Real-world use of inotuzumab ozogamicin is associated with lower health care costs than blinatumomab in patients with acute lymphoblastic leukemia in the first relapsed/refractory setting.

Aim: To compare all-cause and acute lymphoblastic leukemia (ALL)-related healthcare resource utilization (HCRU) and costs among patients receiving inotuzumab ozogamicin (InO) and blinatumomab (Blina) for ALL in the first relapsed/refractory (R/R) setting. Patients & methods: We studied retrospective claims for adult commercial and Medicare Advantage enrollees with ALL receiving InO (n = 29) or Blina (n = 23) from 1 January 2015 to 16 February 2021. Mean per-patient-per-month (PPPM) HCRU and total costs were described and multivariable-adjusted PPPM total all-cause and ALL-related predicted costs were calculated. Results: Mean monthly ALL-related hospitalizations were the same for patients receiving InO and Blina (PPPM = 0.8 stays); however, the length of ALL-related hospital stay was almost twice as long among patients receiving Blina versus InO (ALL-related: InO = 7.6 days; Blina = 14.1 days; p = 0.346). In multivariable models, total ALL-related costs were 43% lower for InO compared with Blina (PPPM costs: InO = $93,767; Blina = $163,470; p = 0.021). Conclusion: In the first R/R setting, patients who used InO had significantly lower all-cause and ALL-related costs compared with patients who used Blina, in part driven by hospitalization patterns.

Correction: The Patient Experience of Acute Lymphoblastic Leukemia and Its Treatment: Social Media Review.

[This corrects the article DOI: 10.2196/39852.].

Incentivizing sustainable fire management in Australia's northern arid spinifex grasslands.

Fire management across Australia's fire-prone 1.2 M km2 northern savannas region has been transformed over the past decade supported by the inception of Australia's national regulated emissions reduction market in 2012. Today, incentivised fire management is undertaken over a quarter of that entire region, providing a range of socio-cultural, environmental, and economic benefits, including for remote Indigenous (Aboriginal and Torres Strait Islander) communities and enterprises. Building on those advances, here we explore the emissions abatement potential for expanding incentivised fire management opportunities to include a contiguous fire-prone region, extending to monsoonal but annually lower (<600 mm) and more variable rainfall conditions, supporting predominantly shrubby spinifex (Triodia) hummock grasslands characteristic of much of Australia's deserts and semi-arid rangelands. Adapting a standard methodological approach applied previously for assessing savanna emissions parameters, we first describe fire regime and associated climatic attributes for a proposed ∼850,000 km2 lower rainfall (600-350 mm MAR) focal region. Second, based on regional field assessments of seasonal fuel accumulation, combustion, burnt area patchiness, and accountable methane and nitrous oxide Emission Factor parameters, we find that significant emissions abatement is feasible for regional hummock grasslands. This applies specifically for more frequently burnt sites under higher rainfall conditions if substantial early dry season prescribed fire management is undertaken resulting in marked reduction in late dry season wildfires. The proposed Northern Arid Zone (NAZ) focal envelope is substantially under Indigenous land ownership and management, and in addition to reducing emissions impacts associated with recurrent extensive wildfires, development of commercial landscape-scale fire management opportunities would significantly support social, cultural and biodiversity management aspirations as promoted by Indigenous landowners. Combined with existing regulated savanna fire management regions, inclusion of the NAZ under existing legislated abatement methodologies would effectively provide incentivised fire management covering a quarter of Australia's landmass. This could complement an allied (non-carbon) accredited method valuing combined social, cultural and biodiversity outcomes from enhanced fire management of hummock grasslands. Although the management approach has potential application to other international fire-prone savanna grasslands, caution is required to ensure that such practice does not result in irreversible woody encroachment and undesirable habitat change.

The Patient Experience of Acute Lymphoblastic Leukemia and Its Treatment: Social Media Review.

