Liso-Cel Proves Active Across High-Risk MCL Subgroups

Efficacy with lisocabtagene maraleucel (liso-cel; Breyanzi) was not hindered by the presence of a high Ki-67 proliferation index, TP53 mutations, blastoid morphology, or secondary central nervous system (CNS) lymphoma in patients with relapsed/refractory mantle cell lymphoma (MCL), according to findings from a subgroup analysis of the phase 1 TRANSCEND NHL 001 trial (NCT02631044) presented at the 2024 Tandem Meetings on Transplantation & Cellular Therapy.¹

Response rates, progression-free survival (PFS), and overall survival (OS) across subgroups were consistent with the overall MCL cohort. PFS was 15.3 months (95% CI, 6.6-24.9) in the overall MCL cohort, and 15.3 months (95% CI, 6.6-24.9) in patients with Ki-67 ≥ 30%, 24.0 months (95% CI, 2.4-NR) in patients with Ki-67 < 30, 7.4 months (95% CI, 3.3-NR) for patients with a TP53 mutation, and 7.8 months (95% CI, 3.1-NR) for patients with blastoid morphology. OS rates in each of the subgroups were 18.2 months (95% CI, 12.9-36.3), 18.2 months (95% CI, 10.7-NR), 13.5 months (95% CI, 2.4-NR), 17.1 months (95% CI, 6.6-NR), and 12.9 months (95% CI, 5.6-NR), respectively.²

Notably, high overall response rates (ORR) and a sustained complete response (CR) rate was observed, as well as extended PFS and OS rates. The ORR in the overall MCL cohort was 83% (95% CI, 73.3%-90.5%). ORRs were 85% (95% CI, 74.2%-93.1%), 71% (95% CI, 41.9%-91.6%), 89% (95% CI, 66.9%-98.7%), and 70% (95% CI, 49.8%-86.2%) in the Ki-67 ≥ 30%, Ki-67 < 30, TP53 mutation, and blastoid morphology subgroups, respectively.¹

While TP53 mutation assessment was limited, the study authors noted, patients in this subgroup experienced a lower median duration of response (DOR) at 6.2 months (95% CI, 2.3-NR), compared with the overall MCL cohort at 15.7 months (95% CI, 6.2-24.0). They added that this is likely due to a higher proportion of objective responders achieving a partial response (PR) rather than a CR.

Among those with a TP53 mutation who achieved a CR, responses were durable with 6 of 11 patients maintaining an ongoing response at the time of the data cutoff. Of the 7 pts with secondary CNS lymphoma, response rates were high, with an ORR of 86% (n = 6) and a CR rate of 71% (n = 5). Three of 5 patients who achieved a CR were in an ongoing response at data cutoff.

“In this analysis of patients with relapsed or refractory mantle cell lymphoma with high-risk disease features consisting of Ki-67 proliferation index of equal or more than 30%, TP53 mutations, or blastoid morphology, and patients with secondary CNS lymphoma, liso-cel demonstrated clinically meaningful efficacy across all the subgroups with high response rates and durable responses,” explained M. Lia Palomba, MD, attending physician from Memorial Sloan Kettering Cancer Center, in a presentation of the data.

High-risk features in relapsed/refractory MCL–such as TP53 mutation, high Ki-67 proliferation index, blastoid morphology, and secondary CNS involvement–are associated with a poor prognosis. Liso-cel is a CAR T-cell therapy that has been shown to be effective in relapsed/refractory MCL treatment.

A clinical trial sought to evaluate the efficacy of liso-cel in 88 patients with relapsed/refractory MCL and high-risk features after they received at least 2 prior lines of therapy. Enrollment in this cohort of the study was open to patients with PET-positive relapsed/refractory MCL after ≥ 2 lines of prior therapy, including a BTK inhibitor, alkylating agent, and CD20-targeted agent.

Once enrolled, patients were treated with liso-cel at a target dose of 50 × 10⁶ or 100 × 10⁶ CAR+ T cells after lymphodepleting chemotherapy. Patients were allowed to have bridging therapy.

The primary end points of the study included treatment-emergent adverse events (TEAEs) and ORR by independent review committee. Secondary end points of the study consisted of CR rate, DOR, PFS, cellular kinetics, health-related quality-of-life, hospital resource utilization, and OS.

Eighty-eight patients were enrolled in the MCL cohort and given liso-cel. Patients were followed for an average of 16 months (range, 0.4-60.5). In the overall MCL cohort, patients were heavily pretreated, having received an average of 3 prior chemotherapy regimens (range, 1-11), and the median age of patients was 68.5 years (range, 36-86). Among the patients treated with liso-cel, 75% had Ki-67 ≥ 30% and 17% had Ki-67 < 30% (not reported, 8%); 23% had TP53 mutation and 39% did not (indeterminate, 5%; not reported, 34%); and 31% had blastoid morphology and 55% did not (not reported, 15%).

The majority of patients with high-risk features also had disease refractory to last therapy received and/or to a prior BTK inhibitor, and had complex karyotype. Additionally, several patients (8%) had secondary CNS lymphoma, including 5 with refractory disease, 5 with Ki-67 ≥ 30%, 1 with a TP53 mutation, and 1 with blastoid morphology.

The safety profile of liso-cel remained consistent across different patient subgroups. This mirrored that observed with overall MCL cohort. Between high-risk and non-high-risk subgroups, TEAEs of special interest–including cytokine release syndrome (CRS) and neurological events–were similar and mostly low grade. Any-grade CRS was observed in 61% of patients and was grade 3 to 4 in 1%, while any-grade neurological events were seen in 31% of patients and were grade 3 to 4 in 9%. No grade 5 CRS or neurological events were observed.

Among the 7 pts with secondary CNS lymphoma, 5 had low-grade CRS and 3 had low-grade neurological events. No cases of grade ≥ 3 CRS or neurological events were observed; however, 1 patient had a grade ≥ 3 infection.

“Safety outcomes in the subgroups were generally consistent with those of the overall study population. There were no clear differences in pharmacokinetics observed across the subgroups,” said Palomba. “After liso-cel infusion, the incidence of B-cell aplasia peaked by month 2 in the overall study population.”

Overall, these results suggest that liso-cel is effective and safe in the MCL setting, even in patients with high-risk features. The study authors noted that more research is needed to confirm these findings, but liso-cel has the potential to improve the outlook for patients with relapsed/refractory MCL and high-risk features.

“While some subgroups were limited by small numbers, these results suggest a favorable benefit-risk profile for liso-cel in patients with high-risk disease features, a patient population for which effective treatment options are at this point very limited,” concluded Palomba.

References

1. Palomba ML, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel (liso-cel) in patients (Pt) with R/R MCL: subgroup analyses in pts with high-risk disease features from the MCL cohort of the TRANSCEND NHL 001. Presented at: 2024 Transplantation and Cellular Therapies Meeting; February 21-24, 2024; San Antonio, TX. Abstract 17.
2. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol. Published online December 10, 2023. doi:10.1200/JCO.23.02214

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