Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study

Abstract Background Ruxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment. Methods Patients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS). Results Forty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was − 17.3% (≥ 10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was − 45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent. Conclusions A dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis. Trial registration ClinicalTrials.gov identifier, NCT01445769 . Registered September 23, 2011.https://deepblue.lib.umich.edu/bitstream/2027.42/145195/1/13045_2018_Article_642.pd

A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges

Simple Summary Risk stratification models, including the European LeukemiaNet 2017 and 2022 guidelines, categorize newly diagnosed acute myeloid leukemia (AML) patients into several subgroups of distinct genetic characteristics and disease outcomes. The intermediate-risk group remains the most heterogenous group, as most AML patients fall into it (i.e., a basket category) by virtue of not fulfilling criteria that identify specific entities (e.g., core-binding factor AML, TP53 mutations, complex karyotypes) of well-recognized prognostic significance. In this review, we aim to discuss the latest updates on intermediate-risk definition and highlight the therapeutic advances and challenges that warrant refining the prognostic classification of this category. Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Stable isotope values and trophic analysis of invasive three-spined stickleback in Upper Lake Constance points to significant piscivory

The three-spined stickleback Gasterosteus aculeatus was introduced into Lake Constance in the 1940s and occupied a limited range until late 2012. Since then the species has expanded from a solely littoral habitat in Upper Lake Constance, but now makes seasonal migrations into the pelagic zone. This behavioral change has been accompanied by a drastic increase in stickleback abundance. In order to integrate information about feeding of sticklebacks in Upper Lake Constance over two consecutive years, stomach content analysis was combined with seasonal stable isotope analysis on two types of tissue (muscle and liver). Isotope values were also obtained for zooplankton, whitefish larvae and eggs. We calculated the contribution of potential food sources for sticklebacks’ diet using a Bayesian mixing model (SIMMR). Furthermore, we determined stickleback trophic position, and δ15N and δ13C values were compared with those of other fish species of Lake Constance. The results of the Bayesian model as well as the stomach content analysis showed clear evidence of stickleback predation on fish eggs and larvae. Stickleback δ15N values were elevated during winter and comparable to those of piscivorous pike, while δ15N values of zooplankton were reduced, and those of whitefish larvae were similar to those of sticklebacks after accounting trophic fractionation of N isotopes. Trophic position calculations further identified sticklebacks as piscivorous, while the δ13C values of the liver and stomach content analysis suggests that a benthic-pelagic species pair may exist in Lake Constance. These findings support the hypotheses that sticklebacks in Lake Constance can display piscivorous feeding behaviour on sympatric fish species, most likely whitefish larvae and eggs

New hadrons as ultra-high energy cosmic rays

Ultra-high energy cosmic ray (UHECR) protons produced by uniformly distributed astrophysical sources contradict the energy spectrum measured by both the AGASA and HiRes experiments, assuming the small scale clustering of UHECR observed by AGASA is caused by point-like sources. In that case, the small number of sources leads to a sharp exponential cutoff at the energy E<10^{20} eV in the UHECR spectrum. New hadrons with mass 1.5-3 GeV can solve this cutoff problem. For the first time we discuss the production of such hadrons in proton collisions with infrared/optical photons in astrophysical sources. This production mechanism, in contrast to proton-proton collisions, requires the acceleration of protons only to energies E<10^{21} eV. The diffuse gamma-ray and neutrino fluxes in this model obey all existing experimental limits. We predict large UHE neutrino fluxes well above the sensitivity of the next generation of high-energy neutrino experiments. As an example we study hadrons containing a light bottom squark. These models can be tested by accelerator experiments, UHECR observatories and neutrino telescopes.Comment: 17 pages, revtex style; v2: shortened, as to appear in PR

Transglutaminase-Mediated Semen Coagulation Controls Sperm Storage in the Malaria Mosquito

The mating plug is a key regulator of mosquito fertility

Prácticas docentes para creatividad en la universidad: estudio en Portugal y Brasil

Creativity is nowadays seen as an essential feature in higher education. Nevertheless, there is a discrepancy between the need for creativity and what higher education classrooms provide. This study assessed the perceptions of 1599 higher education students from two countries (1059 Brazilian and 540 Portuguese students), from two academic domains (Sciences and Technologies – Sc&T; Social Sciences, Arts, and Humanities – SScA&H), about the presence of creativity in their teachers’ instruction and evaluation practices. The study’s findings evidence interactive effects between the variables country and academic domain for most of the assessed factors: encouragement of new ideas, climate for the expression of ideas, and interest in students’ learning. Brazilian Sc&T students presented more negative perceptions of their classroom environments when compared to SScA&H students; Portuguese students showed opposite patterns of results. Some hypothetical explanations are discussed and future directions for research are presented.Criatividade é atualmente tomada como aspecto essencial na Educação Superior. Há, contudo, discrepância entre a necessidade de criatividade e o que a universidade proporciona. Este estudo avaliou percepções de 1599 alunos universitários de dois países (1059 brasileiros e 540 portugueses), de duas áreas curriculares (Ciências e Tecnologias – Sc&T; Ciências Sociais, Artes e Humanidades – SscA&H) sobre a presença de criatividade nas práticas docentes, instrucionais e avaliativas, de que são alvo. Os resultados mostraram efeitos interativos significativos entre as variáveis país e área curricular para a maioria dos fatores avaliados: encorajamento de novas ideias, clima para expressão de ideias e interesse pela aprendizagem dos alunos. Os estudantes brasileiros de Sc&T mostraram percepções mais negativas da sala de aula, comparados com os de SScA&H; os alunos portugueses obtiveram padrões opostos nos resultados. Algumas hipóteses explicativas são discutidas e são apresentadas orientações para pesquisa futura.La creatividad está actualmente considerada como aspecto esencial en la Educación Superior. Sin embargo, existe discrepancia entre la necesidad de creatividad y lo que la universidad ofrece. Este estudio evaluó percepciones de 1.599 estudiantes universitarios (1.059 de Brasil y 540 de Portugal) de dos áreas curriculares (Ciencia y Tecnología – Sc&T; Ciencias Sociales, Artes y Humanidades – SscA&T) acerca de la presencia de creatividad en las prácticas docentes, instructivas y evaluativas dirigidas a ellos. Los resultados mostraron efectos de interacción significativos entre las variables país y área curricular para la mayoría de los factores evaluados: fomento de nuevas ideas, entorno para la expresión de ideas e interés en el aprendizaje del estudiante. Los estudiantes brasileños de Sc&T mostraron percepciones más negativas de la clase en comparación con los de SSCA&H; los estudiantes portugueses obtuvieron patrones opuestos en los resultados. Algunas hipótesis explicativas se discuten y se presentan directrices para investigación futura.Thermo Scientificinfo:eu-repo/semantics/publishedVersio

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n&nbsp;=&nbsp;45) or had a complex karyotype without TP53 mutation (cohort B; n&nbsp;=&nbsp;13) received entospletinib 400&nbsp;mg twice daily with decitabine 20&nbsp;mg/m2 on days 1-10 every 28&nbsp;days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2&nbsp;years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2&nbsp;months, respectively, and the median overall survival was 6.5 and 11.5&nbsp;months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need

Age- and Temperature-Dependent Somatic Mutation Accumulation in Drosophila melanogaster

Using a transgenic mouse model harboring a mutation reporter gene that can be efficiently recovered from genomic DNA, we previously demonstrated that mutations accumulate in aging mice in a tissue-specific manner. Applying a recently developed, similar reporter-based assay in Drosophila melanogaster, we now show that the mutation frequency at the lacZ locus in somatic tissue of flies is about three times as high as in mouse tissues, with a much higher fraction of large genome rearrangements. Similar to mice, somatic mutations in the fly also accumulate as a function of age, but they do so much more quickly at higher temperature, a condition which in invertebrates is associated with decreased life span. Most mutations were found to accumulate in the thorax and less in abdomen, suggesting the highly oxidative flight muscles as a possible source of genotoxic stress. These results show that somatic mutation loads in short-lived flies are much more severe than in the much longer-lived mice, with the mutation rate in flies proportional to biological rather than chronological aging

A Study to Assess the Efficacy of Enasidenib and Risk-Adapted Addition of Azacitidine in Newly Diagnosed IDH2-Mutant AML

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998