ALBERT

Description: Background Venous thrombosis (VT) frequently complicates the clinical course of cancer. Reported incidence of VT in many hematological neoplasms is up to 10%, a value comparable to that of solid tumors. Available data on the incidence and management of VT in Acute Leukemia (AL) are scanty and quite discordant. We have performed a multicenter retrospective study with the primary objective to evaluate the incidence of venous thrombotic complications in a population of patients with AL. Secondary objective was to evaluate the management of these complications in patients with AL. Materials and Methods Available clinical records of out and in-patients diagnosed with AL from January 2008 to June 2013 in 4 Regional Reference Hospitals were analyzed. Cases of venous thrombosis (VT), including thrombosis in atypical sites [Retinal occlusion (RO) and Cerebral Sinus Thrombosis (CST)], were reported in the current study. All data were recorded in a dedicated database. Available laboratory tests at diagnosis of VT included complete blood cells count (CBC), basal coagulation tests (PT, aPTT, fibrinogen), Antithrombin, anticoagulant Protein S and C and D-dimer. Instrumental Diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE) and RO and CST was performed according to ACCP guidelines. In the statistical analysis, logistic regression model was applied. Fisher’s exact test was used to determine relationships between categorical variables. All P-values represented were two-sided, and statistical significance was declared when P〈 0.05. Results Over a population of 831 patients with AL, 37 cases of VT were recorded, mainly (34/37 cases) in hospitalized patients: 24 cases were associated with Acute Myeloid Leukemia (AML) and 13 with Acute Lymphoblastic Leukemia (ALL). In the cohort of patients with VT, 23 were males (14 with AML, 9 with ALL) and 14 females (4 with AML, 10 with ALL), with a mean age of 46 ± 13,1 years; mean age of patients with AML and VT was 49 ± 12,8 years; mean age of patients with ALL and VT was 40,2 ± 12,2 years. Twelve patients presented at least a concomitant chronic disease; no one was receiving anticoagulant prophylactic treatment with low molecular weight heparin (LMWH) during hospitalization. There were 23 cases of DVT of upper arms, 9 cases of proximal DVT of limbs (one complicated with PE), 2 cases of RO, 1 of CST and 1 case of intracardiac clot. In 28/37 (75,6%) cases of recorded VT, a central venous catheter (CVC) was placed (Figure 1); moreover, 21/23 events of DVT of upper arms were significantly associated with a CVC insertion (p〈 0.01). In the other 2 cases, one patient had a bulky mediastinal disease and 1 was diagnosed with promyelocytic AML. VT occurred during chemotherapy (CHT) in 32/37 (86.4%) cases, the remaining 5 cases were diagnosed in concomitance with leukemia: in 20 cases, VT occurred at induction, in 7 at consolidation and in 5 during salvage CHT. In both subgroups with VT, there was no statistical significant difference between time at diagnosis of VT and time at diagnosis of AL. At CBC, thrombocytopenia was the most frequently observed laboratory abnormality. Basal coagulation tests and anticoagulant levels were normal in all cases. Inherited prothrombotic mutations were available only for 9/37 cases, 1 case was heterozygous for Factor V Leiden and 1 for Factor II (G20210A) mutation. Most VT episodes (32/37) were treated with LMWH at therapeutic doses for the first month after diagnosis, a dose reduction was recorded in the following months, mainly related to severe thrombocytopenia after CHT ; 1 case was treated with unfractioned heparin; four cases did not receive any treatment due to severe thrombocytopenia. No cases of VT–related deaths nor fatal complications during treatment for VT were recorded. Treatments with LMWH lasted from 3 to 6 months. All patients clinically recovered from VT, only 2 late recurrences (PEs) were observed. Conclusions The incidence (4.5%) of VT in the analyzed cohort of patients with AL is almost similar to only one previous report, even if the involved sites distribution appears quite different. In particular, RO has never been reported. Atypical sites VT must be suspected to be correctly diagnosed and treated. Anticoagulant treatment schedules and duration in patients with AL is influenced by many factors, mainly related to CHT and severe thrombocytopenia. The optimal management of VT in patients with AL requires further, prospective studies. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 190 Type and duration of anticoagulation is still matter of debate in cancer patients with acute Deep Vein Thrombosis (DVT) of the lower limbs. Residual Vein Thrombosis (RVT) has been proven to be effective for assessing the optimal duration of oral anticoagulants in non cancer patients (Siragusa S et al Blood 2008:112:511-5). In the present study we evaluate the role of a RVT-based management of anticoagulation with Low-Molecular Weight Heparin in cancer patients with acute DVT. Materials and Methods. Patients with active cancer and a first episode of DVT were treated with LMWH for 6 months (the first month at full dosage followed by dose reduction of 25% in the next 5 months). At the end of treatment, they were managed according to RVT findings: those with RVT were randomized to continue anticoagulants for 6 additional months (Group A1) or to stop it (Group A2), while patients without RVT stopped LMWH (Group B). Outcomes were recurrent venous thromboembolism and/or major bleeding; patients were followed up for one year after LMWH discontinuation. Results. Over a period of 36 months, 409 patients were evaluated; 62 were excluded (refusal, need for continuing anticoagulation, etc). In total, 347 were included in the study (Table 1). RVT was detected in 242 (69.7%) patients; recurrent events occurred in 21.9% of those randomized to discontinue and 14.2% of those who continued LMWH. In patients without RVT (105, 30.3%), recurrent events occurred in 3 cases (2.8%) (Table 2 and Figure 1). The adjusted Hazard Ratio (HR) for age and sex between RVT groups (Group A2 vs A1) was 1.58 (95% confidence interval [CI], 0.85–2.93; P=.145). The adjusted HR between group A1 versus RVT-negative group (B) was 4.54 (CI 2.3–6.66; P =.028). Five major bleeding events occurred in Group A1 and two events both in Group A2 and B (Table 2). Overall, 89 (25.6%) patients died due to cancer progression after a median follow-up of 10.2 months after heparin withdrawn. Conclusions. The Cancer DACUS is the first ever study evaluating an individual marker for assessing duration of anticoagulation in active cancer population. Final results of the study show that absence of RVT identifies a group of patients at low risk for recurrent thrombosis who can safely stop LMWH after 6 months. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3327 Background: Critically ill patients are at high risk of developing venous thromboembolism (VTE) during their stay in the intensive care unit (ICU) because of premorbid medical and surgical conditions. The clinical consequences of Deep Vein Thrombosis (DVT) have the potential to be serious yet are frequently unrecognized in the Intensive Care Unit (ICU). In contrast to the extensive documentation on the short and long–term outcomes of patients with DVT evaluated in other clinical settings, little is known about the clinical course of this disease in the ICU setting. We hypothesized that both undetected and clinically evident VTE would affect the prognosis of critically ill patients. Purpose: To systematically review whether a diagnosis of DVT in critically ill patients affects clinically important outcomes including length of stay, duration of mechanical ventilation and mortality. Material and Methods: MEDLINE and EMBASE databases were searched up to June 2010. Two reviewers performed study selection independently. Studies were selected if evaluate one or more of the following outcomes: hospital and ICU mortality, duration of patient stay in hospital and in ICU, and duration of mechanical ventilation. Two investigators independently extracted and reviewed data from each study; including study and patient characteristics and outcomes. Association between DVT and hospital and ICU mortality, and the mean difference of duration of patient stay in hospital and in ICU, and duration of mechanical ventilation in patients with and without DVT were calculated using a random-effects model (DerSimionan and Laird method). Pooled results are reported as relative risk (RR) and mean difference and are presented with 95% confidence interval (CI) and with 2-sided P