Elisa Orna

Translocation (3;8)(q27;q24) in two cases of triple hit lymphoma.

Unclassifiable lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma is a new category of B-cell lymphoma appearing in the new World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. This lymphoma usually shows MYC rearrangements with non-IGH genes in the setting of a complex karyotype possibly involving BCL2 and, less frequently, BCL6 rearrangements. According to the presence of two or three rearrangements, these lymphomas are called double-hit lymphomas or triple-hit lymphomas (THL), respectively. Here we report two cases of THL with MYC, BCL2, and BCL6 rearrangements and t(3;8)(q27;q24) diagnosed in one center in the last two years.

Comparación de la flebotomía con eritrocitaféresis en la sobrecarga de hierro en portadores de mutaciones del gen HFE

Fundamento y objetivo Aunque la sangria terapeutica se considera el tratamiento de eleccion de la sobrecarga ferrica (SF), la eritrocitaferesis (EA) se presenta como un metodo seguro y rapido para retirar el exceso de hierro, sin perdida asociada de volumen, plasma ni plaquetas. En este estudio se compara la eficacia de la EA con la del metodo clasico. Pacientes y metodo Se revisaron los datos de 9 pacientes con SF tratados con EA, mediante separador celular automatico de flujo discontinuo por unipuncion, en 24 meses, y se compararon con los de 9 pacientes apareados tratados con sangrias. Resultados En cada EA se retiraron 275 ml de eritrocitos, con reduccion de 23 g/l de la hemoglobina y de 55 μg/l de la ferritina, frente a los 17 μg/l de la sangria, lo que redujo a un tercio el tiempo requerido para la deplecion ferrica. Las pruebas hepaticas se normalizaron en el 80% de los pacientes con EA, y en ninguno de los tratados con sangria. Conclusiones La EA es segura, efectiva y mas rapida que las sangrias para eliminar la SF, aunque se necesitan estudios economicos aleatorizados para determinar si es ademas una alternativa coste-efectiva.

Applicability of the results of thrombophilia studies in clinical practice

The factor V G1691A (factor V Leiden, FVL) and factor II G20210A gain-of-function mutations are the most frequent forms of inherited thrombophilia [1,2]. However, considering their prevalence in the healthy Caucasian population (3–10% depending on the region), the increase in thromboembolic risk is merely 3–5 times that of non-carriers and the large majority of carriers will not suffer any thromboembolic event [1,3]. Therefore, screening for the presence of FVL and G20210A is controversial, particularly in patients without a strong personal or familial history of thrombosis and those in whom the results would not have therapeutic implications. Thrombophilia studies are particularly prone to bias because they are largely case-control studies or case series. Furthermore, the penetrance of thrombosis in patients with gain-of-function genetic mutations (both FVL and G20210A) is greatly determined by thrombotic history. Since testing is largely done because of a thrombotic history (both personal or familial), these mutations might appear thrombogenic where thrombogenicity is largely (although not entirely) conferred by a history of a thrombotic event itself, rather than in themutation. This notion has recently become more generalized and expert opinion now suggests stringent criteria for testing [4]. Indeed, in the 2016 meeting of the American society of Hematology, Dr Middledorp reviewed the evidence and concluded [5], in line with current guidelines, that an essential criteria for testing is a therapeutic implication, which is rarely present. The results of our own experience, in a tertiary healthcare center, seem to show that these recommendations are not followed (Table 1). Although we have not tested healthy individuals, the prevalence in other series from the Northwestern coast of the Mediterranean is 1.6– 5.8% for FVL [1,6] and 3–6.5% for G20210A [2,7]. Therefore, the prevalence of FVL and G20210A in patients in whom a thrombophilia study was ordered is only slightly higher than in the general population, seemingly indicating that the clinical threshold for ordering these tests is very low.

Paraprotein-related Bleeding as a First Symptom of Multiple Myeloma

Specific affinity characteristics of the neoplastic paraprotein have been established as exceptional causes of bleeding in patients with malignant gammopathies. We describe a case in which a relationship between impaired coagulation parameters and the concentration of serum paraprotein, without specific affinity for any coagulation protein, could be established. Alternative causes of bleeding were discarded and a correlation between serum monoclonal paraprotein concentration and activated partial thromboplastin time was established. Multiple myeloma treatments achieved minor responses only, but were otherwise associated with partial improvement in coagulation parameters and, most importantly, control of the bleeding episodes. The interference in the coagulation process appeared to be non-specific and related to paraprotein concentration only but was not related to hyperviscosity. The case emphasizes the need to suspect of atypical effects of paraproteinemia in patients with monoclonal gammopathy of unknown significance and eventually to treat the underlying plasma cell dyscrasia if symptoms, like severe bleeding, justify that intervention.

