Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Are Anti-ß2 Glycoprotein 1 Antibodies Associated with Placenta-Mediated Pregnancy Complications? A Nested Case-Control Study.

BACKGROUND: While anti-ß2 glycoprotein 1 (anti-ß2GP1) antibody positivity is included in the diagnostic criteria for antiphospholipid syndrome (APS), the association between anti-ß2GP1 and the obstetrical complications of APS has been inconsistently reported and remains unclear. OBJECTIVE: We completed a case-control study nested within the Canadian Ottawa and Kingston (OaK) Birth Cohort to evaluate the association between anti-ß2GP1 antibody positivity and placenta-mediated pregnancy complications. STUDY DESIGN: Five hundred cases were randomly selected among pregnant women who experienced any of the following independently adjudicated placenta-mediated pregnancy complications: preeclampsia, placental abruption, late pregnancy loss (≥ 12 weeks' gestation), and birth of a small-for-gestational age (SGA) infant < 10th percentile. Five hundred pregnant women without any placenta-mediated pregnancy complications were selected as controls. Stored blood samples were analyzed for the presence of anti-ß2GP1 antibodies by enzyme-linked immunosorbent assay. RESULTS: Anti-ß2GP1 immunoglobulin G (IgG) and/or immunoglobulin M (IgM) antibodies in titers ≥ 20 G/M units (> 99th percentile) were present in 24 of 497 (4.8%) of controls and 33 of 503 (6.6%) of cases. There was no significant difference between cases and controls for the composite outcome of any placenta-mediated pregnancy complications (odds ratio, 1.38, 95% confidence interval [CI], 0.8-2.37, p = 0.25). CONCLUSION: Our results call into question the association between anti-ß2GP1 antibodies and placenta-mediated pregnancy complications, with further research needed.

The impact of geographic proximity to transplant center on outcomes after allogeneic hematopoietic stem cell transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) need access to specialized care. We hypothesized that access to the transplant center after HSCT may be challenging for patients living in geographically distant areas, and that this would have an adverse effect on their outcome. We analyzed 1912 adult patients who underwent allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) between 1996 and 2009 and who resided within 6 hours driving time of the institution. Driving time from primary residence to DF/BWCC based on zipcode was determined using geographic information systems. The median driving time (range) to DF/BWCC was 72 (2-358) minutes. When patients were stratified by driving time quartile, overall survival (OS) after HSCT was similar in the first year but worse after 1 year in patients in the top quartile (≥ 160 minutes driving time). In a landmark analysis of the 909 patients alive and free of disease at 1 year, 5-year OS was 76% and 65% for patients in the first (≤ 40 minutes) and fourth (≥ 160 minutes) quartiles, respectively (P = .027). This was confirmed in a multivariable analysis. The difference appeared to be mostly because of an increase in nonrelapse mortality. The number of visits to the transplant center between day 100 and 365 after HSCT declined significantly with increasing driving time to the transplant center, which was independently associated with worse survival. Long driving time to the transplant center is associated with worse OS in patients alive and disease-free 1 year after HSCT, independently of other patient-, disease-, and HSCT-related variables. This may be in part related to the lower frequency of post-HSCT visits in patients living farther away.

Vascular progenitor recruitment in critically ill patients with acute kidney injury.

PURPOSE: Endothelial-like vascular progenitor cells (VPCs) are blood-derived angiogenic precursors that can facilitate vascular repair. The mobilization of peripheral blood VPCs and their role in recovery were investigated in patients with acute kidney injury (AKI) in the intensive care unit (ICU) setting. METHODS: Blood samples were drawn on days 0, 3, 7 and 14 in 38 patients admitted to ICU: 30 with AKI and in eight controls with normal renal function. Circulating VPC levels were quantified by the early outgrowth cell cluster-forming assay and/or by flow cytometry. RESULTS: AKI patients (16 males, mean age 62.4) were classified as Risk (R, n=5), Injury (I, n=11) and Failure (F, n=14) according to the RIFLE criteria. VPC clusters increased over time following the diagnosis of AKI (p < 0.01 for day 0 vs. day 14) while VPC clusters were higher at enrollment in control patients and decreased over time (p=0.02). Greater mobilization of VPCs occurred in patients with more severe AKI at enrollment (I and F categories compared with R, p=0.05). A trend towards greater mobilization of VPC clusters was observed in patients with improved renal function (p=0.07). CONCLUSION: Time-dependent increases in circulating VPCs occur in critically ill patients with established AKI. Greater mobilization of VPCs may be associated with recovery of renal function, suggesting a potential role for VPCs in repair after kidney injury.

