Bortezomib for the treatment of multiple myeloma Scott, Kathleen; Hayden, Patrick J; Will, Andrea ...
Cochrane database of systematic reviews,
04/2016, Letnik:
2016, Številka:
4
Journal Article
Recenzirano
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Background
Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first‐in‐class proteasome inhibitor, bortezomib, is ...commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.
Objectives
We conducted a systematic review and meta‐analysis to assess the effects of bortezomib on overall survival (OS), progression‐free survival (PFS), response rate (RR), health‐related quality of life (HRQoL), adverse events (AEs) and treatment‐related death (TRD).
Search methods
We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).
Selection criteria
We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.
Data collection and analysis
Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.
Main results
We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta‐analyses. All trials were randomised and open‐label studies. Two trials were published in form and therefore we were unable to assess potential risk of bias in full.
There is moderate‐quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.
There is high‐quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low‐quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).
Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.
We identified four trials in the meta‐analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.
Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro‐intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high‐quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.
Only four trials analysed HRQoL and the data could not be meta‐analysed.
Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.
Authors' conclusions
This meta‐analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk‐benefit profile, while more studies of HRQoL are also required.
Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, ...tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.
Mental health literacy has received increasing attention as a useful strategy to promote early identification of mental disorders, reduce stigma and enhance help-seeking behaviors. However, despite ...the abundance of research on mental health literacy interventions, there is the absence of evaluations of current available mental health literacy measures and related psychometrics. We conducted a scoping review to bridge the gap.
We searched PubMed, PsycINFO, Embase, CINAHL, Cochrane Library, and ERIC for relevant studies. We only focused on quantitative studies and English publications, however, we didn't limit study participants, locations, or publication dates. We excluded non-English studies, and did not check the grey literature (non peer-reviewed publications or documents of any type) and therefore may have missed some eligible measures.
We located 401 studies that include 69 knowledge measures (14 validated), 111 stigma measures (65 validated), and 35 help-seeking related measures (10 validated). Knowledge measures mainly investigated the ability of illness identification, and factual knowledge of mental disorders such as terminology, etiology, diagnosis, prognosis, and consequences. Stigma measures include those focused on stigma against mental illness or the mentally ill; self-stigma ; experienced stigma; and stigma against mental health treatment and help-seeking. Help-seeking measures included those of help-seeking attitudes, intentions to seek help, and actual help-seeking behaviors.
Our review provides a compendium of available mental health literacy measures to facilitate applying existing measures or developing new measures. It also provides a solid database for future research on systematically assessing the quality of the included measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Theory is often recommended as a framework for guiding hypothesized mechanisms of treatment effect. However, there is limited guidance about how to use theory in intervention development.
We ...conducted a systematic review to provide an exemplar review evaluating the extent to which use of theory is identified and incorporated within existing interventions. We searched electronic databases PubMed, PsycINFO, CENTRAL, and EMBASE from inception to May 2014. We searched clinicaltrials.gov for registered protocols, reference lists of relevant systematic reviews and included studies, and conducted a citation search in Web of Science. We included peer-reviewed publications of interventions that referenced the social cognitive theory of self-regulation as a framework for interventions to manage chronic health conditions. Two reviewers independently assessed articles for eligibility. We contacted all authors of included studies for information detailing intervention content. We describe how often theory mechanisms were addressed by interventions, and report intervention characteristics used to address theory.
Of 202 articles that reported using the social cognitive theory of self-regulation, 52% failed to incorporate self-monitoring, a main theory component, and were therefore excluded. We included 35 interventions that adequately used the theory framework. Intervention characteristics were often poorly reported in peer-reviewed publications, 21 of 35 interventions incorporated characteristics that addressed each of the main theory components. Each intervention addressed, on average, six of eight self-monitoring mechanisms, two of five self-judgement mechanisms, and one of three self-evaluation mechanisms. The self-monitoring mechanisms 'Feedback' and 'Consistency' were addressed by all interventions, whereas the self-evaluation mechanisms 'Self-incentives' and 'External rewards' were addressed by six and four interventions, respectively. The present review establishes that systematic review is a feasible method of identifying use of theory as a conceptual framework for existing interventions. We identified the social cognitive theory of self-regulation as a feasible framework to guide intervention development for chronic health conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mental health literacy has received great attention recently to improve mental health knowledge, decrease stigma and enhance help-seeking behaviors. We conducted a systematic review to critically ...appraise the qualities of studies evaluating the measurement properties of mental health knowledge tools and the quality of included measurement properties.
We searched PubMed, PsycINFO, EMBASE, CINAHL, the Cochrane Library, and ERIC for studies addressing psychometrics of mental health knowledge tools and published in English. We applied the COSMIN checklist to assess the methodological quality of each study as "excellent", "good", "fair", or "indeterminate". We ranked the level of evidence of the overall quality of each measurement property across studies as "strong", "moderate", "limited", "conflicting", or "unknown".
We identified 16 mental health knowledge tools in 17 studies, addressing reliability, validity, responsiveness or measurement errors. The methodological quality of included studies ranged from "poor" to "excellent" including 6 studies addressing the content validity, internal consistency or structural validity demonstrating "excellent" quality. We found strong evidence of the content validity or internal consistency of 6 tools; moderate evidence of the internal consistency, the content validity or the reliability of 8 tools; and limited evidence of the reliability, the structural validity, the criterion validity, or the construct validity of 12 tools.
Both the methodological qualities of included studies and the overall evidence of measurement properties are mixed. Based on the current evidence, we recommend that researchers consider using tools with measurement properties of strong or moderate evidence that also reached the threshold for positive ratings according to COSMIN checklist.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human airway epithelial cells are the principal target of human rhinovirus (HRV), a common cold pathogen that triggers the majority of asthma exacerbations. The objectives of this study were 1) to ...evaluate an in vitro air liquid interface cultured human airway epithelial cell model for HRV infection, and 2) to identify gene expression patterns associated with asthma intrinsically and/or after HRV infection using this model.
Air-liquid interface (ALI) human airway epithelial cell cultures were prepared from 6 asthmatic and 6 non-asthmatic donors. The effects of rhinovirus RV-A16 on ALI cultures were compared. Genome-wide gene expression changes in ALI cultures following HRV infection at 24 hours post exposure were further analyzed using RNA-seq technology. Cellular gene expression and cytokine/chemokine secretion were further evaluated by qPCR and a Luminex-based protein assay, respectively.
ALI cultures were readily infected by HRV. RNA-seq analysis of HRV infected ALI cultures identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial structure and remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1, MUC5AC, CDHR3), and novel ones that were identified for the first time in this study (e.g. CCRL1).
ALI-cultured human airway epithelial cells challenged with HRV are a useful translational model for the study of HRV-induced responses in airway epithelial cells, given that gene expression profile using this model largely recapitulates some important patterns of gene responses in patients during clinical HRV infection. Furthermore, our data emphasize that both abnormal airway epithelial structure and inflammatory signaling are two important asthma signatures, which can be further exacerbated by HRV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three-dimensional (3D) reconstructed human skin (RhS) models featuring fully-differentiated characteristics of in vivo human epidermis have been known for almost 40 years. In this chapter, the topic ...of commercial in vitro tissue models is described, taking RhS models as an example. The need for highly standardised models is evident for regulatory testing purposes, e.g. the classification and labelling of chemicals and formulations, as well as for pharmacology-oriented research and drug development. Following the standardisation of RhS model production by commercial developers, international validation studies and regulatory acceptance, 3D RhS models are now used globally in both industrial and academic research laboratories. Industrial production of standardised 3D RhS models involves GMP-compliant processes together with ISO 9001 documentation in order to control and ensure reproducibility and quality. Key biological, functional, and performance features that are addressed in industrial production include barrier properties, histological and immunohistochemical characterisation, lipid profile characterisation, and tissue viability before and after transport. An up-to-date survey of commercial RhS tissue producers and the regulatory acceptance status of major safety, hazard, and efficacy assays currently available to chemical and pharmaceutical industries is presented in this chapter. Safety and ethical concerns related to the use of human tissue in the industrial production of RhS models are discussed. Finally, innovative approaches to the production of standardised 3D RhS models including automated production, development of more representative 3D RhS models using advanced additive manufacturing tools, microfluidics technologies, and bioprinting are presented. The future outlook for 3D RhS models includes a prevalence of high-quality models which will be fabricated by end-users rather than commercial producers. These will overcome problems with shipments and customs clearance that many users still face when buying RhS from overseas commercial suppliers. Open-source technologies and commercial components for "do-it-yourself" RhS will significantly change the skin model market as well as regulatory acceptance of open-source models during the next decade. All of these developments and improvements will together allow more widespread use of in vitro RhS models for broader application as animal replacements in areas ranging from industrial and regulatory toxicology and pharmacology, to drug development and personalised medicine.
Sequence not salvage Sborov, Douglas W.; Fortuna, Gliceida Galarza; Hayden, Patrick J.
British journal of haematology,
20/May , Letnik:
204, Številka:
5
Journal Article
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Chimeric antigen receptor T‐cell (CAR‐T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains ...incurable. Two CAR‐T products, idecabtagene vicleucel (ide‐cel; Abecma) and ciltacabtagene autoleucel (cilta‐cel, Carvykti), have been FDA‐ and EMA‐approved for the treatment of relapsed/refractory MM (RRMM); both target B‐cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR‐T therapy, most patients will need subsequent treatment, and the optimal next‐line therapy is presently unclear.
Commentary on: Liu et al. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA‐specific CAR‐T therapy: A retrospective analysis of LEGEND‐2. Br J Haematol 2024;204:1780‐1789.
Prognosis research aims to identify factors associated with the course of health conditions. It is often challenging to judge the overall quality of research evidence in systematic reviews about ...prognosis due to the nature of the primary studies. Standards aimed at improving the quality of primary studies on the prognosis of health conditions have been created, but these standards are often not adequately followed causing confusion about how to judge the evidence.
This article presents a proposed adaptation of Grading of Recommendations Assessment, Development and Evaluation (GRADE), which was developed to rate the quality of evidence in intervention research, to judge the quality of prognostic evidence.
We propose modifications to the GRADE framework for use in prognosis research along with illustrative examples from an ongoing systematic review in the pediatric pain literature. We propose six factors that can decrease the quality of evidence (phase of investigation, study limitations, inconsistency, indirectness, imprecision, publication bias) and two factors that can increase it (moderate or large effect size, exposure-response gradient).
We describe criteria for evaluating the potential impact of each of these factors on the quality of evidence when conducting a review including a narrative synthesis or a meta-analysis. These recommendations require further investigation and testing.
PURPOSE OF REVIEWDespite considerable therapeutic advances over the last decade, multiple myeloma remains an incurable disease. Novel treatment strategies are urgently needed. T cells can be ...genetically modified to express chimeric antigen receptors (CARs) targeting defined surface antigens on tumor cells. To date, over 90 clinical trials investigating the use of CAR T cells in multiple myeloma have been registered.
RECENT FINDINGSAlthough two CD19-directed CAR T-cell products have been approved, CD19 surface expression on plasma cells is limited or absent and CAR T-cell therapy in multiple myeloma is less advanced. B-cell maturation antigen (BCMA)-directed CAR T cells have shown promising efficacy and safety profiles in various phase I/II clinical trials. However, almost all treated patients continue to relapse. The current focus is therefore on strategies to overcome resistance mechanisms. These include the targeting of other surface antigens, refinements in T-cell signaling and dual-targeting approaches.
SUMMARYCAR T-cell therapy has finally moved into routine clinical use, the first experiments having taken place over 30 years ago. A BCMA-directed product for the treatment of multiple myeloma is expected to be approved shortly. However, further refinements of both CAR T-cell constructs and treatment protocols will be required to boost persistence, overcome resistance and reduce toxicities.
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