BACKGROUND: Adult patients with acute lymphoblastic leukemia (ALL) report substantial disease- and treatment-related impacts on their health-related quality of life (HRQOL). Patient-reported information (PRI) shared on social media may provide a distinct opportunity to understand the patient experience outside of formal research contexts and help inform the development of novel therapies. OBJECTIVE: This qualitative social media review aimed to assess PRI shared on social media websites to gain a better understanding of the symptom, HRQOL, and treatment impacts on individuals with ALL. METHODS: We identified English-language posts on 3 patient advocacy websites (Patient Power, The Patient Story, and Leukaemia Care) and YouTube that included PRI about experiences with ALL or ALL treatments shared by adults (aged ≥18 years) with a self-reported ALL diagnosis. Patients' demographic and disease characteristics were extracted from posts (where available), and the posts were analyzed thematically. A network analysis was conducted to delineate possible associations among ALL symptoms, HRQOL impacts, and treatment-related symptoms and impacts. RESULTS: Of the 935 social media posts identified, 63 (7%) met the review criteria, including 40 (63%) videos, 5 (8%) comments posted in response to videos, and 18 (29%) blog posts. The 63 posts were contributed by 41 patients comprised of 21 (51%) males, 18 females (44%), and 2 (5%) whose gender was not reported. Among the patients, 13 (32%) contributed >1 source of data. Fatigue (n=20, 49%), shortness of breath (n=13, 32%), and bruising (n=12, 29%) were the symptoms prior to treatment most frequently discussed by patients. Patients also reported impacts on personal relationships (n=26, 63%), psychological and emotional well-being (n=25, 61%), and work (n=16, 39%). Although inpatient treatment reportedly restricted patients' independence and social functioning, it also provided a few patients with a sense of safety. Patients frequently relied on their doctors to drive their treatment decisions but were also influenced by family members. The network analysis indicated that disease-related symptoms were primarily associated with patients' physical functioning, activities of daily living, and ability to work, while treatment-related symptoms were primarily associated with emotional well-being. CONCLUSIONS: This social media review explored PRI through a thematic analysis of patient-contributed content on patient advocacy websites and YouTube to identify and contextualize emergent themes in patient experiences with ALL and its treatments. To our knowledge, this is the first study to leverage this novel tool to generate new insights into patients' experiences with ALL. Patients' social media posts suggest that inpatient care for ALL is associated with restricted independence and social functioning. However, inpatient care also provided a sense of safety for some patients. Studies such as this one that capture patients' experiences in their own words are valuable tools to further our knowledge of patient outcomes with ALL.

The Zero-Price Conundrum: Exploration of Scenarios Where a Clinically Effective New Drug Might Not Be Cost-Effective at Zero Price.

OBJECTIVES: The zero-price conundrum occurs when a clinically effective drug can justify no greater than a price of zero based on cost-effectiveness criteria from a health system perspective. This is relevant for health systems that require evidence of cost-effectiveness, in addition to safety and efficacy for drug approval and other analyses that may shape drug coverage policies, such as budget impact and comparative effectiveness. This study aimed to clarify and explore the zero-price conundrum to provide a resource in the development of practical and methodological solutions. METHODS: We specified equations representing previously identified zero-price scenarios and used them to elucidate factors contributing to the zero-price conundrum and explore relationships between them. We present real-world considerations and discuss solutions from the literature. RESULTS: The analyses demonstrated that a primary cause of the zero-price problem for a new drug that increases quality-adjusted survival pertains to healthcare costs beyond the influence of the new drug, specifically, disease background costs, costs of existing drugs used in a combination regimen, and costs of future health interventions patients may become eligible to receive. Pragmatic solutions have been to exclude such costs from cost-effectiveness analyses. Proposed modifications to cost-effectiveness analysis include assessing each drug in a combination regimen based on its relative contribution to improved health. CONCLUSIONS: The zero-price dilemma may arise more frequently as the number of drugs in high-cost disease areas continues to grow. As cost-effectiveness methods evolve, there is the opportunity to develop robust solutions that can be applied consistently.

Right-way fire in Australia's spinifex deserts: An approach for measuring management success when fire activity varies substantially through space and time.