values. A P value of .05 or less was considered statistically significant. Statistical heterogeneity was evaluated using the I2 statistic, which assesses the appropriateness of pooling the individual study results [22]. The I2 value provides an estimate of the amount of variance across studies due to heterogeneity rather than chance. Cohen's Kappa for inter-rater agreement was used to assess inter-rater reliability. Results: Six studies for a total of 1518 patients were included in the systematic review. Patients diagnosed with DVT compared to those without DVT had increased ICU and hospital stay (7.3 days (95% CI 1.4 to 13.2; P= 0.02) and 16.5 days (95% CI 1.51 to 30.59; P= 0.03), respectively. Duration of mechanical ventilation appeared to be increased in patients with DVT although this difference was not statistically significant (weighted mean difference: 3.41 days 95 % CI –1.12 to 7.94; P=0.14). Patients diagnosed with DVT also had a marginally significant increase in the RR of hospital mortality (RR 1.31 95%CI,0.99 to 1.74,P=0.06), and a non statistically significant increase in the RR of ICU mortality (RR 1.96; 95% CI 0.74 to 5.19; P = 0.17). Conclusions: A diagnosis of DVT upon ICU admission appears to affect clinically important outcomes including length of ICU and hospital stay and hospital mortality. Further research involving larger prospective study designs are warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Cryopreservation for long term storage of platelets (PLTs) represents a clinical useful method for avoiding platelet shortage. Many studies have tried to define, in vitro and in vivo, the entity and weight of storage-related PLTs lesions with discordant results related to different methods. We have performed an in vitro prospective study to evaluate PLTs count, viability and function of buffy coat derived pooled platelet concentrates (BC-PLTs) treated with dimethyl-sulphoxide (DMSO) and cryopreserved at -80°C with an innovative patented system not requiring laminal flow hoods and external manipulations. Materials and methods Each BC-PLTs was obtained from 5 buffy coats and pooled according to standard procedures. The final PLTs concentrates were leukoreduced by filtration and transferred to a 650 mL cryopreservation kit (Promedical ®) which allowed mixing with DMSO 25% in a closed system and following removal of supernatant without further manipulations. BC-PLTs were washed prior freezing with removal of at least 84% supernatant solution, suspended in homologous plasma from 1 of the 5 donors to a final concentration of 200 mL and frozen at – 80°.Selection criteria to make BC-PLTs available for this study was pooled PLTs concentration 〉 1250 x 109/L and a blood units collection time duration shorter than 6 minutes. All the 245 donors were healthy volunteers and they did not take any medication affecting PLTs function. BC-PLTs were analyzed immediately pre-freezing (T0) and 3 months after cryopreservation ( CRY BC-PLTs). The following parameters were assayed: PLTs count (PC), mean platelet volume (MPV), pH, flow cytometry (FACS) expression of CD41a, CD42b, CD61a, CD62p, PAC-1, Annexin V PLTs surface antigens and thromboelastography (TEG). All samples were analyzed also after dilution (1:4) with homologous plasma to approximately 400 x109/L PLTs (data not shown) and for bacterial contamination (BC). CRY BC-PLTs samples were thawed in a bath at 37°C for 5 minutes and evaluated promptly. All the tests were performed according to current European recommendations. PLTs swirl was furthermore visually assessed. Results were expressed as mean +/- standard deviation (SD). Results obtained at T0 and after 3 months were compared by paired sample t-test. Differences were considered as significant at p values

