Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea: European observational study.

BACKGROUND: Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU. METHODS: This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. RESULTS: In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. CONCLUSION: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.

Risk Factors for Bleeding in Cancer Patients Treated with Conventional Dose Followed by Low-Dose Apixaban for Venous Thromboembolism.

BACKGROUND: Incidence of and risk factors for bleeding in cancer patients with venous thromboembolism (VTE) treated with apixaban are poorly described. METHODS: We analyzed data from the prospective CAP study where 298 cancer patients with any type of VTE received 5 mg apixaban twice daily for 6 months, and then 2.5 mg apixaban twice daily for 30 months. For most analyses, major bleedings and clinically relevant nonmajor bleedings were merged to "clinically relevant bleedings." Risk factors were estimated by odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: The incidence of clinically relevant bleedings was 38% per person-year during the first 6 months of treatment, 21% per person-year from 7 to 12 months, and between 4 and 8% per person-year from 13 to 36 months. Clinically relevant bleedings were associated with age above 74 years (OR: 2.0, 95% CI: 1.0-4.1), body mass index (BMI) below 21.7 (OR: 2.3, 95% CI: 1.1-4.8), and hemoglobin at baseline below 10.5 for females (OR: 2.8, 95% CI: 1.1-7.3) and 11.1 for males (OR: 3.3, 95% CI: 1.3-8.4) during the first 6 months. Gastrointestinal (GI) or urogenital cancer was not associated with clinically relevant bleedings compared with other cancers. Among patients with luminal GI cancer, nonresected cancer had increased risk of bleeding (OR: 3.4, 95% CI: 1.0-11.6) compared with resected GI cancer. CONCLUSION: There were very few bleedings while patients were on low-dose apixaban. Factors associated with bleeding in patients treated with full-dose apixaban were high age, low BMI, and low hemoglobin, and probably nonresected luminal GI cancer.

Behandling av eldre med akutt myelogen leukemi uten allogen stamcelletransplantasjon ved Akershus universitetssykehus.

BACKGROUND: It is uncertain what the best treatment is for older patients with acute myeloid leukaemia who are not candidates for allogeneic stem cell transplantation. The purpose of the study was to examine the treatment practices for this patient group at Akershus University Hospital, as well as survival according to treatment choices and the genetic risk of a tumour. MATERIAL AND METHOD: The study is based on a review of the medical records of patients aged 65 and older with recently diagnosed acute myeloid leukaemia treated without allogeneic stem cell transplantation at Akershus University Hospital from 1 January 2006 to 1 January 2021. RESULTS: We included 151 out of 156 identified patients. The median age was 76 years, 42 patients (28 %) received intensive chemotherapy, 38 (25 %) received low-intensity chemotherapy and 71 (47 %) received supportive care only. Supportive care was mainly given in the early part of the period. From 2014 onwards, low-intensity chemotherapy made up a significant part of the treatment. Tumour genetic analyses were available for 88 patients, of which 17, 47 and 24 had a favourable, intermediate and unfavourable genetic risk of a tumour respectively. None of the patients with an unfavourable genetic risk of a tumour survived for 2 years. There were no statistically significant differences in survival between low-intensity and intensive chemotherapy. In the group with a favourable genetic risk of a tumour, the median survival was 573 days with intensive chemotherapy (n=12) and 101 days with low-intensity chemotherapy (n=4) (p=0.09). Patients treated with intensive chemotherapy were in hospital the longest. INTERPRETATION: The results suggest that knowledge of the genetic risk of a tumour is useful when choosing treatment for older patients with acute myeloid leukaemia.

Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

The Effects of Exercise Training in Patients With Persistent Dyspnea Following Pulmonary Embolism: A Randomized Controlled Trial.

