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Transfusion Feb 2024
Meta-Analysis Review
Topics: Humans; COVID-19; COVID-19 Serotherapy; Randomized Controlled Trials as Topic; SARS-CoV-2; Immunization, Passive; Treatment Outcome
PubMed: 38156374
DOI: 10.1111/trf.17701 -
Expert Review of Hematology 2024This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab.
METHODS
PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies.
RESULTS
The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy.
CONCLUSIONS
The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.
Topics: Humans; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Recurrence; Antigens, CD19
PubMed: 38135295
DOI: 10.1080/17474086.2023.2298732 -
BMC Public Health Dec 2023A significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly...
BACKGROUND
A significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly vulnerable to severe disease. In 2015, 44% of global hospitalisations in infants in this age group were secondary to RSV. The objective of this systematic review is to appraise and synthesise the local evidence of RSV infection morbidity among Australian infants aged 0 to 6 months and to assess the implications for future immunisation strategies.
METHODS
Electronic databases (Medline, Embase, Pubmed and Global Health) were searched for full-text articles published between 2000 and 2023 in English language. Studies that examined markers of RSV disease morbidity in infants aged 0 to 6 months in Australia who had laboratory confirmed RSV infection were eligible for inclusion. The outcomes of interest were incidence, prevalence, testing rate, positivity rate, mortality, emergency department visits, community health visits, hospitalisation, intensive care unit admission, supplementary oxygen use, mechanical ventilation, risk factors for disease severity and monoclonal antibody use.
RESULTS
The database search identified 469 studies. After removal of duplicates and full-text review, 17 articles were eligible for inclusion. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Synthesis without meta-analysis guidelines.
CONCLUSIONS
Qualitative analysis of the included studies showed that Australian infants aged 0 to 6 months have higher rates of RSV testing, positivity and incidence; and more likely to develop severe disease that requires hospitalisation, intensive care unit admission or respiratory support, compared to children and adults of all ages. Aboriginal and Torres Strait Islander infants aged 0 to 6 months demonstrated higher rates of RSV infection and hospitalisation, compared to non-Indigenous infants. Age-related trends persisted in geographic areas with varying seasonal transmission of RSV, and during the SARS-CoV-2 pandemic. Passive immunisation strategies targeting infants in their first 6 months of life, either via vaccination of pregnant women or administration of long-acting monoclonal antibody during infancy, could effectively reduce RSV disease burden in Australia.
Topics: Pregnancy; Infant; Child; Adult; Humans; Female; Respiratory Syncytial Virus Infections; Australia; Communicable Diseases; Antibodies, Monoclonal; Respiratory Syncytial Virus, Human; Hospitalization; Prevalence
PubMed: 38129854
DOI: 10.1186/s12889-023-17474-x -
Journal of Medical Virology Dec 2023This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period,... (Meta-Analysis)
Meta-Analysis
This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.
Topics: Humans; COVID-19; Outpatients; COVID-19 Serotherapy; Randomized Controlled Trials as Topic; Antibodies, Monoclonal; Hospitalization; Antiviral Agents
PubMed: 38105461
DOI: 10.1002/jmv.29310 -
Clinical Immunology Communications Dec 2022Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against...
Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.
PubMed: 38013970
DOI: 10.1016/j.clicom.2022.08.003 -
The Lancet. Microbe Nov 2023Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome.
METHODS
In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy.
FINDINGS
We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1.
INTERPRETATION
Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19.
FUNDING
The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Serotherapy; Australia; Treatment Outcome; Antibodies, Monoclonal
PubMed: 37924835
DOI: 10.1016/S2666-5247(23)00194-5 -
International Journal of Molecular... Oct 2023Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients... (Review)
Review
Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.
Topics: Humans; Glioblastoma; Immune Checkpoint Inhibitors; Cancer Vaccines; Neoplasm Recurrence, Local; Glioma; Immunotherapy; Immunotherapy, Adoptive; Brain Neoplasms; Tumor Microenvironment
PubMed: 37894718
DOI: 10.3390/ijms242015037 -
Transplantation and Cellular Therapy Jan 2024Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients... (Meta-Analysis)
Meta-Analysis
Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.
Topics: Humans; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Neurotoxicity Syndromes; Observational Studies as Topic; Pathologic Complete Response; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes
PubMed: 37890589
DOI: 10.1016/j.jtct.2023.10.017 -
Leukemia Dec 2023In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory...
In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD ≤ 0.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS, EFS and RFS were 0.54 (95% CI: 0.41-0.71, p < 0.001), 0.67 (0.52-0.86, p = 0.001) and 0.77 (0.51-1.18, p = 0.233). The OS, EFS and RFS survival probability at 2 years was 59.49% for tisagenlecleucel vs. 36.16% for SOC population, 42.31% vs. 30.23% and 59.60% vs. 54.57%, respectively. Odds ratio for ORR was 1.99 (1.33-2.97, p < 0.001). Results for OS and ORR were statistically significant after adjustment for confounders and provide evidence supporting a superiority of tisagenlecleucel in r/r ALL given the good comparability of cohorts after adjustment for confounders.
Topics: Humans; Child; Young Adult; Standard of Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Austria; Immunotherapy, Adoptive
PubMed: 37880478
DOI: 10.1038/s41375-023-02042-4 -
Journal of Autoimmunity Nov 2023This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy. (Review)
Review
BACKGROUND
This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy.
METHODS
A systematic search of the literature was performed using PubMed, PsycINFO, SCOPUS, EMBASE, Medline, and CINAHL (February 2023). Risk of bias was assessed using the JBI Checklist for Case Reports and the Risk of Bias Assessment Tool for Non-randomised Studies.
RESULTS
Twenty-two studies met inclusion criteria with a total of 1104 participants. There was considerable methodological heterogeneity with differing study designs (e.g., cohort studies, clinical trials, case studies, a qualitative interview, and a focus group), measures of cognition (e.g., self-report, neuropsychological measures, clinician assessed/neurological examinations), and longest follow-up time points (i.e., five days to five years).
DISCUSSION
Results of the studies were heterogenous with studies demonstrating stable, improved, or reduced cognition across differing time points. Overall, cognitive symptoms are common particularly in the acute stage (<2 weeks) post-infusion. Most deficits that arise in the acute stage resolve within one to two weeks, however, there is a subset of patients who continue to experience and self-report persistent deficits in the subacute and chronic stages. Future studies are needed to comprehensively analyse cognition using a combination of self-report and psychometric measures following chimeric antigen receptor T-cell therapy in the acute, subacute, and chronic settings.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Cognition; Treatment Outcome
PubMed: 37837807
DOI: 10.1016/j.jaut.2023.103126