Use of Axi-Cel in Previously Excluded LBCL Populations Supported by Real-World Evidence

Adverse events (AEs) were more common in some populations of elderly patients (≥65 years) and those with other comorbidities with large B-cell lymphoma (LBCL); and ECOG performance status (PS) ≥2 was associated with worse outcomes and more adverse events, despite axicabtagene ciloleucel's (axi-cel; Yescarta) favorable efficacy profile in this population, according to a large real-world study presented at the 2021 ASH Annual Meeting.

“I think these data tell us that if a patient is deemed fit enough to receive CAR T-cell therapy, that age itself should not be used as a criterion to make that decision,” lead investigator Frederick L. Locke, MD, vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center, said during a presentation of the results. “I urge community oncologists and others to refer patients who fit the respective labels for CAR T-cell therapy to centers that do CAR T-cell therapy, and those centers can make a decision on who is fit or who is not.”

The real-world study included data from 1343 patients with relapsed/refractory LBCL who received treatment at 79 centers between October 2017 and August 2020. Approximately half of these patients (51%) had a characteristic that would have made them ineligible for the pivotal ZUMA-1 study, including an ECOG PS of 2 or higher, comorbidities and organ dysfunction, or central nervous system (CNS) lymphoma or metastasis.

The objective response rate (ORR) across all patients analyzed was 73.6%, and the complete response (CR) rate was 56.1%. The median duration of response (DOR) at a median follow-up of 25.1 months was not yet reached, with the low end of the confidence interval at 24.7 months. Response remained consistently positive across variables, except for ECOG performance status of 2 or lower, which significantly impacted outcomes for ORR, DOR, overall survival (OS), and progression-free survival (PFS).

On multivariate analysis, any grade and grade ≥3 cytokine release syndrome (CRS) was statistically more common in those aged ≥65 years and in those with hepatic disease. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade and of grade 3 or higher was more commonly observed in elderly patients and those with an ECOG performance status of 2 or higher.

“The findings from this analysis of axicabtagene ciloleucel postapproval safety study align with efficacy and safety end points from the ZUMA-1 trial,” said Locke. “Advanced age, defined here as 65 years or older, did not negatively impact efficacy outcomes; however, older patients had higher rates of CRS and ICANS. Patients with poor performance status had worse efficacy and safety outcomes consistent with prior real-world reports of axi-cel in large B cell lymphoma. Performance status should be considered in patient selection and treatment decisions with axicabtagene ciloleucel.”

The median age of patients in the study was 62 years, with 38% aged 65 or older. The majority had an ECOG performance status of 0 or 1 (96%) with 4% having an ECOG performance status of at least 2 at the time of infusion of axi-cel. There were 19 patients enrolled with central nervous system lymphoma or metastasis (1%). Prior to receiving axi-cel, patients had received 1 or 2 (28%), 3 (31%), 4 (18%), or ≥5 (19%) prior lines of treatment. Twenty-seven percent of patients had received prior autologous transplant and 66% were chemo-refractory.

Histologies of interest included transformed lymphoma (28%) and double or triple-hit by fluorescence in situ hybridization (15%). Comorbidities at baseline included pulmonary disease (27%), prior cancer (16%), cardiac disease (13%), obesity (9%), renal disease (2%), or hepatic disease (2%). Lactate dehydrogenase was elevated for 28% of patients and 25% had more than 1 site of extranodal involvement. There were 58% of patients with Ann Arbor stage III or IV disease at diagnosis. Most were within 12 months of their diagnosis (58%).

At 1 year, approximately 64% of patients continued to respond to axi-cel. At 2 years, this number was 57%. With a median follow up of 13 months, the median PFS was 8.8 months (95% CI, 6.5-12.1) and the median OS was 22.4 months (95% CI, 17.5-28.8).

The odds ratio (OR) for ORR in those 65 years or older was 1.38, suggesting a trend toward better response in this group compared with younger individuals (P = .0229). Hazard ratios for OS (HR, 1.05; P = .5830) and PFS (HR, 0.87; P = .0862) were not significantly different between groups by age. For those with ECOG performance status of 2 or higher there was a significant reduction in the probability of response compared with lower ECOG scores (OR, 0.31; 95% CI, 0.18-0.53; P <.0001). The same was true for PFS (HR, 2.59; P<.0001) and OS (HR, 3.26; P <.0001).

Hepatic disease was also associated with worse OS (HR, 2.65; P <.0001), PFS (HR, 2.34; P = .0003), and DOR. Additionally, renal and cardiac disease were both associated with lower OS (HR, 2.13 and HR, 1.44, respectively). Male sex, chemoresistance, 3 or more lines of prior therapies, less than a 12-month disease duration, elevated LDH, more than 1 extranodal involvements, stage III/IV disease, and non-White race were also associated with worse outcomes, although the full data for these parameters were not shown in the presentation.

“Patients with coexistent organ dysfunction had generally favorable outcomes with axi-cel, although the presence of moderate to severe hepatic, renal, and cardiac diseases were associated with lower overall survival,” Locke said.

CRS of any grade was reported in 83% of patients, with grade 3 or higher CRS observed in 8% of individuals. The median time to onset was 4 days (range, 1-28) and the median duration was 6 days (range, 1-121). ICANS occurred in 55% of patients, with 25% having a grade 3 or higher event. The median time to onset of ICANS was 7 days (range, 1-36) and the median duration was 8 days (range, 1-115).

Patients who were at least 65 years of age had an approximate 42% higher likelihood of developing any-grade CRS, but not severe CRS, compared with younger individuals (OR, 1.42; 95% CI, 1.03-1.96). Additionally, there was an approximate 78% increase in the likelihood of ICANS in this group (OR, 1.78; 95% CI, 1.39-2.28). Grade 3 or higher CRS was more common in those with hepatic disease, and those with an ECOG performance status of 2 or higher were more than 3 times as likely to experience grade 3 or higher ICANS. CRS rates were similar between those with ECOG 2 or higher and those with lower scores.

In addition to these figures, other factors were associated with a higher incidence of CRS and ICANS, including female sex, chemoresistance, <28 days cell production time, >1 extranodal involvements, nontransformed histology, ≥3 lines of prior therapies, no prior stem cell transplant, use of bridging therapy, non-Hispanic, and White race. These data were not elucidated in the presentation.

_Reference

_{Locke FL, Jacobson C, Ma L, et al. Real-world outcomes of axicabtagene ciloleucel (axi-cel) for the treatment of large B-cell lymphoma (LBCL): impact of age and specific organ dysfunction. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 530.}