Description: Introduction. The optimal duration of Low Molecular Weight Heparin (LMWH) after cancer associated deep vein thrombosis (DVT) is unknown; current guidelines suggest to prolong anticoagulation until cancer is active. We have recently demonstrated, in a randomized trial, that detection of Residual Vein Thrombosis (RVT) after 6 months of LMWH identify patients who require or not extension of therapy with anticoagulants (JCO in press). Now we present data of a prospective study evaluating a RVT-based management of patients with cancer-associated DVT, in whom LMWH has been extended up to 2 years in patients considered at high-risk for recurrent DVT because of persistence of RVT. Material and Methods. Patients were included at the time of a first diagnosis of cancer-associated DVT of the lower limbs. All received LMWH at therapeutic dosage for the first month (approximately 100 UI anti-FXa b.i.d.) then reduced at 75% for the following months. After 6 months of heparin, the presence of RVT was detected: those without RVT (no-RVT group) suspended treatment, while those with RVT (RVT group) continued LMWH for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment and one year after LMWH withdrawal. Baseline differences between groups were assessed by the chi-square test (Yates’ correction) for categorical variables and ANOVA test or Kruskal-Wallis test for parametric and nonparametric analyses. Relative risks (RRs) and 95% confidence intervals (CIs) were evaluated. Results. Between January 2009 and April 2011, 211 cancer patients were enrolled; RVT was detected in 129 patients (61.1%). Recurrent VTE occurred in 19 (14.7%); 4 episodes (3.1%) occurred while on heparin. Among patients without RVT (82), 3 (3.6%) developed recurrent VTE (after LMWH therapy). Adjusted HR for RVT vs no-RVT group was 5.8 (95% CI, 1.9 to 19.2; p 0.0003). Three major bleeding events occurred in RVT group and one in no-RVT group (during LMWH administration). The HR for major bleeding (RVT vs no-RVT group) was 2.58 (95% CI, 0.66 to 12.43;p 0.103). Overall, 44 patients (20.8%) died during follow-up as a result of cancer progression. Conclusions. These results indicate that in patients without RVT, a short period of treatment with a LMWH is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis. However, when still on LMWH, the risk for recurrent VTE is low. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3999 Poster Board III-935 Background Clinical advantage of extensive screening for occult cancer in patients with idiopathic Deep Vein Thrombosis (DVT) is unknown. We have demonstrated that the Residual Vein Thrombosis (RVT)-based screening for occult cancer improves early detection as well as cancer-related mortality (Siragusa S et al. Blood 2007;110(699):OC). Here we report on final analysis of 537 patients over a period of 8 years. Objective of the study We conducted a prospective study evaluating whether a RVT-based screening for cancer is sensitive and influences cancer-related mortality. Study design Prospective with two cohorts of DVT patients: the first cohort was monitored for clinical overt cancer only (Group A), while the second (Group B) received complete screening for occult neoplasm and subsequent surveillance. Materials and methods Consecutive patients with a first episode of DVT who presented RVT after 3 month of anticoagulation and without signs and/or symptoms for overt cancer. Screening for occult cancer was based on: ultrasound and/or CT scan of the abdomen and pelvis, gastroscopy, colonoscopy or sigmoidoscopy, hemoccult, sputum cytology and tumor markers. These tests were extended with mammography and Pap smear for women and ultrasound of the prostate and total specific prostatic antigen (PSA) for men. All investigations had to be completed within four-weeks from the assessment of RVT. All patients were followed-up for at least 2 years. Incidence and cancer-related mortality was compared between the two groups by survival curves (Kaplan-Mayer) and related Breslow test for statistics. Results Over a period of 8 years, 537 patients were included in the analysis: first cohort included 346 patients (Group A), second cohort 191 (Group B). Clinical characteristics between groups were homogenous. During the follow-up, 8.3% of patients developed overt cancer in group A; in group B, 7.8% of patients had diagnosed cancer at the moment of extensive screening while 2 new cases (0.7%) occurred during the follow-up (Table). The sensitivity of this approach was 92.1% (95% confidence intervals 75.2-104.2). Cancer-related mortality was 7.5% in group A and 3.6% in group B (p〈 0.001). Conclusions The RVT-based screening for occult cancer is highly effective for improving early detection as well as cancer-related mortality in a cohort of 537 patient with DVT of the lower limbs. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis.

