Surgical Experience from the STASEY Study of Emicizumab Prophylaxis in People with Hemophilia A with Factor VIII Inhibitors.

Background Guidelines surrounding emicizumab prophylaxis and perioperative treatment for people with hemophilia A (PwHA) with factor (F)VIII inhibitors undergoing surgeries are limited. The phase IIIb multicenter, single-arm STASEY study evaluated safety and tolerability of emicizumab prophylaxis in PwHA aged ≥12 years with FVIII inhibitors. This analysis assesses surgeries during study conduct, associated hemophilia medications, and postoperative bleeds (treated and untreated). Methods PwHA with FVIII inhibitors received emicizumab 3.0 mg/kg/week for 4 weeks, then 1.5 mg/kg/week until 2 years. Surgeries were managed and documented by treating physicians. Bleeds and treatments were recorded by physicians and participants. Results Forty-six participants had ≥1 on-study surgery, 37 underwent 56 minor surgeries, and 13 underwent 22 major surgeries. Four participants underwent both minor and major surgeries. Of 18 (81.8%) and 4 (18.2%) major surgeries managed with/without additional hemostatic medication, 33.3 and 25.0% were associated with a treated postoperative bleed, respectively. Of 24 (42.9%) and 32 (57.1%) minor surgeries managed with/without additional hemostatic medication, 15.6 and 25.0% were associated with a treated postoperative bleed, respectively. Recombinant activated FVII was the most common medication for prophylaxis and bleed treatment. There were no thrombotic microangiopathies (TMAs). One hypertrophic clot, considered unrelated to emicizumab, occurred following tooth extraction. Conclusion In this challenging population with a high bleeding risk, major surgeries were performed in PwHA receiving emicizumab with/without additional hemostatic medication. Postoperative bleeds occurred following 59.1% of major surgeries; 53.8% were treated. No arterial/venous thrombotic events or TMAs occurred due to concomitant emicizumab and bypassing agents. Trial registration This trial is registered at ClinicalTrials.gov (NCT03191799).

Safety and efficacy of long-term emicizumab prophylaxis in hemophilia A with factor VIII inhibitors: A phase 3b, multicenter, single-arm study (STASEY).

Background: The bispecific monoclonal antibody emicizumab bridges activated factor IX and factor X, mimicking the cofactor function of activated factor VIII (FVIII), restoring hemostasis. Objectives: The Phase 3b STASEY study was designed to assess the safety of emicizumab prophylaxis in people with hemophilia A (HA) with FVIII inhibitors. Methods: People with HA received 3 mg/kg emicizumab once weekly (QW) for 4 weeks followed by 1.5 mg/kg QW for 2 years. The primary objective was the safety of emicizumab prophylaxis, including incidence and severity of adverse events (AEs) and AEs of special interest (thrombotic events [TEs] and thrombotic microangiopathies). Secondary objectives included efficacy (annualized bleed rates [ABRs]). Results: Overall, 195 participants were enrolled; 193 received emicizumab. The median (range) duration of exposure was 103.1 (1.1-108.3) weeks. Seven (3.6%) participants discontinued emicizumab. The most common AEs were arthralgia (n = 33, 17.1%) and nasopharyngitis (n = 30, 15.5%). The most common treatment-related AE was injection-site reaction (n = 19, 9.8%). Two fatalities were reported (polytrauma with fatal head injuries and abdominal compartment syndrome); both were deemed unrelated to emicizumab by study investigators. Two TEs occurred (myocardial infarction and localized clot following tooth extraction), also deemed unrelated to emicizumab. The negative binomial regression model-based ABR (95% confidence interval) for treated bleeds was 0.5 (0.27-0.89). Overall, 161 participants (82.6%) had zero treated bleeds. Conclusions: The safety profile of emicizumab prophylaxis was confirmed in a large population of people with HA with FVIII inhibitors and no new safety signals occurred. The majority of participants had zero treated bleeds.

Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the phase III MabCute study.

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers a long-term benefit in terms of progression-free survival in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years' initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed progression-free survival in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 progression-free survival events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log-rank test; hazard ratio 0.76 [95% confidence interval: 0.37- 1.53]). The median progression-free survival was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non- Hodgkin lymphoma. (Clinicaltrials.gov identifier: NCT01461928).

Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study.

GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Efficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1‒2), D8 and D15 of Cycle (C)1, and D1 of C2-6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1-3 of C1-6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.

Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study.

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943).

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study.

GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab-bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2-6; and bendamustine 70/90 mg/m2 D1 and D2 of C1-6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months' median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis.

BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.

Mapping dominant annual land cover from 2009 to 2013 across Victoria, Australia using satellite imagery.

There is a demand for regularly updated, broad-scale, accurate land cover information in Victoria from multiple stakeholders. This paper documents the methods used to generate an annual dominant land cover (DLC) map for Victoria, Australia from 2009 to 2013. Vegetation phenology parameters derived from an annual time series of the Moderate Resolution Imaging Spectroradiometer Vegetation Indices 16-day 250 m (MOD13Q1) product were used to generate annual DLC maps, using a three-tiered hierarchical classification scheme. Classification accuracy at the broadest (primary) class level was over 91% for all years, while it ranged from 72 to 81% at the secondary class level. The most detailed class level (tertiary) had accuracy levels ranging from 61 to 68%. The approach used was able to accommodate variable climatic conditions, which had substantial impacts on vegetation growth patterns and agricultural production across the state between both regions and years. The production of an annual dataset with complete spatial coverage for Victoria provides a reliable base data set with an accuracy that is fit-for-purpose for many applications.

VLUIS, a land use data product for Victoria, Australia, covering 2006 to 2013.

Land Use Information is a key dataset required to enable an understanding of the changing nature of our landscapes and the associated influences on natural resources and regional communities. The Victorian Land Use Information System (VLUIS) data product has been created within the State Government of Victoria to support land use assessments. The project began in 2007 using stakeholder engagement to establish product requirements such as format, classification, frequency and spatial resolution. Its genesis is significantly different to traditional methods, incorporating data from a range of jurisdictions to develop land use information designed for regular on-going creation and consistency. Covering the entire landmass of Victoria, the dataset separately describes land tenure, land use and land cover. These variables are co-registered to a common spatial base (cadastral parcels) across the state for the period 2006 to 2013; biennially for land tenure and land use, and annually for land cover. Data is produced as a spatial GIS feature class.

Improvement in consistency of response to ovarian stimulation with recombinant human follicle stimulating hormone resulting from a new method for calibrating the therapeutic preparation.

Traditionally, therapeutic preparations of gonadotrophins are quantified with a rat in-vivo bioassay in biological international units (IU). This method was developed to cope with variability of production batch quality. The bioassay, however, presents some limitations, and differences in clinical responses when using different batches of urine-derived gonadotrophins have been reported. The production of human FSH by recombinant technology now allows the use of advanced physicochemical methods for quantifying FSH, which can be measured in microg of FSH proteins (in mass). The study reported here was designed and conducted to assess the clinical relevance of this new method for quantifying therapeutic preparation of FSH. Four bulk lots of recombinant human FSH (r-hFSH) were used to prepare batches filled by IU (FbIU) and four batches filled by mass (FbM). These eight batches were compared in a double-blind, randomized study in patients undergoing assisted reproductive technology. One hundred and thirty-one patients were enrolled in this study and met protocol criteria (66 in the FbM group and 65 in the FbIU group). The starting dose of recombinant human FSH (r-hFSH) was either 150 IU or 11 microg/day. Both preparations induced multiple follicular development and all patients underwent oocyte retrieval. The number of follicles >/= 11mm was 14.85 and 14.91, serum oestradiol concentration on day of human chorionic gonadotrophin (HCG) administration was 6524 and 6350 pmol/l, number of oocytes retrieved was 10.76 and 11.28, number of two-pronuclear (2 PN) oocytes was 5.2 and 5.00, number of viable embryos (replaced or cryopreserved) was 4.15 and 3.72, and clinical pregnancy rate was 30.3 and 26.2% respectively in the FbM and FbIU groups. Overall, the patients' response consistency was found to be superior with FbM (P = 0.039), and in particular for clinical pregnancy rates (P < 0.001). This new method for quantifying r-hFSH delivers an improved consistency in clinical outcome.