Liso-Cel Proves to Be Highly Active, Tolerable in Relapsed/Refractory MCL

Lisocabtagene maraleucel (liso-cel) exhibited promising antitumor activity with low rates of grade 3 or higher cytokine release syndrome (CRS) and neurotoxicity in patients with relapsed/refractory mantle cell lymphoma (MCL), according to phase 1 results of the single-arm TRANSCEND NHL 001 trial that were presented during the 2020 ASH Annual Meeting and Exposition.¹

The objective response rate (ORR) among the 32 patients treated in the study was 84%, with a complete response (CR) rate of 66% at a median on-study follow-up of 5.9 months, lead study reported Maria Lia Palomba, MD, reported in a presentation during the virtual meeting.

The median time to first CR or partial response was 0.95 months.

“The median duration of response was not reached after a median follow-up of 3.9 months,” said Palomba, a hematologist/oncologist, Memorial Sloan Kettering Cancer Center. “A total of 6 patients have demonstrated a durable response over 1 year in this ongoing study. Importantly, responses were generally similar in patients with blastoid morphology and in patients who were resistant to ibrutinib [Imbruvica].”

Among the patients with Ki-67 level at 30% or higher, the ORR was 83% and the CR rate was 65%. Of those with blastoid morphology, the ORR and CR rates were 77% and 54%, respectively, and among patients with a TP53 mutation, these rates were 100% and 57%, respectively.

Prognosis is poor in patients with MCL, with disease progression likely following receipt of a BTK inhibitor. The median overall survival with salvage therapy is typically 6 to 10 months.^2-4 Liso-cell previously demonstrated an ORR of 73%, with a CR rate of 53%, among a subcohort of patients with relapsed/refractory large B-cell lymphoma who were enrolled on TRANSCEND NHL 001, in whom the rate of grade 3 or higher CRS was 2% and neurologic events occurred in 10% of these patients.⁵

Liso-cel, a CD19-directed, 4-1BB CAR T-cell product, is administered as separate CD8+ and CD4+ T-cell components at equal target doses. “Importantly, the defined dose and CD8+/CD4+ ratio [of CAR T cells] may influence the incidence and severity of CRS and neurologic events,” she said.

At data cutoff, the relapsed/refractory MCL cohort consisted of 32 patients who, after lymphodepletion, were treated with liso-cel at 1 of 2 dose levels­—6 at dose level 1 (50 x 106 CAR T cells) and 26 at dose level 2 (100 x 106 CAR T cells). Administration of CAR T cells and monitoring were allowed in either the inpatient or outpatient setting. Bridging therapy was permitted and could include chemotherapy or radiotherapy. Eligible patients had at least 2 prior lines of therapy.

“After a protocol amendment, patients were required to have received a BTK inhibitor, an alkylating agent, and an anti-CD20 agent,” said Palomba.

The primary end points were adverse events (AEs), dose-limiting toxicities, and ORR by independent review committee per Lugano classification.

The median time to maximal liso-cel expansion was 10 days after infusion. “Liso-cel showed long-term persistence at 1 year in 67% of patients and at 2 years in 33% of patients with sufficient follow-up,” she said.

The median age was 67 years, 41% had blastoid morphology, 72% had documented Ki-67 at least 30%, and 22% had TP53 mutations. Patients received a median of 3 prior lines of therapy, 81% had disease refractory to their most recent prior therapy, and 31% were refractory to prior ibrutinib.

Eighty-four percent had a grade 3 or higher treatment-emergent (TEAE), including anemia (38%), neutropenia (44%), and thrombocytopenia (31%). Prolonged grade 3 and higher cytopenias present at study day 29 were reported in 34% of patients.

Two grade-5 treatment-emergent adverse events occurred in 2 patients, both at dose level 2 and both were considered related to liso-cel: 1 patient experienced tumor lysis syndrome and 1 patient with cryptococcal meningoencephalitis died. There were no deaths related to CRS or neurologic events.

Grade 3 or higher CRS was reported in 1 patient (3%), with a median time to onset of 6 days and a median to resolution of 4 days. Grade 3 or higher neurologic events were reported in 4 (12.5%), with a median time to onset of 8 days and a median time to resolution of 4 days. For management of CRS and neurologic events, 12.5% of patients required both tocilizumab (Actemra) and corticosteroids, 12.5% required corticosteroids alone, and 6% tocilizumab only.

Enrollment into the study is ongoing at dose level 2 in the MCL cohort, said Palomba.

References

1. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 118.
2. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559-1563. doi:10.1182/blood-2015-10-673145
3. Jain P, Kanagal-Shamanna R, Zhang S, et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. Br J Haematol. 2018;183:578-587. doi:10.1111/bjh.15567
4. Epperla N, Hamadani M, Cashen AF, et al. Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a "real world" study. Hematol Oncol. 2017;35:528-535. doi:10.1002/hon.2380.
5. Abramson JS, Palomba ML, Gordon LI, et al.Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0