Abstract
An increasing number of patients are being prescribed direct oral anticoagulants (DOACs), while the patients who remain on warfarin are becoming more complex. There is currently a lack of a ...standardised anticoagulation review for patients in primary care, resulting in potentially preventable harm events. Our aim was to implement a new service, where a standardised review is carried out by a specialist multidisciplinary secondary care anticoagulation team. Overall, the implementation of a standardised review resulted in better optimisation of anticoagulation management for patients taking either a DOAC or a warfarin. Of the 172 eligible patients prescribed warfarin, 47 (27%) chose to switch a DOAC. The average time in therapeutic range for patients on warfarin before and after the pilot increased from 73.5% to 75%. Of 482 patients taking a DOAC, 35 (7%) were found to be on incorrect dose. In 32 (91%) of 35 patients, the dose was amended after notifying the patient’s general practitioner. We also found a significant number of patients inappropriately prescribed concomitant medication such as antiplatelet or non-steroidal anti-inflammatory drugs, potentially putting the patients at an elevated risk of bleeding. While further research is needed; we believe the results of this pilot can be used to help build a case to influence the commissioning of anticoagulation services. Secondary care anticoagulation teams, like our own, may be well-placed to provide or support such services, by working across the primary care and secondary care interface to support our primary care colleagues.
Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and ...improves symptoms.
MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60;
= .02). Duration of CR was superior for ruxolitinib (hazard ratio HR, 0.38; 95% CI, 0.24 to 0.61;
< .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78;
= .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94;
= .03). Serial analysis of
V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival PFS
= .001, EFS
= .001, overall survival
= .01) and clearance of
V617F stem/progenitor cells.
1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17;
= .003). The safety profile of ruxolitinib was as previously reported.
The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
•Exercise increases the frequency of NK-cells and CLL cells in the blood of patients with treatment-naïve CLL.•Exercise improves the efficacy of rituximab against autologous CLL cells in ...treatment-naïve CLL ex vivo.•Exercise increases the frequency of CLL cells in blood with a phenotype indicating recent egress from lymphoid tissue.
Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for ∼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3−CD56+CD16+) NK-cells in blood, and a 67 % increase in CD5+CD19+CD20+ CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells – independent of rituximab – was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy.
Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed ...patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio HR, 0.40; confidence interval CI, 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.
•A 7-gene signature is derived that can identify myeloma patients who respond better to bortezomib- or lenalidomide-based therapy.•Treatment according to the signature is noninferior to treatment with combined bortezomib, lenalidomide, and dexamethasone.
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