Khalid Saja

The efficacy of teclistamab, a bispecific antibody targeting B-cell maturation antigen and CD3, as early-line monotherapy in relapsed or refractory multiple myeloma is unclear. We randomly assigned patients with relapsed or refractory multiple myeloma who had previously received one, two, or three lines of therapy, including an anti-CD38 monoclonal antibody and lenalidomide, to receive teclistamab or the investigator's choice of pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd). Antimicrobial prophylaxis and immune globulin replacement were recommended. The primary end point was progression-free survival as assessed by an independent review committee. A total of 296 patients were assigned to teclistamab and 297 to PVd or Kd. At the interim analysis (median follow-up, 17.3 months), teclistamab significantly improved progression-free survival as compared with PVd or Kd (estimated 18-month progression-free survival, 69.8% vs. 26.9%; hazard ratio for disease progression or death, 0.29; 95% confidence interval [CI], 0.23 to 0.38; P<0.001). The percentage of patients with a complete response or better was higher with teclistamab than with PVd or Kd (65.9% vs. 16.8%, P<0.001). Overall survival was improved with teclistamab as compared with PVd or Kd (estimated 18-month overall survival, 79.2% vs. 68.6%; hazard ratio for death, 0.60; 95% CI, 0.43 to 0.83; P = 0.002). Adverse events of grade 3 or 4 occurred in 84.9% of teclistamab recipients and in 76.3% of PVd or Kd recipients, with grade 5 adverse events in 6.5% and 3.5%, respectively. Cytokine release syndrome, mostly of grade 1 or 2, occurred in 66.0% of teclistamab recipients, and immune effector cell-associated neurotoxicity syndrome occurred in 4.1%. Grade 3 or 4 infection occurred in 41.6% of teclistamab recipients and in 29.0% of PVd or Kd recipients. Among patients with multiple myeloma and one to three previous lines of therapy, teclistamab significantly improved progression-free and overall survival as compared with PVd or Kd. Infections of grade 3 or 4 were common. (Funded by Johnson & Johnson; MajesTEC-9 ClinicalTrials.gov number, NCT05572515.).

Investigation and treatment of acquired coagulation factor inhibitors.

Nationally, anticoagulation for atrial fibrillation (AF) is improving but remains characterised by marked provider variation. Uncontrolled blood pressure and coronary artery disease further increase cardiovascular risk. Redbridge Clinical Commissioning Group (CCG) and local National Health Service (NHS) hospital trusts supported a programme to improve anticoagulation, blood pressure and cholesterol management; the ABC of AF improvement. The programme was delivered by a clinical pharmacist in 43 general practices, who used Active Patient Link (APL-AF) software to identify and electronically review the records of AF patients potentially suitable for anticoagulation. These patients were invited for a general practitioner (GP)-pharmacist consultation with initiation of anticoagulation where appropriate. Blood pressure and lipid treatment were also optimised. The university-based Clinical Effectiveness Group (CEG) provided software support using standard data entry templates from which the APL-AF software was enabled. This identified suitable patients (eg, on aspirin monotherapy, no treatment or inappropriate dual treatments) for clinical and treatment review. It also reported real-time overall practice performance. Additionally, GP education on direct oral anticoagulant initiation in general practices, use of software and performance reviews, took place for all practices in Redbridge. A weekly multidisciplinary team (MDT) video conference discussed complex patients with a cardiologist, haematologist, GP with specialist interest in cardiology, GP coordinator and clinical pharmacist. This enabled sharing of patient records between GPs and hospital specialists with improved communication and learning. Over 1 year 2016–2017, anticoagulation in eligible AF patients (CHA₂DS₂-VASc≥2) increased significantly by 6.3% from 77.0% to 83.3% (p<0.0001), in comparison to 2.8% average improvement in England. Exception reporting was also significantly reduced from 10.0% to 5.8%; a reduction of 4.2% in comparison to a reduction in England of 1.5%. Use of antiplatelet monotherapy was approximately halved, from 12.3% to 6.4%. These methods are being scaled locally in other London CCGs and are potentially scalable nationally, specifically targeting the poorer performing CCGs.

