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IntroductionRearrangements of the BCL3gene due to the translocation t(14;19)(q32;q13) can be identified in up to 1% of chronic lymphocytic leukemias (CLL) with stimulated karyotype and is associated with an adverse outcome. In this study, we aimed at unraveling the clinico-molecular features of CLL harboring t(14;19), including the response to novel therapies.

McLintock: Novo Nordisk Australasia: Honoraria.

In trauma, the presence of coagulopathy with or without critical bleeding (CB) is associated with poorer outcomes. However in non-trauma patients, it is unknown what proportion of CB patients are coagulopathic. We aimed to characterise the presence of coagulopathy in a representative cohort of massive transfusion (MT) recipients and explore what factors, including coagulopathy, were associated with in-hospital mortality.The Australian and New Zealand Massive Transfusion Registry (ANZ-MTR), established in 2011, collects information on CB in all clinical contexts. In the pilot phase, all adult CB patients who received a MT (defined as ≥5 units of red blood cells [RBC] in 4hrs) were identified at 9 Australian hospitals. Transfusion history, laboratory results and hospital administrative data were extracted. Coagulopathy was defined as INR >1.5 or aPTT >60 s using the most recent laboratory test results following the onset of MT (post-MT). The association between mortality and patient characteristics and therapy were explored using multiple logistic regression.A total of 1263 MT cases occurred in 1242 patients (1% had 2x MTs). Median age was 64 (IQR 49-76) years; 64% were male. The majority of cases of CB were surgical (total 55%) followed by GI bleeding (17%). Of the 1147 (91%) MT cases with an aPTT or INR result available post-MT, 37% (n=472) were coagulopathic. Of these, 44% (n=209) were also coagulopathic preceding the onset of MT (pre-MT). Of the total group, 474 (38%) had no recorded pre-MT coagulation results. Patient characteristics are presented in Table 1. Presence of coagulopathy post-MT was associated with surgical causes of CB, low post-MT Hb level, higher use of all fresh blood components, increased prothrombinex use and in-hospital mortality. Independent predictors of in-hospital mortality following multivariate logistic regression were coagulopathy (OR= 2.94; 95%CI=2.09-4.16, p<0.001), certain causes of CB including medical (mainly hem/onc & liver disease; OR= 4.63; 95%CI=1.85-11.60, p=0.001), vascular surgery (OR= 2.44; 95%CI=1.27-4.66, p=0.007), GI bleeding (OR= 2.12; 95%CI=1.31-3.43, p=0.002), liver surgery (OR= 0.40; 95%CI=0.18-0.90, p=0.03), age (OR= 1.02; 95%CI=1.01-1.03, p<0.001), and units of RBC (OR= 1.01; 95%CI=1.00-1.02, p=0.03) and cryo (OR= 1.02; 95%CI=1.00-1.03, p<0.001).Presence of coagulopathy early in MT varied accordingly to clinical context, with surgical causes of CB having the highest rates of coagulopathy and obstetric haemorrhage the lowest. Coagulopathy remained a predictor of in-hospital mortality independent of the clinical context. Data generated by the Australian and New Zealand Massive Transfusion Registry, provides a unique opportunity to explore differences in the pathophysiology of CB across clinical settings and the management and outcomes of this diverse patient population.Zatta: CSL Behring: Research Funding. Andrianopoulos:Monash University: Consultancy, Honoraria. Phillips:CSL Behring: Research Funding. Isbister:Johnson & Johnson: Honoraria. Wood:CSL Behring: Research Funding.

In trauma, the presence of coagulopathy with or without critical bleeding (CB) is associated with poorer outcomes. However in non-trauma patients, it is unknown what proportion of CB patients are coagulopathic. We aimed to characterise the presence of coagulopathy in a representative cohort of massive transfusion (MT) recipients and explore what factors, including coagulopathy, were associated with in-hospital mortality.

Hemorrhage from disease processes or their therapy commonly complicates the course of patients with malignancies. Recombinant activated factor VII (rFVIIa) was developed for prevention or treatment of bleeding in hemophilia patients who have factor inhibitors, but may also have a role in enhancing coagulation and augmenting conventional therapies in refractory bleeding. However, outcomes are not defined for this indication, and randomized studies are challenging. We explored the safety and efficacy of rFVIIa in the treatment of hemorrhage associated with malignancy or stem cell transplantation (SCT) using prospective clinical registry data.The Australia and New Zealand Haemostasis Registry (ANZHR) documented all rFVIIa use in non-hemophilia patients in both countries. More than 90 institutions participated in its operation from 2000 to 2009, capturing an estimated 85% of use in these countries. Participating institutions obtained approval from local institutional review boards to provide de-identified data. They were required to report all usage to limit bias and registry data were audited regularly. We identified episodes of rFVIIa use where the primary diagnosis at the time of hemorrhage was a malignancy or SCT. Response to rFVIIa reported by the treating clinician, transfusion requirements, adverse events and 28 day survival were analyzed. Logistic regression and multiple linear regression models were used to identify factors associated with response.Of 3446 episodes reported to ANZHR, 362 eligible episodes were identified in 325 patients (10.5% the total). Median patient age was 56 years (IQR 39–67); 205 (63%) were male. Episodes were reported from 51 institutions (57% of participating), median 5 (IQR 3–8) per institution. Primary diagnosis was hematological in 173 cases (48%); non-hematological malignancy in 189 (52%). 321 (88.6%) were receiving disease-directed therapy (initial therapy in 200 [55% of the total], 19 [5%] supportive care, unreported in 22 [6%]). Intent of care was curative in 218 (60%), palliative in 122 (34%), 22 (6%) unreported. 33 (9.1%) were undergoing allogeneic SCT and 5 (1.4%) autologous SCT. Primary sites of bleeding were gastrointestinal in 165 (46%), pulmonary 47 (13%), intracranial 36 (10%), genitourinary 34 (9%), hepatic 28 (8%), others 52 (14%). Causes of bleeding were 116 (34%) surgical (including resection of tumor or metastases), disease-induced coagulopathy 48 (14%), disease invasion 62 (18%), mucositis (including graft-versus-host disease) 53 (15%), others 65 (19%); 6 (2%) received rFVIIa prophylactically prior to procedures. In 255 episodes (70%) a single dose of rFVIIa only was administered. Median dose was 90μg/kg (IQR 77–100). Prior to administration median (IQR) hemoglobin was 82 g/L (69–93); platelet count 82 × 109/L (43–127), fibrinogen 2.1 g/L (1.4–3.1), INR 1.4 (1.2–1.8), pH 7.3 (7.2–7.4), temperature 36.7°C (36.0–37.1), and patients had received 5 (2–12) units red cells, 2 (0–4) platelet doses, 4 (0–8) plasma units, and 0 (0–8) cryoprecipitate doses. Bleeding stopped or decreased in 175 (60%) of cases where response was reported (prophylactic cases were excluded from response assessment). Transfusion requirements fell to 2 (0–4) red cells, 0 (0–2) platelets, 0 (0–3) plasma, and 0 (0–8) cryoprecipitate following the first dose. Response decreased with low pH in univariate analysis (p=0.014). In multivariate analysis, low pH and hematological malignancy were independent predictors of poor response (p=0.001). 18 patients (5.5%) had thromboembolic events reported within 28 days of administration. 202 patients (57%) survived to 28 days. Survival was significantly higher in rFVIIa responders (71% vs 38% p<0.001, Figure 1).This is the first comprehensive exploration of rFVIIa in hemorrhage associated with malignancy. Usage in this setting was higher than anticipated. Reported efficacy and safety were promising in this heterogeneous group with severe refractory bleeding and elevated baseline risk of thrombosis. Clinician-reported bleeding response was supported by reduced transfusion requirements and survival benefit. Response was associated with pH and type of malignancy, suggesting that these factors may assist in patient selection. Use of rFVIIa may be an effective adjunct to conventional therapies in carefully selected cancer patients with refractory hemorrhage.Off Label Use: Recombinant Activated Factor VII, for bleeding associated with malignancy.