Adoption of Bio/Data Collagen for the assessment of platelet function with the Multiplate® Analyzer

The Multiplate® Analyzer (Roche Diagnostics, Mannheim, Germany) uses whole blood to assess platelet function, thus avoiding the technical complexity of light transmission aggregometry [1]. Production was recently stopped on the COLtest reagent (Roche Diagnostics), which was used for the assessment of collagen-induced aggregation with the Multiplate® Analyzer. We therefore set out to adapt another reagent, Collagen (Bio/Data Corporation, Horsham, USA), originally intended for platelet-poor and platelet-rich plasma, for whole blood with the Multiplate® Analyzer. Collagen reagent (COL) is a lyophilized preparation of soluble calf skin collagen (Type 1) and the recommended concentration of reconstituted reagent is 1.9 mg/mL. We tested 54 healthy individuals to 1) assess the ideal concentration and volume of COL to test platelet function by means of the Multiplate® Analyzer and 2) establish a reference range for its use. No individuals had taken any medication with potential effects on platelet function in the last 14 days. None of them had a history of bleeding diathesis or any acute or significant chronic illness. All individuals provided informed consent for their participation in the study. Samples were obtained from an antecubital vein, in a fasting state and through a non-traumatic venipuncture. They were drawn directly into a 3 mL Hirudin Blood Tube (Roche Diagnostics, Mannheim, Germany) which was used for the assessment of collagen-induced platelet activation by means of the Multiplate® Analyzer. Samples were processed 30 min to 1 h after collection and according to the manufacturers instructions. Briefly, 300 μL of hirudin whole blood were mixed with 300 μL normal 37 °C-preheated saline in several cuvettes to which different concentrations and volumes of COL were added, triggering platelet activation. After incubating for 6 min, the results of the test are provided by the Multiplate® Analyzer as aggregation units (AU) [1] or area under the aggregation curve (AUC = AU × 10). The different COL concentrations and volumes assayed were: COL1 = 9.5 μg of Collagen (10 μL at 0.95 mg/mL), COL2 = 19 μg of Collagen (20 μL at 0.95 mg/mL), COL3 = 47.5 μg of Collagen (50 μL at 0.95 mg/mL) and COL4 = 95 μg of Collagen (50 μL at 1.9 mg/mL). All four volumes and concentrations were tested in the first 15 individuals (dosefinding cohort). After a first analysis, COL2 and COL3 were chosen for the remaining 39 (extension cohort). After the final selection of COL3, we assessed the repeatability of the results in 2 individuals by analyzing the same sample 9 times (as many as possible with 3 mL) and reproducibility (the day-to-day variation by testing 2 individuals on 5 consecutive days). Furthermore, we analyzed the correlation between the AU and demographic and analytical characteristics of the cohort. Kolmogorov–Smirnoff test was applied to verify the non-Gaussian distribution of collagen values on normal population. Correlation coefficients (r) were calculated by Spearmans method. The reference range was determined by nonparametric analysis. Kruskal-Wallis test was performed for the median comparison between four different COL and Mann-Whitney test was used to compare differences between COL2 and COL3. P values< 0.05 were considered to be statistically significant. Data were analyzed with computerized statistical package for social sciences (SPSS) version 20.0. Demographic and analytic characteristics of the dose-finding and extension cohorts are shown in Table 1. The median age of the 54 individuals was 38.5 (range 19–63) and 78% were female. The dose-finding cohort showed higher median AU for COL2 and COL3 (58.0 [interquartile range (IQR) 50.0–67.5] and 62.0 [IQR 53.0–68.5], respectively, vs. 38.0 [IQR 21.5–51.0] for COL1 and 43 [IQR 32.7–47.5] for COL4; p < 0.001, Fig. 1A); therefore they were chosen for the extension cohort, as they were deemed to be more discriminating and similar to those reported in the literature. COL3 showed a significantly higher median value and smaller interquartile range than COL2 (57.5 [IQR 51.0–65.0] vs. 34.0 [IQR 25.0–54.0] AU; p < 0.001, Fig. 1B), leading us to conclude that COL3 would be the most discriminating. Taking the percentile 5 to 95 as normal, our reference range goes from 32.0 to 78.7 AU (AUC 320 to 787 AU ∙min). The repeatability and reproducibility variation coefficients of COL3 were acceptable (7.38% and 10.12%, respectively). Leukocyte count correlated significantly with AU for COL3 (r: 0.429; p= 0.002), contrary to age, gender, platelet count or hemoglobin levels, which were not significantly correlated with AU. In this study, we determined a reference range for Bio/Data Collagen for the Multiplate® Analyzer, a standardized and easy-to-use platelet function testing device. The recent stop in the production of COLtest reagent makes it essential to find an alternative collagen reagent. Based on the results of the present study, 47.5 μg of Collagen at a concentration of 0.95 mg/mL, for a final volume of 50 μL, seems to be a good option. Although wide (32.0 to 78.7 AU or 320 to 787 AU ∙min), the width of the reference range is similar to those previously reported for other agonists used with the Multiplate® Analyzer [2,3]. We found good repeatability and reproducibility variation coefficient of the results in 2 individuals, in line with previous authors [3], therefore we did not test it further. There was a notable difference between the dose-finding and extension cohort in AU values obtained

Indications and use of, and incidence of major bleeding with, antithrombotic agents in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) and antithrombotic medication both increase the risk of bleeding. We set out to analyze the prevalence of use, indications and bleeding risk of antithrombotic therapy in patients with MDS in a retrospective, single-center study including all patients with MDS with >20 × 109/L platelets. 193 patients (59% male, median age 75 years) were included; 122 did not receive antithrombotic treatment, 51 received antiplatelet agents and 20 received anticoagulants. The cumulative incidence of major bleeding was higher in both the antiplatelet group (11.8% at 4 years, 95% confidence interval [95%CI]: 4.7-22.3%) and the anticoagulation group (21.2% at 4 years, 95%CI 6-42.5%) than in the control group (2.8% at 4 years 95%CI: 0.7-7.3%). The prevalence of use of antithrombotic medication in this cohort of patients with MDS was high and bleeding risk was increased in these patients.