Description: Abstract 1244 Introduction. We tested the efficacy and safety of fixed doses of Low-Molecular Weight Heparin (LMWH) in cancer patients requiring interruption of Vitamin-k Antagonist (VKA) because of invasive procedures (defined as major and non major surgery) or chemotherapy inducing platelets depletion. Methodology. Cancer patients were defined to be at high (atrial fibrillation [AF] with previous stroke, prosthetic mitralic valves and venous thromboembolism [VTE] lasting 〈 3months) or low risk of thrombosis (AF without previous stroke, VTE lasted 〉 3 months, and prosthetic aortic valves). They discontinued VKA 5 + 1days before surgery or chemotherapy; in those at low-risk for thrombosis, LMWH was given at a prophylactic dosage of 3.800 U.I. (nadroparin) or 4.000 U.I. (enoxaparin) anti-FXa once daily the night before the procedure or the beginning of chemotherapy. In patients at high-risk for thrombosis, LMWH was started early after VKA cessation (when an INR 〈 1.5) and given at fixed sub-therapeutic doses (3.800 or 4.000 UI anti-FXa twice daily) until procedure or beginning of chemotherapy. In patients undergoing procedures, LMWH was reinitiated 12 hours after procedure while VKA the day after; in patients receiving chemotherapy, LMWH was reinitiated 12 h after a stable platelet count 〉 30.000 mmc3 and VKA 12 h after a stable platelet count 〉 50.000 mmc3. Heparin was continued until a therapeutic INR value was reached. The primary efficacy endpoints were the incidence of thromboembolism and major bleeding from VKA suspension to 30 + 2 days post-procedure or next chemotherapy. Results. A total of 156 patients (68, 53.9% at low-risk and 58, 46.1% at high-risk for thrombosis) were enrolled (Table 1); 44 (28.2%) underwent major surgery, 53 (33.9%) non-major surgery and 29 (18.5%) chemotherapy. Overall, thromboembolic events occurred in 5 patients (3.2%, 95% confidence intervals 0.5–5.9), 4 belonging to high-risk and 1 to low-risk group. Overall, major bleeding occurred in 5 patients (3.2%, 95 CI 0.5–5.9), all belonging to high-risk group (3 during major surgery and 2 during chemotherapy). The mean time of anticoagulation with LMWH was 7.5 days in patients underwent procedures and 13.2 days in those who received chemotherapy. Conclusion. LMWH given at fixed sub-therapeutic doses appears to be a feasible and relatively safe approach for bridging therapy in chronic anticoagulated cancer patients requiring VKA interruption. Disclosures: No relevant conflicts of interest to declare.

Description: Background In the last decades, evaluation of thrombotic complications secondary to acute leukemia (AL) has been poorly investigated. Only scant data are available on management and prevention of thrombosis in this setting. We performed a multicenter retrospective study with the aim to evaluate the management of venous thromboembolism (VTE) in patients with AL and to report the most commonly adopted regimens of treatment. Materials and methods Available clinical records of out and in-patients diagnosed with AL from January 2008 to June 2013 in 7 Reference Regional Hospitals were analyzed. Cases of VTE, including thrombosis in atypical sites [Retinal occlusion (RO) and Cerebral Sinus Thrombosis (SCT)], were reported. All data were recorded in a dedicated electronic database. The patient’s basic demographic data (age, gender, race), medical history, disease-related information, and laboratory data were extracted. Instrumental diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE) and RO and SCT was performed according to ACCP guidelines. Data were collected and analysed by the IBM SPSS Software 21.0 version (SPSS, Inc., Chicago, Ill, US) and the Epi Info software, version 3.2.2, (Centers for Disease Control and Prevention). Statistical analysis of quantitative and qualitative data, included descriptive statistics, was performed for all the items. Results Over a population of 1461 patients with AL, 99 (6.8%) cases of VTE were recorded, mainly in hospitalized patients: 72 cases were associated with Acute Myeloid Leukemia (AML) and 27 with Acute Lymphoblastic Leukemia (ALL), with a mean age of 52.2 ± 15.4 years (median age: 53years). In particular the incidence/ratio over the sub-population of AML-patients was 6.0%, that is 72/1191 cases; with a mean age of 54.7 ± 14.3 years (median age: 57 years). VTE occurred during chemotherapy (CHT) in 90/99 (90%) cases, mainly during the induction phase of treatment (in 70% of cases ),the remaining 9 cases were diagnosed in concomitance with acute leukemia. In both subgroups with VT, there was no statistical significant difference between time at diagnosis of VT and time at diagnosis of AL. Treatment of VTE was mainly based on Low Molecular Weight Heparin (LMWH), in accordance with results from previous studies and current guidelines (full dosage for the first month from diagnosis and reduced dosage at 75% for the following months). Thrombocytopenia occurred in 55 patients at diagnosis of AL, in 33 cases platelets were

