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Eva Futtrup Maksten,1,2,* Rasmus Rask Kragh Jørgensen,1,2,* Mathilde Selmar Pedersen,1,2 Kirsten Fonager,2,3 Rie Sander Bech,1,2 Ingolf Mølle,4 Andreas Due Ørskov,5 Claudia Schöllkopf,6 Ulrik Malthe Overgaard,6 Gunhild Nynke Thomsen,7 Tarec C El-Galaly,1,2 Marianne Tang Severinsen1,2 1Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department of Social Medicine, Aalborg University Hospital, Aalborg, Denmark; 4Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Hematology, Zealand University Hospital, Roskilde, Denmark; 6Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark; 7Department of Hematology, Odense University Hospital, Odense, Denmark*These authors contributed equally to this workCorrespondence: Eva Futtrup Maksten, Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Sdr. Skovvej 15, Aalborg, 9000, Denmark, Tel +45 97666864, Fax +45 97666323, Email efm@rn.dkPurpose: Most adult patients diagnosed with acute lymphoblastic leukemia (ALL) are below retirement age. The overall survival of patients with ALL has improved with implementation of high intensity pediatric-inspired treatment protocols. However, this treatment comes with a risk of long-term complications, which could affect the ability to work. The aim of this study was to investigate the risk of disability pension (DP) and return to work (RTW) for patients with ALL.Patients and Methods: Patients aged 18– 60 years diagnosed with ALL between 2005 and 2019 were identified in the Danish National Acute Leukemia Registry. Each patient was matched with five comparators from the general population on birth year, sex, and Charlson Comorbidity Index. The Aalen-Johansen estimator was used to calculate the cumulative risk of DP for patients and comparators from index date (defined as 1 year after diagnosis) with competing events (transplantation or relapse, death, retirement pension, or early retirement pension). Differences in cumulative incidences were calculated using Gray’s test. RTW was calculated as proportions one, three, and five years after the index date for patients holding a job before diagnosis.Results: A total of 154 patients with ALL and 770 matched comparators were included. The 5-year cumulative risk of DP was increased fivefold for patients with ALL compared with the general population. RTW was 41.7%, 65.7%, and 60.7% one, three, and five years after the index date, respectively.Conclusion: The risk of DP in patients with ALL increased significantly compared with the general population. Five years after the index date, RTW was 60.7% for patients with ALL.Keywords: acute lymphoblastic leukemia, disability pension, return to work

Eva Futtrup Maksten,1,2 Lasse Hjort Jakobsen,1,3 Kristian Hay Kragholm,4 Joachim Baech,1,2 Mikkel Porsborg Andersen,5 Jakob Madsen,1,2 Judit Mészáros Jørgensen,6 Michael Roost Clausen,7 Robert Schou Pedersen,8 Andriette Dessau-Arp,9 Thomas Stauffer Larsen,10 Christian Bjørn Poulsen,11 Anne Ortved Gang,12 Peter Brown,12 Kirsten Fonager,2,13 Tarec C El-Galaly,1,2 Marianne Tang Severinsen1,2 1Department of Haematology, Clinical Cancer Research Unit, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department Mathematical Sciences, Aalborg University, Aalborg, Denmark; 4Department of Cardiology & Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark; 5Department of Cardiology, Nordsjaellands Hospital, Hillerød, Denmark; 6Department of Haematology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Haematology, Vejle Hospital, Vejle, Denmark; 8Department of Medicine, Section of Haematology, Regionshospital Goedstrup, Goedstrup, Denmark; 9Department of Haematology, Hospital South West Jutland, Esbjerg, Denmark; 10Department of Haematology, Odense University Hospital, Odense, Denmark; 11Department of Haematology, Zealand University Hospital, Roskilde, Denmark; 12Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 13Department of Social Medicine, Aalborg University Hospital, Aalborg, DenmarkCorrespondence: Eva Futtrup Maksten, Department of Haematology, Clinical Cancer Research Unit, Aalborg University Hospital, Sdr. Skovvej 15, Aalborg, 9000, Denmark, Tel +45 97663872, Fax + 45 97666323, Email efm@rn.dkPurpose: 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.Keywords: lymphoma, disability pension, return to work

Josephine Galsklint,1 Søren Kold,2,3 Søren Risom Kristensen,1,2 Marianne Tang Severinsen,2,4 Inger Lise Gade2,4,5 1Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department of Orthopedic Surgery, Aalborg University Hospital, Aalborg, Denmark; 4Department of Hematology and Clinical Cancer Research, Aalborg University Hospital, Aalborg, Denmark; 5Department of Hematology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Marianne Tang Severinsen, Department of Hematology, University Hospital, Aalborg, Denmark, Email m.severinsen@rn.dkBackground: Healthcare databases can be a valuable source of epidemiological research regarding postoperative venous thromboembolism (VTE), ie, deep vein thrombosis (DVT) and pulmonary embolism (PE), following orthopedic procedures, but only if the diagnoses are valid. We examined the validity of VTE diagnosis codes in the Danish National Patient Registry (DNPR) by calculating their positive predictive value (PPV) and negative predictive value (NPV) versus actual medical records.Methods: We identified patients who had undergone lower limb surgery during the period 2009– 2019 at a hospital in the North Denmark Region. Of these, 420 patients had at least one VTE diagnosis registered in the DNPR within 180 days after lower limb surgery. Each patient with a VTE diagnosis was matched with two patients on age and sex, as well as type, location and period of surgery. The entire medical record and diagnostic imaging were reviewed to confirm VTE diagnosis.Results: The overall PPVs was 85.2% (95% CI: 81.5– 88.5%) for first time VTE diagnosis following lower limb surgery, 82.6% (95% CI: 77.5– 82.8%) for DVT, and 90.3% (95% CI: 84.3– 94.6%) for PE. We found improvement in PPV during the study period when stratifying for three periods of the whole period. There were no significant differences when stratifying for sex, age, or surgery site. All negative predictive values were higher than 99%. A total of 113 additional VTE diagnoses were registered among 88 VTE patients during follow-up. Only four of the suspected recurrent VTEs were confirmed to be true recurrent VTEs.Conclusion: The VTE diagnosis codes in the DNPR after lower limb orthopedic surgery were highly valid against the actual medical records, and we observed better PPV over recent years.Keywords: epidemiology, venous thromboembolism, orthopedic procedures, positive predictive value, PPV, negative predictive value, NPV, validity