Summary: The lack of antidotes for activated factor X‐inhibitor direct oral anticoagulants (DOACs) means that management of bleeding consists largely of existing supportive therapies. This study aimed to: (i) examine the relative frequency of DOAC‐related major bleeding in relation to DOAC prescriptions over the study period; (ii) describe the presentation and haematological management of DOAC‐related major bleeding; and (iii) evaluate the association between the use of prothrombin‐complex‐concentrate (PCC) and in‐hospital mortality. Over a 3‐year period, 32 UK hospitals submitted data on haematological management of DOAC‐related bleeding. Data consisted of 421 episodes (67%, 21%, 11% and 1% on rivaroxaban, apixaban, dabigatran and edoxaban respectively) of major bleeding on DOACs. The proportion of major bleeds on DOACs and DOAC prescriptions increased throughout the study. Overall, 44% and 37% of patients presented with gastrointestinal bleeding and intracranial haemorrhage (ICH) respectively. Drug concentrations were seldom measured. Compared to no PCC, there was a borderline evidence that receiving low dose PCC (≤25 iu/kg) was associated with better outcomes in terms of mortality (sub‐distribution hazard ratio: 0·15; 95% confidence interval: 0·02–1·19; P = 0·07): but this was not the case for higher doses. DOAC concentrations are seldom measured. There was no evidence of benefit for PCC on in‐hospital mortality.

Background Patients with atrial fibrillation (AF) are at high risk of serious cardiovascular complications such as stroke. Oral anticoagulation is an effective prevention but the rate of appropriate anticoagulation remains suboptimal in England. A London CCG initiated an AF-improvement scheme in 2017: a specialist cardiovascular pharmacist in secondary care led on clinically supporting general practitioners (GPs) in optimising the management of AF-patients. Purpose To assess the impact of a specialist pharmacist on improvement of anticoagulation in AF-registered patients. Material and methods Over 4 months a specialist pharmacist reviewed 20 GPs’ electronic systems (Emis^®) using an electronic program (APL-tool^®) to extract and select global and individual patients’ data to assess for anticoagulation. Patients without anticoagulant/on antiplatelet monotherapy were listed in four categories: Anticoagulation to be initiated. Multidisciplinary team (MDT) referral for complex patients to decide about anticoagulation. Contra–indication for anticoagulation. Anticoagulation not indicated i.e. CHA2DS2–VASc=0. The pharmacist reviewed every clinical record for confirmation of AF, patient’s characteristics and blood results. Based on national guidelines, eligible AF-patients were initiated either on a direct oral anticoagulant (DOAC) or warfarin. The primary endpoint was the difference in the percentage of anticoagulated patients before and after intervention (McNemar test). The secondary endpoints include type of pharmacist’s intervention, number and types of exceptions/referrals to community pharmacists and patients’ refusal (all presented in final results). Results 1315 AF-registered patients were reviewed, of which 814 patients (62%) were anticoagulated at baseline. Following pharmacist intervention, 501 patients were identified as not receiving anticoagulation, and were assessed into the following categories: 283 patients (57%). 70 patients (14%). 82 patients (16%). 66 patients (13%). GPs agreed with 100% of the pharmacists’ decisions for anticoagulation. So far, 241 new patients from category 1 and 2 are now on appropriate anticoagulation, leading to an interim improvement of 18% (62 to 80%, pConclusion Our interim results highlight the benefit of a specialist pharmacist working in GP practices with increases of anticoagulation among AF-patients. This is an innovative example of working across traditional boundaries between primary and secondary care, with an integrated and patient-centred approach. Future developments includes GP educational tools to facilitate initiating anticoagulation and integration of community pharmacists to support patients’ adherence. No conflict of interest

The outcomes of patients developing major bleeding on oral anticoagulants remain largely unquantified. Objectives are to: 1) describe the burden of major haemorrhage associated with all available oral anticoagulants in terms of: proportion of bleeds which are intracranial-haemorrhages, in-hospital mortality and duration of hospitalisation following major bleeding; 2) identify risk factors for mortality; 3) compare characteristics of major haemorrhage between warfarin and direct-oral anticoagulants for the subgroup of atrial fibrillation and venous-thromboembolism patients. A multi-centre, three-year prospective cohort study of patients aged ≥18 on oral anticoagulants who developed major haemorrhage leading to hospitalisation. Follow-up was for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 UK hospitals. Bleed sites were: intracranial-haemorrhage (44%); gastrointestinal (33%); and other (24%). The in-hospital mortality was 21% (95%CI: 19%-23%) overall, and 33% (95%CI: 30%-36%) for intracranial haemorrhage patients. Intracranial-haemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin, direct-oral anticoagulant patients were comparatively older and were associated with lower odds of subdural/epidural, subarachnoid and intracerebral bleeding, versus lower gastrointestinal bleeding. Mortality of major bleeding on warfarin and direct-oral anticoagulants were not different. Major bleeding on oral anticoagulants leads to considerable hospital stays and short-term mortality. Direct-oral anticoagulants were associated with lower odds of an intracranial haemorrhage versus gastrointestinal bleeding, compared to warfarin. The case-fatalities of major bleeding on warfarin and direct- oral anticoagulants were similar.