Description: Abstract 5183 Background: The advantage of using interim 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) scan in the clinical work-up of patients with non-Hodgkin's lymphoma (NLH) is unclear. Data from meta-analyses are inconclusive, mainly because of the low number of patients evaluated and heterogeneity among studies. New clinical investigations, focused on this topic, have been recently published. We conducted an updated systematic review on the role of 18PDG-PET for the interim evaluation in patients with aggressive lymphomas. Materials and Methods: Medline, Embase, Scopus and Databases were searched for relevant studies through March 2011. We included studies that evaluated FDG-PET performed between the first and the fourth cycle of first-line chemotherapy. Patients were selected when they were evaluated for response assessment with interim 18FDG-PET. For each study, we constructed a 2 × 2 contingency table consisting of true positive (TP), false positive (FP), false negative (FN), and true negative (TN), where all patients were categorized according to whether they were PET positive or negative, and whether they experienced treatment failure. A meta-analysis of the prognostic accuracy was performed. Results: We selected 16 out of 46 studies, involving 1256 patients with aggressive NHLs (90% with Diffuse Large B-Cell Lymphoma); 1157 patients met our inclusion criteria and were considered for the final analysis. Interim18FDG-PET, performed after a median of 3 cycles of chemotherapy (range 1–6 cycles), gave true and false negative results in 641 (56 %) and 65 (6%) patients, respectively. Therefore, 18FDG-PET had an overall sensitivity of 0.80 (95% CI, 0.69 to 0.88) and a specificity of 0.84 (95% CI, 0.76 to 0.90) (figure). Heterogeneity among studies was substantial. Conclusion: Because of data heterogeneity, interim 18FDG-PET for aggressive NHL patients remains an unproven test for routine clinical practice. Its role should be further evaluated in clinical researches with homogeneous treatments and standardized imaging. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Cryopreservation of platelets (PLTs) at -80°C with dimethyl sulfoxide (DMSO) can extend their shelf life up to 2 years. Cryopreserved PLTs (CRY-PLTs) are reported to have a greater in vivo hemostatic effect than liquid-stored PLTs. Aims of this study were: i. to evaluate the thrombin generation potential of buffy coat derived cryopreserved PLTs (CRY- BC PLT) in comparison with fresh buffy coat derived platelets concentrates; ii. to determine the efficacy and safety of CRY-PLTs transfusion in hematological patients with severe thrombocytopenia. Materials and methods: BC PLTs were obtained from 5 buffy coats and pooled. The final PLTs concentrates were leukoreduced by filtration and transferred to a 650 mL patented cryopreservation kit (Promedical ®) which allowed mixing with DMSO 25% in a closed system and following removal of supernatant without further manipulations. BC-PLTs were washed prior freezing, suspended in homologous plasma from 1 of the 5 donors to a final concentration of 200 mL and frozen at - 80°. CRY- BC PLTs were preserved at -80°C with 6% DMSO. A system of 3 accessory bags directly connected to the mother bag was adopted for the in vitro study, to avoid repeated freezing/thawing of samples. In vitro assays were performed before freezing and at 3,6 and 9 months after thawing. Before assay, CRY-BC PLT were thawed at 37°C and diluted in plasma to adjust to 300× 109/L PLTs. Fresh BC PLTs underwent the same dilution to adjust to 300 ×109/L PLTs. Thrombin generation (TGA) was tested in CRY BC-PLTs and compared to TG potential of fresh BC PLTs. TGA was triggered by the addition of 0.5 pmol/L of recombinant human tissue factor. Endogenous thrombin potential (ETP) and peak height (PH) were determined. Flow Cytometry assays for PLTs activation markers and thromboelastography were also determined on each sample. CRY-BC PLTs, separately prepared according to the above described method for in vivo study, were infused in five hematological patients with acute leukemia (AL) and severe thrombocytopenia (PLTs