Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies

Abstract

Background: Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia.

Objectives: This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies.

Design: A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Data sources and methods: Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022.

Results: We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs (N = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); I ² = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI (N = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low.

Conclusion: So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies.

Registration: https://doi.org/10.12688/openreseurope.14390.1.

Prospero/osf preregistration: 10.17605/OSF.IO/V6HDX.

Keywords: CAR-T therapy; chemotherapy cytokine-release syndrome; donor leukocyte infusion; graft-versus-host disease; hematologic stem cell transplantation; leukemia; lymphoma; myeloma; systematic review.

Figure 1.

PRISMA flowchart. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Figure 2.

Overall survival comparing CAR-T with SoC therapy in RCTs including patients with R/R B-cell lymphoma. CAR-T, chimeric antigen receptor T-cell; RCT, randomized controlled trial; R/R, recurrent/relapsed; SoC, standard of care.

Figure 3.

Complete response/remission rate comparing CAR-T with DLI therapy in patients with R/R B-ALL. CAR-T, chimeric antigen receptor T-cell; DLI, donor lymphocyte infusion; R/R B-ALL, relapsed/refractory B-cell acute lymphoblastic leukemia.

Figure 4.

Serious adverse events in RCTs comparing CAR-T with SoC therapy in patients with R/R B-cell lymphoma. CAR-T, chimeric antigen receptor T-cell; RCT, randomized controlled trial; R/R B-ALL, relapsed/refractory B-cell acute lymphoblastic leukemia; SoC, standard of care.

Figure 5.

Partial response in RCTs comparing CAR-T versus SoC therapy in people with R/R B-cell lymphoma. CAR-T, chimeric antigen receptor T-cell; RCT, randomized controlled trial; R/R B-ALL, relapsed/refractory B-cell acute lymphoblastic leukemia; SoC, standard of care.