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BACKGROUND: Immune response to COVID-19 vaccine is diminished in patients with hematologic malignancy. There is limited data regarding response to vaccine doses in these patients. PURPOSE: To quantify the humoral immune response engendered by 4th and subsequent doses of SARS-CoV-2 vaccination as measured by anti-Spike (anti-S) antibody levels, based on dried blood spot (DBS) testing, in patients with hematologic malignancies. Anti-S binds to the spike protein of the SARS-CoV-2 virus and is indicative of vaccine immunogenicity. METHODS: We conducted a prospective study of hematologic malignancies between August 2021 and January 2023 at 12 sites across Canada. Participants were followed longitudinally and submitted finger-prick DBS cards at set intervals associated with vaccination. Samples were processed via high throughput ELISA assay to detect serum antibodies against nucleocapsid (N) and spike (S) proteins. RESULTS: We obtained 3071 samples on 790 unique patients. Of these, 372 unique participants with 1840 samples had anti-S results available post-4th, 5th or 6th COVID-19 vaccine dose and were included for analysis. Three hundred thirty-three patients of the 372 participants submitted a DBS sample post 4th dose. Of these, 257 patients (77.2%) had a positive anti-S antibody. A total of 198 patients had paired samples pre- and post-dose 4, of which 59 (29.7%) had a negative anti-S antibody pre-dose 4. Of these, 20 (33.4%) developed positive anti-S antibody post-dose 4. One hundred forty-nine patients submitted a DBS sample post-dose 5. Of these, 135 patients (90.6%) had positive anti-S antibody. A total of 52 had paired samples pre- and post-dose 5. Six (8.7%) had a negative anti-S antibody pre-dose 5, of which two (33.3%) developed positive anti-S antibody post-dose 5. Of these 372 patients, 123 (34%) reported COVID-19 infection and 4 (1%) had a COVID-19 related hospitalization. There were no reported deaths from COVID-19. CONCLUSIONS: This prospective cohort study showed that humoral immune response improved with subsequent doses of COVID-19 vaccines.
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The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.
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Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE.
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Encefalomielitis Autoinmune Experimental , Ratas , Animales , Ratones , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/prevención & control , Inmunidad Innata , Médula Espinal/patología , Microglía , Células Th17 , Células TH1 , Ratones Endogámicos C57BLRESUMEN
Primary central nervous system lymphoma (PCNSL) is primarily treated with combination chemotherapy, while whole-brain radiotherapy (WBRT) can be used as consolidative treatment or as a salvage option for central nervous system (CNS) relapse. We investigated whether fractionated stereotactic radiosurgery (fSRS) could replace WBRT in cases where patients had poor performance status or minimal disease at the time of consolidation, to spare patients the adverse effects of WBRT. We retrospectively identified 10 patients who completed 14 courses of fSRS for PCNSL or for CNS relapse of systemic lymphoma. Of 14 fSRS treatments, there were 10 distant brain recurrences among 6 patients, occurring on average 13.6 months after fSRS. A total of 4 of the 10 recurrences were treated with further fSRS, and 4 were treated with WBRT. There was one late in-field recurrence after both fSRS and WBRT, which occurred 27 months after fSRS. The median survival after fSRS was 36 months, and side effects after fSRS were minimal. This case series represents a potential treatment option for patients with CNS lymphoma, for whom WBRT is indicated but where the toxic effects of this treatment would be prohibitive.
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Radiocirugia , Humanos , Estudios Retrospectivos , Encéfalo , Sistema Nervioso CentralRESUMEN
The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation.
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INTRODUCTION: As the Canadian population ages, older adults comprise an increasing proportion of those diagnosed and treated for hematologic malignancies. A geriatric oncology curriculum has been recognized as a top priority in the care of older patients with cancer. It is not clear, however, whether hematology trainees receive training in geriatric oncology. We sought to understand residents' views and needs for a geriatric oncology curriculum during hematology residency in Canada. MATERIALS AND METHODS: We conducted a cross-sectional needs assessment of hematology trainees enrolled in a Canadian residency or advanced fellowship training program within hematology. The survey, which was piloted with three non-hematology residents to ensure user-friendliness, used a combination of Likert scale, multiple-choice, and open-ended questions. The survey comprised three sections: (1) demographic data, (2) current state of geriatric oncology training (amount, content) and (3) attitudes towards learning about geriatric oncology and preferred curriculum components and identified needs. The survey was administered by the study team and distributed electronically to program directors in June 2020. The program directors were asked to forward the survey to trainees registered within their Division of Hematology. Data were analyzed descriptively. RESULTS: Twenty-nine hematology residents participated (41.4% estimated response rate). Most respondents had not received geriatric oncology teaching (58.6%, n = 17) and have never been taught about geriatric oncology assessment tools (72.4%, n = 21) during hematology residency. Most respondents felt that their program should deliver a geriatric oncology curriculum (96.6%, n = 28). Respondents were most interested in learning about use of geriatric assessment tools for pre-treatment chemotherapy decision-making (86.2%, n = 25), prediction of chemotherapy toxicity (82.8%, n = 24), and to facilitate conversations regarding treatment initiation, continuation, or termination (79.3%, n = 23). DISCUSSION: Our study highlights the paucity of geriatric oncology training in hematology residency training programs. Our results highlight both the need and interest for a future dedicated geriatric oncology curriculum integrated into hematology training and provide guidance about which topics are most valued by trainees.
