Time-Limited Ibrutinib Plus CAR-T Cell Therapy May Improve Outcomes in Relapsed/Refractory MCL

A time-limited combination of ibrutinib and tisagenlecleucel may be a tolerable and effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL), according to early data from the phase 2 TARMAC trial (NCT04234061) presented at the 2022 American Society of Hematology (ASH) Annual Meeting.

Among 20 patients (median age, 66 years; range, 41-74) treated with the combination, the rates of complete and partial response were 85% and 5%, respectively, after a median follow-up of 13 months (range, 3.5-21.4). As such, the overall response rate (ORR) was 90%; the median time to best response was 1 month (range, 1-4).

Sixteen patients (80%) showed complete responses (CRs) at 4 months post-infusion, whereas 4 had disease progression. Analysis of peripheral blood and bone marrow samples using flow cytometry demonstrated MRD negativity in 14 patients (70%); high throughput immunoglobulin sequencing demonstrated the same in 8.

The CR rate at month 4 in patients naïve to BTK inhibition was 90% vs 70% in those with prior exposure.

At 12 months, an estimated 83% of responding patients retained their response. A median duration of response has not been reached, meaning more than half of the study participants retained a treatment response at follow up.

The estimated rate of progression-free survival was 75% at this point, and the rate of overall survival was 100%. Outcomes differed little between patients with TP53 wildtype and TP53-mutated disease, with complete response rates of 78% and 71%, respectively.

“This is the first study to report on the combination of a BTK inhibitor and CD19-directed CAR T cells in MCL, and one of the first to use CAR T cells in second-line treatment,” said lead study author Adrian Minson, MBBS, hematologist and clinical trials fellow at the Peter MacCallum Cancer Center in Melbourne, Australia. “The combination was highly effective…the vast majority of responding patients were able to cease therapy at 6 months and continue in remission despite no active treatment.”

Patients enrolled onto the trial had received a median of 2 prior lines of therapy (range, 1-5), and 55% had undergone prior autologous stem cell transplantation. Half the group (n = 10) had undergone prior BTK inhibitor therapy, and 9 were refractory. Four patients required bridging using either venetoclax (Venclexta; n = 1) or chemotherapy (n = 3).

Investigators acquired genomic results from 18 patients, 8 of whom had at least a single TP53 mutation. Eight patients were found to have deletion 17p, including 7 of those with a TP53 mutation, suggesting biallelic TP53 dysfunction.

Daily treatment with ibrutinib at 560mg commenced no less than 7 days prior to leukapheresis and continued throughout any optional bridging therapy or lymphodepletion (using fludarabine at 25mg/m2 and cyclophosphamide at 250mg/m2 daily for 3 cycles), and for 6 months after tisagenlecleucel infusion. The ibrutinib therapy achieved a mean dose intensity of 97%.

Grade 3 and 4 toxicities affected 75% and 50% of patients, respectively. Three-quarters of the patient group experienced cytokine release syndrome (CRS) following tisagenlecleucel infusion; 73% of these were grade 1/2 and the rest (27%) were grade 3.

There was a single instance of grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS) which was resolved completely. Atrial fibrillation associated with infection occurred in 1 patient.

“This study met its primary end point and provides strong support for further exploration of [this] combination…to better characterize the synergy between these agents and define the optimal role of the combination in treatment sequencing,” Minson concluded.

Reference

Ruan J, Leonard JP, Chen GZ, et al. Time-limited ibrutinib and tisagenlecleucel is highly effective in the treatment of patients with relapsed or refractory mantle cell lymphoma, including those with TP53 mutated and BTKi-refractory disease: first report of the TARMAC study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 75.