-
Clinical Lymphoma, Myeloma & Leukemia Jun 2024The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate.
METHODS
In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL.
RESULTS
After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel.
CONCLUSIONS
Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.
Topics: Humans; Immunotherapy, Adoptive; Lymphoma, Non-Hodgkin; Receptors, Chimeric Antigen
PubMed: 38582666
DOI: 10.1016/j.clml.2024.02.007 -
Expert Review of Anticancer Therapy Jun 2024Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted.
METHODS
Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling.
RESULTS
Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel.
CONCLUSIONS
We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.
Topics: Humans; Bayes Theorem; Biological Products; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Network Meta-Analysis; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Salvage Therapy
PubMed: 38646700
DOI: 10.1080/14737140.2024.2343801 -
Cytotherapy Sep 2023The advanced therapy product tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that has brought hope for children and young adults...
A systematic review on the cost-effectiveness assessment of tisagenlecleucel for refractory or relapsing B-cell acute lymphoblastic leukemia (R/R B-ALL) treatment in children and young adults.
BACKGROUND AIMS
The advanced therapy product tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that has brought hope for children and young adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We sought to evaluate the cost-effectiveness of tisagenlecleucel compared with conventional salvage therapies in pediatric and young adult patients with R/R B-ALL.
METHODS
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses parameters as registered in International Prospective Register of Systematic Reviews (CRD42021266998). Literature was searched using the MEDLINE databases via PubMed, EMBASE, Lilacs, the Cochrane Central Register of Controlled Trials and Web of Science in January 2022. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts were reviewed.
RESULTS
In total, 5627 publications were identified, from which six eligible studies were selected. The conventional therapies identified were blinatumomab (Blina), clofarabine monotherapy (Clo-M), clofarabine combined with cyclophosphamide and etoposide (Clo-C) and the combination of fludarabine, cytarabine and idarubicin (FLA-IDA). The discounted incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained for tisagenlecleucel compared with Clo-C and Blina averages was $38 837 and $25 569, respectively. In relation to the cost of the drug, the average of tisagenlecleucel was approximately 4.3 times, 10.8 times or 4.7 times greater than the Clo-M, Clo-C and Blina, respectively.
CONCLUSIONS
This systematic review highlighted that tisagenlecleucel is a much more expensive therapy than conventional alternatives. However, tisagenlecleucel performed well on the ICER, not exceeding $100 000/QALY. It was also found that the advanced therapy product was more effective than the conventional small molecule and biological drugs, in terms of life years and QALY gained.
Topics: Humans; Young Adult; Child; Clofarabine; Cost-Benefit Analysis; Receptors, Antigen, T-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 37341664
DOI: 10.1016/j.jcyt.2023.05.011 -
Critical Reviews in Oncology/hematology Jan 2024The development of immune checkpoint inhibitors(ICIs) has revolutionized the progress of solid tumors. Ongoing clinical trials are exploring the use of checkpoint... (Meta-Analysis)
Meta-Analysis Review
The development of immune checkpoint inhibitors(ICIs) has revolutionized the progress of solid tumors. Ongoing clinical trials are exploring the use of checkpoint inhibitors in recurrent small-cell lung cancer and achieving specific results. Although studies have been conducted to systematically review this issue, we conducted this single-arm meta-analysis in light of the emergence of several new clinical studies. In total, 854 individuals from 11 clinical investigations were enrolled in this single-arm meta-analysis. Median progression-free survival, median overall survival, and objective response rate were 1.65 months, 6.83 months, and 20.5%, respectively, according to pooled analyses. The best treatment regimen in the subgroup analysis was a dual checkpoint inhibitor combined with other treatments, and the drug that worked well for treatment was pembrolizumab. The benefit of programmed death 1/programmed cell death-ligand 1(PD-1/PD-L1) inhibitors alone is limited, and their combination with other therapies is a promising treatment option. Among PD-1/PD-L1 inhibitors, pembrolizumab is the recommended drug.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Small Cell Lung Carcinoma; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Risk Assessment; B7-H1 Antigen
PubMed: 38036155
DOI: 10.1016/j.critrevonc.2023.104222 -
Knee Surgery, Sports Traumatology,... Oct 2023This study aimed to review studies comparing transtendon repair (TTR) with tear completion repair (TCR) techniques for partial articular-sided supraspinatus tendon... (Meta-Analysis)
Meta-Analysis Review
Similar outcomes between transtendon repair and tear completion repair techniques for partial articular-sided supraspinatus tendon avulsion lesions: a systematic review and meta-analysis.
PURPOSE
This study aimed to review studies comparing transtendon repair (TTR) with tear completion repair (TCR) techniques for partial articular-sided supraspinatus tendon avulsion (PASTA) lesions according to postoperative patient-reported outcomes and complications.
METHODS
Databases, including PubMed, Embase, Scopus, and Cochrane, were searched for studies published between 2008 and 2022 that directly compared the postoperative patient-reported outcomes and complications of the TTR and TCR techniques for PASTA lesions. Odds ratios (ORs) were calculated for dichotomous outcomes, while mean differences (MDs) were calculated for continuous outcomes.
