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Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.
Yu, S, Zhang, Y, Yu, G, Wang, Y, Shao, R, Du, X, Xu, N, Lin, D, Zhao, W, Zhang, X, et al
Journal of internal medicine. 2024;(2):216-228
Abstract
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION Clinical Trials Registry: NCT04424147.
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Reevaluation of the protein requirement in Chinese elderly adults without sarcopenia with the indicator amino acid oxidation technique.
Wu, W, Zhang, Y, Ma, H, Lu, J, Chen, F, Zhou, H, Nie, S, Yang, Y, Wang, R, Yue, W, et al
The British journal of nutrition. 2024;(8):1377-1383
Abstract
It is now generally believed that elderly may have slightly higher dietary protein requirements than those of the young-middle-aged adults. We have previously conducted related studies by the indicator amino acid oxidation (IAAO) technique, but more research data are needed to revise the protein requirements of the elderly. The main objective was to reevaluate the dietary protein requirements of healthy Chinese adults (65-80 years) without sarcopenia by using the IAAO technique. Nine healthy adult men and seven healthy adult women participated in the study, with protein intakes ranging from 0·1 to 1·8 g/(kg·d). Diets that delivered energy at a 1·5 resting energy expenditure were isocaloric. The amounts of phenylalanine and tyrosine needed to remain constant for each protein dosage. By applying a nonlinear mixed-effects model analysis on the F13CO2 data, which revealed a breakpoint in F13CO2 in response to graded protein intakes, the mean protein requirement was calculated. The mean estimated average requirement (EAR) for healthy elderly Chinese adults without sarcopenia was determined to be 0·94 g/(kg·d). The protein recommended nutrient intake (RNI) determined using various derivation approaches ranged from 1·13 to 1·36 g/(kg·d). The EAR for Chinese adults without sarcopenia aged 65-80 years in this study is 6·8 % higher than the current recommended EAR (0·88 g/(kg·d)). The RNI derived using various derivation approaches are all greater than the current RNI (0·98 g/(kg·d)). This trial was registered with the Chinese clinical trial registry as ChiCTR2200061382.
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3.
The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.
Zhang, Y, Tao, S, Coid, J, Wei, W, Wang, Q, Yue, W, Yan, H, Tan, L, Chen, Q, Yang, G, et al
Current neuropharmacology. 2024;(1):159-167
Abstract
BACKGROUND Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study. METHODS Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response. RESULTS At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (p < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time (p < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores (p < 0.05). CONCLUSION TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.
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Plasma Amino Acid Neurotransmitters and Ischemic Stroke Prognosis: A Multicenter Prospective Study.
Zhu, Z, Yang, P, Jia, Y, Wang, Y, Shi, M, Zhong, C, Peng, H, Sun, L, Guo, D, Xu, Q, et al
The American journal of clinical nutrition. 2023;(4):754-762
Abstract
BACKGROUND Plasma amino acid neurotransmitter dysregulation is suggested to be implicated in the development of ischemic stroke, but its prognostic value for ischemic stroke remains controversial. OBJECTIVE We aimed to prospectively investigate the associations between plasma amino acid neurotransmitters levels and adverse outcomes after ischemic stroke in a large-scale multicenter cohort study. METHODS We measured 4 plasma amino acid neurotransmitters (glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine) among 3486 patients with ischemic stroke from 26 hospitals across China. The primary outcome is the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 mo after ischemic stroke. RESULTS After multivariate adjustment, the odds ratios of death or major disability for the highest versus the lowest quartile were 2.04 (95% confidence interval [CI]: 1.60,2.59; P-trend < 0.001) for glutamic acid, 2.03 (95% CI: 1.59, 2.59; P-trend < 0.001) for aspartic acid, 1.35 (95% CI: 1.06, 1.71; P-trend = 0.016) for gamma-aminobutyric acid, and 0.54 (95% CI: 0.42, 0.69; P-trend < 0.001) for glycine. Each standard deviation increment of log-transformed glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine was associated with a 34%, 34%, and 9% increased risk, and a 23% decreased risk of death or major disability, respectively (all P < 0.05), in a linear fashion as indicated by spline regression analyses (all P for linearity < 0.05). Addition of the 4 plasma amino acid neurotransmitters to conventional risk factors significantly improved the risk reclassification, as evidenced by integrated discrimination improvement and net reclassification improvement (all P < 0.05). CONCLUSIONS Increased glutamic acid, aspartic acid, and gamma-aminobutyric acid and decreased glycine in plasma are associated with adverse outcomes after ischemic stroke, suggesting that plasma amino acid neurotransmitters may be potential intervention targets for improving prognosis of ischemic stroke. The CATIS trial was registered at clinicaltrials.gov (registration number: NCT01840072; URL: ===https://clinicaltrials.gov/ct2/show/NCT01840072?cond=NCT01840072&draw=2&rank=1).
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Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.
Xuan, L, Wang, Y, Yang, K, Shao, R, Huang, F, Fan, Z, Chi, P, Xu, Y, Xu, N, Deng, L, et al
The Lancet. Haematology. 2023;(8):e600-e611
Abstract
BACKGROUND Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING None. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Probio-X Relieves Symptoms of Hyperlipidemia by Regulating Patients' Gut Microbiome, Blood Lipid Metabolism, and Lifestyle Habits.
Wang, H, Ma, C, Li, Y, Zhang, L, A, L, Yang, C, Zhao, F, Han, H, Shang, D, Yang, F, et al
Microbiology spectrum. 2023;11(3):e0444022
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Plain language summary
A long-term high-fat diet will not only disrupt the balance of lipid metabolism in the body and cause metabolic disorders but also lead to chronic diseases, such as hyperlipidaemia, type 2 diabetes, hypertension, and obesity. Hyperlipidaemia is also an important contributing factor in cardiovascular disease. The aim of this study was to analyse the effects of a mixed probiotic formulation on hyperlipidaemia, with focus on changes in patients’ gut microbiota and their metabolic potential. This study was a 3-month randomised controlled intervention trial. A total of 56 hyperlipidaemic patients were recruited and randomised into either the placebo or probiotic (receiving a mixed probiotic formulation) group. Results show that the intake of the probiotic mix effectively reduced the serum levels of total cholesterol and low-density lipoprotein cholesterol, while increasing serum high-density lipoprotein cholesterol levels, in patients with hyperlipidaemia. In fact, there was a strong association between the desirable changes in patients’ lifestyle habits and lowering of these indexes. Furthermore, although insignificant changes were observed in the lipid metabolome and gut microbiota structure, some interesting fecal bacteria and blood metabolites increased significantly after Probio-X intervention. Authors conclude that their findings show that probiotic administration is a promising approach in managing hyperlipidaemia and improving public health.
Abstract
Hyperlipidemia is a key risk factor for cardiovascular disease, and it is associated with lipid metabolic disorders and gut microbiota dysbiosis. Here, we aimed to investigate the beneficial effects of 3-month intake of a mixed probiotic formulation in hyperlipidemic patients (n = 27 and 29 in placebo and probiotic groups, respectively). The blood lipid indexes, lipid metabolome, and fecal microbiome before and after the intervention were monitored. Our results showed that probiotic intervention could significantly decrease the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (P < 0.05), while increasing the levels of high-density lipoprotein cholesterol (P < 0.05) in patients with hyperlipidemia. Probiotic recipients showing improved blood lipid profile also exhibited significant differences in their lifestyle habits after the 3-month intervention, with an increase in daily intake of vegetable and dairy products, as well as weekly exercise time (P < 0.05). Moreover, two blood lipid metabolites (namely, acetyl-carnitine and free carnitine) significantly increased after probiotic supplementation cholesterol (P < 0.05). In addition, probiotic-driven mitigation of hyperlipidemic symptoms were accompanied by increases in beneficial bacteria like Bifidobacterium animalis subsp. lactis and Lactiplantibacillus plantarum in patients' fecal microbiota. These results supported that mixed probiotic application could regulate host gut microbiota balance, lipid metabolism, and lifestyle habits, through which hyperlipidemic symptoms could be alleviated. The findings of this study urge further research and development of probiotics into nutraceuticals for managing hyperlipidemia. IMPORTANCE The human gut microbiota have a potential effect on the lipid metabolism and are closely related to the disease hyperlipidemia. Our trial has demonstrated that 3-month intake of a mixed probiotic formulation alleviates hyperlipidemic symptoms, possibly by modulation of gut microbes and host lipid metabolism. The findings of the present study provide new insights into the treatment of hyperlipidemia, mechanisms of novel therapeutic strategies, and application of probiotics-based therapy.
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Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study.
Daines, CL, Tullis, E, Costa, S, Linnemann, RW, Mall, MA, McKone, EF, Polineni, D, Quon, BS, Ringshausen, FC, Rowe, SM, et al
The European respiratory journal. 2023;(6)
Abstract
BACKGROUND In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.
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Change in the Estimated Glomerular Filtration Rate Over Time and Risk of First Stroke in Hypertensive Patients.
He, P, Li, H, Zhang, Z, Zhang, Y, Lin, T, Song, Y, Liu, L, Liang, M, Nie, J, Wang, B, et al
Journal of epidemiology. 2023;(3):142-149
Abstract
BACKGROUND The association between changes in estimated glomerular filtration rate (eGFR) over time and the risk of stroke remains inconclusive. We aimed to evaluate the relation of eGFR change during the China Stroke Primary Prevention Trial (CSPPT) with the risk of first stroke during the subsequent post-trial follow-up. METHODS A total of 11,742 hypertensive participants with two eGFR measurements (median measure interval, 4.4; interquartile range, 4.2-4.6 years) and without a history of stroke from the CSPPT were included in this analysis. RESULTS Over a median post-trial follow-up of 4.4 years, 729 first strokes were identified, of which 635 were ischemic, 88 were hemorrhagic, and 6 were uncertain types of strokes. Compared with those with 1 to <2% per year increase in eGFR (with the lowest stroke risk), those with an increase in eGFR of ≥4% per year had significantly increased risks of first stroke (adjusted hazard ratio [HR] 1.96; 95% confidence interval [CI], 1.10-3.50) and first ischemic stroke (adjusted HR 2.14; 95% CI, 1.17-3.90). Similarly, those with a decline in eGFR of ≥5% per year also had significantly increased first stroke (adjusted HR 2.13; 95% CI, 1.37-3.31) and first ischemic stroke (adjusted HR 1.89; 95% CI, 1.19-3.02) risk. However, there was no significant association between eGFR change and first hemorrhagic stroke. A similar result was found when the change in eGFR was quantified as an absolute annual change. CONCLUSION In Chinese hypertensive patients, both the decline and increase of eGFR levels were independently associated with the risks of first stroke or first ischemic stroke.
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Prevalence and prognostic importance of malnutrition, as assessed by four different scoring systems, in elder patients with heart failure.
Liang, L, Zhao, X, Huang, L, Tian, P, Huang, B, Feng, J, Zhou, P, Wang, J, Zhang, J, Zhang, Y
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2023;(5):978-986
Abstract
BACKGROUND AND AIMS The lack of standard diagnostic criteria in elder patients with heart failure (HF) makes it challenging to diagnose and manage malnutrition. We aimed to explore the prevalence of malnutrition, its associations and prognostic significance among elder patients with HF using four different nutritional scoring systems. METHODS AND RESULTS Consecutively presenting patients aged ⩾65 years, diagnosed with HF, and admitted to HF care unit of Fuwai Hospital CAMS&PUMC (Beijing, China) were assessed for nutritional indices. In total, 1371 patients were enrolled (59.4% men; mean age 72 years; median NT-proBNP 2343 ng/L). Using scores for the prognostic nutritional index (PNI) ≤38, controlling nutritional status (CONUT) score >4, geriatric nutritional risk index (GNRI) ≤91, and triglycerides, total cholesterol, and body weight index (TCBI) ≤1109, 10.4%, 18.3%, 9.2%, and 50.0% of patients had moderate or severe malnutrition, respectively. There was a strong association between worse scores and lower body mass index, more severe symptoms, atrial fibrillation, and anemia. The mortality over a median follow-up of 962 days (interquartile range (IQR): 903-1029 days) was 28.3% (n = 388). For those with moderate or severe condition, 1-year mortality was 35.2% for PNI, 28.3% for CONUT, 28.0% for GNRI, and 19.1% for TCBI. Malnutrition, defined by any of the included indices, showed added prognostic value when incorporated into a model and included preexisting prognostic factors (C-statistic: 0.711). However, defining malnutrition by the CONUT score yielded the most significant improvement in the prognostic predictive value (C-statistic: 0.721; p < 0.001). CONCLUSION Malnutrition is prevalent among elder patients with HF and confers increased mortality risk. Among the nutritional scores studied, the CONUT score was most effective in predicting the mortality risk. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov; Unique Identifier: NCT02664818.
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Safety, tolerability, pharmacokinetics and effects of diet on AD16, a novel neuroinflammatory inhibitor for Alzheimer's disease: a randomized phase 1 study.
Peng, D, Xu, S, Zou, T, Wang, Y, Ouyang, W, Zhang, Y, Dong, C, Li, D, Guo, J, Shen, Q, et al
BMC medicine. 2023;(1):459
Abstract
BACKGROUND AD16 is a Class 1.1 new drug candidate for Alzheimer's disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults. METHODS Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed. RESULTS Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred. CONCLUSIONS The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD. TRIAL REGISTRATION ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.