ALBERT

Description: Introduction Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase for treatment of chronic lymphocytic leukemia (CLL). Ibrutinib has demonstrated superior efficacy for patients with TP53 aberration or relapsed/refractory (R/R) CLL; and more recently superior progression free survival (PFS) has been demonstrated compared to chemoimmunotherapy as first line therapy. However, knowledge about the outcomes and adverse events (AE) upon ibrutinib among patients at a population-based level are still limited. The aim of the here presented study is to explore outcomes of ibrutinib treatment in a population-based cohort of patients with CLL treated with ibrutinib in Denmark. Methods In this retrospective study, patients from 8 hospitals in Denmark, who were diagnosed with CLL and treated with ibrutinib from April 2014 until February 2019 were included. Medical records were retrospectively reviewed to obtain information. Patients receiving ibrutinib within clinical trials were excluded. Overall survival (OS) was defined as time from ibrutinib start to death from any cause while PFS was defined as time from ibrutinib start to progression or death from any cause. PFS and OS were analyzed with the Kaplan-Meier method while cumulative incidence was calculated with the Aalen-Johansen estimator. Results In total, 205 patients with CLL receiving ibrutinib treatment were identified from hospital records and registries. The median follow-up was 21.4 months (IQR, 11.9-32.8) and the median time on ibrutinib was 16.8 months (IQR, 6.0-28.1). The median age at treatment initiation was 72.8 years (IQR, 65.7-77.8), 128 (62.4%) were male, and 111 (63.4%) were Binet stage B/C at treatment initiation out of 175 with available information regarding clinical stage. Thirty-nine (19.0%) received ibrutinib as first-line, and 166 for R/R CLL with a median of 2 (range, 1-8) prior treatment regimens. Information on TP53 aberration was available for 149 and regarding IGHV mutation for 147 patients, 111 (74.5%) had TP53 aberration and 107 (72.8%) were IGHV unmutated. Eighty-six patients (42.0%) discontinued ibrutinib during follow-up with a median time until discontinuation of 9.3 months (IQR, 3.0-23.2). Forty-seven (54.7%) discontinued due to AEs, 19 (22.1%) due to progression (12 had progression of CLL and 7 had Richter's transformation) while the remaining 20 (23.2%) discontinued due to other reasons. The estimated cumulative incidence of discontinuation at 12 months was 24.8% (95% CI: 18.6-30.9). The estimated OS after 12 and 24 months was 88.8% (95%CI: 84.3-93.3) and 76.8% (95%CI: 70.4-83.2) and the estimated PFS after 12 and 24 months was 87.3% (95%CI: 82.5-92.1) and 72.4% (95%CI: 65.5-79.2). One hundred and eighty-eight (91.7%) experienced at least one AE, among these 45 (23.9%) experienced a grade 3+. The most common AEs were hemorrhage (tendency to bruise, epistaxis etc.) which occurred in 86 (42.0%) of all and musculoskeletal and connective tissue disorders (arthralgia, myalgia etc.) which occurred in 82 (40.0%). Thirty-one (15.1%) patients experienced atrial fibrillation while on ibrutinib and 14 (6.8%) developed hypertension. One hundred and thirty-seven patients (66.8%) had at least one infection and among these 80 (58.4%) were hospitalized with an infection. The most common infections were lower respiratory tract infections and urinary tract infections that occurred for 88 (42.9%) and 41 (20.0%). The estimated cumulative incidence for any infection was 58.9% (95%CI: 52.0-65.9) at 12 months. Conclusion This is the first study describing outcomes for a population-based cohort of CLL patients treated with ibrutinib in Denmark. Real-world studies are warranted, to confirm the results from clinical trials. In this study, patients appear to have comparable OS and types of AE compared with the RESONATE trial. Differences in frequency of AEs compared to the clinical trial may reflect the focus of clinicians in routine practice. Discontinuation in this cohort was higher compared to clinical trials but comparable to previously reported real-world studies. While ibrutinib can be safely managed in routine clinical practice, this study demonstrates that a quarter of patients discontinue treatment due to mainly AEs. Further patient training and information, and in some instances personalized treatment with other targeted agents based on adverse event profile, may improve treatment adherence. Disclosures Aarup: Research Committee, Rigshospitalet: Research Funding. Enggaard:Abbie: Other: Advisory board; Gilead: Other: Advisory board; Janssen: Other: Advisory board. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: 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; Gilead: Other: Travel Grant; Abbvie: Consultancy, Other: Travel Grant, Research Funding.

