Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy.

ABSTRACT: Gilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3-tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed.

Mortality attributable to excess adiposity in England and Wales in 2003 and 2015: explorations with a spreadsheet implementation of the Comparative Risk Assessment methodology.

BACKGROUND: Our aim was to estimate the burden of fatal disease attributable to excess adiposity in England and Wales in 2003 and 2015 and to explore the sensitivity of the estimates to the assumptions and methods used. METHODS: A spreadsheet implementation of the World Health Organization's (WHO) Comparative Risk Assessment (CRA) methodology for continuously distributed exposures was used. For our base case, adiposity-related risks were assumed to be minimal with a mean (SD) BMI of 21 (1) Kg m-2. All cause mortality risks for 2015 were taken from the Government Actuary and alternative compositions by cause derived. Disease-specific relative risks by BMI were taken from the CRA project and varied in sensitivity analyses. RESULTS: Under base case methods and assumptions for 2003, approximately 41,000 deaths and a loss of 1.05 years of life expectancy were attributed to excess adiposity. Seventy-seven percent of all diabetic deaths, 23% of all ischaemic heart disease deaths and 14% of all cerebrovascular disease deaths were attributed to excess adiposity. Predictions for 2015 were found to be more sensitive to assumptions about the future course of mortality risks for diabetes than to variation in the assumed trend in BMI. On less favourable assumptions the attributable loss of life expectancy in 2015 would rise modestly to 1.28 years. CONCLUSION: Excess adiposity appears to contribute materially but modestly to mortality risks in England and Wales and this contribution is likely to increase in the future. Uncertainty centres on future trends of associated diseases, especially diabetes. The robustness of these estimates is limited by the lack of control for correlated risks by stratification and by the empirical uncertainty surrounding the effects of prolonged excess adiposity beginning in adolescence.

Arthropod larvae misidentified as parasitic worm infection.

A healthy, asymptomatic man living in London, presented with seeing 'worms' in his toilet for two successive summer seasons. Repeated microscopic examination and cultures of both his faeces and urine were normal. He was empirically treated with multiple courses of antihelminthics without resolution of this problem. A sample of the worms was obtained, and positively identified as arthropod larvae under microscopic examination. These larvae do not parasitically colonise humans. It was subsequently deduced that a flying arthropod (most likely Culex pipiens mosquito) had laid eggs in standing toilet water, and the hatched larvae had been mistaken for parasitic worms. The patient was declared free of parasites and remains healthy. This case illustrates the dangers of starting empirical treatment without positive confirmation of causative organisms, which can result in unnecessary and potentially harmful treatment.