Background: Splanchnic vein thrombosis (SVT) includes extrahepatic portal vein obstruction (EHPVO), Budd-Chiari syndrome (BCS) and mesenteric vein thrombosis. Myeloproliferative neoplasms (MPN) account for the majority of non-cirrhotic SVT and are diagnosed in 30% of patients with EHPVO and 40% with BCS. Recurrent thrombosis is a common and significant complication in patients with PVT and MPN. Causes of thrombosis in this patient group are unknown; it is likely multifactorial, with proposed risk factors including increased platelet mass and platelet hyper-reactivity. There is evidence that in general, patients with MPN have increased platelet reactivity when compared to healthy controls, but, there is no data looking specifically at patients with SVT. However patients with SVT clearly demonstrate a significantly more aggressive phenotype in terms of systemic thrombosis, with risk of recurrent thrombotic episodes. MASCOT is a multicenter observational study assessing morbidity and portal circulation in patients with SVT, in a subset of whom we have assessed platelet activity. Methods: Whole blood flow cytometry was used to assess platelet activity by surface expression of P-selectin (CD62P) an established marker of platelet activity. We measured CD62P at baseline in unstimulated platelets and following stimulation with increasing concentrations of thrombin receptor activator protein (TRAP), range 10-50μmol. The guidelines from the European consensus on platelet flow cytometry were used for this assay (Schmitz G et al 1998). Demographic and clinical data were collected. Results were analysed in GraphPad Prism using t-tests; all values displayed as mean (95% confidence interval). Results: We assessed platelet activity in 14 patients with SVT using healthy controls (n=6) for comparison. In our patient cohort 8/14 (57%) were male and 6/14 (42%) female. The average age of our patients was 49 years. 12/14 (85%) were positive for the JAK2 mutation and 2/14 (15%) had a positive calreticulin mutation (CALR+). 2/14 (14%) patients had myelofibrosis (MF), 6/14 (42%) polycythaemia vera (PV), 4/14 (28%) essential thrombocytosis (ET) and 2/14 (14%) were positive for the JAK2 mutation but did not show evidence of MPN in their bone marrow and had normal blood counts. 10/14 (71%) were on warfarin alone, 2/14 (14%) on warfarin and aspirin, 1/14 (7%) on rivaroxaban and 1/14 (7%) on aspirin alone. Platelet activity as measured by CD62P expression was increased in patients with SVT at baseline compared with controls 13.1% (5.5-20.7) vs 0.5% (0.2-0.7) (p=0.003). Platelet activation and reactivity was significantly greater in the patient group compared with controls at all concentrations of TRAP (figure 1). Control platelets were relatively unreactive to trap stimulation and a significant increase from baseline in CD62P at the highest concentration of TRAP used (50 μmol) 0.5% (0.2-0.7) vs 7.31% (1.17-13.4) (p=0.03), however this is a modest increase, the biological significance of which is uncertain. In the patient population, the platelets were hyper-reactive to TRAP induced up-regulation of CD62P. This was significant when comparing unstimulated platelets at the 25 and 50 μmol concentrations 13.1% (5.5-20.7) vs 22.6% (13.8-39.4) (p=0.0008) and 13.1% (5.5-20.7) vs 34.9% (22.6-47.1) (p<0.0001) respectively. Although not significant at the lower concentration of 10 μmol TRAP there was a trend towards significance 13.1% (5.5-20.7) vs 22% (12.1-38.9) (p=0.07). Discussion: These results demonstrate that patients with SVT have both significantly increased baseline markers of platelet activation and increased reactivity to stimulation. As part of this longitudinal study, we propose to monitor changes in platelet activity in this patient cohort over time to assess whether or not changes in treatment modality influence platelet activity and whether or not changes in platelet activity can predict further thrombotic episodes; this data will be available in the coming year. Our data provides a platform for further investigation; in due course we will control this data using patients with MPN without thrombosis, as further patients within our study group are analysed. Disclosures: Chen: Novartis: Other: Advisory Board. Sekhar:Novartis: Research Funding.