Description: 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.

Description: Patients with chronic myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are at increased risk of new hematologic malignancies, but their risk of nonhematologic malignancies remains unknown. In the present study, we assessed the risk of both types of malignancies after an ET, PV, or CML diagnosis. We linked 2 population-based nationwide registries, the Danish National Registry of Patients, covering all Danish hospitals and the Danish Cancer Registry, and assessed subsequent cancer risk in a cohort of all 7229 patients diagnosed with a chronic myeloproliferative neoplasm during 1977-2008. We compared the incidence of subsequent cancer in this cohort with that expected on the basis of cancer incidence in the general population (standardized incidence ratio). Overall, ET, PV, and CML patients were at increased risk of developing both new hematologic and nonhematologic cancers. The standardized incidence ratio for developing a nonhematologic cancer was 1.2 (95% confidence interval [95% CI]): 1.0-1.4) for patients with ET, 1.4 (95% CI: 1.3-1.5) for patients with PV, and 1.6 (95% CI: 1.3-2.0) for patients with CML. We conclude that patients with chronic myeloproliferative neoplasms are at increased risk of developing a new malignant disease.

Description: Introduction: Optimized therapeutic targeting of CD20 is one among several currently explored strategies to improve the overall prognosis of patients with chronic lymphocytic leukemia (CLL). Obinutuzumab (GA101) is an optimized (i.e. glycoengineered and type 2) CD20-targeting antibody that has been investigated in the CLL11 study comparing obinutuzumab plus chlorambucil (G-Clb) with rituximab plus chlorambucil (R-Clb) and with chlorambucil alone (Clb) in patients with previously untreated CLL and comorbidities. The study had demonstrated clinically meaningful and statistically significant superiority of G-Clb over Clb (with regard to PFS and OS) and over R-Clb (with regard to PFS, but not for OS) at previous pre-planned analyses. Here, we report updated results on survival and time to next treatment (TTNT) from a pre-planned analysis with data cut-off in May 2015. Methods: A total of 781 treatment-naïve patients with CLL in need of therapy and cumulative illness rating scale (CIRS) total score 〉 6 and/or estimated creatinine clearance (CrCl) 〈 70 mL/min were randomized in a 1:2:2 fashion to receive Clb alone (0.5 mg/kg po d1 and d15 q28 days, 6 cycles), R-Clb (rituximab: 375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6), or G-Clb (obinutuzumab: 100 mg iv d1, 900 mg d2, 1000 mg d8 and d15 of cycle 1, 1000 mg d1 cycles 2-6). The study was powered for PFS as the primary endpoint, but not for OS and TTNT as secondary endpoints. P values are taken from a log rank test, hazard ratios (HR) from stratified Cox regression. Results: The study population was characterized by a median age of 73 years and median CIRS total score of 8. No new safety signals have been identified in this updated analysis. Updated results of the G-Clb (n=238) vs. Clb (n=118) comparison: The median observation time was 42.4 months. Confirming previously reported results, treatment with G-Clb compared with Clb alone was associated with substantially improved outcome (median PFS 31.1 vs. 11.1 months - HR 0.20, 95%CI 0.15-0.26, p