BACKGROUND: Persistent dyspnea, functional limitations, and reduced quality of life (QoL) are common following pulmonary embolism (PE). Rehabilitation is a potential treatment option, but the scientific evidence is limited. RESEARCH QUESTION: Does an exercise-based rehabilitation program improve exercise capacity in PE survivors with persistent dyspnea? STUDY DESIGN AND METHODS: This randomized controlled trial was conducted at two hospitals. Patients with persistent dyspnea following PE diagnosed 6 to 72 months earlier, without cardiopulmonary comorbidities, were randomized 1:1 to either the rehabilitation or the control group. The rehabilitation program consisted of two weekly sessions of physical exercise for 8 weeks and one educational session. The control group received usual care. The primary end point was the difference in Incremental Shuttle Walk Test between groups at follow-up. Secondary end points included differences in the Endurance Shuttle Walk Test (ESWT), QoL (EQ-5D and Pulmonary Embolism-QoL questionnaires) and dyspnea (Shortness of Breath questionnaire). RESULTS: A total of 211 subjects were included: 108 (51%) were randomized to the rehabilitation group and 103 (49%) to the control group. At follow-up, participants allocated to the rehabilitation group performed better on the ISWT compared with the control group (mean difference, 53.0 m; 95% CI, 17.7-88.3; P = .0035). The rehabilitation group reported better scores on the Pulmonary Embolism-QoL questionnaire (mean difference, -4%; 95% CI, -0.09 to 0.00; P = .041) at follow-up, but there were no differences in generic QoL, dyspnea scores, or the ESWT. No adverse events occurred during the intervention. INTERPRETATION: In patients with persistent dyspnea following PE, those who underwent rehabilitation had better exercise capacity at follow-up than those who received usual care. Rehabilitation should be considered in patients with persistent dyspnea following PE. Further research is needed, however, to assess the optimal patient selection, timing, mode, and duration of rehabilitation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03405480; URL: www. CLINICALTRIALS: gov.

[Factor Xa inhibitors in the prevention and treatment of venous thromboembolism in cancer patients]. / Faktor Xa-hemmere til forebygging og behandling av venøs tromboembolisme ved kreft.

Venous thromboembolism is a common complication of cancer. The prevalence varies according to cancer type and increases proportionally with the stage of cancer. In the past 15-20 years, low molecular weight heparin has been recommended as the first-line treatment. New international guidelines now allow for use of direct factor Xa inhibitors both as prophylaxis and treatment for venous thromboembolism. Prophylaxis should as a general rule only be initiated in patients with moderate to high risk. Bleeding risk assessment is important before starting anticoagulation. Both thrombosis and bleeding risk can change and should therefore be assessed on an ongoing basis. In this clinical review, use of anticoagulation therapy in cancer patients is discussed with particular emphasis on the use of direct factor Xa inhibitors.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Low diagnostic accuracy and inter-observer agreement on CT and MRI in diagnosis of spinal fractures in multiple myeloma.

Skeletal disease is common in multiple myeloma. We investigated the inter-observer agreement and diagnostic accuracy of spinal fractures diagnosed by computer tomography (CT) and magnetic resonance imaging (MRI) from 12 myeloma patients. Two radiologists independently assessed the images. CT, MRI, and other images were combined to a gold standard. The inter-observer agreement was assessed with Cohen's kappa. Radiologist 1 diagnosed 20 malignant spinal fractures on CT and 26 on MRI, while radiologist 2 diagnosed 12 malignant spinal fractures on CT and 22 on MRI. In comparison the gold standard diagnosed 10 malignant spinal fractures. The sensitivity for malignant fractures varied from 0.5 to 1 for CT and MRI, and the specificity varied from 0.17 to 0.67. On MRI, the specificity for malignant spinal fractures was 0.17 for both radiologists. The inter-observer agreement for malignant spinal fractures on CT was -0.42 (Cohen's kappa) and -0.13 for MRI, while for osteoporotic fractures it was -0.24 for CT and 0.53 for MRI. We conclude that malignant spinal fractures were over-diagnosed on CT and MRI. The inter-observer agreement was extremely poor.

Cancer and Thrombosis: New Treatments, New Challenges.

The direct-acting oral anticoagulant (DOAC) has become an alternative to low-molecular-weight heparin (LMWH) for treatment and prophylaxis of venous thromboembolism (VTE) in cancer patients. The clinicians are, however, faced with difficult decisions regarding DOAC treatment: Which patients cannot use DOACs? Should incidental VTE be treated similar to symptomatic VTE? Is it safe to give DOACs to patients with gastrointestinal or urogenital cancers? How about drug-drug interactions? Should all cancer patients receive thromboprophylaxis? Is arterial thrombosis a problem? The current article reviews the available literature regarding these questions and aims to provide practical solutions based on data from the clinical trials and new guidelines.

