Essentials
Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE).
We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy.
A ...DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model.
The DASH score performed better in younger (< 65 years old) subjects.
Summary
Background
The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort.
Aims
To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years.
Methods
Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D‐dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D‐dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time‐dependent analysis. Observed 12‐month and 24‐month recurrence rates were compared with recurrence rates predicted by the DASH model.
Results
We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a ‘low‐risk’ (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51–1.45). The c‐statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72).
Conclusions
These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.
The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To ...tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.
Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this ...study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or γ-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL.
We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis ...(SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.
While many prognostic markers in B-cell chronic lymphocytic leukemia provide insight into the biology of the disease, few have been demonstrated to be useful in the daily management of patients. ...B-cell receptor signaling is a driving event in the progression of B-cell chronic lymphocytic leukemia and markers of B-cell receptor responsiveness have been shown to be of prognostic value. Single cell network profiling, a multiparametric flow cytometry-based assay, allows functional signaling analysis at the level of the single cell. B-cell receptor signaling proteins (i.e. p-SYK, p-NF-κB p65, p-ERK, p-p38, p-JNK) were functionally characterized by single cell network profiling in samples from patients with B-cell chronic lymphocytic leukemia in an exploratory study (n=27) after stimulation with anti-IgM. Significant associations of single cell network profiling data with clinical outcome (i.e. time to first treatment), as assessed by Cox regression models, were then confirmed in patients' samples in two other sequential independent studies, i.e. test study 1 (n=30), and test study 2 (n=37). In the exploratory study, higher responsiveness of the B-cell receptor signaling proteins to anti-IgM was associated with poor clinical outcomes. Patients' clustering based on signaling response was at least as powerful in discriminating different disease courses as traditional prognostic markers. In an unselected subgroup of patients with Binet stage A disease (n=21), increased anti-IgM-modulated p-ERK signaling was shown to be a significant, independent predictor of shorter time to first treatment. This result was independently confirmed in two test cohorts from distinct populations of patients. In conclusion, these findings support the utility of the single cell network profiling assay in elucidating signaling perturbations with the potential for the development of a clinically useful prognostic test in patients with early stage B-cell chronic lymphocytic leukemia. These data support the clinical relevance of B-cell receptor signaling in B-cell chronic lymphocytic leukemia, and suggest a key role of ERK activation in the physiopathology of this leukemia.
Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and ...PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT), accounting for 31.5% of portal vein thrombosis (PVT) and 40.9% of Budd Chiari syndrome (BCS). In patients (pts) with MPN and SVT, splenomegaly can arise as the consequence of the hematological disease and/or blood flow abnormalities consequent to the thrombosis itself. Splenomegaly and the compensatory enlarged splanchnic vessels are responsible for several complications including esophageal and gastric varices. Splenomegaly may cause abdominal discomfort; furthermore pts may present symptomatic burden due to the MPN. Current treatment strategies for MPN pts with SVT include anticoagulants and cytoreductive therapy (ie hydroxyurea, interferon) that have little influence in the control of splenomegaly and symptoms and do not improve flow abnormalities. Ruxolitinib, a JAK1/2 inhibitor, was highly effective in reducing spleen volume and improving symptoms in patients with MF and PV in phase II and III studies. We hypothesized that the decrease of the enlarged spleen determined by Ruxolitinib could result in a reduction of the local pressure in splanchnic vessels, producing both symptomatic improvement of splenomegaly-related symptoms and of splanchnic circulation. We designed an investigator-initiated multicentre phase 2 study of Ruxolitinib in pts with splenomegaly due to an underlying MPN associated with SVT. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. The primary study objective was to evaluate the proportion of subjects achieving ≥ 50% reduction in spleen length from left costal margin (LCM) measured by palpation at any time from baseline to week 24 (w24) and at w24, or a ≥ 35% reduction in spleen volume by MRI or CT at week 24. The secondary objectives included: evaluation of safety of Ruxolitinib in MPN-associated SVT; assessment of splanchnic circulation through Doppler analysis, measurement of hyperdynamic arterial circulation by echocardiography and stiffness of hepatic/splenic parenchyma by fibroscan; status of esophageal varices at w24 compared to baseline. Quality of Life assessment was performed using MPN-SAF questionnaire. Exploratory objectives include evaluations of changes in JAK2V617F or MPLW515 allelic burden, association of baseline mutations with response to treatment, changes in cytokine and microRNAs profiles, quantification of circulating endothelial cells. At the time of abstract submission 7 out of 21 pts have been enrolled, of which 5 completed the 24 weeks of treatment; two additional pts are in screening phase. Three pts had PMF, two ET, one PV and one PPV-MF, associated to spleno-porto-mesenteric thrombosis (5 pts) and Budd Chiari syndrome (2 pts). All pts were under oral anticoagulation therapy. Initial dose of Ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with baseline platelet count of 100 to 200x109/L and 20 mg BID for those with baseline platelet count >200x109/L. A palpable splenomegaly greater than 5 cm below LCM was a criterion for enrollment; the 5 patients who completed the 24 weeks of treatment had a median splenomegaly of 8 cm below LCM at baseline, and obtained a median reduction of 69% measured by palpation at week 24, associated with a significant reduction in abdominal discomfort as measured by MPN-SAF questionnaire (median score at screening 5 vs 1.5 at week 24). The total symptom score calculated by using BFI and MPN-SAF was reduced from 50 at screening to 35 at week 24. Instrumental evaluations of splanchnic and systemic circulation showed that 3 pts obtained a reduction of the spleen stiffness from a median value of 66 to 49.6 kilopascals (KPa), 2 pts had a reduction of the liver stiffness from a median value of 23.85 to 18.2 KPa and 1 pt a reduction of the cardiac output from 5.871 to 4.6 L/min. Evaluation of esophageal varices at week 24 showed stabilization with neither worsening nor need of banding. Ruxolitinib was well tolerated, with no SAE reported; one pt developed anemia G2 and one G3 leading to dose reduction. Other adverse events include G1 asthenia and G≤2 AST/ALT increase in 3 pts, one case of Herpes Zoster and one case of abdominal pain both G1. Updated results will be presented at the meeting.
Marchioli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Vannucchi:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Background:
Management of venous thromboembolism (VTE) in patients with haematological malignancies (HM) and thrombocytopenia challenges clinicians because this scenario is encumbered with several ...risks. Our panel, composed by elected members of the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Working Party on Thrombosis and Haemostasis (WPHT). has recently published a consensus,reached by RAND method, focused on the platelet cut‐off for safely administering Low Molecular Weight Heparin (LMWH) in adult patients with hematological malignancies, acute (no later than 1 month) or non‐acute VTE and thrombocytopenia (PLT< 100 × 109/L).
Aims:
Aim of the current study was to produce a formal consensus, not achieved by the previous method, focused on anticoagulant treatment with LMWH in adult patients with HM affected by acute or non‐acute catheter‐related VTE and severe thrombocytopenia
Methods:
Delphi methodology was adopted to allow members of the GIMEMA‐WPHT to achieve consensus on the above reported issue, starting from available scientific data. For each indication, the panel members (N = 21, 3 validators and 18 participants) rated the benefit‐to‐harm ratio of the indication on a scale of 1 to 5, where 1 means that the expected harms greatly outweigh the expected benefits, and 5 means that the expected benefits greatly outweigh the expected harms. The first survey consisted of 7 different statement; after analysis of the first results, it was decided to discuss and re‐formulate 3 items, panel members were then asked to rate again items for which no consensus had been achieved. The interventions considered were the administration of different doses of LMWH (therapeutic, reduced dose at 50% of full therapeutic dose, prophylactic dose) and PLT transfusions, according to platelet counts >30 <50 × 109/L, in patients with catheter‐related VTE. LMWH doses were defined according to the datasheet for each LMWH molecule.
Results:
After the first round, an agreement >80%was reached for 4 out of the initial 7 items. Three items were thus reformulated nd partecipants were asked to reasses them After the second round, an agreement was reached for all items. The panel of experts expressed the following consensus: for the management of acute‐catether related VTE with platelet counts >30 <50 × 109/L in patients with HM, anticoagulant treatment with reduced dose to 50% of LMWH is appropriate (90%agreement); for the management of non‐acute catheter‐related VTE, treatment with reduced dose to 50% of LMWH is also appropiate. PLTs transfusions were deemed inappropriate in both,acute (90% agreement) and non‐acute (100% agreement) catheter‐related VTE. The administration of prophylactic dose of LMWH was deemed inappropriate with an agreement of 90% in patients with acute catheter‐related VTE and 80% in subjects with non‐acute catheter‐related VTE.
Summary/Conclusion:
Delphi method has allowed to reach consensus on a still debated issue, where scientific evidences are lacking.GIMEMA‐WPHT suggests anticoagulant treatment with reduced dose to 50% of LMWH for platelet counts >30 <50 × 109/L in patients with haematological malignancies and either acute or non‐acute catheter‐related VTE.
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