Description: Abstract 2835 Background: The classical chronic myeloproliferative neoplasms (CMPNs), including essential thrombocytemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are disorders characterized by accelerated proliferation of hematopoietic tissue. Systemic mastocytosis, also a chronic myeloproliferative neoplasm, has been associated with increased risk of osteoporosis. However, to our knowledge, no data is available on the risk of osteoporosis among patients with classical CMPNs. Method: We conducted a Danish population-based cohort study of the risk of osteoporosis among patients with ET, PV, and CML using data from the Danish health care system. ET, PV, and CML patients were identified from Danish National Registry of Patients (DNRP), and linked to the Danish Civil Registration System (CRS) in the study period 1 January 1980 to 31 December 2010. Each Danish resident has a unique, permanent 10-digit civil registry number allowing unambiguous individual-level linkage among all Danish registries. Patients with a first-ever CMPN diagnosis in the DNRP were identified by means of their ICD-8 diagnosis code until 1994 and ICD-10 diagnosis code thereafter. By this means, we established three distinct cohorts of ET, PV, and CML patients. For each CMPN patient, 50 general population comparison cohort members without CMPN were identified in the CRS matched on age, sex, and calendar year, creating three comparison cohorts. Follow-up started 1-year from the date of diagnosis for CMPN patients. The comparison cohort members were assigned the same index date as their index CMPN case. A diagnosis of proximal femoral fracture was used an indicator of osteoporosis, since this fracture type invariably leads to hospitalization, and therefore would be registered in the DNRP throughout our observation period. The CMPN and comparison cohorts were followed until a diagnosis of femoral fracture, emigration, death, or 31 December 2010, whichever came first. Patients and comparison cohort members with a previous diagnosis of osteoporosis or osteoporotic fractures were excluded. The Kaplan-Meier method was used to estimate the cumulative rate of fractures. Cox regression was used to estimate hazard ratios (HRs) as a measure of relative risk of femoral fracture for each CMPN cohort compared to the comparison cohort, adjusted for comorbidity. Results: We identified 7,595 MPN patients (1,864 with ET; 4,418 with PV; and 1,313 with CML) and 338,974 comparison cohort members. The cumulative rate of proximal femoral fractures was higher among CMPN patients than among comparison cohort members, as depicted in the Figures. The rate of fractures per 1,000 person-years were: 6.6 (95% confidence interval (CI): 5.2–8.3) for ET patients [comparison group: 5.3 (95% CI: 5.1–5.4)], 9.9 (95% CI: 8.8–11.0) for PV patients [comparison group: 6.2 (95% CI: 6.1–6.3)]; and 8.2 (95% CI: 6.0–10.7) for CML patients [comparison group: 4.4 (95% CI: 4.3–4.6)]. The resulting adjusted hazard ratios (HR) were: HRET = 1.2 (95% CI: 0.9–1.5), HRPV = 1.8) (95% CI: 1.6–2.0), and HRCML = 2.7 (95% CI: 2.0–3.6). Conclusion: CMPN patients are at higher risk of osteoporotic fractures than the general population. Disclosures: No relevant conflicts of interest to declare.

Description: Background. Patients with Chronic Myeloproliferative Neoplasms (MPNs) already have increased comorbidity at time of diagnosis, and studies show association with ophthalmic manifestations. Retinal vascular symptoms including vascular occlusions and hemorrhages are present, but other manifestations of the eye have not been thoroughly investigated in these patients. Previously reported studies show signs of systemic inflammation in patients with MPN as well as in patients with Age-Related Macular Degeneration (AMD). Our hypothesis is that the presence of MPN predisposes some individuals to develop AMD and this might be explained by the degree of systemic inflammation. Objective. To describe the prevalence of Age-Related Macular Degeneration in patients with Chronic Myeloproliferative cancer at time of diagnosis compared to the general population in Denmark. Materials and Methods. We conducted a retrospective population-based matched cohort study using Danish registries. We included all patients age 18+ or older with a first listed diagnosis of MPN in the Danish National Patient Registry between 1994 and 2013. Patients with Essential Thrombocythemia (ET), Polycythemia Vera (PV), Myelofibrosis (MF), Unclassifiable MPN (MPN-U) and Chronic Myeloid Leukemia (CML) were included. To compare the prevalence of AMD with the general population we identified 10 sex-and-age matched individuals without MPN, for each corresponding patient. The controls were identified through the Danish Civil Registration System. Index date was defined as date of MPN diagnosis, and controls had to be alive at their corresponding patient's index date. We searched for all primary AMD diagnoses in the Danish National Patient Registry within a ten-year period preceding index date + 30 days. For all patients and controls, baseline characteristics, including smoking-related conditions (yes/no), were registered. We calculated number of events in all groups, including only patients' and controls' first AMD diagnosis. Prevalence of AMD at time of diagnosis was calculated using descriptive statistics. Results. We included 9679 patients (ET=2714; PV=3170; MF=600; MPN-U=1839; CML=1356) and a total of 96737 sex-and-age matched controls in the study. Mean age of included patients with MPN at time of diagnosis was: 64 years (ET); 66 (PV); 71 (MF); 70 (MPN-U) and 61 (CML) − all with comparable age-distribution in the matched control groups. There was a higher percentage of females in the ET group (65%), an equal sex-distribution in PV (females 49 %) and MPN-U (females 51 %) and a higher percentage of men in the CML group (59 %). Significant more patients with ET, PV and MPN-U had smoking related diagnoses compared to controls (p

Description: Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls. Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately. Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value 〈 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1). Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (