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European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS.
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There is a growing need to implement high quality chronic care to address the global burden of chronic conditions. However, to our knowledge, there have been no systematic attempts to define and specify aims for chronic care quality. To address this gap, we conducted a scoping review and Delphi survey to establish and validate comprehensive specifications. The Institute of Medicine's (IOM) quality of care definition and aims were used as the foundation. We purposively selected articles from the scientific (n=48) and grey literature (n=26). We sought papers that acknowledged and unpacked the plurality of quality in chronic care and proposed or utilised frameworks, studied their implementation, or investigated at least two IOM quality care aims and implementation. Articles were analysed both deductively and inductively. The findings were validated through a Delphi survey involving 49 international chronic care experts with varied knowledge of, and experience in, low-and-middle-income countries. Considering the natural history of chronic conditions and the journey of a person with a chronic condition, we defined and identified the aims of chronic care quality. The six IOM aims apply with specific meanings. We identified a seventh aim, continuity, which relates to the issue of chronicity. The group endorsed our specifications and several participants gave contextualised interpretations and concrete examples. Chronic conditions pose specific challenges underscoring the relevance of tailoring quality of care aims. The next steps require a tailored definition and specific aims to improve, measure and assure the quality of chronic care.
Main findings: While previously defined aims of good-quality care may also apply to chronic care quality, the nature of chronic conditions and ensuing healthcare needs warrant specifications for good-quality chronic care.Added knowledge: Our proposed definition and specific aims are tailored to the natural history of chronic conditions, and can serve as a guide on determining what can be deemed as good-quality chronic care.Global health impact for policy and action: This work, developed to guide further work on designing purchasing instruments to improve quality of chronic care, particularly in low- and middle-income countries, may also be a source of inspiration for other interventions aiming at improving quality of chronic care.
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Técnica Delphi , Qualidade da Assistência à Saúde , Humanos , Doença Crônica/terapia , Qualidade da Assistência à Saúde/organização & administração , Qualidade da Assistência à Saúde/normasRESUMO
PURPOSE: Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic. METHODS: Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers NCT02257567, NCT02500407; 20% holdout in ClinicalTrials.gov identifier NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review. RESULTS: The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses. CONCLUSION: These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.
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Aprendizado Profundo , Fluordesoxiglucose F18 , Linfoma não Hodgkin , Humanos , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Feminino , MasculinoRESUMO
Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Neutropenia , Sulfonamidas , Humanos , Seguimentos , Leucemia Mieloide Aguda/tratamento farmacológico , Azacitidina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
As a member state of the International Health Regulations 2005, Cambodia is continuously strengthening its capacity to respond to health emergencies and prevent the international spread of diseases. Despite this, Cambodia's capacity to prevent, detect and rapidly respond to public health threats remained limited at the onset of the pandemic, as was the case in most countries. This paper describes epidemiological phases, response phases, strategy and lessons learnt in Cambodia between 27 January 2020 and 30 June 2022. We classified epidemiological phases in Cambodia into three phases, in which Cambodia responded using eight measures: (1) detect, isolate/quarantine; (2) face coverings, hand hygiene and physical distancing measures; (3) risk communication and community engagement; (4) school closures; (5) border closures; (6) public event and gathering cancellation; (7) vaccination; and (8) lockdown. The measures corresponded to six strategies: (1) setting up and managing a new response system, (2) containing the spread with early response, (3) strengthening the identification of cases and contacts, (4) strengthening care for patients with COVID-19, (5) boosting vaccination coverage and (6) supporting disadvantaged groups. Thirteen lessons were learnt for future health emergency responses. Findings suggest that Cambodia successfully contained the spread of SARS-CoV-2 in the first year and quickly attained high vaccine coverage by the second year of the response. The core of this success was the strong political will and high level of cooperation from the public. However, Cambodia needs to further improve its infrastructure for quarantining and isolating cases and close contacts and laboratory capacity for future health emergencies.
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COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , Camboja/epidemiologia , Emergências , SARS-CoV-2RESUMO
Polatuzumab vedotin, marketed under the trade name POLIVY®, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin's lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.
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Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Estados Unidos , Adulto , Humanos , Rituximab/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoconjugados/efeitos adversos , Linfoma não Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológicoRESUMO
BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR]â¯=â¯0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HRâ¯=â¯0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.
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Leucemia Mieloide Aguda , Humanos , Estados Unidos , Idoso , Decitabina/uso terapêutico , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is the best candidate for a global standard but would benefit from additional specification. METHODS: Ethical analysis of ICH guidance for permission and assent for pediatric trials, with recommendations for clarification. RESULTS: ICH guidance regarding permission and assent would be enhanced by additional detail in the following areas: (1) what information should be provided to parents, guardians, and children considering a trial, and how that information should be provided; (2) the definition of "assent," the criteria for when assent should be required, and the need to include children in discussions even when assent is not mandated; (3) criteria for requiring children's signatures indicating agreement; (4) greater specificity regarding children's right to decline or withdraw; and (5) clarification of when children's wish to decline or withdraw from participation may be overridden and of what the overriding process should entail. CONCLUSION: ICH guidance provides a global standard for decision making regarding children's participation in trials. Several clarifications would facilitate the conduct of multinational pediatric research. IMPACT: Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor. Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials. The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research.
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Criança , Consentimento Livre e Esclarecido , Participação do Paciente , Humanos , Participação do Paciente/legislação & jurisprudência , Ensaios Clínicos como AssuntoRESUMO
INTRODUCTION: Mitogen-activated protein kinase pathway mutations are present in >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM. PATIENTS AND METHODS: Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1-21 (nâ¯=â¯6), cobi 40 mg/day on days 1-21â¯+â¯ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, nâ¯=â¯22; cobi-ven-atezo, nâ¯=â¯21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels. RESULTS: Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade ≥3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders to the cobi-ven combination. CONCLUSIONS: Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach for ven in MM.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2RESUMO
Background: Collecting data on antimicrobial resistance (AMR) is an essential approach for defining the scope of the AMR problem, developing evidence-based interventions and detecting new and emerging resistances. Our study aimed to identify key factors influencing the implementation of a laboratory-based AMR surveillance system in Cambodia. This will add additional insights to the development of a sustainable and effective national AMR surveillance system in Cambodia and other low- and middle-income countries. Methods: Key informants with a role in governing or contributing data to the laboratory-based surveillance system were interviewed. Emerging themes were identified using the framework analysis method. Laboratories contributing to the AMR surveillance system were assessed on their capacity to conduct quality testing and report data. The laboratory assessment tool (LAT), developed by the World Health Organisation (WHO), was adapted for assessment of a diagnostic microbiology laboratory covering quality management, financial and human resources, data management, microbiology testing performance and surveillance capacity. Results: Key informants identified inadequate access to laboratory supplies, an unsustainable financing system, limited capacity to collect representative data and a weak workforce to be the main barriers to implementing an effective surveillance system. Consistent engagement between microbiology staff and clinicians were reported to be a key factor in generating more representative data for the surveillance system. The laboratory assessments identified issues with quality assurance and data analysis which may reduce the quality of data being sent to the surveillance system and limit the facility-level utilisation of aggregated data. A weak surveillance network and poor guidance for outbreak response were also identified, which can reduce the laboratories' opportunities in detecting critical or emerging resistance occurring in the community or outside of the hospital's geographical coverage. Conclusion: This study identified two primary concerns: ensuring a sustainable and quality functioning of microbiology services at public healthcare facilities and overcoming sampling bias at sentinel sites. These issues hinder Cambodia's national AMR surveillance system from generating reliable evidence to incorporate into public health measures or clinical interventions. These findings suggest that more investments need to be made into microbiology diagnostics and to reform current surveillance strategies for enhanced sampling of AMR cases at hospitals.
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Laboratórios , Saúde Pública , Humanos , Camboja/epidemiologia , Surtos de Doenças , Organização Mundial da SaúdeRESUMO
INTRODUCTION: Integrated care interventions for type 2 diabetes (T2D) and hypertension (HT) are effective, yet challenges exist with regard to their implementation and scale-up. The 'SCale-Up diaBetes and hYpertension care' (SCUBY) Project aims to facilitate the scale-up of integrated care for T2D and HT through the co-creation and implementation of contextualised scale-up roadmaps in Belgium, Cambodia and Slovenia. We hereby describe the plan for the process and scale-up evaluation of the SCUBY Project. The specific goals of the process and scale-up evaluation are to (1) analyse how, and to what extent, the roadmap has been implemented, (2) assess how the differing contexts can influence the implementation process of the scale-up strategies and (3) assess the progress of the scale-up. METHODS AND ANALYSIS: A comprehensive framework was developed to include process and scale-up evaluation embedded in implementation science theory. Key implementation outcomes include acceptability, feasibility, relevance, adaptation, adoption and cost of roadmap activities. A diverse range of predominantly qualitative tools-including a policy dialogue reporting form, a stakeholder follow-up interview and survey, project diaries and policy mapping-were developed to assess how stakeholders perceive the scale-up implementation process and adaptations to the roadmap. The role of context is considered relevant, and barriers and facilitators to scale-up will be continuously assessed. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Institutional Review Board (ref. 1323/19) at the Institute of Tropical Medicine (Antwerp, Belgium). The SCUBY Project presents a comprehensive framework to guide the process and scale-up evaluation of complex interventions in different health systems. We describe how implementation outcomes, mechanisms of impact and scale-up outcomes can be a basis to monitor adaptations through a co-creation process and to guide other scale-up interventions making use of knowledge translation and co-creation activities.
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Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Bélgica , Eslovênia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Camboja , Hipertensão/epidemiologia , Hipertensão/terapiaRESUMO
BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Adulto , Humanos , Idoso , Decitabina/efeitos adversos , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
OBJECTIVES: Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP). METHODS: This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed. RESULTS: Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment. DISCUSSION: We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Fotoferese , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Fotoferese/efeitos adversos , Fotoferese/métodos , Estudos Retrospectivos , Transplante Homólogo/efeitos adversosRESUMO
Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee-assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee-assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
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Protocolos de Quimioterapia Combinada Antineoplásica , Imunoconjugados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/uso terapêutico , Humanos , Rituximab/uso terapêuticoRESUMO
PURPOSE: The CD79b-targeted antibody-drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. METHODS: The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI-142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI-142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. RESULTS: PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI-142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. CONCLUSION: Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure-response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.
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Anticorpos Monoclonais/farmacocinética , Povo Asiático/estatística & dados numéricos , Antígenos CD79/imunologia , Imunoconjugados/farmacocinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Anticorpos Monoclonais/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Seguimentos , Humanos , Imunoconjugados/administração & dosagem , Linfoma Difuso de Grandes Células B/etnologia , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/etnologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component. METHODS: Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods. RESULTS: Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients. CONCLUSION: Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
OBJECTIVE: mHealth interventions have the potential to facilitate self-management. This TEXT4DSM study implemented a mobile phone intervention in existing diabetes programmes in three low- and middle-income countries (Democratic Republic of Congo, Cambodia, and the Philippines). RESEARCH DESIGN AND METHODS: Sub-studies with a similar randomised controlled trial design were conducted in three different countries. Each sub-study included 480 adults with diabetes. Subjects were randomised to receive either routine care or routine care plus text message self-management support. The primary outcome was the difference in the proportion of subjects with well-controlled diabetes after 2 years. RESULTS: Baseline and 2-year HbA1c measurements were available for 781 individuals. After 2 years, the proportion of subjects with controlled HbA1c was 2.8% higher in the intervention group than in the control group (difference not statistically significant). In the logistic regression model, the odds ratio for having controlled diabetes after the intervention was 1.1, after adjusting for baseline HbA1c level, sex, receiving insulin treatment, and participating in the routine programme. The HbA1c dynamics over time differed between programmes; the number of people with controlled diabetes tended to increase in DR Congo and decrease in Cambodia. CONCLUSION: This study was the first to test the same mHealth intervention in different countries. The finding that text messages did not show an additional effect on diabetes control implied that expectations about mHealth should be cautious. The degree of coverage, the quality of the routine programme, and the progression of disease can interfere with the expected impact. Trial registration: ISRCTN registry (86247213).
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Introduction Evidence about mobile health (mHealth) approaches to manage diabetes shows modest effects on outcomes, but little is known about implementation variability. This is a process evaluation of an mHealth intervention to improve diabetes self-management through Short Message Service (SMS) provision in three diabetes care programmes in the Democratic Republic of Congo (DRC), Cambodia and the Philippines. Methods The intervention involved Diabetes Self-Management Support via text messages. The content and process of the intervention is based upon the core principles of diabetes self-management and behaviour theory. In each country, messages were sent by project managers to 240 participants in each country, who were randomly assigned to the intervention group. Contracts were negotiated with national phone providers and open access software was used to send the messages. Participants received a mobile phone and SIM card. We analysed data about the implementation process over a one year period. Results The mean monthly number of messages delivered to recipients' phones was 67.7% of the planned number in DRC, 92.3% in Cambodia and 83.9% in the Philippines. A telephone check revealed problems with one-third of the phones, including breakage, loss and cancelled subscriptions. The number of people reached at least once was 177 (70.0%) in DRC; 147 (60.7%) in Cambodia; five in the Philippines (2.0%). Those reached each time was 144 in DRC (56.9%), 28 (9.9%) in Cambodia, none in the Philippines. People used their phone more frequently than before the intervention. Discussion Implementation of the intervention meets constraints at every step in the process. Barriers relate to the technology, the context and the participants.
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Diabetes Mellitus/terapia , Sistemas de Alerta , Autocuidado/métodos , Envio de Mensagens de Texto , Idoso , Camboja , República Democrática do Congo , Diabetes Mellitus/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Filipinas , Avaliação de Processos em Cuidados de Saúde , Avaliação de Programas e Projetos de Saúde , Sistemas de Alerta/economia , Envio de Mensagens de Texto/economiaRESUMO
The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common consequences of cancer and cancer treatment. They are intended to aid health care professionals who work with survivors of adult-onset cancer in the posttreatment period, including those in general oncology, specialty cancer survivor clinics, and primary care practices. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors. This article summarizes the NCCN Survivorship panel's discussions for the 2016 update of the guidelines regarding the management of anxiety, depression, posttraumatic stress disorder-related symptoms, and emotional distress in survivors.
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Neoplasias/mortalidade , Humanos , Neoplasias/terapia , Taxa de SobrevidaRESUMO
Stem cell transplantation (SCT) and palliative care (PC) may initially appear to be distant extremes in the continuum of care of patients with hematologic malignancies, opposed by multiple obstacles preventing their integration. Rather, we will posit that both fields share many similarities and have much to learn from one another. PC has increasing relevance in cancer care given recent studies that link PC to improved quality-of-life, survival, and decreased cost of care. Understanding modern conceptualizations of PC and its role within SCT is key. Through the report of a single academic medical center experience with an integrated SCT and PC model over the last decade, we will discuss future opportunities for strengthening collaboration between SCT and PC. PC in SCT should be considered from the day of diagnosis and tied to need, not to prognosis.