Indigenous Australians used fire in spinifex deserts for millennia. These practices mostly ceased following European colonisation, but many contemporary Indigenous groups seek to restore 'right-way fire' practices, to meet inter-related social, economic, cultural and biodiversity objectives. However, measuring and reporting on the fire pattern outcomes of management is challenging, because the spatio-temporal patterns of right-way fire are not clearly defined, and because spatio-temporal variability in rainfall makes fire occurrence highly variable in these desert environments. We present an approach for measuring and reporting on fire management outcomes to account for spatio-temporal rainfall variability. The purpose is to support Indigenous groups to assess performance against their management targets, and lay the groundwork for developing an accredited method for valuing combined social, cultural and biodiversity outcomes. We reviewed fire management plans of desert Indigenous groups to identify spatial fire pattern indicators for right-way fire in spinifex deserts. We integrated annual rainfall surfaces with time-since fire mapping (using Landsat imagery) to create a new spatial dataset of accumulated rainfall-since-last-fire, that better represents post-fire vegetation recovery as categorised by local Indigenous people. The fire pattern indicators were merged into a single score using an environmental accounting approach. To strengthen interpretation, we developed an approach for identifying a control area with matching vegetation and fire history, up to the point of management. We applied these methods to a 125,000 ha case study area: Durba Hills, managed by the Martu people of Western Australia. Using a 20-year time series, we show that since right-way fire management at Durba Hills was re-introduced (2009), the fire pattern indicators have improved compared to those in the matched control area, and the composite result is closer to the fine-scaled mosaic of right-way fire pattern targets. Our approach could be used by Indigenous groups to track performance, and inform annual fire management planning. As the indicators are standardised for rainfall variation, results from multiple sites can be aggregated to track changes in performance at larger scales. Finally, our approach could be adapted for other fire-prone areas, both in Australia and internationally with high spatio-temporal rainfall variability, to improve management planning and evaluation.

Altered cyclone-fire interactions are changing ecosystems.

Global change is altering interactions between ecological disturbances. We review interactions between tropical cyclones and fires that affect woody biomes in many islands and coastal areas. Cyclone-induced damage to trees can increase fuel loads on the ground and dryness in the understory, which increases the likelihood, intensity, and area of subsequent fires. In forest biomes, cyclone-fire interactions may initiate a grass-fire cycle and establish stable open-canopy biomes. In cyclone-prone regions, frequent cyclone-enhanced fires may generate and maintain stable open-canopy biomes (e.g., savannas and woodlands). We discuss how global change is transforming fire and cyclone regimes, extensively altering cyclone-fire interactions. These altered cyclone-fire interactions are shifting biomes away from historical states and causing loss of biodiversity.

Empowering Indigenous natural hazards management in northern Australia.

Northern Australia is prone to recurring severe natural hazards, especially frequent cyclones, flooding, and extensive wildfires. The region is sparsely populated (≪ 0.5 persons km-2), with Indigenous (Aboriginal) residents comprising 14% of the population, and typically the majority in remote regions. Despite national policy committed to addressing emergency management (EM) in vulnerable Indigenous communities, implementation remains unfunded. We synthesise participatory intercultural research conducted over seven years exploring core challenges, opportunities and potential solutions towards developing effective EM partnerships. Similar EM engagement and empowerment issues face First Nations and local communities in many international settings. In search of solutions, we explore developing effective partnership arrangements between EM agencies and culturally diverse Indigenous communities. Observing that government already provides substantial investment in cultural and natural resource management programmes conducted by over 150 Indigenous Ranger Groups (IRGs) nationally, we demonstrate that expansion of IRG roles to incorporate EM community engagement and service delivery can provide multiple cost-effective community and business development benefits for many remote communities.

Systematic review and pooled analysis of survival outcomes in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia who have undergone haematopoietic stem cell transplant.

OBJECTIVE: Information about the long-term survival impact of hematopoietic stem cell transplant (HSCT) in adults with relapsed/refractory B-cell acute lymphoblastic leukaemia is limited. The objective was to conduct a systematic review identifying studies reporting survival in HSCT-receiving patients and apply parametric analyses to predict long-term survival. MATERIALS AND METHODS: Twenty-five relevant studies were identified. Analyses were conducted in 10 studies (n=503; "global" analysis) reporting overall survival (OS) data as Kaplan-Meier curves or at patient level. Four studies (n=217; "subgroup" analysis) measured OS from the point of HSCT. Patient-level data were recreated from Kaplan-Meier curves and pooled, with six models tested for longer-term extrapolation. Additionally, a sensitivity analysis was undertaken involving removal of data from the oldest study cohort (recruited between 1981-1997) to determine if the year which patients received HSCT impacted survival compared to post-2009 data. RESULTS: Median OS and five-year survival probability were 11.4 months and 24.4% (95% CI, 20.5-28.5%) in the global analysis, and 12.0 months and 28.4% (95% CI, 22.1-34.9%) in the subgroup analysis. The generalised gamma and Gompertz models fit longer-term extrapolation criteria. The generalised gamma model predicted survival at 10.4% vs. 14.8% (15 years), 8.3% vs. 12.8% (20 years), and 6.9% vs. 11.4% (25 years) for the global and subgroup analysis, respectively. The Gompertz model predicted survival to plateau at 23% vs. 25.6% just before 10 years. The sensitivity analysis excluding older data found median survival increased two-fold (25.3 vs. 12 months). CONCLUSIONS: Results synthesize long-term evidence of outcomes for HSCT-receiving patients, providing a basis for treatment comparison. Risk of death is low beyond four years and newer data appears correlated with improved outcomes.

Efficacy of non-intensive therapies approved for relapsed/refractory acute myeloid leukemia: a systematic literature review.

Aim: De novo relapsed and/or refractory acute myeloid leukemia (rrAML) has limited treatment options for patients not eligible ('unfit') to receive intensive chemotherapy-based interventions. The authors aimed to summarize outcomes for licensed therapies in this setting. Materials & methods: A systematic literature review identified licensed therapies in this setting. A feasibility assessment was made to conduct a network meta-analysis to evaluate comparative efficacy. Results: Seven unique trials were identified. Median survival months were 13.8 for gemtuzumab ozogamicin (GO), 9.3 for gilteritinib (FLT3 mutated rrAML), 5.6 for low-dose cytarabine and 3.2 for best supportive care; transplant rates with gilteritinib and GO were 25.5 and 19%, respectively. A network meta-analysis was not feasible. Conclusion: There remains a high unmet need in de novo rrAML patients not eligible for intensive therapy, with GO and gilteritinib (only FLT3-mutated AML) providing the best current options.

Some patients with acute myeloid leukemia (AML) have no response to initial treatment or have a response that is subsequently lost. Follow-on treatment options after that initial stage are limited, especially for patients who are not able to have intensive therapy, such as chemotherapy, due to age, physical or cognitive function, existing comorbidities or symptoms. This study aimed to review the published literature to identify data associated with treatments that are licensed for use in patients ineligible for intensive therapy who do not maintain a response from their initial therapy. The study found that the drug gilteritinib was an option for the subgroup of AML patients with FLT3-mutated disease with an average life expectancy just under 1 year, while gemtuzumab ozogamicin was an option for a wider group of AML patients with a life expectancy just over 1 year. Between a fifth and a quarter of patients went on to receive a stem-cell transplant after treatment with one of these. With limited options, this patient group needs further attention; however, the availability of the previously mentioned treatments is promising.

Cost-Effectiveness of Inotuzumab Ozogamicin Compared to Standard of Care Chemotherapy for Treating Relapsed or Refractory Acute Lymphoblastic Leukaemia Patients in Norway and Sweden.

OBJECTIVE: The aim was to estimate the cost-effectiveness of inotuzumab ozogamicin (InO) versus standard of care chemotherapy (SoC) for adults with relapsed or refractory B cell acute lymphoblastic leukaemia (R/R ALL) in Sweden and Norway, and compare this to evaluations made by the health technology assessment (HTA) authorities Tandvårds- och läkemedelsförmånsverket (TLV) and the Norwegian Medicines Agency (NoMA). MATERIALS AND METHODS: A partitioned survival model was developed to determine incremental cost-effectiveness ratios (ICERs) for InO versus SoC. Parametric survival models were fit to overall survival and progression-free survival Kaplan-Meier data from the INO-VATE ALL phase III trial. Two base cases were run using (1) Swedish and (2) Norwegian inputs (costs and discount rates). Core clinical inputs and utilities did not differ between countries. Analyses were then conducted to reflect the preferred assumptions of TLV and NoMA. Univariate and multivariate sensitivity analyses were performed. RESULTS: The base case deterministic ICERs for InO versus SoC were €16,219/quality-adjusted life years (QALY) in Sweden (probabilistic €19,415) and €44,405/QALY in Norway (probabilistic €47,305). The ICERs using our model but applying the preferred assumptions of TLV or NoMA were €74,061/QALY (probabilistic €77,484) and €59,391/QALY (probabilistic €63,632), respectively. Differences between our base cases and the ICERs with TLV and NoMA settings were mainly explained by the exclusion of productivity costs and use of pooled post-haematopoietic stem-cell transplant (post-HSCT) survival in Sweden and use of higher HSCT costs in Norway. All ICERs remained below the approximated willingness-to-pay thresholds. The probability of InO being cost-effective ranged from 77 to 99% versus SoC. CONCLUSIONS: InO can likely be considered cost-effective versus SoC under our and the HTA-preferred settings.

Patterns of undertreatment among patients with acute myeloid leukemia (AML): considerations for patients eligible for non-intensive chemotherapy (NIC).

Acute myeloid leukemia (AML) is a life-threatening malignancy that is more prevalent in the elderly. Because the patient population is heterogenous and advanced in age, choosing the optimal therapy can be challenging. There is strong evidence supporting antileukemic therapy, including standard intensive induction chemotherapy (IC) and non-intensive chemotherapy (NIC), for older patients with AML, and guidelines recommend treatment selection based on a patient's individual and disease characteristics as opposed to age alone. Nonetheless, historic evidence indicates that a high proportion of patients who may be candidates for NIC receive no active antileukemic treatment (NAAT), instead receiving only best supportive care (BSC). We conducted a focused literature review to assess current real-world patterns of undertreatment in AML. From a total of 25 identified studies reporting the proportion of patients with AML receiving NAAT, the proportion of patients treated with NAAT varied widely, ranging from 10 to 61.4% in the US and 24.1 to 35% in Europe. Characteristics associated with receipt of NAAT included clinical factors such as age, poor performance status, comorbidities, and uncontrolled concomitant conditions, as well as sociodemographic factors such as female sex, unmarried status, and lower income. Survival was diminished among patients receiving NAAT, with reported median overall survival values ranging from 1.2 to 4.8 months compared to 5 to 14.4 months with NIC. These findings suggest a proportion of patients who are candidates for NIC receive NAAT, potentially forfeiting the survival benefit of active antileukemic treatment.

Cost Effectiveness of Gemtuzumab Ozogamicin in the First-Line Treatment of Acute Myeloid Leukaemia in the UK.

BACKGROUND AND OBJECTIVE: The phase III ALFA-0701 study demonstrated the efficacy and safety of gemtuzumab ozogamicin (GO) versus standard of care (SOC) chemotherapy (daunorubicin and cytarabine) for the treatment of adult patients with de novo CD33+ acute myeloid leukaemia (AML). This study analysed the cost-effectiveness of GO from the perspective of the UK health care payer. METHODS: A cohort state-transition model was developed to estimate direct health care costs and quality-adjusted life-years (QALYs) over a lifetime time horizon from AML diagnosis to death using monthly cycles. Data on complete remission, overall survival, relapse-free survival (RFS), haematopoietic stem-cell transplantation, and adverse events for GO plus SOC versus SOC were obtained from the ALFA-0701 study. Overall survival and RFS were extrapolated beyond the trial horizon using mixture cure models. Unit costs were obtained from standard national sources. Utilities were identified in a systematic literature review. Costs and outcomes were discounted at 3.5%. Analyses were performed for the base-case population, excluding patients with an unfavourable cytogenetic profile, and the overall population. RESULTS: For the base-case and overall populations respectively, incremental per-patient costs (£13,456 and £14,773) and QALYs (0.99 and 0.68) for GO plus SOC versus SOC resulted in incremental cost-effectiveness ratios (ICERs) of £13,561 and £21,819 per QALY gained. The mean probabilistic ICERs were £14,217 and £23,245, respectively. Univariate sensitivity analyses supported the robustness of the results. CONCLUSIONS: The ICERs for both populations met NICE's £20,000-£30,000 willingness-to-pay threshold for medicines and supported the current approval for GO.

Transforming fire management in northern Australia through successful implementation of savanna burning emissions reductions projects.

Savannas are the most fire-prone of Earth's biomes and currently account for most global burned area and associated carbon emissions. In Australia, over recent decades substantial development of savanna burning emissions accounting methods has been undertaken to incentivise more conservative savanna fire management and reduce the extent and severity of late dry season wildfires. Since inception of Australia's formal regulated savanna burning market in 2012, today 25% of the 1.2M km2 fire-prone northern savanna region is managed under such arrangements. Although savanna burning projects generate significant emissions reductions and associated financial benefits especially for Indigenous landowners, various biodiversity conservation considerations, including fine-scale management requirements for conservation of fire-vulnerable taxa, remain contentious. For the entire savanna burning region, here we compare outcomes achieved at 'with-project' vs 'non-project' sites over the period 2000-19, with respect to explicit ecologically defined fire regime metrics, and assembled fire history and spatial mapping coverages. We find that there has been little significant fire regime change at non-project sites, whereas, at with-project sites under all land uses, from 2013 there has been significant reduction in late season wildfire, increase in prescribed early season mitigation burning and patchiness metrics, and seasonally variable changes in extent of unburnt (>2, >5 years) habitat. Despite these achievements, it is acknowledged that savanna burning projects do not provide a fire management panacea for a variety of key regional conservation, production, and cultural management issues. Rather, savanna burning projects can provide an effective operational funded framework to assist with delivering various landscape-scale management objectives. With these caveats in mind, significant potential exists for implementing incentivised fire management approaches in other fire-prone international savanna settings.

Opportunities and challenges for savanna burning emissions abatement in southern Africa.

Savanna fires occurring in sub-Saharan Africa account for over 60% of global fire extent, of which more than half occurs in the Southern Hemisphere contributing ~29% of global fire emissions. Building on experience in reducing savanna fire emissions in fire-prone north Australian savannas through implementation of an internationally accredited 'savanna burning' emissions abatement methodology, we explore opportunities and challenges associated with the application of a similar approach to incentivise emissions reduction in fire-prone southern African savannas. We first show that for a focal region covering seven contiguous countries, at least 80% of annual savanna large fire (>250 ha) extent and emissions occur under relatively severe late dry season (LDS) fire-weather conditions, predominantly in sparsely inhabited areas. We then assess the feasibility of adapting the Australian emissions abatement methodology through exploratory field studies at the Tsodilo Hills World Heritage site in north-west Botswana, and the Niassa Special Reserve in northern Mozambique. Our assessment demonstrates that application of a savanna burning emissions abatement method focused on the undertaking of strategically located early dry season (EDS) burning to reduce LDS wildfire extent and resultant emissions meets key technical criteria, including: LDS fine fuels tend to be markedly greater than EDS fuels given seasonal leaf litter inputs; LDS fires tend to be significantly more severe and combust more fuels; methane and nitrous oxide emission factors are essentially equivalent in EDS and LDS periods under cured fuel conditions. In discussion we consider associated key implementation challenges and caveats that need to be addressed for progressing development of savanna burning methods that incentivise sustainable fire management, reduce emissions, and support community livelihoods in wildfire-dominated southern African savannas.

Norwich COVID-19 Testing Initiative: feasibility project evaluation

BackgroundThere is a high prevalence of COVID-19 in university-age students, who are returning to university campuses. There is little evidence regarding the feasibility of universal, asymptomatic testing to control outbreaks in this population. This study aimed to pilot mass COVID-19 testing on a university research park, to assess the feasibility and acceptability of scaling up to all staff and students. MethodsThis was a cross-sectional feasibility study on a university research park in the East of England. Staff and students (5,625) on the research park were eligible to participate. Polymerase chain reaction (PCR) testing was offered to all participants. Participants were offered 4 swabs, which they self-administered over a two-week period. Outcome measures included: uptake; drop-out rate; positivity rates; participant acceptability measures; laboratory processing measures. Results798/1053 (76%) of those who registered provided at least one swab and of these, 687 (86%) provided all four. 681/687 (99%) had all negative results. 6 participants had one inconclusive result. There were no positive results. 458/798 (57%) participants responded to a post-testing questionnaire. 446/458 (97.5%) of those who responded agreed that they would be interested in repeat testing in the future. ConclusionsRepeated self-testing is feasible and acceptable to a university population.

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study.

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.

The legacy of colonial fire management policies on traditional livelihoods and ecological sustainability in savannas: Impacts, consequences, new directions.

Land occupation and management systems have defined fire regimes and landscapes for millennia. The savanna biome is responsible for 86% of all fire events, contributes to 10% of the total carbon emissions annually and is home to 10% of the human population. European colonization has been associated with the implementation of fire suppression policies in many tropical savanna regions, markedly disrupting traditional fire management practices and transforming ecosystems. In this paper we assess savanna burning approaches from pre-colonial to contemporary eras in three regions: northern Australia, southern Africa and Brazil. In these regions, fire suppression policies have led to (i) conflicts between government authorities and local communities; (ii) frequent late dry season wildfires and/or (iii) woody encroachment. Such consequences are facilitating changes to fire management policies, including recognition and incorporation of traditional ecological knowledge in contemporary community-based adaptive savanna fire management. Such programs include implementation of prescribed early dry season fires and, in some regions, generating income opportunities for rural and traditional communities through the reduction of late dry season wildfires and associated greenhouse gas emissions. We present a brief history of fire management policies in these three important savanna regions, and identify ongoing challenges for implementation of culturally and ecologically sustainable fire management policies.

Biodiversity responds to increasing climatic extremes in a biome-specific manner.

An unprecedented rate of global environmental change is predicted for the next century. The response to this change by ecosystems around the world is highly uncertain. To address this uncertainty, it is critical to understand the potential drivers and mechanisms of change in order to develop more reliable predictions. Australia's Long Term Ecological Research Network (LTERN) has brought together some of the longest running (10-60years) continuous environmental monitoring programs in the southern hemisphere. Here, we compare climatic variables recorded at five LTERN plot network sites during their period of operation and place them into the context of long-term climatic trends. Then, using our unique Australian long-term datasets (total 117 survey years across four biomes), we synthesize results from a series of case studies to test two hypotheses: 1) extreme weather events for each plot network have increased over the last decade, and; 2) trends in biodiversity will be associated with recent climate change, either directly or indirectly through climate-mediated disturbance (wildfire) responses. We examined the biodiversity responses to environmental change for evidence of non-linear behavior. In line with hypothesis 1), an increase in extreme climate events occurred within the last decade for each plot network. For hypothesis 2), climate, wildfire, or both were correlated with biodiversity responses at each plot network, but there was no evidence of non-linear change. However, the influence of climate or fire was context-specific. Biodiversity responded to recent climate change either directly or indirectly as a consequence of changes in fire regimes or climate-mediated fire responses. A national long-term monitoring framework allowed us to find contrasting species abundance or community responses to climate and disturbance across four of the major biomes of Australia, highlighting the need to establish and resource long-term monitoring programs across representative ecosystem types, which are likely to show context-specific responses.

An evaluation of contemporary savanna fire regimes in the Canastra National Park, Brazil: Outcomes of fire suppression policies.

Fire has shaped plant evolution and biogeochemical cycles for millions of years in savanna ecosystems, but changes in natural fire regimes promoted by human land use threaten contemporary conservation efforts. In protected areas in the Brazilian savannas (Cerrado), the predominant management policy is fire suppression, reflecting a cultural heritage which considers that fire always has a negative impact on biodiversity. Here we compare resultant fire-regimes in Canastra National Park (CNP), southeast Brazil, associated with areas under and without fire suppression management, based on a 16-year Landsat imagery record. In open grasslands of the Canastra plateau (CP), firefighting is undertaken under government-sanctioned regulation, whereas in the Babilonia sector, non-sanctioned fire management is undertaken by small farmers to promote cattle grazing and cropping. Fire regimes in the Canastra sector are characterized by few, very large, late dry season wildfires recurring at intervals of two years. Fire regimes in lowlands of the Babilonia sector are characterized by many small-scale, starting at the beginning of the dry season (EDS). In Babilonia uplands fire regimes are characterized by higher frequencies of large fires. The study illustrates major challenges for managing fire-prone areas in conflict-of-interest regions. We suggest that management planning in CNP needs to effectively address: i) managing conflicts between CNP managers and local communities; and ii) fire management practices in order to achieve more ecologically sustainable fire regimes. The study has broader implications for conservation management in fire-prone savannas in South America generally.