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SN Comprehensive Clinical Medicine 2020Immune thrombocytopenia, often known as immune thrombocytopenic purpura (ITP), has emerged as an important complication of COVID-19. A systematic review was done to... (Review)
Review
Immune thrombocytopenia, often known as immune thrombocytopenic purpura (ITP), has emerged as an important complication of COVID-19. A systematic review was done to analyze the clinical profile and outcomes in a total of 45 cases of new-onset ITP in COVID-19 patients described in literature until date. A comprehensive approach is essential for diagnosing COVID-19-associated ITP after excluding several concomitant factors that can cause thrombocytopenia in COVID-19. Majority of ITP cases (71%) were found to be elderly (> 50 years) and 75% cases had moderate-to-severe COVID-19. Three patients (7%) were in the pediatric age group. Reports of ITP in asymptomatic COVID-19 patients (7%) underscore the need for COVID-19 testing in newly diagnosed patients with ITP irrespective of COVID-19 symptoms amid this pandemic. ITP onset occurred in 20% cases 3 weeks after onset of COVID-19 symptoms, with many reports after clinical recovery. SARS-CoV-2-mediated immune thrombocytopenia can be attributed to the underlying immune dysregulation, susceptibility mutations in SOCS 1, and other mechanisms, including molecular mimicry, cryptic antigen expression, and epitope spreading. No bleeding manifestations were reported in 31% cases at diagnosis. Severe life-threatening bleeding was uncommon. One case of mortality was attributed to intracranial hemorrhage. Secondary Evans syndrome was diagnosed in one case. Good initial response to short course of glucocorticoids and intravenous immunoglobulin has been found with the exception of delayed lag response in one case. Thrombopoietin receptor agonist usage as a second-line agent has been noted in few cases for short duration with no adverse events. In the relatively short follow-up period, four relapses of ITP were found.
PubMed: 32984764
DOI: 10.1007/s42399-020-00521-8 -
Critical Reviews in Oncology/hematology Apr 2022Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM.
METHODS
A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed.
RESULTS
We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%).
CONCLUSIONS
Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking.
Topics: B7-H1 Antigen; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mesothelioma, Malignant; Programmed Cell Death 1 Receptor; Progression-Free Survival
PubMed: 35192932
DOI: 10.1016/j.critrevonc.2022.103639 -
PharmacoEconomics - Open Mar 2024In this ever-expanding treatment landscape, there is a lack of consolidated health-related quality of life (HRQOL) outcomes and utility reports in relapsed or refractory...
BACKGROUND
In this ever-expanding treatment landscape, there is a lack of consolidated health-related quality of life (HRQOL) outcomes and utility reports in relapsed or refractory (R/R) large B cell lymphoma (LBCL) to inform health care policy and decision-maker assessments for both old and new products. These assessments can have a direct effect on what treatment options are available to patients and physicians.
OBJECTIVE
A systematic literature review (SLR) was performed to understand the HRQOL evidence for treatments in R/R LBCL and identify associated health utility values.
METHODS
The SLR searched and screened literature published from 1 January 2003 to 2 May 2022. Studies were screened based on Population, Intervention, Comparator, Outcome, Study design criteria established a priori and were assessed by two independent reviewers; quality assessments of the evidence were performed in accordance with health technology assessment recommendations from the National Institute for Health and Care Excellence. Several types of therapies were included, such as chimeric antigen receptor (CAR) T cell products (lisocabtagene maraleucel, axicabtagene ciloleucel, tisagenlecleucel), novel therapies (selinexor, nivolumab, polatuzumab vedotin, and bendamustine), salvage therapies, and rituximab.
RESULTS
The review identified 33 unique studies reporting HRQOL, including 15 economic studies that reported health state utility values, 9 clinical trials, 7 health technology assessment reports, and 1 each of a vignette-based study and a point-in-time survey. Improvements in general and/or lymphoma-specific HRQOL measures were observed with CAR T cell therapy in both the second-line and third-line or later settings. On-treatment utility values for CAR T cell therapies ranged from 0.50 to 0.74. Values for remission/progression-free survival (0.70-0.90) and for disease progression (0.39-0.59) were similar across studies. For novel therapies, utility values were 0.83 for progression-free survival and ranged from 0.39 to 0.71 for disease progression. On-treatment utility values for salvage chemotherapy ranged from 0.63 to 0.67.
CONCLUSIONS
Overall, the evidence synthesized in this SLR provides a comprehensive understanding of the HRQOL evidence in R/R LBCL. This article identified several sources for utility values in the published literature showing variation in the HRQOL outcomes for patients across a variety of therapeutics. Treatment of R/R LBCL with CAR T cell therapies was associated with improvement in health utility values. Mixed results were found for novel therapies and salvage therapies. More data are needed as new therapies are used in this patient population to inform treatment decision-making.
