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Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population-based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008–2017) were included. Up to 50 CLL-free matched comparators were identified. First-line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3–1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2–19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.

Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997–2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.

Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997-2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.

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

We present a case of Ruminococcus gnavus sepsis in a woman suffering from multiple myeloma and myelodysplastic syndrome. R. gnavus , a Gram-positive coccus and a gut commensal, has been described in nine cases of infection in the literature, with most infections having occurred in patients with either gastrointestinal symptoms or prosthesis infections. In this case, R gnavus was identified by mass spectrometry, and showed susceptibility to penicillin, meropenem, tetracycline, metronidazole and clindamycin. The patient was successfully treated initially with intravenous piperacillin/tazobactam and metronidazole, and then switched to oral penicillin and metronidazole. The cause of infection is hypothesized to have been a shift in the gut microbiota towards an excess growth of R. gnavus caused by immunosuppression, and bacterial translocation across a vulnerable mucosal barrier due to prednisolone treatment and severe thrombocytopenia.

Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.

Introduction In chronic lymphocytic leukemia (CLL), few randomized clinical trials include patients who are older or have significant comorbidity, despite constituting a large proportion of the CLL-population. Therefore, detailed data on the association of specific comorbidities with CLL-prognosis are missing and decisions on treatment and follow-up are poorly informed in comorbid patients. We present data on the association of comorbidity with prognostic factors, treatment patterns and causes of death in patients from the world's largest cohort of unselected CLL-patients. Methods All patients diagnosed with CLL in the CLL-registry (2008-2017) or the Danish Cancer Register (1997-2017) were followed through the Civil Registration System from 1 month after CLL-diagnosis until death, emigration or January 2017. Data from Danish nationwide population-based health registers were linked through personal unique identification numbers. Data on comorbidities based on the modified Charlson Comorbidity Index was attained from the Danish National Patient Register, from 20 years prior to the CLL-diagnosis and until 1 month after. Multimorbidity was defined as ≥ 2 comorbidities. Prognostic baseline data such as Binet Stage, IGHV-status, cytogenetics and β2-microglobuline (B2M) level were available through the CLL-registry. Causes of death were ascertained through the National Register of Causes of Death, further sub-categorized as CLL-related (including CLL, all other malignancies and infections) and CLL-unrelated death. Hazard ratios (HR) for mortality were calculated using Cox regression models, adjusting for age, sex, calendar period (5-year intervals) and internally for all other comorbidities. The association between IGHV-status and overall survival (OS) and treatment-free survival (TFS) was assessed by means of Kaplan-Meier and fully adjusted Cox models, stratifying for age and comorbidity-burden. Results The study included 8055 patients with a median follow-up time of 4.2 years; 59 % were male and the median age at diagnosis was 71 years. Overall 2816 patients (35%) were comorbid and 965 (12%) multimorbid. At diagnosis 818 (10%) patients had a history of chronic heart failure or myocardial infarction, 672 (8%) cerebrovascular disease, 626 (8%) diabetes (type 1 or 2), 620 (8%) chronic pulmonary disease, 399 (5%) peripheral vascular disease, 307 (4%) peptic ulcer, 264 (3%) connective tissue disease, 172 (2%) psychiatric disease, 148 (2%) renal disease, 87 (1%) dementia and 86 (1%) hepatic disease. Elevated B2M (>4.0 mg/L) was more common in comorbid (20%) and multimorbid (24%) patients compared with non-comorbid (11%), while Binet Stage B/C, unmutated IGHV-status and del(17p) were evenly distributed across the groups (18-20%, 31-33% and 6-8%, respectively). Among comorbid patients, 56% died during follow-up, compared with 42% among non-comorbid patients. For comorbid patients, death was more commonly caused by cardiovascular disease (14% vs 6%) or other causes (14% vs 10%), while hematological malignancy was less common (25% vs 34%) compared with non-comorbid patients. Other malignancies (11% vs 13%), infection (34% vs 35%) and cerebrovascular disease (2% vs 2%) were equally common causes of death in the two groups. All individual comorbidities were associated with increased all-cause mortality. Except for connective tissue disease, dementia and chronic pulmonary disease, all comorbidities were associated with increased CLL-related mortality (Fig 1A) and as for CLL-unrelated mortality, only ulcer disease, psychiatric disease, renal disease and connective tissue were not associated with an increase. Unmutated IGHV status was associated with inferior TFS for all patients regardless of age and comorbidity burden (range of HRs 1.47-3.70), while IGHV status was associated with inferior OS for non-comorbid patients only (range of HRs 1.43-1.66). Of comorbid patients who died from CLL-related causes, 59% had not received treatment for CLL, compared with 43% among non-comorbid patients. Conclusions All individual types of comorbidity were associated with increased all-cause mortality and most also with higher CLL-related mortality. Improved management is warranted for comorbid CLL-patients, who should be prioritized in clinical trials of agents with high tolerability to further inform treatment guidelines and reduce CLL-related mortality for these patients. Disclosures Curovic Rotbain: Abbvie: Other: Travel Grant; AstraZeneca: Consultancy, Research Funding; Janssen: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Abbvie: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant. Da Cunha-Bang:Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; AstraZeneca: Consultancy; Roche: Other: Travel Grant. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

