Retrospective Analysis Shows Efficacy and Safety of CAR T-Cell Therapy in MCL With SCNS

Gulrayz Ahmed, MD

Anti-CD19 CAR T-cell therapy is effective and tolerable in patients with mantle cell lymphoma (MCL) regardless of whether they have secondary central nervous system (SCNS) involvement, according to findings from a retrospective multicenter study that were published in Blood Advances.¹

At 1 month post–CAR T-cell therapy, the best systemic response was complete response (CR; n = 11/12; 92%); 1 patient experienced a best systemic response of partial response. The best CNS responses were CR (92%) and stable disease (n = 1). At 3 months post–CAR T-cell therapy, 92% of patients had CR, and 1 patient had progressive disease (PD). The best CNS responses at this time point were CR (92%) and PD (n = 1).

CD19-directed CAR T-cell therapy has become a standard treatment option for patients with relapsed/refractory MCL based on findings from studies such as the phase 2 ZUMA-2 trial (NCT02601313). Results from the trial showed that, at a median follow-up of 35.6 months (range, 25.9-56.3), the CAR T-cell product brexucabtagene autoleucel (brexu-cel; Tecartus) elicited an overall response rate (ORR) of 91% (95% CI, 81.8%-96.7%) in patients with relapsed/refractory MCL (n = 68).² However, patients were excluded from ZUMA-2 if they had SCNS involvement.³

“With limited availability of data, additional studies are required to assess safety and efficacy of CAR-T in MCL with SCNS involvement,” lead study author, Gulrayz Ahmed, MD, an assistant professor of hematology and oncology at the Medical College of Wisconsin in Milwaukee, and coauthors, wrote in the paper.¹

This retrospective study included 12 patients with MCL who had SCNS involvement at any point in their disease history and received CAR T-cell therapy at 1 of 6 United States centers between 2016 and 2022.

“This study is the biggest retrospective study to date showing encouraging results with CAR T[-cell therapy] use in MCL with SCNS involvement,” Ahmed said in an exclusive comment to OncLive^®.

Key outcomes of this study included systemic response, CNS response, progression-free survival (PFS) and overall survival (OS) for the overall patient cohort, as well as for patient subsets with and without active CNS disease at the time of CAR T-cell infusion.

The median age of patients at the time of CAR T-cell infusion was 72 years (range, 50-82), and 75% were male. At the time of CAR T-cell infusion, 8 patients had active CNS disease and half of patients without CNS disease (n = 4) displayed active systemic disease. Patients had received a median of 4 prior lines of therapy (range, 2-6). Bridging therapy with cranial radiation was administered to 3 patients, with a median interval of 16 days (range, 11-55) prior to CAR T-cell infusion. Most patients (n = 11) received brexu-cel, and 1 patient received a CD19/CD20-directed investigational CAR T-cell product.

The median follow-up among survivors was 16.7 months (range, 13.4-33.7). At last follow-up, 6 patients were alive, and 6 patients had relapsed (systemic relapse, n = 3; CNS relapse, n = 2; both CNS and systemic relapse, n = 1).

Among patients with active CNS disease, the CNS ORRs at 1 month and 3 months post–CAR T-cell therapy were 100% (n = 8) and 88% (n = 7). At 3 months, 1 patient experienced PD. Among patients without active CNS disease at CAR T-cell infusion, the ORRs at 1 month and 3 months post–CAR T-cell therapy were 100% (n = 4) and 100% for both CNS and systemic responses. Two patients without active CNS disease relapsed, 1 each with CNS and systemic disease.

In the overall population, the respective 6- and 12-month PFS rates were 58% (95% CI, 36%-94%) and 33% (95% CI, 15%-74%), and the respective OS rates were 83% (95% CI, 65%-100%) and 67% (95% CI, 45%-99%). In the population of patients with active CNS disease, the respective 6- and 12-month PFS rates were 50% (95% CI, 25%-100%) and 25% (95% CI, 7.5%-83%); the respective OS rates were 75% (95% CI, 53%-100%) and 63% (95% CI, 37%-100%). In the population of patients without active CNS disease at CAR T-cell infusion, the respective 6- and 12-month PFS rates were 75% and 50%, and the respective OS rates were 100% and 75%.

“Notable differences in PFS and OS benefit are evident between patients with and without active CNS disease at the time of CAR T infusion on our analysis, which suggests that controlling CNS disease prior to infusion could lead to better outcomes in this population,” the authors added.

At 12 months, the non-relapse mortality rate in the overall population was 10% (95% CI, 0.43%-38%). The 12-month cumulative incidences of relapse in the overall cohort and cohort of patients with active CNS disease, respectively, were 50% (95% CI, 19%-75%) and 50% (95% CI, 11%-80%).

A total of 11 patients (91.67%) developed cytokine release syndrome (CRS); all cases were grade 1/2, and 9 patients received tocilizumab. The median time to CRS onset was 3 days (range, 0-8). Furthermore, 10 patients (83.33%) developed immune effector cell–associated neurotoxicity syndrome (ICANS). Grade 3/4 ICANS arose in 7 patients, including 62% of patients with active CNS disease and 50% of those without active CNS disease. The median time to ICANS onset was 6 days (range, 2-8). All patients with ICANS also presented with grade 1/2 CRS.

Eight patients with ICANS had elevated ferritin and C-reactive protein levels, with respective medians of 958 ng/mL and 11.89 mg/dL. ECOG performance status (P = .43), elevated lactate dehydrogenase levels at lymphodepletion (n = 7; P = .29), marrow involvement (n = 3; P ≥ .99), and leukemic phase (n = 2; P = .47) were not associated with ICANS. ICANS was managed with systemic corticosteroids (n = 10), anakinra (n = 3), intrathecal steroids (n = 1), and intrathecal chemotherapy (n = 1).

The rates of CRS (87.5% vs 100%) or ICANS (87.5% vs 75%) were similar among patients with and without active CNS involvement.

Limitations of this study include its retrospective nature and small sample size with broad confidence intervals, investigators noted.

“CAR T[-cell therapy] was effective in this patient population with no significant safety concerns, but the responses did not sustain, which potentially opens up consideration for post–CAR T[-cell therapy] maintenance therapy. Another interesting finding was higher rates of ICANS. This does warrant further investigation,” Ahmed concluded.

References

1. Ahmed G, Alsouqi A, Szabo A, et al. CAR T-cell therapy in mantle cell lymphoma with secondary CNS involvement - a multicenter experience. Blood Adv. Published online May 3, 2024. doi:10.1182/bloodadvances.2023012255
2. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol. 2023;41(3):555-567. doi:10.1200/JCO.21.02370
3. Study of brexucabtagene autoleucel (KTE-X19) in participants with relapsed/refractory mantle cell lymphoma (cohort 1 and cohort 2) (ZUMA-2). ClinicalTrials.gov. Updated February 12, 2024. Accessed May 13, 2024. https://clinicaltrials.gov/study/NCT02601313