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Hematología , Internado y Residencia , Neoplasias , Humanos , Anciano , Estudios Transversales , Canadá , Oncología Médica/educación , Curriculum , Encuestas y CuestionariosRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to summarize the epidemiology, mechanisms, and management of cardiovascular complications of Bruton's Tyrosine Kinase inhibitors (BTKIs). RECENT FINDINGS: Ibrutinib increases the risk of atrial fibrillation, bleeding, and hypertension compared with non-BTKI therapies. The evidence to support an association between ibrutinib and other cardiovascular complications including ventricular tachyarrhythmias or cardiomyopathy is limited. Ibrutinib metabolism can be inhibited by some medications used to treat cardiovascular complications. The cardiovascular effects of more selective BTKIs, such as acalabrutinib, remain to be determined. Future research should address the mechanisms underlying the cardiovascular complications of BTKIs and how best to manage them. The risks and benefits of more selective BTKIs as compared with ibrutinib require further evaluation.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Fibrilación Atrial/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Adenina/efectos adversos , Adenina/análogos & derivados , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/prevención & control , Cardiotoxicidad/prevención & control , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/prevención & control , Hemorragia/inducido químicamente , Hemorragia/diagnóstico , Hemorragia/prevención & control , Humanos , Hipertensión/inducido químicamente , Hipertensión/diagnóstico , Hipertensión/prevención & control , Piperidinas/efectos adversos , Taquicardia Ventricular/inducido químicamente , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/prevención & controlRESUMEN
INTRODUCTION: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted. CONCLUSIONS: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver.
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Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/economía , Clorhidrato de Bendamustina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/economía , Piperidinas/economía , Piperidinas/uso terapéutico , Rituximab/economía , Rituximab/uso terapéutico , Adenina/economía , Adenina/farmacología , Adenina/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Clorhidrato de Bendamustina/farmacología , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Piperidinas/farmacología , Estudios Prospectivos , Rituximab/farmacología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CONTEXT: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. OBJECTIVE: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. METHODS: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. RESULTS: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (Pâ <â .001 and Pâ <â .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (Pâ <â .001 and Pâ =â .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (Pâ =â .03 and Pâ =â .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (Pâ <â .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (Pâ >â .10). Fezolinetant was well tolerated. CONCLUSION: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.
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Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/uso terapéutico , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Gonadotropinas/sangre , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Humanos , Hiperandrogenismo/tratamiento farmacológico , Hormona Luteinizante/sangre , Persona de Mediana Edad , Pruebas de Función Ovárica , Testosterona/sangre , Tiadiazoles/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS).Areas covered: This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS.Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.
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Compuestos Heterocíclicos con 2 Anillos/farmacología , Menopausia/fisiología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/farmacología , Femenino , Sofocos/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Calidad de Vida , Receptores de Neuroquinina-3/metabolismoRESUMEN
Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.
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Enfermedad de Fabry/enzimología , Enfermedad de Fabry/terapia , Terapia Genética/métodos , Lentivirus/genética , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico , Adulto , Antígenos CD34 , Células de la Médula Ósea , Enfermedad de Fabry/genética , Vectores Genéticos , Células Madre Hematopoyéticas , Humanos , Leucocitos , Masculino , Persona de Mediana Edad , Trihexosilceramidas/sangre , Trihexosilceramidas/orinaRESUMEN
Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analyzed for their effectiveness in virtual screening against FFAR2. To evaluate the performance of these methods, retrospective virtual screening was performed. Statistical quality of the methods was evaluated by BEDROC and RIE. The results revealed that electrostatic similarity search protocol using EON (ET combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary to hits found from electrostatic similarity searching. These results suggest that considering electrostatic similarity searching first increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign. Accordingly, prospective virtual screening using electrostatic similarity searching was used to identify novel FFAR2 ligands. The discovered compounds provide new chemical matter starting points for the initiation of a medicinal chemistry campaign.
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Antiinflamatorios no Esteroideos/farmacología , Receptores de Superficie Celular/agonistas , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
OBJECTIVE: In the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs). METHODS: In this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90âmg BID or 30, 60, or 120âmg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs). RESULTS: Of 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6). CONCLUSIONS: Oral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.
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Calidad de Vida , Receptores de Neuroquinina-3 , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 2 Anillos , Sofocos/tratamiento farmacológico , Humanos , Menopausia , Medición de Resultados Informados por el Paciente , Posmenopausia , Tiadiazoles , Resultado del TratamientoRESUMEN
We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p (n = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286]; p < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822]; p = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.
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Leucemia Linfocítica Crónica de Células B , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas , Rituximab/uso terapéuticoRESUMEN
OBJECTIVE: Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. METHODS: Menopausal women aged >40-65 years with moderate/severe VMS (≥50âepisodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90âmg BID or 30, 60, 120âmg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS ×â2] + [number of severe VMS ×â3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (≥50% reduction in moderate/severe VMS frequency) was a key secondary outcome. RESULTS: Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by -1.9 to -3.5/day at week 4 and -1.8 to -2.6/day at week 12 (all Pâ<â0.05 vs placebo). Mean difference from placebo in VMS severity score was -0.4 to -1 at week 4 (all doses Pâ<â0.05) and -0.2 to -0.6 at week 12 (Pâ<â0.05 for 60 and 90âmg BID and 60âmg QD). Response (50% reduction) relative to placebo was achieved by 81.4% to 94.7% versus 58.5% of participants at end of treatment (all doses Pâ<â0.05). Treatment-emergent adverse events were largely mild/moderate; no serious treatment-related treatment-emergent adverse events occurred. CONCLUSIONS: Fezolinetant is a well-tolerated, effective nonhormone therapy that rapidly reduces moderate/severe menopausal VMS. : Video Summary:http://links.lww.com/MENO/A572; video script available at http://links.lww.com/MENO/A573.
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Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Sofocos/tratamiento farmacológico , Menopausia , Receptores de Neuroquinina-3/administración & dosificación , Tiadiazoles/administración & dosificación , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Humanos , Persona de Mediana Edad , Receptores de Neuroquinina-3/agonistas , Tiadiazoles/efectos adversosRESUMEN
BACKGROUND & AIMS: Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. METHODS: We performed studies with ApcMin/+ mice, ApcMin/+Ffar2-/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas. RESULTS: ApcMin/+Ffar2-/- mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2-/- mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2-/- mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs, than mice not given the agonist. DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production. CONCLUSIONS: Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC.
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Colitis/patología , Neoplasias del Colon/inmunología , Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Células Dendríticas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Grasos no Esterificados/metabolismo , Femenino , Humanos , Interleucinas/inmunología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Noqueados , Permeabilidad , Cultivo Primario de Células , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.
Asunto(s)
Inmunidad Innata , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Microbioma Gastrointestinal/inmunología , Expresión Génica , Humanos , Inmunomodulación , Mucosa Intestinal/patología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt , Receptores de Superficie Celular/agonistas , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: Certain genomic features, such as del(11q), expression of unmutated immunoglobulin heavy-chain variable region (IGHV) gene, or complex karyotype, predict poorer outcomes to chemotherapy in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: We examined the pooled long-term follow-up data from PCYC-1115 (RESONATE-2), PCYC-1112 (RESONATE), and CLL3001 (HELIOS), comprising a total of 1238 subjects, to determine the prognostic significance of these markers in patients treated with ibrutinib. RESULTS: With a median follow-up of 47 months, ibrutinib-treated patients had longer progression-free survival (PFS) than patients treated in the comparator arm, regardless of genomic risk factors. Among patients treated with ibrutinib, we found that high-risk genomic features were not associated with shorter PFS (63-75% across all subgroups at 42 months) or overall survival (79-83% across all subgroups at 42 months). Surprisingly, we observed that ibrutinib-treated patients with del(11q) actually had a significantly longer PFS than ibrutinib-treated patients without del(11q) (42-month PFS rate 70% vs. 65%, P = .02). CONCLUSION: These analyses not only demonstrate that genomic risk factors previously associated with poor outcomes lose their adverse prognostic significance but also that del(11q) can be associated with a superior PFS with ibrutinib therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 11 , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Cariotipo Anormal , Adenina/análogos & derivados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ensayos Clínicos como Asunto , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Piperidinas , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Resultado del TratamientoRESUMEN
CONTEXT: The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). OBJECTIVE: To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. DESIGN: Twelve-week, double-blind, randomized, placebo-controlled study. SETTING: Eight Belgian centers from September 2015 to October 2016. PARTICIPANTS: Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. INTERVENTIONS: Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. MAIN OUTCOME MEASURES: Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability. RESULTS: Of 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (-26.5 vs -12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6). CONCLUSIONS: Fezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.
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Enfermedades del Sistema Nervioso Autónomo/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Menopausia/fisiología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/uso terapéutico , Sistema Vasomotor/efectos de los fármacos , Adulto , Anciano , Enfermedades del Sistema Nervioso Autónomo/etiología , Bélgica , Método Doble Ciego , Femenino , Sofocos/tratamiento farmacológico , Sofocos/etiología , Humanos , Persona de Mediana Edad , Calidad de Vida , Resultado del TratamientoRESUMEN
INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .