Summary Background Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated ...whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. Methods The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0–2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov , number NCT01650805. Findings Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight 80% of ten patients given ponatinib and five 38% of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five 3% of 154 vs one 1% of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 14% of 154 vs three 2% of 152 with imatinib), thrombocytopenia (19 12% of 154 vs ten 7% of 152 with imatinib), rash (ten 6% of 154 vs two 1% of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 8% of 152 vs five 3% of 154 with ponatinib) and thrombocytopenia (ten 7% of 152 vs 19 12% of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. Interpretation The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. Funding ARIAD Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This paper presents an investigation into the electromagnetic design and performance of a fault-tolerant (FT) magnetically geared pseudo-direct-drive (PDD) electrical machine for primary flight ...control surface electromechanical actuation. It is shown that a large number of combinations of high-speed rotor pole pairs, pole-piece numbers, and stator slot numbers exist, for which a duplex three-phase FT configuration can be realized. Furthermore, in addition to facilitating a lower mass solution, it is also shown that a PDD presents a significantly lower inertia referred to the screw when compared to direct-drive or mechanically geared motor solutions. The findings are validated on a prototype PDD, which has been designed and built to meet the requirements of a primary control surface electromechanical actuator.
•Oil extraction is often assumed to negatively affect indigenous livelihoods.•To test this, we use a unique longitudinal dataset from the Ecuadorian Amazon.•We examine the effects of two measures of ...oil exposure on five livelihood outcomes.•Oil activities had both positive and negative effects on livelihoods.•The results only partly support hypotheses from the Dutch disease literature.
Globally, the extraction of minerals and fossil fuels is increasingly penetrating into isolated regions inhabited by indigenous peoples, potentially undermining their livelihoods and well-being. To provide new insight to this issue, we draw on a unique longitudinal dataset collected in the Ecuadorian Amazon over an 11-year period from 484 indigenous households with varying degrees of exposure to oil extraction. Fixed and random effects regression models of the consequences of oil activities for livelihood outcomes reveal mixed and multidimensional effects. These results challenge common assumptions about these processes and are only partly consistent with hypotheses drawn from the Dutch disease literature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; ...however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound.
Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided.
We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of controlSD, NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.017.9% vs 24.08.4%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04).
Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.
•We examine changes over time in wild product harvesting by indigenous households.•Data are derived from a longitudinal household survey conducted in 2001 and 2012.•Hunting, fishing and non-timber ...forest product collection declined over time.•Characteristics of households predict these activities but not declines over time.•A changing regional context appears to drive declining reliance on wild resources.
Wild product harvesting by forest-dwelling peoples, including hunting, fishing, forest product collection and timber harvesting, is believed to be a major threat to the biodiversity of tropical forests worldwide. Despite this threat, few studies have attempted to quantify these activities across time or across large spatial scales. We use a unique longitudinal household survey (n=480) to describe changes in these activities over time in 32 indigenous communities from five ethnicities in the northern Ecuadorian Amazon. To provide insight into the drivers of these changes, we also estimate multilevel statistical models of these activities as a function of household and community characteristics. These analyses reveal that participation in hunting, fishing, and forest product collection is high but declining across time and across ethnicities, with no evidence for a parallel decline in resource quality. However, participation in timber harvesting did not significantly decline and there is evidence of a decline in resource quality. Multilevel statistical models additionally reveal that household and community characteristics such as ethnicity, demographic characteristics, wealth, livelihood diversification, access to forest, participation in conservation programs and exposure to external markets are significant predictors of wild product harvesting. These characteristics have changed over time but cannot account for declining participation in resource harvesting. This finding suggests that participation is declining due to changes in the regional-scale social and economic context, including urbanization and the expansion of government infrastructure and services. The lesson for conservationists is that macro-scale social and economic conditions can drive reductions in wild product harvesting even in the absence of successful conservation interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Drought conditions are expected to increase in frequency and severity as the climate changes, representing a threat to carbon sequestered in peat soils. Downstream water treatment works are also at ...risk of regulatory compliance failures and higher treatment costs due to the increase in riverine dissolved organic carbon (DOC) often observed after droughts. More frequent droughts may also shift dominant vegetation in peatlands from Sphagnum moss to more drought-tolerant species. This paper examines the impact of drought on the production and treatability of DOC from four vegetation litters (Calluna vulgaris, Juncus effusus, Molinia caerulea and Sphagnum spp.) and a peat soil. We found that mild droughts caused a 39.6 % increase in DOC production from peat and that peat DOC that had been exposed to oxygen was harder to remove by conventional water treatment processes (coagulation/flocculation). Drought had no effect on the amount of DOC production from vegetation litters; however large variation was observed between typical peatland species (Sphagnum and Calluna) and drought-tolerant grassland species (Juncus and Molinia), with the latter producing more DOC per unit weight. This would therefore suggest the increase in riverine DOC often observed post-drought is due entirely to soil microbial processes and DOC solubility rather than litter layer effects. Long-term shifts in species diversity may, therefore, be the most important impact of drought on litter layer DOC flux, whereas pulses related to drought may be observed in peat soils and are likely to become more common in the future. These results provide evidence in support of catchment management which increases the resilience of peat soils to drought, such as ditch blocking to raise water tables.
Summary
Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients’ quality of life. ROBUST, a UK, open‐label, phase II study, evaluated ...the safety and efficacy of ruxolitinib in patients with myelofibrosis (N = 48), including intermediate‐1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success ≥50% reduction in palpable spleen length and/or a ≥50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF‐SAF TSS) at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF‐SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate‐1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66·7%) experienced ≥50% reductions from baseline in spleen length at any time. Improvements in MF‐SAF TSS were seen in 80·0%, 72·7%, and 72·2% of intermediate‐1, intermediate‐2, and high‐risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate‐1 risk patients, may benefit from ruxolitinib treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Diabetes in Older Adults: A Consensus Report Sue Kirkman, M.; Briscoe, Vanessa Jones; Clark, Nathaniel ...
Journal of the American Geriatrics Society (JAGS),
December 2012, Volume:
60, Issue:
12
Journal Article
Peer reviewed
Open access
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable ...MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission.
The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response MMR) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.
Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8-10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64-80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25-53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption.
Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR.
Newcastle University and Bloodwise.
Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior ...to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.
Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success.
Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.
Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.
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