ALBERT

Description: Background: Several studies have shown a high incidence of venous thromboembolism (VTE) in hematological cancers, comparable with solid cancers, although bleeding is also a prominent complication of the hematological patients. Cancer patients, who develop VTE, have a reduced survival and impaired quality of life if compared to those who do not develop VTE. Hematological cancers are rather rare diseases and most studies have described only some of the entities. Here we want to compare the incidence of VTE in seven subtypes in a large cohort. Aim: To investigate the risk of VTE in hematological malignancies compared to matched controls in a prospective population based cohort study, the Scandinavian Thrombosis and Cancer (STAC) Cohort. Methods: TheSTAC Cohort includes 144.952 participants from three population based prospective cohort studies, i.e. The Tromsø Study and the HUNT2 study from Norway, and the Danish Diet, Cancer and Health Study. The participants were enrolled during 1993-1997, and mean follow-up time was 11.7 years. The cohort profile and outcome of first time objectively confirmed VTE events have been described in prior studies. For this study we collected data from the national cancer registries using morphology codes to identify cohort subjects with hematological cancers, divided into 7 groups: multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute leukemia (myeloid and lymphoblastic) (AL), chronic myeloproliferative neoplasms and myelodysplastic syndrome (CMN/MDS), aggressive non-Hodgkin lymphoma (aggr. NHL), Hodgkin lymphoma (HL), and indolent lymphoma (Ind. L). Subjects with a VTE event more than one year before cancer diagnosis were excluded. For each of the cases 5 controls matched on country, sex and age were identified. We used Cox regression models to estimate the relative risk of VTE across the seven different subtypes of hematological malignancies with a time axis starting one year before the diagnosis of cancer (and similar for matched controls) and ending at a VTE event or end of follow-up. Data were adjusted for age by spline regression. Results: During follow-up 891 participants were diagnosed with a hematological malignancy, and in this group 41 VTE events were observed corresponding to an incidence of 12.0 events per 1000 person-years (10-3 p-y). In the control group of 4455 participants 55 VTE events were observed which gave an incidence of events on 2.3* 10-3 p-y. Having a hematological cancer including all seven investigated types was associated with a six-fold increased risk of developing VTE compared to the matched controls. During follow-up 203 participants were diagnosed with MM, and 10 VTE events were observed giving an event rate of 14.6*10-3 p-y; hazard ratio (HR) for VTE was 7.2, 95% confidence interval (CI): 3.6-14.3. CLL was diagnosed in 176 cases, and 11 VTE events were observed in this group (event rate 11.5*10-3 p-y; HR 5.3; 95% CI: 2.7-10.1). Among the 63 participants who were diagnosed with AL during follow-up 2 VTE events were observed corresponding to an event-rate on 12.8*10-3 p-y; (HR 6.9; 95% CI: 1.7-29.0). In the group of CMN/MDS 4 VTE events were observed among 104 patients (event-rate 12.0*10-3 p-y; HR 6.4, 95% CI: 2.3-18.0). In aggressive NHL 10 VTE events were observed among 158 patients resulting in an event-rate of 18.9*10-3 p-y (HR 10.4; 95% CI: 5.2-20.8). Forty-four participants were diagnosed with HL, and 2 VTE events were observed which corresponds to an event-rate of 10.6*10-3 p-y among these patients (HR 5.1; 95% CI: 1.2-21.4). Indolent lymphoma was diagnosed in 143 subjects, and 2 VTE events were observed (event-rate 3.5*10-3 p-y; HR 1.9; 95% CI: 0.47-8.0). The results are summarized in the table: Table. MM CLL AL CMN/MDS Aggr. NHL HL Ind. L N 203 176 63 104 158 44 143 VTE (n) 10 11 2 4 10 2 2 Incidence (*10-3 p-y) 14.6 11.5 12.8 12.0 18.9 10.6 3.5 HR 7.2 5.3 6.9 6.4 10.4 5.1 1.9 95 % CI 3.6-14.3 2.7-10.1 1.7-29.0 2.3-18.0 5.2-20.8 1.2-21.4 0.47-8.0 Conclusion: Indolent lymphoma was the only investigated hematological malignancy that was not associated with a significant increased risk of VTE. The other types of hematological malignancies had an increased risk of VTE ranging from approximately 5-10 times, highest in aggressive non-Hodgkin lymphoma and lowest in Hodgkin lymphoma. However a limitation of the study is the small numbers in some of the groups in spite of the large cohort. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3985 Poster Board III-921 Background Venous thrombosis has genetic and acquired risk factors, and it has been proposed that several risk factors are needed for the occurrence of the disease. The identification of common gene variants associated with venous thrombosis may improve the ability to predict the risk and understanding of this disease. In a recent study, we aimed to identify genetic variants that are associated with deep vein thrombosis in individuals aged younger than 70 years (JAMA 2008; 299:1306-14). Of nearly 20000 single nucleotide polymorphisms (SNPs) that were genotyped, 7 SNPs were associated with deep vein thrombosis (range odds ratios, 1.1-1.3). However, studies of thousands of SNPs can lead to false-positive associations. Replication studies are therefore pivotal to account for false-positive associations. Objective To assess the risk of venous thrombosis of aforementioned SNPs in a large population based study. Methods From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94194), we identified all patients with an objectively verified diagnosis of venous thrombosis that occurred between 1995 and 2001. By this date we had registered 515 patients with a first venous thrombosis; an age- and sex-stratified random sample of 1476 controls without previous venous thrombosis was drawn from the original cohort. Patients and diagnosis characteristics were retrieved from medical records. Of the 7 SNPs that were associated with deep vein thrombosis in our previous study, 6 were analyzed in the present study, i.e. rs13146272 in CYP4V2; rs2227589 in SERPINC1; rs1613662 in GP6; rs670659 in RGS7; rs1523127 in NR1I2; and rs6048 in F9. DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes, Invitrogen Corp, Carlsbad, CA, USA) fluorescent dye. Genotyping of individual DNA samples were demonstrated by polymerase chain reactions using the TaqMan assay. The technicians were blinded to whether the samples came from patients or control subjects. Results The median age of both cases and controls at baseline was 70 years (range, 20-98). Almost half of patients and controls were men. Two thirds of the patients had deep vein thrombosis and one third had pulmonary embolism. Among the 515 events, 246 were idiopathic (48%). The prevalences of the 6 analyzed risk alleles were 17-96% in the patients and 16-96% in the control group. Only the F9 (rs6048) risk allele in men was consistently associated with an increased risk of venous thrombosis with odds ratios of 1.27 (95% CI, 0.83-1.93) for deep vein thrombosis, 1.62 (95% CI, 0.91-2.89) for pulmonary embolism, and 1.38 (95% CI, 0.97-1.97) for total venous thrombosis. For all other risk alleles we found odds ratios for venous thrombosis close to 1.0 compared to their reference allele. Odds ratios for provoked or idiopathic venous thrombosis again showed that only the F9 risk allele in men was consistently associated with an increased risk with an odds ratio of 1.30 (95% CI, 0.82-2.08) for provoked venous thrombosis and 1.47 (95% CI, 0.90-2.38) for idiopathic venous thrombosis, respectively, compared to men with the G allele. To make the current analysis more similar with our previous study, we restricted the analysis to those who were younger than 70 years. This resulted in slightly higher odds ratios for venous thrombosis in CYP4V2, SERPINC1 and GP6 variants (Table). Conclusion This population based study confirmed the previous finding that men with the A allele of rs6048 in F9 have an increased risk of venous thrombosis, while we could not replicate the association of gene variants in CYP4V2, SERPINC1, GP6, RGS7 and NR1I2 with venous thrombosis, possibly excepted for CYP4V2, SERPINC1 and GP6 gene variants in individuals aged younger than 70 years. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 453 Background: The reason why a high BMI predisposes to venous thrombosis is not clarified. People with overweight or obesity tend to be more immobile which may lead to clot formation through stasis. It is also possible that these subjects acquire a prothrombotic state. Factor (F) VIII can be released by adipose tissue through inflammatory cytokines, which consequently might induce APC-resistance. This APC-resistance could be aggravated in case FV Leiden is also present. In addition, presence of high levels of FVIII in non-O blood group subjects could worsen this further. Objective: To determine whether an association exists between BMI and APC-resistance, and whether the combination of both high BMI and APC-resistance increased the risk of venous thrombosis in the Leiden Trombophilia Study (LETS). Whether increasing FVIII levels induced APC-resistance was also studied. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified if FV Leiden modified the risk of increasing BMI on the occurence of venous thrombosis and whether these risks were further increased by blood group non-O. Methods: Linear regression was used to determine the relation between increasing APC-resistance and BMI, increasing FVIII levels and BMI, increasing APC-resistance and FVIII levels, and between increasing APC-resistance and BMI adjusted for FVIII levels. Cut-off points needed to create tertile categories of APC-resistance were derived from the control-group of the LETS and the TROL population separately. Logistic regression was used to calculate odds ratios and their 95% confidence intervals, adjusted for age and sex. To make the TROL and LETS population more similar for the current analysis, we restricted the analysis