Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.
Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.
Funding Acknowledgements
Type of funding sources: None.
Background
Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis which strongly correlates to cardiovascular morbidity and mortality and increased risk of limb loss, and despite the wide use of guideline-based antiplatelet therapy, patients remain at high risk for cardiovascular and limb events. There has been increasing interest in novel anticoagulants to improve prevention of complications secondary to PAD.
Purpose
This study aims to determine the effectiveness and safety of combined direct oral anticoagulant plus antiplatelet in reducing MACE, MALE and all-cause mortality among patients with PAD.
Method
Randomized controlled trials with outcomes on major adverse cardiac events (MACE), major adverse limb events (MALE), all-cause mortality and bleeding were searched through PubMed, Cochrane and EBSCOHost.
Result
Pooled analysis of studies on patients peripheral arterial disease showed that anticoagulant combined with antiplatelet have significant benefits compared with antiplatelet alone in reducing major adverse limb events (RR 0.72, 95% CI 0.62 to 0.83) and stroke (RR 0.74, 95% CI 0.57 to 0.97) but had inconclusive results in reducing myocardial infarction (RR 0.85, 95% CI 0.70 to 1.03).There was no significant benefit in reducing cardiovascular death (RR 1.04, 95% CI 0.88 to 1.23) and all-cause mortality (RR 1.02, 95% CI 0.90 to 1.16). Likewise, there was increased risk of bleeding (RR 1.46, 95% CI of 1.18 to 1.80) compared with antiplatelet alone.
Conclusion
Anticoagulant (Rivaroxaban) combined with antiplatelet (aspirin) as alternative to traditional antiplatelet (aspirin) therapy significantly reduced major adverse limb events and stroke. However, there was a higher incidence of bleeding for the combined cohort. Therefore, it is deemed necessary to identify high-risk PAD patients with low risk of bleeding who can benefit the most with the combined intervention.
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