Background: In 2018, the first two CAR-T cell therapies were approved by the EMA as third-line therapies: Kymriah® is used for patients with B-cell acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Yescarta® is approved for patients with DLBCL and primary mediastinal B-cell lymphoma (PMBCL). For these patients, therapy is usually associated with high expectations due to previous treatment failures. In this systematic review, the results of the pivotal trials were compared with those of the real-world evidence (RWE). The results include patient characteristics, efficacy and safety data. In addition, the results of international HTA reports regarding the available evidence and their critical evaluation of CAR-T cell therapies were summarised.

Method: The evidence synthesis for B-ALL included 12 studies (n=641). For DLBCL and PMBCL, 17 studies (n=2,105) were identified. Most of the real-world studies were retrospective observational studies.

Results: Patient characteristics differed between the RWE and pivotal studies, as the eligibility criteria were more restrictive in the latter. For B-ALL, overall survival at 12 months ranged from 76% in the pivotal trial to 38.5-100% in the RWE. For DLBCL and PMBCL, survival at 12 months ranged from 48-59% in the pivotal trials and was between 49-73.4% in the RWE studies. The most common adverse events were cytokine release syndrome, neurotoxicity, infections and cytopenias. Adverse events were reported in 100% of patients in the pivotal trials.

Conclusion: The variability of efficacy and safety results was often very high in the RWE, making a comparison with the pivotal trials difficult. In addition, due to the study quality the bias potential of the RWE studies was classified as moderate to high thus reducing reliability. Due to the lack of a control arm, the unblinded, retrospective study design, heterogeneous cohorts and heterogeneous grading systems, the evidence for the efficacy and safety of Kymriah® and Yescarta® in patients with B-ALL, DLBCL and PMBCL is uncertain. Evidence of superiority of CAR-T cell therapies compared to standard therapies remains uncertain.