Venous thromboembolism in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with lenalidomide: a systematic review

Abstract Lenalidomide has been associated with an increased risk of venous thromboembolism (VTE) in multiple myeloma. It is unclear whether patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are also at such risk. We conducted a systematic review of the incidence of VTE in prospective trials of lenalidomide-treated patients with NHL or CLL. Sixty-eight unique reports were assessed for inclusion. For grade ≥3 VTE, 98 events were reported in 3043 patients (60 studies) (crude incidence: 3.22% [95% confidence interval: 2.6–3.9%]). For any grade VTE, 97 events were reported in 2244 patients (46 studies) (crude incidence: 4.32% [3.5–5.2%]). Subgroup analysis showed no difference based on histological subtype or use of prophylaxis. The study is at risk of bias, largely due to insufficient data from the individual studies. Within the limitations of this systematic review, we found a low risk of VTE in patients with NHL treated with lenalidomide.

Incidence, predictive factors, management, and survival impact of atrial fibrillation in non-Hodgkin lymphoma

Atrial fibrillation (AF) and cancer are common disorders in the general population but there are few studies in patients with both diseases. More specifically, there are scarce data on AF in patients with non-Hodgkin lymphoma (NHL). We assessed the incidence, predictive factors, management, and survival impact of AF in a cohort of patients with NHL from a single institution between 2002 and 2016 (n = 747). Twenty-three patients were diagnosed with AF before and 40 after the diagnosis of NHL (of the later, 16 were secondary to an extracardiac comorbidity and 24 unrelated to any triggering event [primary AF]). The 5-year cumulative incidence of new-onset AF was 4% (95% confidence interval [CI] 3–6%). Age and hypertension were the only predictive factors for the development of AF. Management of AF was heterogeneous, primarily with anti-vitamin K agents but also antiplatelet therapy in a significant proportion of patients. Among the 63 patients, there were six episodes of ischemic stroke/transient ischemic attack and four venous thromboembolic events, with four major bleeding episodes. Overall survival (OS) was inferior in patients with AF (HR 0.1, 95% CI 0.01–0.7, p = 0.02), largely due to secondary AF. We conclude that the incidence of new-onset AF in NHL patients seemed somewhat higher than in the general population, although with similar predictive factors. The management was heterogeneous, and the risk of ischemic and hemorrhagic events did not seem higher than in cancer-free patients. Survival was particularly poor for patients with secondary AF.

Hemorragia intracraneal durante el tratamiento con apixabán

latente y con un título de anticuerpos reagínicos (VDRL/RPR) superior a 1:325. Con las limitaciones del escaso número de pacientes y el carácter retrospectivo del estudio, y habida cuenta de las con5. Sun JJ, Wang ZY, Shen JY, Shen YZ, Liu L, Wang JR, et al. Serum TRSUT titer ≥ 1:16 predictor for neurosyphilis among HIV-infected patients with concurrent syph and no neurological symptoms. Medicine (Baltimore). 2015;94:e2023.

Número de pacientes necesario a tratar con anticoagulantes orales directos con respecto a warfarina en la fibrilación auricular

RE-LY2 Ensayo clínico 18.113 Dabigatrán 150 mg/12 h vs. warfarina 1,11 vs. 1 HR: 0,66 p < 0,001 Dabigatrán 110 mg/12 h vs. warfarina 1,53 vs. 1 HR: 0,91 p = 0,34 ROCKET-AF3 Ensayo clínico 14.264 Rivaroxabán vs. warfarina 2,1 vs. 2, HR: 0,88 p = 0,12 ARISTOTLE4 Ensayo clínico 18.201 Apixabán vs. warfarina 1,27 vs. 1 HR: 0,79 p = 0,01 Graham et al.5, 2015 Vida real 134.414 Dabigatrán (150 o 75 mg/12 h) vs. warfarina 1,13 vs. 1 HR: 0,8 ( p = 0,02d Yao et al.6, 2016b Voda real 125.243 Dabigatrán (150 o 75 mg/12 h) vs. warfarina 1,18 vs. 1 HR: 0,98 p = 0,88 Apixabán (5 o 2,5 mg/12 h) vs. warfarina 1,33 vs. 1 HR: 0,67 p = 0,04 Rivaroxabán (20 o 15 mg/24 h) vs. warfarina 1,26 vs. 1 HR: 0,93 p = 0,56