Real-world experience with axicabtagene ciloleucel and tisagenlecleucel in DLBCL

The treatment landscape of lymphoid malignancies has evolved with the approval of chimeric antigen receptor (CAR) T-cell therapies. Clinical trials of CAR T-cell therapies in patients with relapsed/refractory (R/R) disease demonstrated promising response rates, however, durable responses in the long-term were limited. The design of clinical trials has very strict patient eligibility and exclusion criteria and investigates therapies in a limited study period, which may not be reflective of real-world settings. Therefore, real-world experience with CAR T-cell therapies, in a more generalized patient population, is valuable to elucidate the efficacy and safety and to obtain long-term outcomes.

David Sermer et al. compared outcomes in patients with R/R diffuse large B-cell lymphoma (DLBCL) who were treated with CAR T-cell or alternative therapies (non-CAR T-cell), in a single-center, retrospective study.¹ Here, we are pleased to summarize the findings, which were recently published in Blood Advances.

Outcomes with CAR T-cell in DLBCL in real-world settings

Study design¹

• A single center retrospective study in adult patients with R/R DLBCL.
• De novo DLBCL (including T-cell/histiocyte-rich large B-cell lymphoma [THRLBCL]), transformed indolent lymphoma, primary mediastinal B-cell lymphoma, and high-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6 histology were allowed in both cohorts.
• Patients who received bridging therapy were included, however, this was not considered a separate line of therapy.
• The criteria for the CAR T-cell cohort were as follows:
  • On-label treatment with either tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel)
  • Two or more prior lines of systemic therapy.
• The criteria for the alternative treatment cohort included:

• • Two prior lines of aggressive systemic therapy for lymphoma
  • Sufficient follow-up data covering the first response assessment to third-line therapy
  • Patients with central nervous system disease at time of third-line therapy were included if there was concurrent systemic disease.

The primary objective was to compare treatment outcomes between the CAR T-cell cohort and the alternative cohort in terms of response rate (complete response [CR] and objective response rate [ORR]), progression-free survival (PFS), and overall survival (OS). Subgroup analyses included:

• PFS in patients who achieved either CR or partial response (PR).
• Outcomes in patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal and bulky disease.
• Outcomes by number of prior lines of therapy.

Results

Patients

A total of 215 patients were included (CAR T-cell cohort, n = 69; alternative cohort, n = 146). The proportion of patients > 60 years of age was 62% in both cohorts (p > 0.9). The majority of patients had a good performance status (Eastern Cooperative Oncology Group [ECOG] 0–1, 87% in the CAR T-cell cohort and 92% in the alternative cohort). In both cohorts, 84% of patients had advanced disease (p > 0.9). In the alternative cohort, seven patients had primary mediastinal B-cell lymphoma and four patients had THRLBCL. In the CAR T-cell cohort, one patient had THRLBCL. Transformed low-grade lymphoma was more common in the CAR T-cell cohort compared with the alternative cohort (p = 0.005). The median number of prior therapy lines was 3 (range, 2–7) in the CAR T-cell cohort. Seven patients treated with alternative therapy had known prior or active central nervous system disease, compared with one in the CAR T-cell group. Patient and disease characteristics are summarized in Table 1.

Table 1. Baseline characteristics¹

The most common third-line therapies in the alternative group included:

• Platinum-based regimens: 29%
• Investigational agents: 26%
• Etoposide-based regimens: 8.9%
• Anthracycline-based regimens: 8.9%
• Consolidation with autologous hematopoietic cell transplantation and allogeneic hematopoietic cell transplantation: 8.2%, and 6.8%, respectively.

In the CAR T-cell cohort, 47 patients received axi-cel, and 22 received tisa-cel.

Outcomes

The median follow-up was 14.6 months (range, 1.2–18.9) in the CAR T-cell cohort and 30.6 months (range, 2.1–162) in the alternative cohort. Treatment outcomes are presented in Table 2.

Table 2. Outcomes¹

For patients who achieved CR in the CAR T-cell cohort (n=36) and the alternative cohort (n=32), PFS was as follows:

• 12-month PFS: 70% and 81%, respectively
• Median PFS: not reached and 65 months, respectively.

For patients who achieved PR in the CAR T-cell and alternative cohorts, the following PFS was observed:

• 12-month PFS: 18% and 50%, respectively
• Median PFS: 2.2 months and 9.9 months, respectively.

The subgroup analyses evaluating outcomes by number of prior lines of therapy are shown in Table 3.

Table 3. Outcomes by treatment cohort and number of prior lines of therapy¹

In univariate analysis, the adverse factors identified that were associated with inferior PFS and OS included Eastern Cooperative Oncology Group (ECOG) score > 1 before treatment, elevated LDH, tumor bulk, more than one extranodal site, and refractory disease (all p < 0.05). In the multivariate analysis, receiving non-CAR T-cell therapy was also associated with inferior survival outcomes, however, treatment type was not significant for PFS or OS. Only pre-treatment LDH and tumor bulk remained significant for both PFS and OS, whereas ECOG remained significant for PFS, and EN sites were significant for OS (Table 4).

In univariate analysis, the likelihood of response to treatment was lower with elevated LDH before treatment, two or more extranodal sites, refractory disease, and alternative treatment. In a multivariate model only elevated pre-treatment LDH and alternative treatment were significant for ORR (Table 4).

Table 4. Prognostic factors associated with inferior PFS, OS, and ORR on multivariable analysis

Conclusion

This study reported similar response rates, PFS, and OS to those reported in the pivotal CAR T-cell trials, and these were significantly better in the CAR T-cell cohort compared with the alternative, non-CAR T-cell cohort. When analyzing each cohort by number of prior treatment lines, the benefit of CAR T-cell therapy persisted, irrespective of the number of lines of prior therapy. However, adjusting for unfavorable pre-treatment characteristics, the benefit of CAR T-cell became less clear; ORR remained significantly better with CAR T-cell, but overall PFS and OS did not. In addition, the analysis that evaluated outcomes in responding patients showed that the rate of relapse or progression was higher in patients who received CAR T-cell compared with alternative therapies.

The authors conclude that axi-cel and tisa-cel play an important role in treating this patient population, however, alternative treatment options may be as effective in specific cases. Randomized prospective trials are warranted to investigate this further.