Bias in animal studies of estrogen effects on cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials on menopausal hormone therapy in humans have not confirmed the benefit of estrogens on cardiovascular disease found in animal studies. Flawed methodology or publication bias in animal studies may explain the dicrepancy. OBJECTIVES: The aim of this study was to investigate whether publication of the randomized controlled trials Heart and Estrogen/Progestin Replacement Study and Women's Health Initiative influenced study authors' assessment of research findings (confirmation bias) as well as to investigate publication bias and small-study effects in animal studies of estrogen effects on atherosclerosis. METHODS: The data source for this study was PubMed from inception to 2018. We selected animal studies with cardiovascular outcomes comparing 17-ß-estradiol, its natural metabolites, or conjugated equine estrogen with control. Qualitative data were extracted on authors' conclusions about estrogen effects on cardiovascular disease, as well as quantitative data for atherosclerosis outcomes. Fixed- and random-effects meta-analyses were used. Publication bias/small-study effects were assessed using funnel plots and Egger's regression. Trim-and-fill plots and extrapolation from Egger's regression were used to adjust for publication bias. The main outcomes and measures were the primary study authors' interpretation of their own results, and estrogen effects on cardiovascular disease in general before and after publication of the Women's health Initiative study (2003). The effects of estrogens on atherosclerosis were measured as standardized mean difference between intervention and control. RESULTS: Of 1925 studies retrieved, 360 were eligible for analyses. Study-specific statements concluded that estrogens were protective against cardiovascular disease in 75% of studies before 2003 and 78% after, but the percentage of general statements about estrogens being cardioprotective changed from 70% to 40%. Meta-analyses showed less atherosclerosis in estrogen-treated animals. Extremely skewed funnel plots and P < .01 in Egger's regression suggested publication bias and/or exaggerated effects in small studies, which was more pronounced after 2002. There was substantial heterogeneity of effects (I 2 = 68%-86%) overall and in all subgroups except cynomolgus monkeys (I 2 = 9%), the only animal subgroup without clear bias. Adjusting for publication bias, overall estimates of estrogen effects on atherosclerosis were close to null effect. CONCLUSIONS: We found substantial evidence of publication bias but not of confirmation bias. Publication bias and flawed small studies may partly explain why findings differ between animal studies and clinical trials on the effect of estrogens on cardiovascular disease.

Venous thrombosis with oral postmenopausal hormone therapy: Roles of activated protein C resistance and tissue factor pathway inhibitor.

BACKGROUND: Oral postmenopausal hormone therapy (HT) increases the risk of venous thrombosis (VT). We postulated that activated protein C (APC) resistance induced by HT is one of the mechanisms causing VT, and also assessed the role of one of the main determinants of APC resistance (i.e., tissue factor pathway inhibitor [TFPI]). METHODS: We performed a nested case-control study embedded within two Women's Health Initiative hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after 1 year in 217 cases and 817 controls. RESULTS: Increased APC resistance and decreased TFPI at baseline were associated with VT (odds ratio 1.20-2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. Although there was no change in APC resistance or TFPI in placebo group after 1 year, HT group showed prothrombotic changes in the biomarkers (i.e., an increase in APC resistance) (mean [standard deviation] 0.39 [0.54]) and decrease in TFPI (-0.21 [0.50]: free TFPI, -0.24 [0.22]: TFPI activity -0.22 [0.20]: total TFPI). However, HT induced prothrombotic change in biomarkers did not increase risk of VT. CONCLUSION: Women with prothrombotic levels of APC resistance and TFPI at baseline were not at increased risk of VT when randomized to HT compared with placebo. This suggests that testing for these biomarkers before starting HT is not required. HT led to prothrombotic change in these biomarkers after one year, but this did not relate to increased risk of VT.

Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and ß-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated ß-catenin and the Wnt/ß-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

Safety of a strategy combining D-dimer testing and whole-leg ultrasonography to rule out deep vein thrombosis.