in the TROL subjects to those who were younger than 70 and to those who had a DVT only (n=183 cases and n=696 controls). Results: APC-resistance increased linearly with increasing BMI. A same phenomenon was observed for FVIII, i.e. an increase of BMI led to higher FVIII levels. Increased APC-resistance was in its turn associated with an increase of FVIII levels. FVIII explained part of the relation between APC and BMI, as the slope of the regression line of APC-resistance on BMI levels decreased after adjustment for FVIII. To examine the effect of increasing BMI, independent of existing APC-resistance, on the risk of venous thrombosis, we restricted the analysis to subjects from the LETS in whom APC-resistance was not related to other factors such as FV Leiden or oral contraceptive use. In these subjects (n=237 cases and n=369 controls), the risk of venous thrombosis increased 1.4-fold for those with a BMI in the median tertile (odds ratio 1.4; 95% CI, 0.9-2.3) and 2.5-fold for those in the upper tertile (odds ratio 2.5; 95% CI, 1.6-3.9), as compared to subjects in the lowest tertile. Adjustment for APC-resistance or FVIII led to a slight decrease in these relative risk estimates. Non-FV Leiden-carriers with blood group O were only at risk of venous thrombosis when they had a BMI in the upper tertile compared to non-FV Leiden-carriers with blood group O and a BMI in the lowest tertile; (adjusted odds ratio 1.9). This risk was modestly increased when non FV Leiden carriers with non-O blood group were compared with this reference group, with adjusted odds ratios of 1.5, 2.4 and 3.4, respectively, within the BMI tertiles. This risk was strongly increased when FV Leiden carriers with blood group O were compared to the reference group, with adjusted odds ratios of 3.0, 8.3 and 9.7, respectively, within the BMI tertiles. Risk of FV Leiden carriers with non-O blood group showed the highest risk of venous thrombosis compared to the reference group, no longer in a dose-response way, with adjusted odds ratios of 40.6, 23.3 and 25.2, respectively, within the BMI tertiles. Conclusion: The increased risk of venous thrombosis in subjects with high BMI is mediated by FVIII induced APC-resistance. Subjects with FV Leiden and increasing BMI had a higher risk of venous thrombosis compared to non-carriers, and this risks was more than 20 fold increased in carriers of blood group non-O and FV Leiden. Future studies are needed to show if these risks can be downgraded by weight loss. Disclosures: No relevant conflicts of interest to declare.

Description: Purine analogues are effective treatment for CLL, but despite improved response rates and durations for purine analogues as compared to chlorambucil no survival advantage was documented. Our trial is the first comparing CdA and fludarabine (F) as first-line treatment of symptomatic B-CLL with high dose intermittent chlorambucil (Chl) as control. Patients aged 18–75 years from Scandinavia, Australia and UK were since November 1997 randomised between monthly courses of Chl 10mg/sqm orally day 1–10, F 25mg/sqm iv day 1–5, or CdA 5mg/sqm iv/sc day 1–5. Protocol is seen at www.cck.ki.se/CLL-study/index.html. Randomisation was stratified according to age and stage. Up to six courses were given according to response and toxicity. We now report a scheduled interim analysis of the first included 150 patients; 139 were evaluable and 5 excluded for not fulfilling eligibility criteria and 6 for incomplete data reporting. There was no significant difference in age, Binet stage or time from diagnosis to inclusion between the groups. Median age was 63 years and median time from diagnosis to inclusion was 16 months. Overall responses according to NCI criteria and intention to treat were documented in 57%/67%/74% of patients in the Chl/F/CdA arms, respectively (Chl vs CdA, p=0.06, Chi-test). The number of CR/nPR/PR in the different treatment groups were for Chl 2/3/22 (n=47), for F 0/2/28 (n=45), and for CdA 2/3/30 (n=47). NCI grade III and IV platelet toxicity was seen in 25% and 20% for Chl, 24% and 5% for F, and 36% and 11% for CdA. NCI grade III–V infections were seen in 25%/28%/30%, respectively. One F patient died in septic shock from E coli, and two CdA patients died from RS virus infection and aspergillosis, respectively; none of them responded to CLL-treatment. Autoimmune hemolysis was seen only with purine analogues, 4 during F and 3 during CdA treatment. We conclude that toxicity was feasible, and infections did not differ between arms. So far there is no significant difference in response rates between the therapies, but CdA seems at least as good as F. Inclusion is currently ongoing but will close during 2004, and a full evaluation is scheduled thereafter.

Description: Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993–1997 to 2008–2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12–1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96–1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.