RESULTS
A total of seven studies (497 shoulders) were analysed. No statistically significant differences in the postoperative clinical outcomes at the final follow-up were observed between the TTR and TCR techniques for PASTA lesions. The overall retear rates of the TTR and TCR techniques were 7.7% and 11.6%, respectively (corresponding healing rates were 92.3% and 88.4%), whereas the overall occurrence rates of adhesive capsulitis were 4.7% and 3.3%, respectively. Furthermore, no significant difference was observed in postoperative range of motion (forward flexion, MD = - 1.22, 95% confidence interval (95%CI) - 5.28 to 3.34, n.s.; external rotation, MD = - 1.39, 95% CI - 3.19 to 0.42, n.s.), overall retear rate (OR 0.72, 95% CI 0.29-1.08, n.s.), and occurrence rate of adhesive capsulitis (OR 1.11, 95% CI 0.35-3.52, n.s.) between the two techniques.
CONCLUSION
Both techniques improve clinical outcomes while having a low complication rate and a high rate of healing. No significant difference in clinical outcomes was observed between the two techniques.
LEVEL OF EVIDENCE
III.
Topics: Humans; Rotator Cuff; Rotator Cuff Injuries; Treatment Outcome; Rupture; Range of Motion, Articular; Bursitis; Receptors, Antigen, T-Cell; Arthroscopy
PubMed: 37452830
DOI: 10.1007/s00167-023-07502-z -
The Journal of Surgical Research Jun 2024Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging... (Review)
Review
INTRODUCTION
Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging functional outcomes of VCA, the consequences of long-term immunosuppression remain the main obstacle in its application. In this review, we provide researchers and surgeons with a summary of the latest advances in the field of cell-based therapies for VCA tolerance.
METHODS
Four electronic databases were searched: PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature , and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as the basis of our organization.
RESULTS
Hematopoietic stem cells prolonged VCA survival. A combination of immature dendritic cells and tacrolimus was superior to tacrolimus alone. T cell Ig domain and mucin domain modified mature dendritic cells increased VCA tolerance. Bone marrow-derived mesenchymal stem cells prolonged survival of VCAs. A combination of adipose-derived mesenchymal stem cells, cytotoxic T-lymphocyte antigen 4 immunoglobulin, and antilymphocyte serum significantly improved VCA tolerance. Ex-vivo allotransplant perfusion with recipient's bone marrow-derived mesenchymal stem cells increased VCA survival. Recipient's adipose-derived mesenchymal stem cells and systemic immunosuppression prolonged VCA survival more than any of those agents alone. Additionally, a combination of peripheral blood mononuclear cells shortly incubated in mitomycin and cyclosporine significantly improved VCA survival. Finally, a combination of donor recipient chimeric cells, anti-αβ-T cell receptor (TCR), and cyclosporine significantly prolonged VCA tolerance.
CONCLUSIONS
Evidence from animal studies shows that cell-based therapies can prolong survival of VCAs. However, there remain many obstacles for these therapies, and they require rigorous clinical research given the rarity of the subjects and the complexity of the therapies. The major limitations of cell-based therapies include the need for conditioning with immunosuppressive drugs and radiation, causing significant toxicity. Safety concerns also persist as most research is on animal models. While completely replacing traditional immunosuppression with cell-based methods is unlikely soon, these therapies could reduce the need for high doses of immunosuppressants and improve VCA tolerance.
PubMed: 38851085
DOI: 10.1016/j.jss.2024.04.079 -
Breast Cancer : Basic and Clinical... 2024Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2... (Review)
Review
Association Between Ki-67 Proliferative Index and Oncotype-Dx Recurrence Score in Hormone Receptor-Positive, HER2-Negative Early Breast Cancers. A Systematic Review of the Literature.
BACKGROUND
Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, node-negative, or 1 to 3 lymph node-positive early breast cancers (EBCs). The cost of the test, which is not available in low-middle income countries (LMICs), is not within the means of most individuals. The Ki-67 index is a marker of tumor proliferation that is cost-effective and easily performed and has been substituted in many cases to obtain prognostic information.
OBJECTIVE
We aimed to identify the correlation between the ODx recurrence score (RS) and the Ki-67 index in HR-positive EBCs and to determine whether Ki-67, like the ODx, can help facilitate clinical decision-making.
DESIGN
Systematic review correlating Ki-67 index and ODx in HR-positive and HER2-negative EBCs as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
DATA SOURCES AND METHODS
We searched different databases between January 2010 and May 2023 and included retrospective/prospective cohorts, clinical trials, case-control, and cross-sectional studies involving HR-positive and HER2-negative EBCs correlating the Ki-67 index and ODx RS categories.
RESULTS
Of the 18 studies included, 16 indicated a positive or weakly positive correlation between ODx and the Ki-67 index. The combined value of the included studies is <0.05 ( = .000), which shows a statistical significance between the 2. Our review also discusses the potential of machine learning and artificial intelligence (AI) in Ki-67 assessment, offering a cost-effective and reproducible alternative.
