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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.

Background The management of chronic lymphocytic leukemia (CLL) is in rapid transition and tailored individual therapy is a likely future scenario for those needing treatment. Previous studies of CLL have revealed an increased risk of second cancers. The underlying mechanisms are unclear, but may involve shared risk factors, weakened immune surveillance, and chemotherapy exposure. However, little is known about the impact of CLL treatment on second cancer risk. We followed Danish population-based cohorts of treated and untreated CLL patients and compared their risk of second cancers with that of matched controls. Methods All patients registered with a diagnosis of CLL in the Danish Cancer Registry 2002-2013 were included in the analyses. For each CLL patient, we randomly selected 50 CLL-free control persons matched on age and gender from the general population. Patients and controls were followed for new cancers registered in the Danish Cancer Registry 2002-2013 using ICD10 codes. Information about CLL treatment was available from The Danish National Patient Registry allowing us to stratify patients accordingly. Follow up of the patients and controls were done separately for each cancer type without competing risk. Adjusted hazard ratios (HR) and 95% confidence intervals (95%CI) for new cancers by time since CLL diagnosis /matching date for controls were calculated using Cox regression analyses. Results Overall, 4,919 CLL patients with a median person-years of follow-up (PYFU) of 3.9 and 245,877 controls with a median PYFU of 4.6 were included. During follow-up, a total of 694 new malignancies, 54 hematological (excluding CLL) and 640 non-hematological, were registered among the CLL patients (eight patients developed both hematological and non-hematological malignancies). This corresponded to increased relative risks for combined groups of hematological (HR, 1.3; 95% CI, 1.0 to 1.7) and of non-hematological (HR, 1.4; 95% CI, 1.3 to 1.5) cancers, respectively, compared to the controls. Chemotherapy treatment was registered for 1,664 (34%) of the CLL patients during follow-up, and this was accompanied by increased relative risks of both hematological cancers excluding CLL (HR, 2.7; 95% CI, 1.9 to 4.1) and non-hematological cancers (HR, 1.8; 95% CI, 1.6 to 2.1). In contrast, risks of hematological cancer were not increased (HR, 0.9; 95% CI, 0.6 to 1.3) and risk of non-hematological cancers only slightly increased (HR, 1.3; 95% CI, 1.1 to 1.4), among untreated CLL patients. In site-specific analyses the increased risk among treated CLL patients pertained to Hodgkin and non-Hodgkin lymphomas, myelodysplastic syndrome, lung, skin, and thyroid cancer with HR's ranging from 1.8 to 13.3. Conclusions CLL patients treated with chemotherapy are at increased risk of other hematological and non-hematological malignancies. Increased awareness and possibly cancer screening programs are warranted for CLL patients receiving chemotherapy. Detailed analyses of the role of different types of CLL specific treatments on risk of second cancers based on the Danish Cancer Registry, the Danish National Patient Registry and the Danish National CLL Registry are ongoing. Disclosures Geisler: Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy.

Background The treatment of chronic lymphocytic leukemia (CLL) is in rapid transition. As single agents, Fludarabine (F) was shown to be superior to chlorambucil (Rai, NEJM, 2000). Soon after F with Cyclophosphamide (C), showed superiority to F alone (Eichhorst, Blood, 2006; Flinn, JCO, 2007, Catovsky, Lancet, 2007). Subsequently, the addition of CD20 antibody rituximab (R) to FC for the first time showed a survival benefit for fit patients in a clinical trial (Hallek, Lancet, 2010). Likewise, in unfit patients the addition of CD20 antibodies to chlorambucil led to increased overall survival (Goede, NEJM, 2014). Eventually, BCR-targeted treatment for patients harboring TP53 aberrations demonstrated promising results (Farooqui, Lancet Onc, 2015). Here we assess the impact of these successive changes of therapy on the survival of patients with CLL in a Danish population-based cohort. Methods We studied the survival of a population-based cohort of CLL patients reported to the Danish Cancer Registry 1978-2013. Patients were categorized according to year of diagnosis from 1978-1994, 1995-2000, 2001-2005 and 2006-2013. For each CLL patient, we randomly selected 50 controls from the general population matched on age, gender and municipality. Kaplan MeierÕs survival curves and Hazard ratios (HR) and 95% confidence interval (95%CI) for death since time of diagnosis /matching date for controls were calculated. Change in survival probability relative to the controls with stratification on gender, age and calendar period of diagnosis was assessed. Results In total, 10500 patients were diagnosed with CLL in Denmark from 1978 to 2013 as follows: 1978-1994: 4651, 1995-2000: 1622, 2001-2005: 1664 and 2006-2013: 2563. Thus, the reported incidence of CLL increased slightly after year 2000. Overall, we observed a continuously decreasing risk of death for patients with CLL compared to matched controls, with HRs from 3.47 (3.37 - 3.58) to 2.09 (1.96 - 2.24) for patients diagnosed 1978-1994 and 2005-2013, respectively. In inter group analyses, a significant stepwise reduction in risk of death was observed for each period (Figure 1). In all age groups and calendar periods, male patients had an inferior survival compared to female patients and younger patients survived longer than older patients (p Discussion A significant improvement in survival probability for patients with CLL over time was found. This coincides with the introduction of FCR as standard therapy for younger patients with CLL (approval by EMA in 2009, affecting the cohort diagnosed 2006-2013). Significant survival improvement was also observed in the 2001-2005 cohort, possibly due to a shift to combination chemotherapy. Also for elderly patients, otherwise expected to get less intensive treatment in part due to co-morbidities, the survival improved over time. This may be accounted for by the introduction of semi-intensive chemotherapy like bendamustine, reduced intensity FC(R) and more recently chlorambucil combined with CD20-targeting antibodies. For the first time, we here present population-based data showing significant improvement in survival for patients with CLL in parallel with the introduction of new chemo-immunotherapeutic regimens into clinical practice. These data substantiate the reported increased survival for patients treated with chemo-immunotherapy in clinical studies. Further investigation and cross-reference with treatment databases are warranted in order to assess the impact of new targeted treatment options for CLL. Figure 1. Overall survival for patients (70-79 and 50-59 years), lower four curves; upper four curves represent matched controls. Figure 1. Overall survival for patients (70-79 and 50-59 years), lower four curves; upper four curves represent matched controls. Disclosures Geisler: GlaxoSmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy. Niemann:Novartis: Other: Travel grant; Janssen: Consultancy; Roche: Consultancy; Gilead: Consultancy.