Abstract 3311This icon denotes a clinically relevant abstract

Recombinant activated factor VII (rFVIIa, NovoSeven®) is approved for the treatment of spontaneous and surgical bleeding in patients with haemophilia A or B and with antibodies to either factor VIII or factor IX. However rFVIIa has increasingly been used for indications outside the approved areas as a last resort treatment in trauma, cardiac surgery and other critical bleeding episodes despite the absence of conclusive randomized clinical trial (RCT) data.The aim of the Haemostasis Registry was to collect data (including dose, adverse events and outcome) on the off-license use of rFVIIa in Australia and New Zealand.Monash University established the Haemostasis registry in 2005 with an educational grant from Novo Nordisk Pharmaceuticals. More than 100 hospitals (including all major users of rFVIIa in Australia and New Zealand) contributed data to the Registry covering a ten year period (2000 to 2010).More than 3600 off-license rFVIIa cases have been reported to the Registry. 65% of cases were male and the median age was 56 years. Major areas of use were cardiac surgery (∼43%), other surgery (18%) and trauma (13%). The majority (∼77%) of patients received a single dose of rFVIIa with a median (IQR) dose of 91 (73-103) mcg/kg. Seventy-four percent of cases documented a response (decrease or cessation of bleeding) following rFVIIa. Patient mortality rate at 28 days was lower if bleeding was reportedly stopped or decreased (88% or 82% vs. 39% no change, respectively) (χ22=533, p<0.001). Stepwise logistic regression analysis identified the number of units of RBC's, pH and context of bleeding as significant independent predictors of patient response to rFVIIa administration and pH, context of bleeding and units of FFP were included in the best predictive model of patient outcome at 28 days. Thromboembolic adverse events were reported in 7.5% of all patients however risk-adjusted adverse event rates in Haemostasis Registry cardiac patients were not significantly different from those seen in non-rFVIIa treated cardiac patients recorded in the ASCTS registry (www.ascts.org).The Haemostasis Registry is the largest dataset of its kind and provides critical observational data on the importance of pH, temperature and coagulopathic state in determining the response to rFVIIa. Although the role of rFVIIa in critical bleeding is still not clear, the Haemostasis Registry has been an invaluable resource for rigorously tracking adverse events and helping to guide clinical practice in an arena unlikely to be supported by new RCT data.Phillips: Novo Nordisk: Educational Grant. Off Label Use: rFVIIa; used for the treatment of critical bleeding in trauma, cardiac surgery, liver and obstetrics. Zatta:Novo Nordisk: Educational Grant. McNeil:Novo Nordisk: Educational Grant. Cameron:Novo Nordisk: Educational Grant.

Abstract 3352

Most hospitals have clinical guidelines for the off-label use of recombinant activated Factor VII (rFVIIa, Novoseven), primarily as part of a massive transfusion protocol. Over the past years rFVIIa has increasingly been used outside the approved indications in haemophilia with inhibitors and Glanzmann's Thrombasthenia, particularly in trauma, cardiac surgery and other critical bleeding episodes. Use in these areas remains controversial.Monash University established the Haemostasis Registry in 2005 (with an educational grant from NovoNordisk Pharmaceuticals) to monitor the use of rFVIIa throughout Australia and New Zealand. More than 95 hospitals are contributing data to the Registry including all major users of rFVIIa in Australia and New Zealand. As part of the process of joining the Registry project, participating hospitals are asked to supply copies of their protocols for use of rFVIIa.Approximately 3000 cases of rFVIIa use have been reported to the Register. Major areas of use are cardiac surgery (∼ 41%), other surgery (∼17%) and trauma (∼15%). The majority(77.3%) of hospitals have documented protocols for rFVIIa use. Many of these are similar and are centred around situations of massive transfusion. However, 64.5% of cases of rFVIIa use submitted to the Haemostasis Registry, from hospitals where protocols exist, do not conform with the numerical components of these protocols.This is the largest dataset of rFVIIa cases published to date and can now provide greater insight into the actual rather than theoretical use of rFVIIa in Australia and New Zealand. Lack of compliance with hospital protocols for rFVIIa use indicates either that the protocols do not reflect actual and appropriate use or that clinicians need to be further educated regarding what is currently considered appropriate use. In the absence of sound clinical trial evidence, consensus regarding appropriate use has not been achieved. In these circumstances, data from the Haemostasis Registry continues to be important in elucidating the safety and efficacy of rFVIIa and providing important feedback to doctors and hospitals.The Haemostasis Registry is funded through an unrestricted Educational Grant from NovoNordisk Pharmaceuticals Pty Ltd. None of the authors have a financial interest in the outcomes of the study.Off Label Use: Recombinant activated Factor VII (rFVIIa, Novoseven). FVIIa is a naturally occurring initiator of haemostasis. Its recombinant form, rFVIIa, is approved for the treatment of spontaneous & surgical bleeding in patients with haemophilia A or B and with antibodies to either factor VIII or factor IX. It has been extensively used amongst haemophiliacs and appears to enhance clotting at the site of bleeding without systemic activation of the coagulation cascade At high doses rFVIIa binds to the surface of activated platelets and initiates the coagulation cascade at these sites Recently various case series and case reports have reported the efficacy of rFVIIa in patients with life-threatening bleeding in patients with coagulation disturbances but without coagulation inhibitors.

Abstract 4192