Oda Jensen,1 Andreas Kiesbye Øvlisen,1,2 Lasse Hjort Jakobsen,1,2 Anne Stidsholt Roug,1,2 René Ernst Nielsen,2,3 Claus Werenberg Marcher,4 Lene Hyldahl Ebbesen,5 Kim Theilgaard-Mönch,6 Peter Møller,7 Claudia Schöllkopf,8 Christian Torp-Pedersen,9,10 Tarec Christoffer El-Galaly,1,2 Marianne Tang Severinsen1,2 1Department of Haematology, Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark; 4Department of Haematology, Odense University Hospital, Odense, Denmark; 5Department of Haematology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Haematology, Rigshospitalet, Copenhagen, Denmark; 7Department of Haematology, Roskilde Sygehus, Roskilde, Denmark; 8Department of Haematology, Herlev Hospital, Herlev, Denmark; 9Unit of Clinical Biostatistics and Epidemiology, Aalborg University Hospital, Aalborg, Denmark; 10Department of Cardiology, Nordsjællands Hospital, Hillerød, DenmarkCorrespondence: Marianne Tang Severinsen, Department of Haematology, Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark, Email m.severinsen@rn.dkIntroduction: The diagnosis of a life-threatening disease can lead to depression and anxiety resulting in pharmacological treatment. However, use of psychotropic drugs (antidepressants, anxiolytics, and antipsychotics) in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) is undetermined.Methods: Prescription of psychotropic drugs in Danish AML and MDS patients was compared to a cohort matched on age, sex, and country of origin from the Danish background population using national population-based registries.Results: In total, 2404 AML patients (median age 69 years) and 1307 MDS patients (median age 75 years) were included and each matched to five comparators from the background population. Two-year cumulative incidences showed that AML (20.6%) and MDS (21.2%) patients had a high risk of redemption of a psychotropic drug prescription compared to the background population (7.0% and 7.9%). High age, low educational level, and Charlson Comorbidity Index score ≥ 1 was associated with a higher risk in AML and MDS patients. Furthermore, non-curative treatment intent and performance status in AML patients, and high risk MDS were associated with elevated risk of psychotropic drug prescription.Conclusion: In conclusion, diagnoses of AML and MDS were associated with a higher rate of psychotropic drugs prescription compared to the background population.Keywords: acute myeloid leukaemia, myelodysplastic syndrome, depression, anxiety, psychotropic drugs

Tine Bichel Lauritsen,1 Jan Maxwell Nørgaard,1 Kirsten Grønbæk,2– 4 Anders Pommer Vallentin,5 Syed Azhar Ahmad,6 Louise Hur Hannig,7 Marianne Tang Severinsen,8,9 Kasper Adelborg,10,11 Lene Sofie Granfeldt Østgård11,12 1Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 3Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark; 4Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 5Zealand University Hospital, Roskilde, Denmark; 6Department of Hematology, Herlev Hospital, Herlev, Denmark; 7Department of Hematology, Vejle Hospital, Vejle, Denmark; 8Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; 9Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 10Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 12Department of Hematology, Odense University Hospital, Odense, DenmarkCorrespondence: Tine Bichel LauritsenDepartment of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200 Email tinelaur@rm.dkBackground: The Danish Myelodysplastic Syndromes Database (DMDSD) comprises nearly all patients diagnosed with myelodysplastic syndromes (MDS) in Denmark since 2010. The DMDSD has not yet been used for epidemiological research and the quality of registered variables remains to be investigated.Objective: To describe characteristics of the patients registered in the DMDSD and to calculate predictive values and the proportion of missing values of registered data records.Methods: We performed a nationwide cross-sectional validation study of recorded disease and treatment data on MDS patients during 2010– 2019. Patient characteristics and the proportion of missing values were tabulated. A random sample of 12% was drawn to calculate predictive values with 95% confidence intervals (CIs) of 48 variables using information from medical records as a reference standard.Results: Overall, 2284 patients were identified (median age: 76 years, men 62%). Of these, 10% had therapy-related MDS, and 6% had an antecedent hematological disease. Hemoglobin level was less than 6.2 mmol/L for 59% of patients. Within the first two years of treatment, 59% received transfusions, 35% received erythropoiesis-stimulating agents, and 15% were treated with a hypomethylating agent. For the majority of variables (around 80%), there were no missing data. A total of 260 medical records were available for validation. The positive predictive value of the MDS diagnosis was 92% (95% CI: 88– 95). Predictive values ranged from 64% to 100% and exceeded 90% for 36 out of 48 variables. Stratification by year of diagnosis suggested that the positive predictive value of the MDS diagnosis improved from 88% before 2015 to 95% after.Conclusion: In this study, there was a high accuracy of recorded data and a low proportion of missing data. Thus, the DMDSD serves as a valuable data source for future epidemiological studies on MDS.Keywords: myelodysplastic syndromes, cohort, validation, accuracy, database

Inger Lise Gade,1,2 Marianne Tang Severinsen,2,3 Kristian Hay Kragholm,4,5 Søren Risom Kristensen,1,3 Christian Torp-Pedersen,3,5,6 Signe Juul Riddersholm7 1Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 2Department of Hematology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; 3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 4Department of Cardiology, North Denmark Regional Hospital, Hjørring, Denmark; 5Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark; 6Department of Cardiology and Clinical Investigation, North Zealand Hospital, Hillerød, Denmark; 7Department of Medicine, Randers Regional Hospital, Randers, DenmarkCorrespondence: Inger Lise GadeDepartment of Hematology, Aalborg University Hospital, Mølleparkvej 4, Aalborg 9000, DenmarkTel +45 61656584Email inlg@rn.dkBackground: Venous thromboembolism (VTE) is a serious, yet preventable, complication in cancer. Some patients are diagnosed with a second cancer; however, little is known about the epidemiology of VTE in this population.Methods: From Danish national healthcare registries, we studied all patients diagnosed with a first breast, prostate, lung, or colorectal cancer from 1995 to 2015. We estimated incidence rates (IRs) of VTE according to the timing of the diagnosis of a second cancer. We controlled for confounder variables in Poisson regression models.Results: In total, 309,077 patients with a first breast, prostate, lung, or colorectal cancer were included in the study. A second cancer was diagnosed in 20,090 (6.5%) of these patients. In total, 11,908 VTEs were observed in the study period, 786 of these occurred after a diagnosis of second cancer. Second cancer types such as pancreas and stomach cancer were associated with fivefold higher IRs of VTE compared with second cancer types such as breast and prostate cancer. The IR of VTE was highest within the first 6 months after the second cancer was diagnosed (IR 40.5 per 1000 person-years, 95% CI 36.3– 42.2) with no differences based on how long since the first cancer it was diagnosed.Conclusion: The epidemiology of VTE after a second cancer is similar to the epidemiology of VTE after a first cancer with higher rates within the first months after aggressive second cancer types.Keywords: venous thromboembolism, second cancer, epidemiology, incidence, cancer

