Real-world data show superior efficacy of Axicabtagene Ciloleucel compared to chemoimmunotherapy in elderly patients with relapsed/refractory Large B-Cell Lymphoma after ≥2 lines of prior therapy

In recent years, results of the ZUMA-1 and ZUMA-7 studies demonstrated that CAR T cell therapy with axicabtagene ciloleucel (axi-cel) is more effective than conventional salvage chemotherapy in the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Data from a real-world, propensity score matching analysis presented at ASH 2022 illustrate the superior efficacy of axi-cel compared to chemoimmunotherapy (CIT) in the treatment of R/R LBCL patients who received ≥2 prior lines of therapy, with a more pronounced benefit for axi-cel in patients aged ≥65 years.¹ In addition to this, results from a small pilot study suggest that axi-cel may also be safe and effective in patients with R/R central nervous system lymphoma (CNSL).²

A larger relative response benefit with axi-cel vs. CIT in elderly R/R DLBCL patients ¹

Previously, real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) showed a more favorable overall response rate (ORR) with axi-cel in patients aged ≥65 years compared to younger patients. In clinical practice, however, a higher age often remains a criterion to forego on this therapeutic modality. To address this issue in more detail, Lunning et al. performed a propensity score matching (PSM) analysis comparing the efficacy of axi-cel vs. CIT in a real-world elderly population.

The presented analysis included a total of 1,146 R/R LBCL patients treated with commercial axi-cel between October 2017 and August 2020. A second cohort used for this analysis consisted of 469 R/R LBCL patients treated with CIT beyond second line in the SCHOLAR-1 trial. Subsequently, a propensity score matching (PSM) analysis was performed to balance the distribution of baseline characteristics between the axi-cel and CIT groups. Overall, patients treated with axi-cel were older (median age: 62.3 vs. 55.4 years for CIT), were more likely to have an ECOG performance score of ≤1 prior to treatment (96% vs. 85%) and received a higher number of prior treatment lines (66% with ≥3 prior lines of therapy vs. 4% for CIT). PS matching adequately corrected for most of these imbalances, except for the proportion of patients who received ≥3 prior treatment lines.

After a median follow-up of 24 and 60 months in the axi-cel and CIT group, respectively, the ORR was reported at 76% for axi-cel vs. 28% with CIT, with corresponding CR rates of 58% and 16%, respectively. At 12 months, the OS rate was 62% with axi-cel as compared to 28% for patients treated with CIT. Interestingly, a more pronounced ORR and CR benefit with axi-cel vs. CIT was observed in patients ≥65 years (ORR: 82% vs. 25%; CR: 68% vs. 13%) compared to patients below the age of 65 (ORR: 75% vs. 29%; CR: 56% vs. 17%).

In the PSM analysis, axi-cel proved to be associated with a significantly better ORR and CR than CIT, with corresponding odds ratios of 7.73 (95%CI: 5.21-11.45) and 6.07 (95%CI: 4.15-8.86), respectively. In patients below the age of 65, these odds ratios were fairly similar at 7.14 (95%CI: 4.62-11.02) and 5.16 (95%CI: CI 3.45-7.71) for ORR and CR, respectively. Interestingly, the magnitude of benefit obtained with axi-cel vs. CIT was markedly higher in patients aged ≥65 years. In fact, these elderly patients were 15 times more likely to obtain a CR with axi-cel than with CIT (odds ratio [95%CI] for CR: 15.38 [4.69-50.51]; odds ratio for ORR: 18.11 [5.28-62.04]). The adjusted OS rate at 12 months in the PSM analysis was reported at 65% with axi-cel as compared to 23% for patients treated with CIT. Compared to CIT, axi-cel was associated with a significantly longer OS (HR[95%CI]: 0.30[0.24-0.37]) and this benefit was comparable in patients ≥65 years (HR[95%CI]: 0.32[0.22-0.48]) and <65 years of age (HR[95%CI]: 0.29[0.22-0.38]).

No increased risk for neurological toxicity with axi-cel in patients with relapsed/refractory central nervous system lymphoma ²

As discussed above, axi-cel has become standard of care in the treatment of patients with R/R LBCL. However, given the risk for neurological toxicity that has been described with CAR-T cell therapy, lymphoma patients with CNS involvement, or patients with primary CNS lymphoma were excluded from clinical trials and CNS involvement is currently an absolute exclusion criterion for axi-cel in the current label. Nevertheless, axi-cel can cross the blood-brain barrier and anecdotal reports show that axi-cel can safely be administered to patients with secondary CNS lymphoma. To assess this in more detail, a pilot study was conducted evaluating axi-cel in patients with R/R CNSL. During ASH 2022, results were presented for 9 patients with CNS disease only (i.e., no systemic disease). No treatment limiting toxicities were observed with axi-cel in this cohort. There was one serious adverse event (staphylococcus meningitis related to Ommaya infection requiring transplant) and two deaths due to progressive disease occurred during the study. In total, 8 of the 9 patients experienced cytokine release syndrome (CRS), but this did not reach grade ≥3 in any of the cases. ICANS was reported in 4 patients, mounting to grade 3 in 3 of them (33%, no grade 4). The median duration of neurological toxicity was 5.5 days.

In terms of efficacy, a best ORR of 78% was reported, with a CR rate of 67% CR. The median time to response was 3 months, while the median duration of response at this early timepoint was 11.3 month. As responses can still deepen in some of the patients with short follow-up, this median response duration may increase with longer follow-up. The median progression-free survival was 11.5 months, with a median OS of 19.0 months. Finally, axi-cel pharmacokinetics in these CNSL patients were comparable to what was observed in ZUMA-1, despite the fact that the patients included in this analysis did not have systemic disease.

Conclusions

ZUMA-1 and ZUMA-7 have established axi-cel as a standard of care for patients with R/R LBCL. Results of a study estimating the real-world effectiveness of axi-cel compared to CIT in patients with R/R LBCL who received ≥2 prior lines of therapy demonstrate a significant benefit for axi-cel over CIT, irrespective of age. Moreover, patients ≥65 years even seemed to derive a more pronounced clinical benefit from axi-cel compared to younger patients. As such, these findings further support the broader use of axi-cel in elderly patients. In addition to this, results of a small pilot study suggest that axi-cel may also be safe and effective in patients with primary or secondary CNSL.

References

1. M. Lunning, et al. Outcomes of Axicabtagene Ciloleucel in Comparison with Chemoimmunotherapy (CIT) in an Elderly Population for Treatment of Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) after Two or More Lines of Prior Therapy. Presented at ASH 2022; Abstract 765.
2. Jacobson C, et al. A Pilot Study of Axicabtagene Ciloleucel (axi-cel) for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphoma (CNSL). Presented at ASH 2022; Abstract 440.