PURPOSE: Our aim was to assess the validity of the ICD-10 code for splenomegaly in the Danish National Registry of Patients (DNRP), as well as to investigate which underlying diseases explained the observed splenomegaly.BACKGROUND: Splenomegaly is a common finding in patients referred to an internal medical department and can be caused by a large spectrum of diseases, including haematological diseases and liver cirrhosis. However, some patients remain without a causal diagnosis, despite extensive medical work-up.PATIENTS AND METHODS: We identified 129 patients through the DNRP, that had been given the ICD-10 splenomegaly diagnosis code in 1994-2013 at Odense University Hospital, Denmark, excluding patients with prior splenomegaly, malignant haematological neoplasia or liver cirrhosis. Medical records were reviewed for validity of the splenomegaly diagnosis, diagnostic work-up, and the underlying disease was determined. The positive predictive value (PPV) with 95% confidence interval (CI) was calculated for the splenomegaly diagnosis code. Patients with idiopathic splenomegaly in on-going follow-up were also invited to be investigated for Gaucher disease.RESULTS: The overall PPV was 92% (95% CI: 85, 96). Haematological diseases were the underlying causal diagnosis in 39%; hepatic diseases in 18%, infectious disease in 10% and other diseases in 8%. 25% of patients with splenomegaly remained without a causal diagnosis. Lymphoma was the most common haematological causal diagnosis and liver cirrhosis the most common hepatic causal diagnosis. None of the investigated patients with idiopathic splenomegaly had Gaucher disease.CONCLUSION: Our findings show that the splenomegaly diagnosis in the DNRP is valid and can be used in registry-based studies. However, because of suspected significant under-coding, it should be considered if supplementary data sources should be used in addition, in order to attain a more representative population. Haematological diseases were the most common cause, however in a large fraction of patients no causal diagnosis was found.

Background Splenomegaly is a common finding in general medical patients. The cause of splenomegaly is often found outside the spleen and therefore an extensive diagnostic medical work-up is frequently required. There is very little data on the distribution of causal diagnoses and, to the best of our knowledge, accurate data on the risk of hematological malignancies, hepatic diseases and storage diseases among patients with splenomegaly have never been reported. The aim of this pilot study is to investigate the validity of the splenomegaly ICD-10 diagnoses, in order to ascertain if a nationwide registry study of the above stated risks can be undertaken, and to investigate which causal diagnoses are most common. Method The study was conducted as a cohort with data from the Danish health care system. Patients with an ICD-10 diagnosis of splenomegaly at Odense University Hospital (OUH) from January 1st 1994 to December 31st 2013 were identified through the Danish National Registry of Patients (DNRP). Patients with a known diagnosis of a malignant hematological disease, liver cirrhosis, or splenomegaly before January 1st 1994 were excluded. The clinical records from OUH provided data, and splenomegaly was, in accordance with current literature, defined as; 1. clinically palpable spleen by abdominal examination on two occasions or by two physicians on the same occasion, 2. the longest diameter being ≥13 cm by ultrasonography or >10 cm by computed tomography or 3. wet weight >291g at excision or autopsy. The analyses presented in this abstract are interim analyses. Results At the time of analysis 65 out of 132 (49.2%) medical records had been reviewed. Two patients with diagnoses of chronic myeloproliferative neoplasms prior to 1994 were excluded. The mean age of the population at the time of splenomegaly diagnosis was 55 years. 63% of the patients were males and 37% were females. In 56 of the 63 patients the splenomegaly diagnosis was considered valid, the positive predictive value (PPV) was 88.9% (95% CI: 78.4, 95.4). The mean time from confirmation of splenomegaly until it was coded was 10 months; distribution can be seen in figure 1. The most common method for determining enlarged spleen, as seen in table 1, was ultrasonic imaging. Table 2 shows that hematological diseases was the most common underlying causal disease group (50%), followed by hepatic diseases (25%), other diseases (12.5%) and idiopathic causes (12.5%). Lymphomas was the single most common causal diagnosis (n=12) and liver cirrhosis the second most common (n=9). Conclusion The high PPV indicates that the ICD-10 splenomegaly diagnosis is valid and together with the relatively short delay of coding it indicates that registry information could be used in future studies to estimate risks of hematological malignancies, liver cirrhosis and storage diseases among patients with an enlarged spleen. Table 1. Methods of Determining Splenomegaly (n = 56) (%) Method Palpable 4 7.1 ≥13 cm by US 33 58.9 >10 cm by CT 16 28.6 ≥13 cm by other method of scanning 2 3.6 >291 g by excision or autopsy 1 1.8 Total 56 100 Table 2. Underlying Causes of Splenomegaly Diagnostic group Hepatic Hematologic Other Unknown Total Disease Lymphoma - 12 - - 12 MPN - 7 - - 7 CLL/HCL - 4 - - 4 Hemolytic disease - 1 - - 1 Other hematological disease - 4 - - 4 Other cancer 1 - - - 1 Liver cirrhosis 9 - - - 9 Portal hypertension 3 - - - 3 Other liver disease 1 - - - 1 Infection - - 3 - 3 Inflammatory disease - - 1 - 1 Primary splenic - - 1 - 1 Other disease - - 2 - 2 Unknown/idiopathic - - - 7 7 Total, n 14 28 7 7 56 Total, % 25.0 50.0 12.5 12.5 100.0 Disclosures Curovic Rotbain: Genzyme: Research Funding. Lund Hansen:Genzyme: Research Funding. Frederiksen:Genzyme: Research Funding.