 by general practitioners in the greater Copenhagen area. We identified 72,044 individuals with T2D on whom data concerning prescription medicine and clinical outcomes were obtained from national registries. RESULTS: The number of individuals with T2D greatly increased from 2001 to 2015. Hemoglobin A1c, estimated glomerular filtration rate and urine albumin creatinine ratio did not change, but cholestrol levels improved. The proportion redeeming anti-diabetics remained around 80%, with an increase for metformin. The use of cardiovascular drugs increased. All-cause and especially cardiovascular mortality decreased over the period. Hospital admissions for non-fatal cardiovascular events dropped. CONCLUSION: The number of individuals with T2D in primary care increased dramatically whereas pharmacological management, control of risk factors and clinical outcomes seem to have improved. Nevertheless, a conspicuous minority did not receive diabetes-related medication.

Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study.

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

Pre-diagnostic trajectories of lymphocytosis predict time to treatment and death in patients with chronic lymphocytic leukemia.

Background: The dynamics of pre-diagnostic lymphocytosis in patients with ensuing chronic lymphocytic leukemia (CLL) need to be explored as a better understanding of disease progression may improve treatment options and even lead to disease avoidance approaches. Our aim was to investigate the development of lymphocytosis prior to diagnosis in a population-based cohort of patients with CLL and to assess the prognostic information in these pre-diagnostic measurements. Methods: All patients diagnosed with CLL in the Greater Copenhagen area between 2008 and 2016 were included in the study. Pre-diagnostic blood test results were obtained from the Copenhagen Primary Care Laboratory Database encompassing all blood tests requested by Copenhagen general practitioners. Using pre-diagnostic measurements, we developed a model to assess the prognosis following diagnosis. Our model accounts for known prognostic factors and corresponds to lymphocyte dynamics after diagnosis. Results: We explore trajectories of lymphocytosis, associated with known recurrent mutations. We show that the pre-diagnostic trajectories are an independent predictor of time to treatment. The implementation of pre-diagnostic lymphocytosis slope groups improved the model predictions (compared to CLL-IPI alone) for treatment throughout the period. The model can manage the heterogeneous data that are to be expected from the real-world setting and adds further prognostic information. Conclusions: Our findings further knowledge of the development of CLL and may eventually make prophylactic measures possible.

Biochemical abnormalities among patients referred for celiac disease antibody blood testing in a primary health care setting.

To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000-2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD.

A retrospective cohort study of patients with eosinophilia referred to a tertiary centre.

INTRODUCTION: Patients with eosinophilia (an increased number of eosinophilic granulocytes > 0.5 × 108/l in the blood) are encountered in all medical specialties and frequently need thorough workup to identify the eliciting causes and decide whether treatment is indicated. In Denmark, highly specialised centres for eosinophilic diseases or conditions have been established to provide a foundation for the management of complicated cases. Here, we present experiences from such a multidisciplinary centre. METHODS: This was a retrospective study of all patients seen in our tertiary centre for eosinophilia in the 2016-2019 period. RESULTS: Referrals mainly derived from specialised secondary care and to a lesser degree from primary care physicians. Patients were either asymptomatic or exhibited symptoms from up to three organ systems and presented a median eosinophil count of 1.7 × 108/l. Up to eight new clonality analyses or imaging studies per patient were performed after referral. One of these, T-cell receptor analysis, was performed frequently but provided limited information, whereas, e.g., flow cytometry proved more clinically applicable owing to its broader diagnostic range. In total, 51 patients were evaluated and classified as secondary (59%), myeloid neoplasm with PDGFRA rearrangement (2%), idiopathic hypereosinophilic syndrome (31%) and idiopathic hypereosinophilia (8%). CONCLUSION: The value of a multidisciplinary and versatile approach in a highly specialised centre has a positive impact on diagnostic processes as well as on the evaluation of treatment need. FUNDING: none. TRIAL REGISTRATION: not relevant.

A national Danish proof of concept on feasibility and safety of home -based intensive chemotherapy in patients with acute myeloid leukemia.

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211.