Michael Tøstesen,1 Mette Nørgaard,2 Jan Maxwell Nørgaard,3 Bruno C Medeiros,4 Claus Werenberg Marcher,5 Ulrik Malthe Overgaard,6 Marianne Tang Severinsen,7 Claudia Schoellkopf,8 Lene Sofie Granfeldt Østgård1–31Department of Clinical Medicine, Holstebro Regional Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Hematology, Stanford University, School of Medicine, Stanford, CA, USA; 5Department of Hematology, Odense University Hospital, Odense, Denmark; 6Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark; 7Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 8Department of Hematology, Herlev University Hospital, Herlev, DenmarkCorrespondence: Lene Sofie Granfeldt ØstgårdDepartment of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, DenmarkTel +45 2 972 8127Email lenoestg@rm.dkBackground: Treatment of acute myeloid leukemia (AML) is widely centralized. Longer distances to a specialized treatment center may affect patients’ access to curative-intended treatment. Especially during outpatient treatment, distance may also affect survival.Methods and patients: The authors conducted a national population-based cohort study including all AML patients diagnosed in Denmark between 2000 and 2014. We investigated effects of distance (100) to the nearest specialized treatment facility on the probability of receiving intensive chemotherapy, HSCT, and achieving a complete remission (CR) using logistic regression analysis (odds ratios; ORs). For overall survival, we used Cox proportional hazards regression (hazard ratios [HRs]) and adjusted (a) for relevant baseline characteristics.Results: Of 2,992 patients (median age=68.5 years), 53% received intensive chemotherapy and 12% received low-dose chemotherapy outpatient regimens. The median distance to a specialized treatment center was 40 km (interquartile range=10–77 km). No impact of distance to specialized treatment centers was seen on the probability of receiving intensive chemotherapy (10–25 km, aOR=1.1 (CI=0.7–1.7), 25–50 km, aOR=1.1 (CI=0.7–1.7), 50–100 km, aOR=1.3 (CI=0.9–1.9), and >100 km, aOR=1.4 [CI=0.9–2.2]). Overall survival in patients regardless of therapy (100 km, aOR=1.0 [CI=0.9–1.2]), in intensive therapy patients, or in patients’ choice of post-remission was not affected by distance to specialized treatment center. Distance to a transplant center also did not affect the probability of HSCT or survival post-HSCT.Conclusion: In Denmark, distance to a specialized treatment facility offering remission-induction chemotherapy and HSCT does not negatively affect access to curative-indented therapy, treatment-response, or survival in AML patients.Keywords: hematology, allogeneic transplantation, socioeconomics, prognosis, epidemiology

Lene Sofie Granfeldt Østgård,1–3 Mette Nørgaard,2 Lars Pedersen,2 René Østgård,4 Lone Smidstrup Friis,5 Claudia Schöllkopf,6 Marianne Tang Severinsen,7,8 Claus Werenberg Marcher,9 Bruno C Medeiros,10 Morten Krogh Jensen11 1Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Medicine, Holstebro Regional Hospital, Holstebro, Denmark; 4Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark; 5Department of Hematology, The University Hospital Rigshospitalet, Copenhagen, Denmark; 6Department of Hematology, Herlev University Hospital, Herlev, Denmark; 7Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 8Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 9Department of Hematology, Odense University Hospital, Odense, Denmark; 10Stanford University, School of Medicine, Stanford, CA, USA; 11Department of Hematology, Roskilde University Hospital, Roskilde, Denmark Background: Most cases of acute leukemia arise without identifiable risk factors. Studies investigating the impact of autoimmune diseases and infections on leukemogenesis have revealed conflicting results. If inflammation increases the risk of acute myeloid leukemia (AML), ­nonsteroidal anti-inflammatory drug (NSAID) use may decrease the risk of leukemia.Methods: We conducted a case-control study of 3,053 patients with AML diagnosed between 2000 and 2013, who were registered in the Danish National Acute Leukemia Registry, and 30,530 population controls matched on sex and age. We identified prescriptions through the Danish National Health Service Prescription Database. We used conditional logistic regression analysis to compute ORs associating AML with NSAID use overall, in patients with inflammatory diseases, and for specific AML subtypes (de novo AML, AML related to previous hematological disease, ie, secondary AML [sAML], or therapy-related AML [tAML; exposed to previous cytotoxic therapy]).Results: Overall, NSAID use was not associated with a lower risk of AML (OR 1.1, 95% CI=1.0–1.2), de novo AML (OR 1.0, 95% CI=0.9–1.1), and sAML/tAML (OR 1.3, 95% CI=1.1–1.5). In addition, in patients with known inflammatory diseases, NSAIDs did not affect AML risk (OR 0.9, 95% CI=0.5–1.6). Number of prescriptions, type of NSAID, age, or sex did not influence the results.Conclusion: In line with our recent findings that showed no association between autoimmune diseases and infections and de novo AML, NSAID use was not found to reduce the risk of AML. Keywords: acute myeloid leukemia, population controls, population-based, risk, NSAIDs, inflammation

Lene Sofie Granfeldt Østgård,1,2 Jan Maxwell Nørgaard,1 Klas Kræsten Raaschou-Jensen,3 Robert Schou Pedersen,4 Dorthe Rønnov-Jessen,5 Per Troellund Pedersen,6 Inge Høgh Dufva,7 Claus Werenberg Marcher,8 Ove Juul Nielsen,9 Marianne Tang Severinsen,10,11 Lone Smidstrup Friis9 1Department of Hematology, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3Department of Hematology, Copenhagen University Hospital, Roskilde, 4Department of Medicine, Holstebro Hospital, Holstebro, 5Department of Hematology, Vejle Hospital, Vejle, 6Department of Medicine, Esbjerg Hospital, Esbjerg, 7Department of Hematology, Copenhagen University Hospital, Herlev, 8Department of Hematology, Odense University Hospital, Odense, 9Department of Hematology, The National University Hospital, Rigshospitalet, Copenhagen, 10Department of Hematology, Aalborg University Hospital, Aalborg, Denmark, 11Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 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. Keywords: data quality, registries, population-based, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome

Hilde Jensvoll,1,2 Marianne T Severinsen,3,4 Jens Hammerstrøm,5 Sigrid K Brækkan,1,2 Søren R Kristensen,4,6 Suzanne C Cannegieter,7 Kristine Blix,1,2 Anne Tjønneland,8 Frits R Rosendaal,1,7,9 Olga Dziewiecka,1 Kim Overvad,10,11 Inger Anne Næss,12 John-Bjarne Hansen1,21Department of Clinical Medicine, KG Jebsen – Thrombosis Research and Expertise Center (TREC), UiT – The Arctic University of Norway, 2Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway; 3Department of Hematology, Aalborg University Hospital, 4Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 5Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 6Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 7Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 8Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark; 9Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands; 10Department of Cardiology, Aalborg University Hospital, Aalborg, 11Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; 12Department of Hematology, Trondheim University Hospital, Trondheim, NorwayBackground: Although venous thromboembolism (VTE) is a known common complication in cancer patients, there is limited knowledge on patient-related and cancer-specific risk factors in the general population. The Scandinavian Thrombosis and Cancer (STAC) Cohort was established by merging individual data from three large Scandinavian cohorts (The Tromsø Study, the second Nord-Trøndelag Health Study, and the Danish Diet, Cancer and Health Study). Here, we present the profile of the STAC cohort and provide age-specific incidence rates of VTE and cancerMethods: The STAC cohort includes 144,952 subjects aged 19–101 years without previous VTE or cancer. Baseline information collected in 1993–1997 included physical examination, self-administered questionnaires, and blood samples. Validated VTE events and cancer diagnoses were registered up to 2007–2012.Results: There were 2,444 VTE events (1.4 per 1,000 person-years [PY]) during follow-up, and the incidence increased exponentially from 0.3 per 1,000 PY in subjects aged 20–29 years to 6.4 per 1,000 PY in subjects aged 80+. Overall, 51% of the VTE events were provoked, and cancer was the most common provoking factor (19%), followed by immobilization and surgery (both 15%). In total, 19,757 subjects developed cancer during follow-up (9.8 per 1,000 PY), and the 5-year age-specific incidence rates of cancer were coherent with corresponding rates from the Norwegian Cancer Registry.Conclusion: The STAC cohort will provide a unique opportunity to explore the epidemiology and impact of genetic and environmental patient-related and cancer-specific risk factors for VTE in the general population.Keywords: venous thromboembolism, incidence rates, person-years, pulmonary embolism, population-based cohort, prospective, cancer

Lene Sofie Granfeldt Østgård,1,2 Jan Maxwell Nørgaard,1 Marianne Tang Severinsen,3 Henrik Sengeløv,4 Lone Friis,5 Morten Krogh Jensen,6 Ove Juul Nielsen,7 Mette Nørgaard2 1Department of Hematology, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 5Department of Hematology, Odense University Hospital, Odense, Denmark; 6Department of Hematology, Herlev Hospital, Herlev, Denmark; 7Department of Hematology, Rigshospitalet, Copenhagen, Denmark Background: The Danish National Acute Leukemia Registry (DNLR) has documented coverage of above 98.5%. Less is known about the quality of the recorded data. Objective: To describe the present coverage of the DNLR, its completeness, and accuracy of individual variables for acute myeloid leukemia (AML). Furthermore, as a second measure of true coverage of the DNLR, to estimate AML incidence in Denmark from DNLR data and compare it to incidence reported from other AML registries. Patients and methods: By the end of December 2011, the DNLR (established January 2000) included detailed data on a large, well-defined, and nonselected Danish population of 2,665 AML patients. We estimated positive predictive values (PPVs) and completeness for 30 variables, which included patient and disease characteristics, treatment, and treatment outcomes. We identified 260 AML patients (10% of all AML patients recorded in the DNLR). We used information from medical records as the gold standard. Results: Using the Danish National Registry of Patients as a reference, the coverage of the DNLR was 99.6%. The PPVs of the individual variables ranged from 89.4% to 100%. The completeness of individual variables varied between 60.7% and 100%. Stratification by time of registration in the DNLR (before 2006 versus 2006 and later) revealed higher PPVs and lower frequencies of missing data from 2006. Sex-adjusted incidence rates were 6.2/100,000 person-years (95% confidence interval 5.8–6.6) in males and 4.9/100,000 person-years (95% confidence interval 4.5–5.4) in females. Yearly incidence rates of AML were higher than the incidence rates reported from Sweden (4.5 and 4.2/100,000) and the US (4.5 and 3.1/100,000 in Caucasians). Conclusion: With few exceptions, there were high values for PPVs and completeness of recorded data. Data accuracy and completeness have improved since the registry was established. The estimated incidence may indicate that the DNLR truly is more complete than other registries. In conclusion, the DNLR is a valuable resource for clinical research of AML. Keywords: acute myeloid leukemia, incidence, registration completeness, validation studies

Background: Previous studies have shown continuous improved overall survival (OS) up to 2015 for young adults with acute lymphoblastic leukaemia (ALL). However, recently several important advances have been made justifying a more contemporary analysis of outcomes in adult with ALL., Methods: In this nationwide population-based cohort study, we included patients above 18 years of age diagnosed with ALL between January 1, 1998, and December 31, 2020. Patients were followed until December 31, 2022. By employing flexible parametric survival models, we quantified progress in OS using the key endpoint of 2-year age standardized OS for all patients and clinical subgroups of interest., Findings: This study includes 657 patients and demonstrates a significant improvement in OS over time with the 2-year age standardized OS increasing from 36·4 % (95 % CI, 27·0-45·8 %) for patients diagnosed in 1998 to 68·6 % (95 % CI, 60·2-76·9)for patients diagnosed in 2020, corresponding to an absolute increase in 2-year OS of 32·2 % points (95 % CI, 19·1-45·2). Stratified analysis revealed improvements for both Philadelphia chromosome positive and negative ALL, across cytogenetic risk groups, and for B- and T-cell ALL, whereas the latter did not reach statistical significance. Improvements were seen across all ages; however, most pronounced for Philadelphia chromosome positive ALL and patients below 60 years of age., Interpretation: These results show a universal and continuous improvement in the treatment of adult ALL. Currently, novel treatment combination and advances in cellular therapy occur rapidly, and we expect even further improvements in the years to come., Funding: Northern Region of Denmark., Competing Interests: Declaration of Competing Interest D.T.K: Consulting/advisory board: AbbVie, Atheneum, Astellas Pharma (non-related, potential); A.S.R: Consulting fees: AbbVie. Travel grant; Jazz Pharmaceuticals (non-related, potential). Other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Hospital discharge diagnoses from administrative registries are frequently used in studies of cancer-associated venous thromboembolism, but the validity of International Classification of Diseases (ICD) codes for identifying such events is unknown., Materials and Methods: Using patient samples from the Danish National Patient Register, we calculated positive predictive values (PPV), i.e., the proportion of registered ICD codes, which could be confirmed after manual search of the electronic health record. Sensitivity was estimated in a sample of patients with imaging-verified venous thromboembolism but without prior knowledge about their ICD coding status. Sensitivity was calculated as the proportion of these patients, who were discharged with an ICD code for venous thromboembolism., Results: The overall PPV of an ICD-10 diagnosis of cancer-associated venous thromboembolism was 75.9 % (95 % confidence interval 71.3-80.0). In subgroups, the PPV was particularly low for recurrent venous thromboembolism (44.2 %), diagnoses in a secondary position (55.7 %), outpatient diagnoses (65.3 %), and diagnoses given at surgical (66.7 %), emergency wards (48.4 %), or via hospices/palliative teams (0 %). The overall sensitivity was 68 %, meaning 32 % of patients with cancer diagnosed in hospital with venous thromboembolism were discharged without any registered ICD code for venous thromboembolism., Conclusions: The positive predictive value of an ICD diagnosis of cancer-associated venous thromboembolism in the Danish Patient Register was overall adequate for research purposes, but with notable variation across subgroups. Sensitivity was limited, as 1/3 of patients with venous thromboembolism were discharged without any relevant ICD code. Cautious interpretation of incidence of cancer-associated venous thromboembolism based on administrative register-based data is warranted., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Previous studies have suggested that metformin has beneficial effects beyond its glucose-lowering properties, particularly in terms of its potential as an antineoplastic and cancer-preventive agent. In this study, we aimed to investigate the association between metformin use and the risk of myeloproliferative neoplasms (MPN). We conducted a population-based case-control study using Danish registers. Cases with MPN diagnosed between 2010 and 2018 were identified, and metformin use before the MPN diagnosis was ascertained. We compared metformin use among cases with MPN and an age- and sex-matched control group from the Danish general population to estimate age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs) for the association between metformin use and risk of MPN. The study population included 3816 cases and 19 080 controls. Overall, 7.0% of cases and 8.2% of controls were categorized as ever-users of metformin, resulting in an OR for MPN of 0.84 (95% confidence interval [CI], 0.73-0.96) and an aOR of 0.70 (95% CI, 0.61-0.81). Long-term metformin use (≥5 years) was more infrequent and comprised 1.1% of cases and 2.0% of controls, resulting in an OR of 0.57 (95% CI, 0.42-0.79) and an aOR of 0.45 (95% CI, 0.33-0.63). A dose-response relationship was observed when cumulative duration of treatment was analyzed, and this was consistent in stratified analyses of sex, age, and MPN subtypes. In conclusion, metformin use was associated with significantly lower odds of an MPN diagnosis, indicating its potential cancer-preventive effect. Given the retrospective design, causality cannot be inferred., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000-2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57-58%) for Danish-born patients, 57% (55-60%) for Western, and 56% (53-58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5-2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13-1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level., (© 2024. The Author(s).)

Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Late toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin-containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population-based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age- and sex-matched comparators from the background population. Median follow-up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30-3.68]), with a 10-year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35-26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43-2.76]), with a 10-year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43-1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B-symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work-up of pulmonary symptoms., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To explore haematological cancer survivors' experience of chemotherapy-induced peripheral neuropathy (CIPN) in everyday life., Methods: Data were generated by means of individual semi-structured interviews with 12 haematological cancer survivors who experience CIPN after completion of treatment. Data were analysed using thematic analysis., Results: The thematic analysis yielded an in-depth description of the experience of CIPN symptoms and the influence of the symptoms on everyday life as being unwell despite being cured. Four main themes emerged from the analysis: (1) A diffuse and contradictory sensation which is impossible to ignore in everyday life, (2) Not feeling well, even though I'm cured, (3) Living with CIPN, despite limitations, and (4) An invisible companion, that everybody knows about., Conclusion: The findings shows that survival from haematological cancer does not always equal well-being, as experiencing CIPN has extensive consequences on everyday life. CIPN affects haematological cancer survivors' transition to an ordinary everyday life, with disturbances in the physical function, daily activities, social relationships, psychological aspects, and work ability. As a diffuse and contradictory symptom, CIPN appears as an invisible companion that leads to a feeling of being alone., Implications for Cancer Survivors: A better and deeper understanding of haematological cancer survivors' experience of CIPN in everyday life may improve communication, guidance, and treatment of CIPN symptoms. The results suggest a need for interventions and strategies to accommodate the gap in practice and to address the impact of CIPN in everyday life., (© 2024. The Author(s).)

Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)-bendamustine versus G/R-CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2-17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Importance: In recent years, there has been a focus on reducing the socioeconomic gap in survival for hematological malignant neoplasms. Understanding recent developments is important to develop further intervention to improve care., Objective: To investigate the temporal trend in associations of socioeconomic status (SES) with survival among 3 aggressive hematological malignant neoplasms: multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL)., Design, Setting, and Participants: This nationwide, population-based cohort study used retrospectively collected data from 3 clinical registries of patients diagnosed in Denmark between January 1, 2005, and December 31, 2020, with follow-up until December 31, 2021. Analyses were stratified by diagnosis year (2005-2009, 2010-2014, and 2015-2020). Participants were patients aged 25 to 65 years with hematological malignant neoplasms. Patients with missing data on education were excluded. Data were analyzed from October 14, 2022, to January 2, 2024., Exposure: Education was used as a proxy for SES and defined low- and high-SES groups based on the completion of tertiary education., Main Outcomes and Measures: The main outcome was overall survival (OS), analyzed using Kaplan-Meier (log rank) method and Cox proportional hazards regression adjusted for age, sex, performance status, comorbidities, and disease-specific prognostic indices. Two-year OS through time and survival difference were estimated using flexible parametric survival models., Results: A total of 5677 patients (median [IQR] age, 58 [51-62] years; 3177 [57.0%] male) were assessed, including 1826 patients with MM, 1236 patients with AML, and 2509 patients with DLBCL. The 2-year OS increased over time for patients with MM (78.8% [95% CI, 75.4%-82.3%] to 91.4% [95% CI, 89.3%-93.5%]), AML (42.2% [95% CI, 37.8%-47.1%] to 52.7% [95% CI, 48.0%-57.9%]), and DLBCL (80.1% [95% CI, 77.4%-82.8%] to 88.1% [95% CI, 86.0%-90.3%]). For MM and DLBCL, no association of SES with survival was observed after adjustment (MM: hazard ratio [HR], 0.99 [95% CI, 0.85-1.15]; DLBCL: HR, 1.08 [95% CI, 0.91-1.29]). For AML, a negative association was observed between low SES and survival (HR, 1.49 [95% CI, 1.25-1.76]), but the association was attenuated in recent years. The difference in hazard for patients with low SES and AML was observed in the first 2 years after diagnosis., Conclusions and Relevance: These findings suggest that survival has improved among patients with these hematological malignant neoplasms. While patients with MM and DLBCL had increased survival in all groups, disparities were observed in AML outcomes, primarily in the first years after diagnosis. These results suggest that differences originate in factors specific to AML.

Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m 2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of Competing Interest E.F.M., L.H.J., B.M., H.J., K.H.K., R.S.P., A.D-A., C.B.P., A.O.G., T.C.E-G., and M.T.S.: has nothing to declare. J.M.J.: Advisory board/consultancy: Roche, Giled/KITE, Novartis, Celgene/BMS, Abbvie, SOBI, Incyte, and Orion. M.R.C.: Consultancy: Gilead, AstraZeneca, AbbVie, Janssen, and Incyte. Travel Expenses: AbbVie, Genmab, and Roche. Speaker fee: Genmab. T.S.L.: Advisory Board: Roche, Gilead, Novartis, and BMS. P.B.: Advisory board/consultancy: Roche, Gilead and Swedish Orphar (SOBI)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains challenging and outcomes extremely poor. The introduction of venetoclax has transformed the treatment of AML and emerging data suggest that venetoclax-based therapy may enforce salvage treatment., Materials and Methods: In this nationwide Danish retrospective study, we analysed treatment outcomes of venetoclax-based salvage treatment for R/R AML between 2019 and 2022. Only venetoclax-naive patients who had previously received treatment with intensive chemotherapy therapy were included., Results: The cohort consisted of 43 R/R patients with a median age of 57 years. Nine (20.9%) were primary refractory and 34 (79.1%) patients had relapsed, including 21 after previous allogeneic stem cell transplantation. The overall response rate was 76.2% including 61.9% with composite complete remission (CRc: CR + CRi). Among CRc-responders with information on measurable residual disease (MRD), 8/13 (61.5%) obtained an MRD-negativity response. The overall survival was 9.3 months for all patients with an estimated 1-year overall survival of 34%. For CRc-responders the median overall survival was 13.3 months, and the median relapse-free survival was 12.8 months., Conclusion: Venetoclax-based salvage treatment for R/R AML produced high response rates; however, for most patients the response was of limited duration. This study is limited by an observational design and prone to selection bias., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

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.

Background: Second primary malignancies (SPMs) are known complications after chemotherapy, but the risk is not well characterised for patients with lymphoma treated with high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the rate of SPMs in this population relative to matched control individuals from the general population., Methods: In this retrospective, population-based cohort study, patients aged 18 years or older with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT in Denmark between Jan 1, 2001, and Dec 31, 2017, were included from the Danish Lymphoma Registry and matched (1:5) to control individuals from the general population on birth year and sex via the Danish Civil Registration System. Patients were eligible if they had a registered date of autologous HSCT and patients with primary CNS lymphoma were excluded. Exclusion criteria for both patients and matched control individuals were HIV infection, organ transplantation, or other malignancies before inclusion. The key endpoint was the incidence of SPMs assessed in all study participants. The effect of treatment on SPMs was also investigated in patients who were followed up from first lymphoma diagnosis, with high-dose chemotherapy and autologous HSCT as a time-dependent exposure., Findings: Of 910 patients with lymphoma assessed, 803 were included (537 [67%] were male and 266 [33%] were female); 4015 matched control individuals were included (2685 [67%] were male and 1330 [33%] were female). Ethnicity data were not available. Median follow-up was 7·76 years (IQR 4·77-11·73). The SPM rate was higher among patients receiving high-dose chemotherapy and autologous HSCT than matched control individuals (adjusted hazard ratio [HR] 2·35, 95% CI 1·93-2·87, p<0·0001). Patients receiving high-dose chemotherapy and autologous HSCT had a higher rate of non-melanoma skin cancer (2·94, 2·10-4·11, p<0·0001) and of myelodysplastic syndrome or acute myeloid leukaemia (AML; 41·13, 15·77-107·30, p<0·0001) than matched control individuals, but there was no significant difference in the rate of solid tumours (1·21, 0·89-1·64, p=0·24). The cumulative risk of SPMs at 10 years was 20% (95% CI 17-23) in patients compared with 14% (13-15) in matched control individuals. High-dose chemotherapy and autologous HSCT was associated with an increased risk of SPMs when analysed as a time-dependent exposure from first lymphoma diagnosis (adjusted HR 1·58, 95% CI 1·14-2·17, p=0·0054)., Interpretation: High-dose chemotherapy and autologous HSCT was associated with an increased risk of non-melanoma skin cancer and myelodysplastic syndrome or AML but not with increased risk of solid tumours in patients treated for lymphoma. These findings are relevant for future individualised risk-benefit assessments when choosing between high-dose chemotherapy and autologous HSCT and chimeric antigen receptor T-cell therapy in this setting., Funding: Danish Cancer Society., Competing Interests: Declaration of interests TT has received payment for teaching from The Danish Association of the Pharmaceutical Industry and financial support from Janssen–Cilag A/S Denmark. JB has received financial support from Gilead Sciences Denmark. LHJ has received honoraria for lectures, presentations, speakers' bureaus, manuscript writing, and educational events from Roche. SE has received grants from the Swedish Cancer Society, Åke Wiberg Foundations, and Karolinska Institutet Foundations; a travel grant from Nordic Cancer Union; and is a partner in Red Door Analytics. JSG has received financial travel support from Takeda. JMJ has received financial travel support from Gilead and has participated on safety monitoring boards or advisory boards for Gilead, Roche, Novartis, Abbvie, Swedish Orphan Biovitrum, Celgene, and Incyte. TSL has received a grant from Genentech; received payment for expert testimony and financial travel support from Roche; and has participated on data safety monitoring boards or advisory boards for Roche, Novartis, Gilead, and Bristol Myers Squibb. PB has participated on data safety monitoring boards or advisory boards for Gilead, Roche, Swedish Orphan Biovitrum, and Novartis. TCE-G has received payment for teaching from AbbVie and was previously employed at Roche. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies., (© 2023. The Author(s).)

Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and this combination is reported to result in poorer survival compared with cancer alone. This study aimed to investigate the impact of VTE on the survival of patients with cancer in a general population. The Scandinavian Thrombosis and Cancer (STAC) cohort, a population-based cohort including 144 952 participants without previous VTE or cancer, was used. During follow-up, cancer and VTE incidences were registered. "Cancer-related VTE" was defined as VTE diagnosed in patients with overt or occult cancer. The survival of participants without cancer and/or VTE ("disease-free") was compared with the survival of participants with cancer and cancer-related VTE. Cox regression models with cancer and VTE as time-varying exposures were performed to calculate hazard ratios for death. Subanalyses were performed across cancer types and stages and VTE type (deep vein thrombosis or pulmonary embolism). During follow-up (mean, 11.7 years), 14 621 participants developed cancer, and 2444 developed VTE, of which 1241 were cancer-related. The mortality rates (per 100 person years) for disease-free participants, VTE only, cancer only, and cancer-related VTE were 0.63, 5.0, 9.2, and 45.3, respectively. Compared with patients with cancer only, the risk of death for patients with cancer-related VTE was increased 3.4-fold. Within all cancer types, the occurrence of VTE increased the mortality risk 2.8- to 14.7-fold. In a general population, patients with cancer with VTE had a 3.4-fold higher mortality risk than patients with cancer without VTE, independent of cancer type., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients suffering from acute myeloid leukemia (AML) carry a high risk of serious bleeding complications due to severe thrombocytopenia for long periods of time during treatment. Prior to prophylactic platelet transfusion becoming the standard of care, intracranial bleeding was a major contributor to death in AML patients. However, despite prophylactic platelet transfusions, up to 79% of patients with AML experience clinically significant bleeding during treatment. Antifibrinolytics are effective and well tolerated hemostatic agents widely used in many patient groups, and in this study, we investigated the effect of low dose tranexamic acid (TXA) in patients with AML and thrombocytopenia. We compared bleeding and thrombosis between 113 thrombocytopenic AML patients receiving TXA 500 mg three times daily ( n  = 36) versus no-TXA ( n  = 77). Clinical information was obtained systematically from electronic medical records, and laboratory data were collected from the laboratory information system. No difference was demonstrated in number of patients with at least one bleeding episode (TXA: 89% vs. no-TXA: 93%, p  = 0.60), median number of bleeding days (TXA: 2.5 days vs. no-TXA 2.0 days, p = 0.30), bleeding location or transfusion needs between the two groups. However, platelet count was found to be a significant risk factor for bleeding, with a probability of bleeding of 35% with a platelet count below 5 × 10 9 /L (logistic regression, p  < 0.01). We found no difference in thromboembolic events between the two groups (TXA: 8% vs. no-TXA 10%, p  = 0.99). In conclusion, treatment with low dose TXA is safe, but we found no evidence to suggest that it reduces bleeding in AML patients with thrombocytopenia., Competing Interests: STB has no conflict regarding the present work but has received unrestricted research support from CSL Behring. AMH has no conflict of interest regarding the present work but has the following general conflict of interest: Unrestricted research support from CSL Behring. Other authors have no conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)-based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy-related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30- and 90-day mortality between DR and non-DR patients. Furthermore, DR did not affect median relapse-free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0-41.7) months; non-DR, 15.0 (12.3-19.3)] with an adjusted difference in five-year restricted mean survival time (Δ5y-RMST) of 0.2 (-8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non-DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y-RMST of 0.8 (-5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Patients admitted to an intensive care unit (ICU) with active haematological malignancy and hypoxaemic respiratory failure have a high mortality. Oxygen supplementation is essential, but limited information exists on the optimum oxygenation targets in these patients., Methods: This subgroup analysis was specified before completion of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial. The trial investigated the effects of a lower (8 kPa) vs a higher (12 kPa) arterial oxygenation target and was stratified for active haematological malignancy, chronic obstructive pulmonary disease, and site. We here report the primary outcome (90-day mortality) and selected secondary outcomes in the subgroup of patients with active haematological malignancy., Results: The HOT-ICU trial included 168 patients with active haematological malignancy; 82 were randomly allocated to an arterial oxygenation target of 8 kPa, and 86 to 12 kPa. At 90 days, 53/81 patients (65%) in the lower-oxygenation group and 47/86 patients (55%) in the higher-oxygenation group had died: adjusted relative risk 1.22 (95% confidence interval 0.95-1.56); at 1 year, the numbers were 58/81 (72%) vs 56/86 (65%): adjusted relative risk 1.11 (95% confidence interval 0.90-1.36). No statistically significant differences were found for any secondary outcomes., Conclusion: In ICU patients with active haematological malignancies and hypoxaemic respiratory failure, we found a high mortality at 90 days and 1 year. Our results did not preclude clinically relevant benefits or harms of a lower oxygenation target in patients with active haematological malignancy. A randomised trial may, therefore, be worthwhile for these patients., Clinical Trial Registration: NCT03174002., (© 2022 The Authors.)

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., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The Khorana score is recommended for guiding primary venous thromboembolism (VTE) prophylaxis in cancer patients, but its clinical utility overall and across cancer types remains debatable. Also, some previous validation studies have ignored the competing risk of death, hereby potentially overestimating VTE risk. We identified ambulatory cancer patients initiating chemotherapy without other indications for anticoagulation using Danish health registries and estimated 6-month cumulative incidence of VTE stratified by Khorana levels. Analyses were conducted with and without considering death as a competing risk using the Kaplan-Meier method vs the cumulative incidence function. Analyses were performed overall and stratified by cancer types. Of 40 218 patients, 35.4% were categorized by Khorana as low risk (score 0), 53.6% as intermediate risk (score 1 to 2), and 10.9% as high risk (score ≥3). Considering competing risk of death, the corresponding 6-month risks of VTE were 1.5% (95% confidence interval [CI], 1.3-1.7), 2.8% (95% CI, 2.6-3.1), and 4.1% (95% CI, 3.5-4.7), respectively. Among patients recommended anticoagulation by guidelines (Khorana score ≥2), the 6-month risk was 3.6% (95% CI, 3.3-3.9). Kaplan-Meier analysis overestimated incidence up to 23% compared with competing risk analyses. Using the guideline-recommended threshold of ≥2, the Khorana score did not risk-stratify patients with hepatobiliary or pancreatic cancer, lung cancer, and gynecologic cancer. In conclusion, the Khorana score was able to stratify ambulatory cancer patients according to the risk of VTE, but not for all cancer types. Absolute risks varied by methodology but were lower than in key randomized trials. Thus, although certain limitations with outcome identification using administrative registries apply, the absolute benefit of implementing routine primary thromboprophylaxis in an unselected cancer population may be smaller than seen in randomized trials., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Lymphoma patients often receive high glucocorticoid doses as part of standard therapy. Observational studies have shown a substantial risk of glucocorticoid-induced osteoporosis (GIO) with associated fractures. The aim of the SIESTA trial was to determine if oral alendronate (ALN) is a safe and effective prophylaxis against GIO in lymphoma. SIESTA was a single-center, randomized, double-blinded, phase 2 study of lymphoma patients planned for glucocorticoid-containing chemotherapy. After randomization, patients received weekly ALN 70 mg or placebo for a total of 52 weeks. Bone mineral density (BMD) was assessed at baseline, after completion of chemotherapy (end of treatment [EOT]) (4 to 6 months), and at the end of the study (EOS) (12 months). Vertebral fracture and biomarkers were assessed at baseline and EOS. Patients with baseline BMD assessment and at least 1 follow-up BMD assessment were analyzed for efficacy. The primary endpoint was a change in lumbar spine T-score from baseline to EOS. Of the 59 patients enrolled, 23 of 30 in the ALN arm and 24 of 29 in the placebo arm were analyzed for efficacy. The mean change in T-score from baseline to 12 months at the lumbar spine was +0.15 for ALN and -0.12 for placebo (P = .023). The difference in ΔTEOS between the ALN and placebo groups was larger among females (ALN 0.28; placebo -0.28; P = .01). Biomarker analyses confirmed reduced bone resorption in ALN-treated patients. In conclusion, ALN is a safe and effective primary prophylaxis against loss in BMD following glucocorticoid-containing chemotherapy. Despite reduced BMD loss in the ALN arm, the treatment did not influence fracture risk in this small cohort of patients., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments., Methods: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression., Results: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5., Conclusions: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression., Trial Registration: NCT01208766., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Background: Patients with hematological cancer who experience relapse or progressive disease often face yet another line of treatment and continued mortality risk that could increase their physical and emotional trauma and worsen their health-related quality of life. Healthcare professionals who use patient-reported outcomes to identify who will have specific sensitivities in particular health-related quality of life domains may be able to individualize and target treatment and supportive care, both features of precision medicine. Here, in a cohort of patients with relapsed or progressive hematological cancer, we sought to identify health-related quality of life domains in which they experienced deterioration after relapse treatment and to investigate health-related quality of life patterns., Method: Patients were recruited in connection with a precision medicine study at the Department of Hematology, Aalborg University Hospital. They completed the European Organization for Research and Treatment of Cancer questionnaire and the Hospital Anxiety and Depression Scale at baseline and at 3, 6, 9, and 12 months after the relapse diagnosis or progressive cancer. Modes of completion were electronically or on paper. Clinically relevant changes from baseline to 12 months were interpreted according to Cocks' guidelines. We quantified the number of patients with moderate or severe symptoms and functional problems and the number who experienced improvements or deterioration from baseline to 12 months., Results: A total of 104 patients were included, of whom 90 (87%) completed baseline questionnaires and 50 (56%) completed the 12-month assessments. The three symptoms that patients most often reported as deteriorating were fatigue (18%), insomnia (18%), and diarrhea (18%). The three functions that patients most often reported as deteriorating were role (16%) and emotional (16%) and cognitive (16%) functioning., Conclusion: In this study, patient-reported outcome data were useful for identifying negatively affected health-related quality of life domains in patients with relapsed or progressive hematological cancer. We identified patients experiencing deterioration in health-related quality of life during treatment and characterized a potential role for patient-reported outcomes in precision medicine to target treatment and supportive care in this patient group., (© 2021. The Author(s).)

Purpose: The majority of young adults with Hodgkin lymphoma (HL) are cured, but chemotherapy-induced infertility can have profound psychosocial consequences. Providing data on parenthood rates and use of assisted reproductive techniques (ARTs) after contemporary HL treatment is important for patient counseling and survivorship care., Materials and Methods: All Danish patients with HL diagnosed during 2000-2015 at the ages 18-40 years who achieved remission after first-line therapy were included and matched on age, sex, and parenthood status to five random persons from the general population. Parenthood rates were defined as the rate of first live birth per 1,000 person years, starting 9 months after HL diagnosis. Nationwide birth and patient registers were used to capture parenthood outcomes and ARTs use., Results: A total of 793 HL survivors and 3,965 comparators were included (median follow-up 8.7 years). Similar parenthood rates were observed for male and female HL survivors when compared with matched comparators (56.2 v 57.1; P = .871 for males and 63.8 v 61.2; P = .672 for females). For male HL survivors, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) therapy was associated with lower parenthood rates as compared to the matched comparators (28.1 v 60.8; P = .020). Live birth after ARTs were more common for HL survivors than for comparators (males 21.6% v 6.3%; P < .001; females 13.6% v 5.5%; P = .001). There were no differences in gestational age, Apgar score, or newborn measurements between HL survivors and matched comparators., Conclusion: The parenthood rates for HL survivors who have not experienced relapse were generally similar to the general population. However, ARTs were used more often before the first live birth in HL survivors, which is relevant information when discussing possible long-term side effects and fertility-preserving treatment options., Competing Interests: Andreas K. ØvlisenTravel, Accommodations, Expenses: Pfizer, AbbVie Lasse H. JakobsenHonoraria: Takeda Sandra ElorantaResearch Funding: JanssenOther Relationship: Janssen Martin HutchingsConsulting or Advisory Role: Takeda, Roche, Genmab, JanssenResearch Funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen Henrik FrederiksenConsulting or Advisory Role: AbbVie, NovartisResearch Funding: AbbVie, Gilead SciencesTravel, Accommodations, Expenses: Roche, AbbVie Rasmus Bo Dahl-SørensenTravel, Accommodations, Expenses: Takeda Caroline E. WeibullResearch Funding: Janssen Ingrid GlimeliusSpeakers' Bureau: Jansen Cilag Karin E. SmedbyResearch Funding: Janssen-Cilag Christian Torp-PedersenResearch Funding: Bayer, Novo Nordisk Tarec C. El-GalalyEmployment: RocheConsulting or Advisory Role: RocheOther Relationship: RocheNo other potential conflicts of interest were reported.

Myelodysplastic syndrome and acute myeloid leukaemia are neoplastic diseases caused by genetic alterations of the haematopoietic stem cells. Advances in sequencing techniques have led to a profound understanding of the underlying pathogeneses. Somatic mutations and chromosomal aberrations can be found in > 90% of the cases. The improved understanding of the pathogeneses has translated into better risk stratification and drug development. Somatic mutations may affect targetable protein-kinases or neomorphic enzymes, and new treatment options for specific molecular subgroups of patients are in the pipeline.