Meta-Analysis Highlights Differing CAR T Outcomes, Toxicities in Relapsed or Refractory DLBCL

When choosing between chimeric antigen receptor (CAR) T-cell therapies for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), clinicians should consider their distinct efficacy and safety profiles, according to a review published in Transplantation and Cellular Therapy.

Both axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) were initially approved as third-line or subsequent line treatment based on pivotal prospective studies. Both are now considered in earlier treatment lines as well.  

Patient and doctor | Image Credit: © DragonImages - adobe.stock.com

However, with a limited number of randomized trials comparing CAR T therapies, retrospective real-world studies become increasingly important in assessing whether conclusions from pivotal studies are reproducible in routine clinical practice, the authors explained.

“Real-world studies can provide a critical basis for comparative analyses,” they said. “We aimed to systematically assess the best possible basis for evidence generation, using analysis for heterogeneity, detailed assessment of potential risk of bias, and overall quality assessment.”

The researchers focused on published real-world studies that directly compared both products in quantitative fashion, as recommended by current guidelines on conducting systematic reviews and meta-analyses.

To synthesize the studies, researchers searched electronic databases and other sources for relevant published articles, using only fully published articles to minimize reporting bias. They identified 8 studies with a total of 2372 participants.

To meet eligibility requirements, studies must have evaluated safety and effectiveness of the CAR T product, adverse events, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome (ICANS); and reported 1 or more outcomes, such as progression-free survival (PFS), overall survival (OS), relapse/progression, and overall and complete response.

Study characteristics for reporting included number of patients, median age, type of disease, bridging therapy, lactate dehydrogenase levels (LDH), patients’ performance status (using ECOG scale), and turnaround time from apheresis to actual cell infusion.

Regarding outcome measures, PFS was the primary end point. Secondary endpoints included overall survival, response rates at 3 months after CAR T infusion, incidence and severity of CRS and ICANS, hematotoxicity, and resource utilization in terms of toxicities.

Although outcome measures from previous prospective studies have suggested higher efficacy and toxicity associated with the use of axi-cel, study investigators expressed concern that observations from the pivotal trials might have been prone to bias.

Thus, they aimed to synthesize the existing evidence on actual patient outcomes and explore potential differences of axi-cel vs. tisa-cel.

Highlights from their analysis include the following findings:

In terms of efficacy, axi-cel was associated with significantly improved response rates and PFS.

• Based on 7 studies that included data on response within 3 months after CAR-T infusion, axi-cel showed higher odds of complete responses (P < .001), with an OR of 1.65 (95% CI, 1.35-2.02).
• Based on 6 studies that assessed PFS, axi-cel showed higher odds at 1 year (P < .001), with an OR of 0.60 (95% CI, 0.48-0.44). Axi-cel showed significantly improved PFS across age groups.
• Based on the results of 5 studies, axi-cel appeared to be associated with higher odds of improved overall survival (P = .08), with an OR of 0.84 (95% CI, 0.68-1.02).

Conversely, axi-cel was associated with significantly higher toxicity.

• Regarding CRS, assessed in all studies, patients treated with axi-cel showed significantly higher odds of occurrence of any grade (P < 0.001), with an OR of 3.23 (95% CI, 2020-4.74). 
• Regarding neurotoxicity, also assessed in all studies, axi-cel was significantly associated with occurrence of ICANS of any grade (P < .001), with an OR of 4.04 (95% CI, 2.90-5.65). In addition, it was associated with significantly higher odds of occurrence of severe ICANS of grade 3 or higher, showing an OR of 4.03 (95% CI, 2.52-6.46).
• Regarding hematotoxicity, based on results from 5 studies, axi-cel was significantly associated with higher odds of severe neutropenia (grade 3 to 4) at 1 month after infusion (P = .003), showing an OR of 2.06 (95% CI, 1.27-3.33).
• Regarding nonrelapse mortality, based on the results of 4 studies, the investigators found a significant difference (P = .002) in favor of tisa-cel, showing an OR of 2.40 (95% CI, 1.38-4.16). Cumulative incidence of nonrelapse mortality was 11.5% for axi-cel vs 3.7% for tisa-cel.

Meanwhile, tisa-cel showed significantly reduced utilization of resources. The investigators said this may be attributed to the need for less toxicity management, including length of hospitalization stay and intensive care unit admissions.

The authors acknowledged study limitations. Due to the nature of retrospective studies, each study may emphasize different end points in assessing quality. As an example, they point to 1 study in the current analysis that mainly focused on resource utilization, reporting efficacy and safety outcomes as secondary objectives.

Still, investigators believe their study may facilitate clinicians’ choice of CAR T-cell product for a specific patient, balancing safety and efficacy.

Higher toxicity and nonrelapse mortality seen with axi-cel may underscore the need for more careful screening and timely intervention for these patients, the authors concluded.

“Although overall survival might be improved with axi-cel for many patients, our study highlights the necessity to identify certain subgroups that might still benefit from tisa-cel, in terms of both safety and efficacy.”

Reference

Nagelmann N, Bishop M, Ayuk F, Bethge W, et al. Axicabtagene ciloleucel versus tisagenlecleucel for relapsed or refractory large B-cell lymphoma: a systematic review and meta-analysis. Transplant Cell Ther. Published online January 26, 2024. doi:10.1016/j.jtct.2024.01.074