Successful prevention of thrombotic thrombocytopenic purpura (TTP) relapse using monthly prophylactic plasma exchanges throughout pregnancy in a patient with systemic lupus erythematosus and a prior history of refractory TTP and recurrent fetal loss.

BACKGROUND: The occurrence of thrombotic thrombocytopenic purpura (TTP) in the setting systemic lupus erythematosus (SLE) is rare. In women of childbearing age, TTP is associated with high rates of recurrence in pregnancy. Furthermore, both TTP and SLE are associated with a significant risk of adverse pregnancy outcomes. CASE PRESENTATION: We describe the case of a 36 year old female in her first trimester of pregnancy with a prior history of SLE-associated severe refractory TTP who was treated with a combination of corticosteroids and prophylactic plasma exchanges (PLEX) throughout pregnancy to prevent TTP recurrence. She delivered a healthy infant at 33 weeks of gestation after the onset of preterm labor. There was no evidence of TTP recurrence in the antepartum or postpartum period in this high risk patient. CONCLUSION: Prophylactic PLEX should be considered as a therapeutic option to prevent recurrent TTP during pregnancy in high risk patients, including patients with previous SLE-associated TTP.

Novel agents for the treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Currently, the most effective treatment for CLL consists of a combination of fludarabine, cyclophosphamide, and rituximab. Although this approach has encouraging results, patients with CLL eventually relapse and require additional therapies. Many of the current therapeutic regimens for CLL are myelotoxic, immunosuppressive, and associated with infectious complications. Targeted therapies can often minimize these complications. The US Food and Drug Administration has recently approved 2 agents, bendamustine and ofatumumab, for the treatment of CLL. Emerging therapies ranging from new monoclonal antibodies to small molecules that interfere with vital pathways in signal transduction and cell cycle regulation are currently being developed. This article will focus on novel agents in earlier development phases for CLL, including the immunomodulator lenalidomide; monoclonal antibodies, such as lumiliximab, GA-101, and small molecule immunopharmaceuticals; BCL-2 inhibitors, such as oblimersen, obatoclax, and ABT-263; and protein kinase inhibitors, such as flavopiridol, spleen tyrosine kinase inhibitors, and phosphatidylinositol 3-kinase inhibitors.

The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial.

Low-molecular-weight heparin (LMWH) is increasingly being used for prophylaxis of venous thromboembolism (VTE) and prevention of pregnancy associated morbidity in pregnant women with thrombophilia. We sought to determine if the administration of prophylactic doses of LMWH downregulates coagulation activation in high risk pregnant women with thrombophilia. This sub-study was planned as part of a randomized open label controlled trial (Thrombophilia in Pregnancy Prophylaxis Study [TIPPS]) in which patients at high risk of pregnancy complications with confirmed thrombophilia are randomized to receive either dalteparin (5,000 units/day until 20 weeks then 5,000 units q12h until 37 weeks or onset of labor) or no treatment. Blood samples were collected at baseline, day 7-9 (after starting study drug), week 20 (before increasing study drug), week 36 (prior to stopping study drug) and at the time of admission to the labor and delivery unit. Samples were not drawn at fixed times in relation to drug injection. These samples were analyzed for levels of thrombin-antithrombin complexes (TAT), prothrombin fragments 1 + 2 (F1.2), D-dimer and anti-Xa activity. Generalized linear mixed models were used for statistical analysis and model results were controlled for age, smoking status, type of thrombophilia and predisposing risk factors. The effect of dalteparin on TAT levels was defined as the primary outcome. Of 198 patients eligible, 114 were enrolled in TIPPS. Ninety-one were eligible for the TIPPS coagulation activation sub-study and randomized. Thirty-nine patients were analyzed in the treatment group (dalteparin) and 46 patients in the control group (no intervention). Levels of coagulation activation factors F1.2, TAT and D-dimer increased significantly throughout pregnancy in both groups (p < 0.0001). Dalteparin prophylaxis resulted in a significant increase in anti-Xa activity through pregnancy (p < 0.0001) compared to controls. Dalteparin had no significant effects on the levels of TAT, F1.2 and D-dimer throughout pregnancy in thrombophilic women. A post-hoc Monte Carlo power analysis revealed that our study had 100% and 88% power to detect reductions in TAT values on treatment of 50% and 25%, respectively. Prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation in high risk thrombophilic women during pregnancy.

Patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography for initial staging of grade 1-2 follicular lymphoma and its impact on initial treatment strategy in the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database.

We describe the patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the initial staging of patients with newly diagnosed grade 1-2 follicular lymphoma (FL) and its potential impact on treatment. Data were obtained from the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database. Patients who presented between 1 January 2001 and 30 September 2009 with newly diagnosed grade 1-2 FL, with at least 6 months of follow-up, were included. We identified 953 eligible patients and 532 (56%) underwent FDG-PET as part of initial staging. Among patients who underwent FDG-PET for initial staging, 438 (82%) received early treatment compared to 259 (61.5%) of those staged without FDG-PET (p < 0.0001). Of all patients with stage I FL (n = 100), 47% were treated with radiotherapy (RT) alone, and the choice of initial treatment strategy for stage I FL did not vary significantly by use of FDG-PET (p = 0.22). The use of FDG-PET for staging of FL is widespread and is associated with a greater proportion of patients receiving early therapy. Given the widespread use and high cost of FDG-PET, its clinical utility in stage I FL should be further evaluated.

The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis.

BACKGROUND: The association between antiphospholipid antibodies (APLA) and placenta mediated pregnancy complications (pre-eclampsia, intrauterine growth restriction (IUGR), late fetal loss and placental abruption) remains controversial. METHODS: We performed a systematic review of published case-control, cohort and cross sectional studies (MEDLINE (1975 to 2009), EMBASE 16 (1980 to 2009) and all EBM Reviews (2009)) to evaluate the association between APLA and placenta mediated complications in untreated women without autoimmune diseases. RESULTS: Our search strategy identified 1207 potentially relevant studies. Twenty eight were included in the final analysis. LA was associated with pre-eclampsia (OR 2.34; 95% CI 1.18-4.64), IUGR (OR 4.65 95% CI 1.29-16.71) and late fetal loss (OR 4.73; 95% CI 1.08-20.81) amongst case-control studies and only with late fetal loss (OR 10.59 95% CI 1.87-59.88) amongst cohort studies. ACA were associated with pre-eclampsia (OR 1.52; 95% CI 1.05-2.20) and late fetal loss (OR 4.29; 95% CI 1.34-13.68) amongst case-control studies and only late fetal loss (OR 8.85 95% CI 1.84-42.50) amongst cohort studies. Finally, anti-B2 GP1 antibodies showed associations with pre-eclampsia (OR 19.14, 95% CI 6.34-57.77), IUGR (OR 20.03; 95% CI 4.59-87.43) and late fetal loss (OR 23.46, 95% CI 1.21-455.01) in two cohort studies. CONCLUSION: APLAs appear to be associated with late fetal losses. However, the association between APLAs and other placenta mediated complications is inconsistent. LA is most strongly and consistently associated with placenta mediated complications. There are currently insufficient data to support a significant link between anti-B2 GP1 antibodies and pregnancy morbidity.