How have the FDA approvals of axi-cel and liso-cel affected the LBCL treatment paradigm?

Five years ago, irrespective of relapse status or primary refractoriness, the standard of care would have been salvage platinum-containing chemotherapy followed by high-dose therapy and hematopoietic progenitor cell transplant. Nowadays, [based on] head-to-head [data], we have a superior therapy to offer these patients. Axi-cel has been demonstrated to have a benefit in both event-free and overall survival [OS]. Liso-cel confers an early benefit in event-free survival, with OS data still yet to mature as more follow-up is accrued.

Now, the treatment algorithm and what product and approach might be the most beneficial for each patient in any setting [is based on] refractory status, the timing of relapse, and whether a patient is eligible for autologous stem cell transplant, CAR T-cell therapy, or potentially both. Although [CAR T-cell therapy is] a new treatment modality, it has complicated the treatment paradigm and makes decision-making much more difficult, nuanced, and profound when taking into account patients’ overall health, as well as their wishes and desires about how they want to be treated.

What were the findings from the real-world CIBMTR study of axi-cel in patients with relapsed/refractory LBCL?

Studies show that [axi-cel and liso-cel] are effective in trial settings, but real-world data are starting to emerge that support the use of this strategy in practice. The first of the [CAR T-cell therapy] studies to emerge in the real world was from investigators leading a CIBMTR analysis through Stanford University.1 In this CIBMTR analysis, adult patients similar to [those in] the phase 3 ZUMA-7 trial [NCT03391466] population with relapsed/refractory LBCL who received commercial axi-cel in the second-line setting between April 2022, and July 2023, in the United States were included.

[Approximately] 446 patients at [approximately] 90 centers received axi-cel. The median age was [about] 64 years, most patients were male, and most patients had diffuse LBCL [DLBCL] not otherwise specified [NOS]. [Approximately] three-quarters of these patients were refractory to frontline therapy, and most patients required some form of holding or bridging therapy. Interestingly [investigators evaluated] whether these CIBMTR-included patients would have been eligible for the registrational trial, and [about] 52% of these patients would have been deemed ineligible for ZUMA-7 with [around] one-third of patients being ineligible due to some form of organ impairment. This suggests that that this strategy of axi-cel in the second-line setting can be feasible, and the results [can be] extrapolated to people who might not have been enrolled on the [pivotal] study due to performance status or organ dysfunction.

In the real world, at a short median follow-up of 12 months, the overall response rate [with axi-cel] was similar to [that seen in] the trial, at [approximately] 79%, with a complete response rate of [around] 64%. At [about] 12 months, the median duration of response was [approximately] 66%. The progression-free and event-free survival rates were both [near] 53%, and the OS rate was [about] 71% at 1 year. These outcomes were not different among patients who would have been eligible or not eligible for ZUMA-7, according to a subgroup analysis that these investigators performed.

Any-grade cytokine release syndrome [CRS] and neurotoxicity were reported in [about] 87% and 50% of patients, respectively, in this study. Almost all patients received treatment for these complications, including tocilizumab [Actemra], steroids, and anakinra [Kineret], similar to what was observed in the [clinical trials]. The median duration of CRS and neurotoxicity were [approximately] 5 and 6 days, respectively. Interestingly, prolonged cytopenia at 30 days or more post-CAR T-cell therapy was reported in [approximately] 16% of patients, highlighting an emerging and increasingly well-recognized toxicity [associated with] these therapies. Fortunately, even in a group of patients where many would have been excluded from registrational studies and had comorbidities, the cumulative incidence of non-relapse mortality [NRM] at 6 months in this study was low, at only [around] 4%.

What real-world data have been shown with liso-cel in relapsed/refractory LBCL?

A real-world analysis of the use of liso-cel in the second-line setting in high-risk patients has also been carried out another CIBMTR-based effort led by investigators at the University of Utah.2 [This study] described the real-world outcomes of liso-cel use in this population and included patients treated in the second-line between June 2022 and [August] 2024. The median age was a little older compared with the axi-cel patients, at 72 years [range, 27-85], with [approximately] half of the patients in this CIBMTR study being over the age of 70 years. [A total of 8% of] patients had DLBCL NOS, [50%] of patients were primary refractory, and 67% of patients would have been ineligible for the phase 3 TRANSFORM study [NCT03575351] at a short follow-up of [approximately’ 6 months; this was necessarily short because of the shorter time [from the] approval [of liso-cel to the time of the real-world analysis].

The overall and complete response rates were 84% [95% CI, 77%-89%] and 70% [95% CI, 62%-77%] respectively. Median survival outcomes had not yet been reached. CRS and neurotoxicity were common, though lower compared with real-world data on the use of axi-cel. CRS occurred at any grade at a rate of 45%, and immune effector cell–associated neurotoxicity syndrome [(ICANS) occurred at a rate] of 20%. In this real-world population, there were no grade 4 or 5 ICANS events, and there was only 1 death attributable to CRS. Similarly, long-term cytopenias [arising] at least 30 days after the receipt of liso-cel occurred in [11%] of patients, and [33%] of patients had clinically significant infections, though the 6-month cumulative incidence of NRM was only [1.3% (95% CI, 0.3%-4.3%)].

References

  1. Lee D, Kambhampati S, Bobillo MSO, et al. Real-world early outcomes of second-line axicabtagene ciloleucel (axi-cel) therapy in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Blood. 2024;144(suppl 1):526. doi:10.1182/blood-2024-199139
  2. Bobillo MSO, Thiruvengadam SK, et al. Lee D, et al. Real-world (rw) outcomes of lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (lbcl): first results from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry. Blood. 2024;144(suppl 1):470. doi:10.1182/blood-2024.199723