Guidelines for the diagnostic workup of deep vein thrombosis (DVT) recommend assessing the clinical pretest probability before proceeding to D-dimer testing and/or compression ultrasonography (CUS) if the patient has high pretest probability or positive D-dimer. Referring only patients with positive D-dimer for whole-leg CUS irrespective of pretest probability may simplify the workup of DVT. In this prospective management outcome study, we assessed the safety of such a strategy. We included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected DVT between February 2015 and November 2018. STA-Liatest D-Di Plus D-dimer was analyzed for all patients, and only patients with levels ≥0.5 µg/mL were referred for CUS. All patients with negative D-dimer or negative CUS were followed for 3 months to assess the venous thromboembolic rate. One thousand three hundred ninety-seven patients were included. Median age was 64 years (interquartile range, 52-73 years), and 770 patients (55%) were female. D-dimer was negative in 415 patients (29.7%) and positive in 982 patients (70.3%). DVT was diagnosed in 277 patients (19.8%). Six patients in whom DVT was ruled out at baseline were diagnosed with DVT within 3 months of follow-up for a thromboembolic rate of 0.5% (95% confidence interval, 0.2-1.2). A simple diagnostic approach with initial stand-alone D-dimer followed by a single whole-leg CUS in patients with positive D-dimer safely ruled out DVT. We consider this strategy to be a valuable alternative to the conventional workup of DVT in outpatients. This trial was registered at www.clinicaltrials.gov as #NCT02486445.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Safety and feasibility of rivaroxaban in deferred workup of patients with suspected deep vein thrombosis.

Guidelines suggest using empiric low-molecular-weight heparin if the diagnostic workup of deep vein thrombosis (DVT) is expected to be delayed. The role of direct oral anticoagulants for deferred compression ultrasound imaging (CUS) in patients with suspected DVT remains unexplored. The main objective of the study was to assess the safety of deferring CUS with therapeutic doses of rivaroxaban. We prospectively included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected first or recurrent lower-extremity DVT between February 2015 and November 2018. Patients were discharged with rivaroxaban 15 mg twice daily while awaiting CUS within 24 hours if D-dimer level was ≥0.5 mg/L fibrinogen-equivalent units. The primary outcome was the rate of major bleeding incidents from study inclusion until DVT was confirmed and anticoagulation therapy continued, or otherwise up to 48 hours following administration of the last tablet of rivaroxaban. The secondary outcome was the rate of progressive DVT symptoms or symptoms or signs of pulmonary embolism between hospital discharge until venous thromboembolism was diagnosed. Six hundred twenty-four of 1653 patients referred with suspected DVT were included (37.7%; 95% confidence interval [CI], 35.4-40.1). DVT was diagnosed in 119 patients (19.1%; 95% CI, 16.1-22.3). There were no major bleeding incidents, yielding an observed major bleeding rate of 0% (1-sided 95% CI <0.4). No patients experienced major complications in the interval that CUS was deferred (0%; 95% CI, 0.0-0.6). Deferring CUS for up to 24 hours in patients with suspected DVT with therapeutic doses of rivaroxaban is a safe strategy. This trial was registered at www.clinicaltrials.gov as #NCT02486445.

Cold agglutinin disease revisited: a multinational, observational study of 232 patients.

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.

Elevated Complement C3 and C4 Levels are Associated with Postnatal Pregnancy-Related Venous Thrombosis.

High levels of complement C3 are associated with venous thrombosis (VT) in the general population. We investigated if high C3 and C4 levels were associated with pregnancy-related VT. We undertook the Norwegian VIP study, a case-control study of VT in pregnancy or within 3 months postpartum (cases, n = 313) and women without pregnancy-related VT (controls, n = 353). Determinants of C3 and C4 in the control women were investigated with linear regression and the odds ratio (OR) for pregnancy-related VT was calculated with logistic regression. We found that levels of C3 and C4 were associated with body mass index (BMI), C-reactive protein (CRP); with the coagulation factors (F) fibrinogen, FVIII, and FIX; and with the coagulation inhibitors antithrombin, protein C, protein S, and tissue factor pathway inhibitor. These associations were influenced by CRP levels. The crude OR for pregnancy-related VT was 1.8 (95% confidence interval [CI], 1.1-3.0) for C3 above the 90th percentile and 2.0 (95% CI, 1.2-3.2) for C4 above the 90th percentile. Stratification in antenatal and postnatal VT showed that C3 and C4 were only associated with postnatal VT with an OR for high C3 of 3.0 (95% CI, 1.8-5.0), and for high C4 of 2.6 (95% CI, 1.5-4.6). Adjustment for high FIX and BMI reduced the ORs. We conclude that the association between postnatal VT and C3 and C4 suggests that there is clinically relevant crosstalk between the complement and the coagulation system.