10-year nationwide trends in incidence, treatment patterns, and mortality of patients with myelodysplastic syndromes in Denmark.

Further temporal data on incidence, treatment patterns, and prognosis for patients with myelodysplastic syndromes (MDS) are needed. This study examined 10-year trends in incidence, treatment patterns, and all-cause mortality in a population-based cohort of 2309 MDS patients using Danish nationwide registries (2010-2019). We computed annual incidence rates overall and according to sex and age-groups. We examined temporal changes in the cumulative incidence of MDS specific treatments initiated within one year from diagnosis and temporal changes in the absolute risk of death and five-year adjusted hazard ratios (aHRs) for death, adjusting for age, sex and comorbidity. The age-standardized incidence rate of MDS per 100,000 person-years increased slightly from 5.3 in 2010 to 6.4 in 2019. Between 2010-2012 to 2016-2017, the use of azacitidine increased overall (8% to 22%), in patients with intermediate risk MDS (12% to 34%), and in patients with high-risk MDS (22% to 50%), while it remained stable (around 5%) for patients with low-risk MDS. The five-year aHR for death in the most recent calendar period compared to the earliest calendar period remained unchanged in patients with low-risk MDS, aHR = 0.90 (95% CI, 0.72-1.12) and in patients with high-risk MDS, aHR = 1.19 (95% CI, 0.89-1.61), while survival improved over time among patients with intermediate risk MDS, aHR = 0.67 (95% CI, 0.48-0.92). In conclusion the incidence of MDS slightly increased during a 10-year period in Denmark. The use of azacitidine increased markedly but five-year overall survival remained unchanged.

Socioeconomic position and clinical outcomes in patients with myelodysplastic syndromes: A population-based cohort study.

Low socioeconomic position (SEP) may be associated with adverse outcomes in patients with myelodysplastic syndromes (MDS) inherent to for example, delayed diagnosis or reduced treatment intensity, but firm evidence is limited. In this study, we examined the association between SEP and clinical outcomes. We conducted a population-based cohort study (2010-2018) of 2233 Danish patients with MDS. SEP measures included individual-level information on education, cohabitation status and income retrieved from Statistics Denmark. Associations between SEP measures and disease severity at diagnosis were examined using binomial regression analysis. Using time-to-event analysis, we examined the association between SEP measures and treatment with allogeneic stem cell transplantation (allo-HSCT), risk of progression to acute myeloid leukemia (AML), and death. Estimates were adjusted for covariates selected based on direct acyclic graphs and reported with 95% confidence intervals. Patients with a short education were more likely to be transfusion-dependent at diagnosis (RR = 1.25, 95% CI: 1.04-1.45) and more likely to be diagnosed with higher risk MDS according to the International Prognostic Scoring System (RR = 1.29, 95% CI: 1.03-1.62), than patients with a long education. We found no clear association between SEP and risk of progression to AML. In adjusted models, the 1-year risk of dying was higher in patients with short versus long education (RR = 1.34, 95% CI: 1.08-1.65), in patients with low versus high income (RR = 1.42, 95% CI: 1.14-1.77), and among patients who lived alone compared to those who lived with a partner (RR = 1.15, 0.98-1.35). These associations persisted after 3 years and 5 years of follow-up. Notably, patients with a short education had a markedly lower rate of undergoing treatment with allo-HSCT compared to patients with a long education (HR = 0.51, 95% CI: 0.31-0.84). In conclusion, low SEP and especially short education, were poor prognostic factors for adverse clinical outcomes among patients with MDS.

Positive predictive values of hematological procedure codes in the Danish National Patient Registry-A population-based validation study.

BACKGROUND: The Danish National Patient Registry holds data on hematological procedure codes including date and type of treatment from all hematological departments in Denmark. The validity of the hematological procedure codes remains to be clarified before they are used in epidemiological research. PATIENTS AND METHODS: Using the Danish Myelodysplastic Syndromes Database, we identified 897 patients diagnosed with myelodysplastic syndromes or chronic myelomonocytic leukemia treated at five Danish Hospitals between 1 January 2012 and 30 April 2019. From the Danish National Patient Registry, we ascertained information about hematological procedure codes and date of procedure registered on each patient and generated random samples. Using medical record review as the reference standard, we validated procedure codes in the Danish National Patient Registry and calculated positive predictive values (PPVs) with 95% confidence intervals (CIs) for each procedure code. RESULTS: A total of 523 medical records (99% of the total sample) were available for review. PPVs for specific procedure codes ranged from 71% to 100%. The overall PPV was 91% (95% CI: 88%-92%), reflecting PPVs of 95% (95% CI: 92%-97%) for low-dose-chemotherapy, 90% (95% CI: 81%-96%) for high-dose chemotherapy, 99% (95% CI: 93%-100%) for allogeneic stem cell transplantation, 75% (95% CI: 62%-85%) for immuno-modulating agents, 80% (95% CI: 74%-85%) for growth factors, and 99% (95% CI: 99%-100%) for bone marrow examination. The accuracy of coding was consistent across geographic regions and year of registration/coding. CONCLUSIONS: Hematological procedure codes reported to the Danish National Patient Registry had high PPVs and are suitable for epidemiological research.

The Danish Myelodysplastic Syndromes Database: Patient Characteristics and Validity of Data Records.

BACKGROUND: 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.

Longer distance to specialized treatment centers does not adversely affect treatment intensity or outcomes in adult acute myeloid leukemia patients. A Danish national population-based cohort study.

BACKGROUND: 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 (<10 kilometers [km; reference], 10-25, 25-50, 50-100, >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 (<10 km, aOR=1.0 vs >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.

Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: A National Population-Based Cohort Study.

To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.

Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study.

Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.

The Danish National Acute Leukemia Registry.

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

Improved outcome in acute myeloid leukemia patients enrolled in clinical trials: A national population-based cohort study of Danish intensive chemotherapy patients.

Clinical trials are critical to improve AML treatment. It remains, however, unclear if clinical trial participation per se affects prognosis and to what extent the patients selected for trials differ from those of patients receiving intensive therapy off-trial.We conducted a population-based cohort study of newly diagnosed Danish AML patients treated with intensive chemotherapy between 2000-2013. We estimated accrual rates and compared characteristics, complete remission (CR) rates, and relative risks (RRs) of death at 90-day, 1-year, and 3-years in clinical trial patients to patients treated off-trial.Of 867 patients, 58.3% (n = 504) were included in a clinical trial. Accrual rates were similar across age groups (p = 0.55). Patients with poor performance status, comorbidity, therapy-related and secondary AML were less likely to be enrolled in trials. CR rates were 80.2% in trial-patients versus 68.6% in patients treated off- trial. Also, trial-patients had superior survival at 1-year; 72%, vs. 54% (adjusted RR of death 1.28(CI = 1.06-1.54)), and at 3 years; 45% vs. 29% (adjusted RR 1.14(CI = 1.03-1.26)) compared to patients treated off-trial.Despite high accrual rates, patients enrolled in clinical trials had a favorable prognostic profile and a better survival than patients treated off-trial. In conclusion, all trial results should be extrapolated with caution and population-based studies of "real world patients" have a prominent role in examining the prognosis of AML.

Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

BACKGROUND: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. PROCEDURE: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. RESULTS: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. CONCLUSIONS: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study.

PURPOSE: Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. PATIENTS AND METHODS: In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. RESULTS: Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). CONCLUSION: Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

Data quality in the Danish National Acute Leukemia Registry: a hematological data resource.

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.

Mitochondrial cytochrome c oxidase subunit II variations predict adverse prognosis in cytogenetically normal acute myeloid leukaemia.

Alterations in the two catalytic genes cytochrome c oxidase subunits I and II (COI and COII) have recently been suggested to have an adverse impact on prognosis in patients with acute myeloid leukaemia (AML). In order to explore this in further detail, we sequenced these two mitochondrial genes in diagnostic bone marrow or blood samples in 235 patients with AML. In 37 (16%) patients, a non-synonymous variation in either COI or COII could be demonstrated. No patients harboured both COI and COII non-synonymous variations. Twenty-four (10%) patients had non-synonymous variations in COI, whereas 13 (6%) patients had non-synonymous variations in COII. The COI and COII are essential subunits of cytochrome c oxidase that is the terminal enzyme in the oxidative phosphorylation complexes. In terms of disease course, we observed that in patients with a normal cytogenetic analysis at disease presentation (CN-AML) treated with curative intent, the presence of a non-synonymous variation in the COII was an adverse prognostic marker for both overall survival and disease-free survival (DFS) in both univariate (DFS; hazard ratio (HR) 4.4, P = 0.006) and multivariate analyses (DFS; HR 7.2, P = 0.001). This is the first demonstration of a mitochondrial aberration playing an adverse prognostic role in adult AML, and we argue that its role as a potentially novel adverse prognostic marker in the subset of CN-AML should be explored further.

Characterization and prognostic significance of mitochondrial DNA variations in acute myeloid leukemia.

Recent studies have suggested that mutations in the mitochondrial genome (mtDNA) may play a role in the development and response to treatment for human cancer. The aim of this study was to investigate whether mtDNA variations have any prognostic relevance, to clarify the spectra of mtDNA variation and to determine whether there was any correlation to known prognostic factors in acute myeloid leukemia (AML). To elucidate this, we sequenced the entire mtDNA in 56 AML patients and 14 control subjects. When analyzing the biologic impact of the non-synonymous variations in the mtDNA coding genes, we found an inferior disease-free survival for patients exhibiting variations in the two most important catalytic genes of the complex IV of the oxidative phosphorylation complexes (OXPHOS), that is, the cytochrome c oxidase subunit I and the cytochrome c oxidase subunit II (hazard ratio 2.6, P = 0.03; multivariate analysis). In addition, the most frequent variation was the T16311C in the control region, which was found in 11 (20%) of the 56 patients. This observation was confirmed in another cohort of 173 diagnostic AML samples. In this expanded group, the T16311C variation tended to be associated with chromosomal abnormalities.