PubMed: 38198111
DOI: 10.1007/s41669-023-00464-5 -
Journal of Infection and Public Health Apr 2024Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations... (Meta-Analysis)
Meta-Analysis Review
Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations play a crucial role in influencing susceptibility to DHF. Therefore, this investigation conducted a meta-analysis to uncover genetic changes that might have remained undetected in individual studies due to small sample sizes or methodological differences. Among 2212 initially identified studies, 23 were deemed suitable for analysis based on PRISMA guidelines. Toll-like receptors (TLR) and CD209 showed significant association with DHF (odds ratios: TLR=0.56, CD209 =0.55), indicating protective effects. However, tumor necrosis factor (TNF) and human leukocyte antigen (HLA) did not exhibit a statistically significant relationship with DHF. This study emphasizes the relevance of TLR and CD209 in DHF susceptibility and resistance across diverse geographical locations.
Topics: Humans; Severe Dengue; Dengue Virus; Tumor Necrosis Factor-alpha; Serogroup; Case-Control Studies; Dengue
PubMed: 38368646
DOI: 10.1016/j.jiph.2024.02.001 -
Journal of Clinical Medicine Dec 2022Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results... (Review)
Review
Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results against multiple cancers, where they reactivate exhausted T cells primed to eliminate tumor cells. ICI therapies have been particularly successful in hypermutated cancers infiltrated with lymphocytes. However, resistance may appear in tumors evading the immune system through alternative mechanisms than the PD-1/PD-L1 or CTLA-4 pathways. A systematic pan-cancer literature search was conducted to examine the association between alternative immune evasion mechanisms via the antigen presentation machinery (APM) and resistance towards ICI treatments targeting PD-1 (pembrolizumab and nivolumab), PD-L1 (durvalumab, avelumab, and atezolizumab), and CTLA-4 (ipilimumab). The APM proteins included the human leucocyte antigen (HLA) class I, its subunit beta-2 microglobulin (B2M), the transporter associated with antigen processing (TAP) 1, TAP2, and the NOD-like receptor family CARD domain containing 5 (NLRC5). In total, 18 cohort studies (including 21 original study cohorts) containing 966 eligible patients and 9 case studies including 12 patients were reviewed. Defects in the APM significantly predicted poor clinical benefit with an odds ratio (OR) of 0.39 (95% CI 0.24−0.63, p < 0.001). The effect was non-significant, when considering complete and partial responses only (OR = 0.52, 95% CI 0.18−1.47, p = 0.216). In summary, the APM contains important targets for tumorigenic alterations which may explain insensitivity towards ICI therapy.
PubMed: 36615128
DOI: 10.3390/jcm12010329 -
Annals of Translational Medicine May 2022As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety...
BACKGROUND
As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety and efficacy, especially for digestive system cancer (DSC). Various CAR-T cell constructs used in different types of DSCs result in heterogeneous responses. Thus, we aimed to systematically summarize the clinical response of DSCs treated with CAR-T cells and investigate factors associated with heterogeneity in outcomes.
METHODS
Clinical studies of DSC patients treated with CAR-T cell therapy were selected from the PubMed, Cochrane, Embase, Web of Science databases before October 1, 2020. "CAR-T cell", "solid tumor" and their synonymous terms were used to construct the search strategy. Duplicates, reviews, non-English literature, articles not related to clinical studies or CAR-T cells used for digestive tumors were excluded. The included studies were assessed by the Institute of Health Economics (IHE) risk of bias tool to check the methodological quality. The inverse variance method was used to perform data pooling and subgroup analysis to clarify the causes of heterogeneity. Publication bias was examined by funnel plots and Egger's test.
RESULTS
Twelve studies were included, and the risk of bias evaluation was demonstrated as plots using Review Manager 5.3. The pooled overall response rate (ORR) was 2% (95% CI: 0-6%), and the clinical benefit rate (CBR) was 42% (95% CI: 24-61%). According to subgroup analysis, costimulation (P=0.0449), lymphodepletion (P=0.0002), persistence of CAR-T cells (P=0.0443) and transduction method (P=0.0165) were factors contributing to heterogeneity. For adverse effects, pyrexia was the most frequent (35%, 95% CI: 24-61%). No publication bias was found, and the major results were robust within a slight fluctuation for each removal of one of the 12 studies.
DISCUSSION
CAR-T cell therapy is generally beneficial for patients with DSCs though the ORR was still poor. Modified construction with more specific tumor antigens, costimulatory domain and lentiviral vectors is necessary to obtain a better antitumor response of CAR-T cell therapy. Information of survival data are needed for a more comprehensive analysis.
PubMed: 35928759
DOI: 10.21037/atm-21-5019 -
Current Oncology (Toronto, Ont.) Apr 2023Vitamin D deficiency has been correlated with various conditions, including the risk of developing lymphoid malignancies. This systematic review aimed to assess the... (Review)
Review
Vitamin D deficiency has been correlated with various conditions, including the risk of developing lymphoid malignancies. This systematic review aimed to assess the association between vitamin D levels at diagnosis of lymphoid malignancies, patient outcomes, and survival. A systematic review was conducted, encompassing 15 studies published until January 2023, involving 4503 patients, examining the relationship between vitamin D and lymphoid cancers. The median age of the patients was 56.5 years, with a median follow-up duration of approximately 36 months across studies. The overall median vitamin D level at initial measurement was 20.4 ng/mL, while a <20 ng/mL threshold was used to define vitamin D insufficiency. The results demonstrated significant associations between vitamin D levels and patient outcomes in several lymphoid malignancies, with a pooled risk in disease progression of 1.93 and a pooled hazard ratio of 2.06 for overall survival in patients with 25-(OH)D levels below the normal threshold of 20 ng/mL. Among findings, it was demonstrated that supplemental vitamin D improves the chemosensitivity of tumors by reducing the rate of tumor growth compared with vitamin D or chemotherapy alone. Vitamin D had a protective effect for patients with DLBCL under R-CHOP treatment, while vitamin D insufficiency was associated with the impairment of rituximab treatment and showed worse clinical outcomes in chimeric antigen receptor T-cell (CAR-T) recipients. Although one study found no association between vitamin D deficiency and the cause of death, most associated vitamin D insufficiency with early clinical failure and lower survival probability. In conclusion, his systematic review highlights the importance of vitamin D levels in the prognosis and survival of patients with lymphoid malignancies. Further research is needed to better understand the underlying mechanisms and explore the potential benefits of vitamin D supplementation in managing these cancers.
Topics: Humans; Adult; Middle Aged; Vitamin D; Rituximab; Vitamin D Deficiency; Cyclophosphamide; Neoplasms
PubMed: 37185444
DOI: 10.3390/curroncol30040331 -
International Journal of Molecular... Sep 2023The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and... (Review)
Review
The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.
Topics: Humans; Immune Checkpoint Inhibitors; Receptors, Chimeric Antigen; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Hematologic Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37834228
DOI: 10.3390/ijms241914780 -
Cureus Sep 2021Osteosarcoma (OS) is the most common primary bone cancer affecting children and young adults, most often occurring at the metaphysis of long bones. At present, treatment... (Review)
Review
Osteosarcoma (OS) is the most common primary bone cancer affecting children and young adults, most often occurring at the metaphysis of long bones. At present, treatment with combinations of surgery and chemotherapy for the localized OS has only brought minuscule improvements in prognosis. In comparison, the advanced, metastatic, or recurrent forms of OS are often non-responsive to chemotherapy, adding to the dire need to develop new and efficient therapies. The question of interest investigated in this systematic review is whether immunotherapy can play a meaningful role in improving the clinical outcomes of children with OS. This article aims to summarize the preclinical and clinical research conducted thus far on potential therapeutic avenues for pediatric OS using immunotherapy, including methods like checkpoint inhibition, adoptive cellular therapy with T-cells, chimeric antigen receptor T (CAR-T), and natural killer (NK) cells. It also highlights the influence of the innate and adaptive immune system on the tumor microenvironment, allowing for OS progression and metastasis. This systematic review contains 27 articles and analyses of multiple clinical trials employing immunotherapeutic drugs to 785 osteosarcoma participants and over 243 pediatric patients. The articles were obtained through PubMed, PubMed Central, and ClinicalTrials.gov and individually assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist and the Cochrane risk-of-bias tool. The reviews reveal that immunotherapy's most significant impact on pediatric OS includes combining immune checkpoint blockers with traditional chemotherapy and surgery. However, due to the bimodal distribution of this aggressive malignancy, these studies cannot precisely estimate the overall effect and any potential life-threatening adverse events following therapy in children. Further research is required to fully assess the impact of these immunotherapies, including more extensive multinational clinical trials to focus on the pediatric population.
PubMed: 34725602
DOI: 10.7759/cureus.18349 -
Journal For Immunotherapy of Cancer Dec 2022The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently... (Review)
Review
The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50-100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.
Topics: Child; Humans; Adolescent; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Hematologic Neoplasms; Treatment Outcome
PubMed: 36549782
DOI: 10.1136/jitc-2022-005678