Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
1.
Haematologica ; 2024 May 02.
Article in English | MEDLINE | ID: mdl-38695123

ABSTRACT

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

2.
Lancet Haematol ; 10(7): e510-e520, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37407142

ABSTRACT

BACKGROUND: The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia. METHODS: CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged >1 year to <18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m2 orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed. FINDINGS: Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred. INTERPRETATION: Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission. FUNDING: Bristol Myers Squibb.


Subject(s)
Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Male , Female , Imatinib Mesylate/therapeutic use , Dasatinib/adverse effects , Neoplasm, Residual , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Treatment Outcome
3.
Br J Haematol ; 202(5): 942-952, 2023 09.
Article in English | MEDLINE | ID: mdl-37246588

ABSTRACT

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Dasatinib/adverse effects , Protein Kinase Inhibitors/adverse effects , Treatment Outcome , Neoplasm Recurrence, Local , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
4.
Blood ; 141(2): 156-167, 2023 01 12.
Article in English | MEDLINE | ID: mdl-35714312

ABSTRACT

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.


Subject(s)
Isocitrate Dehydrogenase , Leukemia, Myeloid, Acute , Aged , Humans , Cytarabine/therapeutic use , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation
5.
Front Aging Neurosci ; 14: 984178, 2022.
Article in English | MEDLINE | ID: mdl-36158560

ABSTRACT

Introduction: Chronic neuroinflammatory events have been implicated in the pathophysiology of neurodegenerative conditions but no studies have directly examined the neuroinflammatory response to acute systemic infection in older people with dementia. The objective of this study was to determine the magnitude of the neuroinflammatory response triggered by acute systemic infection in older subjects with dementia and/or delirium compared to cognitively healthy controls. Methods: We recruited 19 participants (4 with delirium, 4 with dementia, 4 with delirium superimposed on dementia, 7 cognitively healthy) hospitalized with acute systemic bacterial infection not involving the Central Nervous System. Participants underwent [11C]-PK11195 PET and a neuropsychological assessment during hospital stay. The distribution volume ratio was estimated in the regions-of-interest using the Hammers' brain atlas. Results: In the subcortical analysis, we found that the cognitively healthy group presented regions with significantly higher DVR intensity than the other groups in the choroid plexus. Mean choroid plexus DVR positively correlated with MoCA (r = 0.66, p = 0.036). Conclusion: This study suggests that dementia and/or delirium is associated with a reduced neuroinflammatory response to acute systemic bacterial infection which can be the result of an immunosuppressive brain environment.

6.
Brain Behav Immun Health ; 25: 100503, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36093438

ABSTRACT

Dementia is a known risk factor for acute bacterial infections which may also play a significant role in promoting or accelerating cognitive impairment. Pneumonia and urinary tract infections are the main cause of hospitalisation of dementia patients and infections are a major precipitant of delirium. It is well established that peripheral immune signals induce a neuroinflammatory response largely mediated by microglial cells which is amplified with advanced age, neurodegenerative disorders and genetic characteristics. Reversely, the innate immune response to acute bacterial infection is tightly regulated by the brain. It remains unclear whether dysfunctional neural circuits affected by dementia and/or delirium could alter systemic innate immune responses at the periphery. The current study aims to determine if dementia and/or delirium are associated with an altered systemic inflammatory response to an acute bacterial infection. We recruited 46 hospitalised older patients with acute bacterial infections. From these, 29 participants had cognitive dysfunction (6 with delirium, 12 with dementia and 11 with delirium superimposed on dementia) and 17 had normal cognition. We also included a control group of 11 patients with dementia but with no current infection matched for age and educational status. Baseline characteristics were tested between groups using Kruskal-Wallis test and pairwise comparisons were subsequently assessed with Bonferroni correction for multiple comparisons for continuous variables. Chi square test was used to assess differences between groups in categorical data and correlations between peripheral inflammatory parameters were assessed with Spearman's test. The 4 groups with infection and the control group with no infection had similar characteristics except for cognitive function and functionality which was higher for the group of infected cognitively healthy participants. Levels of C-reactive protein were similar between the infected groups and higher than the non-infected dementia group. Infected patients with cognitive dysfunction (delirium and/or dementia) had higher serum levels of IL-6, TNF-alpha and IL-1beta. These participants had reduced expression of miR-145 in circulating exosomes which correlated negatively with miR-155 levels (r = -0.411, p = 0.027). Expression of CR1 in circulating CD14+ monocytes was higher in infected participants with cognitive dysfunction and, in this group, PICALM correlated both with TNF-alpha and IL-6. In contrast to what was observed in participants with normal cognition, expression of CR1 did not correlate with DAP12 in infected participants with cognitive dysfunction. Taken together, our findings suggest that cognitive dysfunction is associated with an exaggerated proinflammatory response during acute bacterial infection with deregulation of several molecular signalling pathways in circulating exosomes and in monocytes.

7.
Lancet Oncol ; 22(11): 1597-1608, 2021 11.
Article in English | MEDLINE | ID: mdl-34672961

ABSTRACT

BACKGROUND: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. METHODS: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. FINDINGS: Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71-78). 50 (74%; 95% CI 61-84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20-55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0-11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. INTERPRETATION: Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia. FUNDING: Bristol Myers Squibb.


Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Triazines/therapeutic use , Aged , Antimetabolites, Antineoplastic/therapeutic use , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/genetics , Male , Mutation , Progression-Free Survival , Random Allocation , Treatment Outcome
8.
Porto Biomed J ; 6(4): e139, 2021.
Article in English | MEDLINE | ID: mdl-34368490

ABSTRACT

Delirium is a syndrome characterized by impairment of awareness and inattention, that represents a change from the patient's baseline cognitive functioning. It is triggered by an underlying medical condition, reaching a prevalence of 24.7% in geriatric wards. However, undiagnosed delirium remains a reality among inpatient individuals, with an estimated frequency of 24.1%. The inappropriate knowledge of diagnostic criteria and standard screening tools was pointed out as a relevant contributing factor to this paradigm. Liaison Psychiatry Services guarantee psychiatric approach and treatment to patients attending general hospitals. Considering that older adult patient care requires a well-trained and skilled team, the Centro Hospitalar e Universitário de Coimbra has a Geriatric Psychiatry Liaison Service, where delirium is one of the prevailing clinical conditions assessed by this team. The International Delirium Awareness Day is going to be worldwide celebrated on the 11th of March. Given that delirium has been consistently associated with the economic burden and adverse outcomes this symbolic day works as a huge opportunity to raise insight into the preventive strategies that could be implemented among healthcare professionals, patients, and caregivers. Within the Portuguese National Health System there is a need to build a set of systematic epidemiological data about delirium prevalence and incidence in the different settings and it would be essential the employment of a multicomponent intervention package delivered by a multidisciplinary team trained and competent in delirium prevention into routine care.

10.
Blood ; 137(5): 637-645, 2021 02 04.
Article in English | MEDLINE | ID: mdl-32870269

ABSTRACT

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Lymphoma, Follicular/drug therapy , Nivolumab/therapeutic use , Salvage Therapy , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Lymphoma, Follicular/diagnostic imaging , Male , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Nivolumab/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Recurrence , Rituximab/administration & dosage , Tumor Microenvironment
11.
Front Psychiatry ; 12: 754489, 2021.
Article in English | MEDLINE | ID: mdl-34975568

ABSTRACT

Introduction: Dementia is a known risk factor for both delirium and acute systemic infections which may also play a significant role in promoting or accelerating neurodegenerative disease. Infections are both the main causes of hospitalization of dementia patients and can be a major precipitant of delirium but currently it is not possible to predict the risk of cognitive decline in older patients exposed to acute infection. Objectives: We aimed to determine the level of cognitive change at 1-year follow up in individuals with different patterns of cognitive function (dementia, delirium, delirium superimposed on dementia) at the time of their hospitalization due to a systemic infection and to correlate these cognitive patterns with clinical status variables. Methods: We recruited 53 hospitalized geriatric patients with a systemic infection, and we collected 12-months follow up data for 34 patients. These patients were classified in four groups: no cognitive impairment (controls-C), delirium only (D), dementia only (Dem), and delirium superimposed to dementia (DD). Cognitive performance was measured by change in score on the Montreal Cognitive Assessment (MoCA) and delirium was identified using Confusion Assessment Measure (CAM). We examined performance on the MoCA in the first year after hospitalization, controlling for demographic characteristics, coexisting medical conditions, and type of infection. Results: For the 34 patients to whom follow-up data was available, delirium presence in individuals with prior dementia (DD group) was associated with a negative mean change score of 3-point (p < 0.02) at 1 year follow up, whereas dementia patients without delirium had a mean change score of 1.5-point lower at 12-months (p = 0.04), when comparing follow-up and baseline MoCA scores. Cognitively healthy patients did not significantly decrease their MoCA score at follow-up (p = 0.15). MoCA and NPI scores during hospitalization were significantly correlated with the level of cognitive decline in the four groups (r = 0.658, p < 0.01 and r = 0.439, p = 0.02, respectively). Conclusions: Premorbid dementia and delirium superimposed on dementia during hospitalization in older patients with acute infections predict cognitive decline at 1 year following admission. Taken together, our findings suggest a pathophysiological interaction between neurodegenerative changes, acute infection, and delirium.

12.
J Am Med Dir Assoc ; 22(3): 613-620.e9, 2021 03.
Article in English | MEDLINE | ID: mdl-33011097

ABSTRACT

OBJECTIVES: Delirium is an acute neuropsychiatric syndrome associated with poor outcomes. Older adults undergoing surgery have a higher risk of manifesting perioperative delirium, particularly those having associated comorbidities. It remains unclear whether delirium frequency varies across surgical settings and if it has remained stable across the years. We conducted a systematic review to (1) determine the overall frequency of delirium in older people undergoing noncardiac surgery; (2) explore factors explaining the variability of the estimates; and (3) determine the changing of the estimates over the past 2 decades. DESIGN: Systematic review and meta-analysis. Literature search was performed in MEDLINE, PubMed, ISI Web of Science, EBSCO, ISRCTN registry, ScienceDirect, and Embase in January 2020 for studies published from 1995 to 2020. SETTING: Noncardiac surgical settings. PARTICIPANTS: Forty-nine studies were included with a total of 26,865 patients screened for delirium. METHODS: We included observational and controlled trials reporting incidence, prevalence, or proportion of delirium in adults aged ≥60 years undergoing any noncardiac surgery requiring hospitalization. Data extracted included sample size, reported delirium frequencies, surgery type, anesthesia type, delirium diagnosis method, length of hospitalization, and year of assessment. (PROSPERO registration no.: CRD42020160045). RESULTS: We found an overall pooled frequency of preoperative delirium of 17.9% and postoperative delirium (POD) of 23.8%. The POD estimates increased between 1995 and 2020 at an average rate of 3% per year. Pooled estimates of POD were significantly higher in studies not excluding patients with lower cognitive performance before surgery (28% vs 16%) and when general anesthesia was used in comparison to local, spinal, or epidural anesthesia (28% vs 20%). CONCLUSIONS AND IMPLICATIONS: Type of anesthesia and preoperative cognitive status were significant moderators of delirium frequency. POD in noncardiac surgery has been increasing across the years, suggesting that more resources should be allocated to delirium prevention and management.


Subject(s)
Delirium , Postoperative Complications , Aged , Comorbidity , Delirium/diagnosis , Delirium/epidemiology , Humans , Incidence , Postoperative Complications/epidemiology , Prevalence
14.
Leukemia ; 34(8): 2064-2073, 2020 08.
Article in English | MEDLINE | ID: mdl-32265500

ABSTRACT

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.


Subject(s)
Dasatinib/therapeutic use , Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Dasatinib/adverse effects , Female , Humans , Imatinib Mesylate/adverse effects , Leukemia, Myeloid, Chronic-Phase/mortality , Male , Middle Aged , Prospective Studies , Young Adult
15.
Leuk Lymphoma ; 61(3): 650-659, 2020 03.
Article in English | MEDLINE | ID: mdl-31647335

ABSTRACT

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid, Chronic-Phase , Aged , Dasatinib/adverse effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/genetics , Protein Kinase Inhibitors/adverse effects , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...