CONCLUSION
Even although there are limitations, studies indicate a favorable association between ODx and the Ki-67 index in specific situations. This implies that Ki-67 can offer important predictive details, especially regarding the likelihood of relapse in HR-positive EBC. This is particularly significant in LMICs where financial constraints often hinder the availability of costly diagnostic tests.
PubMed: 38779417
DOI: 10.1177/11782234241255211 -
Frontiers in Immunology 2024Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC). However, patients show highly heterogeneous responses to treatment, and predictive biomarkers are lacking. We performed a systematic review and meta-analysis to assess the potential of PD-L1 expression as a biomarker for treatment response and survival in patients with BTC undergoing anti-PD-1/PD-L1 therapy.
METHODS
We conducted a comprehensive systematic literature search through June 2023, utilizing the PubMed, EMBASE, and Cochrane Library databases. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) according to PD-L1 expression. Subgroup analyses and meta-regression were performed to identify possible sources of heterogeneity.
RESULTS
A total of 30 studies was included in the final analysis. Pooled analysis showed no significant differences in ORR (odds ratio [OR], 1.56; 95% confidence intervals [CIs], 0.94-2.56) and DCR (OR, 1.84; 95% CIs, 0.88-3.82) between PD-L1 (+) and PD-L1 (-) patients. In contrast, survival analysis showed improved PFS (hazard ratio [HR], 0.54, 95% CIs, 0.41-0.71) and OS (HR, 0.58; 95% CI, 0.47-0.72) among PD-L1 (+) patients compared to PD-L1 (-) patients. Sensitivity analysis excluding retrospective studies showed no significant differences with the primary results. Furthermore, meta-regression demonstrated that drug target (PD-1 PD-L1), presence of additional intervention (monotherapy combination therapy), and PD-L1 cut-off level (1% ≥5%) significantly affected the predictive value of PD-L1 expression.
CONCLUSION
PD-L1 expression might be a helpful biomarker for predicting PFS and OS in patients with BTC undergoing anti-PD-1/PD-L1 therapy. The predictive value of PD-L1 expression can be significantly influenced by diagnostic or treatment variables.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023434114.
Topics: Humans; B7-H1 Antigen; Biliary Tract Neoplasms; Ligands; Programmed Cell Death 1 Receptor
PubMed: 38605964
DOI: 10.3389/fimmu.2024.1321813 -
Critical Reviews in Oncology/hematology Apr 2024Recent evidence suggests that PD-1/PD-L1 immunotherapy improves outcomes in patients with brain metastatic non-small cell lung cancer. (Review)
Review
BACKGROUND
Recent evidence suggests that PD-1/PD-L1 immunotherapy improves outcomes in patients with brain metastatic non-small cell lung cancer.
METHODS
Records were searched electronically on MEDLINE, Embase and BIOSIS. Hazard ratios and their 95% confidence intervals for overall survival and progression free survival, and treatment-related adverse events data were extracted. Risk of bias was assessed in included studies using the Cochrane Collaboration's revised tool to assess risk of bias in randomized trials.
RESULTS
PD-1/PD-L1 immunotherapy increased overall survival by 33% and progression free survival by 47% compared with chemotherapy. Two studies had a high risk of bias. Treatment-related adverse events were reported in 95%, 89% and 65% of patients receiving chemoimmunotherapy,chemotherapy and single agent immunotherapy, respectively.
CONCLUSION
PD-1/PD-L1 inhibitors alone or in addition to chemotherapy increase overall and progression free survival when compared with chemotherapy alone. Chemoimmunotherapy and chemotherapy patients experienced the most treatment-related adverse events.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Immunotherapy; Brain
PubMed: 38331301
DOI: 10.1016/j.critrevonc.2024.104288 -
Transplantation and Cellular Therapy Jun 2024Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory... (Meta-Analysis)
Meta-Analysis Comparative Study
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Significant costs and complex manufacturing underscore the importance of evidence-based counseling regarding the outcomes of these treatments. With the aim of examining the efficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for response, progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta-analysis and meta-regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P < .001) and was associated with higher odds for PFS at 1 year after infusion (OR, .60; P < .001). OS appeared to be improved with axi-cel (OR, .84; 95% CI, .68 to 1.02; P = .08), whereas the cumulative incidence of nonrelapse mortality (NRM) was 11.5% for axi-cel versus 3.7% for tisa-cel (P = .002). The main predictors for survival were lactate dehydrogenase level, Eastern Cooperative Oncology Group Performance Status, and response to bridging, and axi-cel maintained superior efficacy even in elderly patients. In terms of safety, axi-cel was associated with significantly higher odds of any-grade CRS (OR, 3.23; P < .001), but not of grade ≥3 CRS (P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade ≥3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Biological Products; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Antigen, T-Cell; Cytokine Release Syndrome; Treatment Outcome
PubMed: 38281590
DOI: 10.1016/j.jtct.2024.01.074