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

Handgrip performance in relation to self-perceived fatigue, physical functioning and circulating IL-6 in elderly persons without inflammation

BACKGROUND: Low grip strength is recognized as one of the characteristics of frailty, as are systemic inflammation and the sensation of fatigue. Contrary to maximal grip strength, the physical resistance of the muscles to fatigue is not often included in the clinical evaluation of elderly patients. The aim of this study was to investigate if the grip strength and the resistance of the handgrip muscles to fatigue are related to self-perceived fatigue, physical functioning and circulating IL-6 in independently living elderly persons. METHODS: Forty elderly subjects (15 female and 25 male, mean age 75 ± 5 years) were assessed for maximal grip strength, as well as for fatigue resistance and grip work (respectively time and work delivered until grip strength drops to 50% of its maximum during sustained contraction), self perceived fatigue (VAS-Fatigue, Mob-Tiredness scale and the energy & fatigue items of the WHOQOL-100), self rated physical functioning (domain of physical functioning on the MOS short-form) and circulating IL-6. Relationships between handgrip performance and the other outcome measures were assessed. RESULTS: In the male participants, fatigue resistance was negatively related to actual sensation of fatigue (VAS-F, p < .05) and positively to circulating IL-6 (p < .05). When corrected for body weight, the relations of fatigue resistance with self-perceived fatigue became stronger and also apparent in the female. Grip strength and grip work were significantly related with several items of self-perceived fatigue and with physical functioning. These relations became more visible by means of higher correlation coefficients when grip strength and grip work were corrected for body weight. CONCLUSION: Well functioning elderly subjects presenting less handmuscle fatigue resistance and weaker grip strength are more fatigued, experience more tiredness during daily activities and are more bothered by fatigue sensations. Body weight seems to play an important role in the relation of muscle performance to fatigue perception. Elderly patients complaining from fatigue should be physically assessed, both evaluating maximal grip strength and fatigue resistance, allowing the calculation of grip work, which integrates both parameters. Grip work might best reflect the functional capacity resulting from the development of a certain strength level in relation to the time it can be maintained

Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: final analysis of ALCANTARA study

Aim To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome–positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL). Methods In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment. Results The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%–51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4–not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7–13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1–NE] months) was greater than in those without CR (6.0 [95% CI, 2.9–7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2–NE) months. Treatment-related adverse events were consistent with those previously reported. Conclusion Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL

Early Morning Food Intake as a Risk Factor for Metabolic Dysregulation

Increased risk of obesity and diabetes in shift workers may be related to food intake at adverse circadian times. Early morning shiftwork represents the largest proportion of shift workers in the United States, yet little is known about the impact of food intake in the early morning on metabolism. Eighteen participants (9 female) completed a counterbalanced 16 day design with two conditions separated by ~1 week: 8 h sleep opportunity at habitual time and simulated early morning shiftwork with 6.5 h sleep opportunity starting ~1 h earlier than habitual time. After wake time, resting energy expenditure (REE) was measured and blood was sampled for melatonin and fasting glucose and insulin. Following breakfast, post-prandial blood samples were collected every 40 min for 2 h and the thermic effect of food (TEF) was assessed for 3.25 h. Total sleep time was decreased by ~85 min (p &lt; 0.0001), melatonin levels were higher (p &lt; 0.0001) and post-prandial glucose levels were higher (p &lt; 0.05) after one day of simulated early morning shiftwork compared with habitual wake time. REE was lower after simulated early morning shiftwork; however, TEF after breakfast was similar to habitual wake time. Insufficient sleep and caloric intake during a circadian phase of high melatonin levels may contribute to metabolic dysregulation in early morning shift workers. </div

Allogeneic Hematopoietic Stem Cell Transplantation Following the Use of Hypomethylating Agents among Patients with Relapsed or Refractory AML: Findings from an International Retrospective Study

Abstract Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 – 21.7 months), OS reached 29.7 months (95% CI 7.01 – not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT

Work-family conflict: Evaluating the mediating role of personal intervening strategies

Balancing family and work roles places serious demands on working women most especially in African context where women also doubled as home keepers, and this represents a key factor in achieving sustainable productivity (SDG 8.2.3). The study was to expound work-family conflict experiences by married female workers in financial instit utions, and to determine whether personal interventions play a beneficial role to improve productivity. The study adopted social survey with the use of self-administered questionnaire among 730 randomly selected married women bank employees. The study shows that 78.8% of female bankers experience work-family conflict due to strain to keep the jobs and meet up with expected family roles. In the absence of effective workplace relief, several women resort to personal coping strategies this is statistically insignificant and having a negative relationship depicting it is ineffective. The study concludes that the individual or personal intervention-based approach at minimizing work-family conflict could not be adjudged as effective. Therefore, a systematic and robust organization-based approach may be necessary as panacea for work-family conflict within the sector considered and the country as a whole

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study

Background PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. Methods Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. Results Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported ‘being deferred’ as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. Conclusion The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study