The combination of a BTK inhibitor and chimeric antigen receptor (CAR) T-cell therapy is “highly effective” for relapsed/refractory mantle cell lymphoma (MCL), according to a presentation at the 2022 ASH Annual Meeting.
The combination of ibrutinib and tisagenlecleucel produced an overall response rate (ORR) of 85%. At a median follow-up of 13 months, the median progression-free survival (PFS) was not reached, and all patients were still alive.
These results come from the phase 2 TARMAC trial (ClinicalTrials.gov Identifier: NCT04234061), which included 20 evaluable patients with relapsed/refractory MCL. The median age was 66 (range, 41-74) years, and 75% of patients were men. Nine patients had TP53 mutations or deletions, and 8 had SWI/SNF aberrations.
Patients had received a median of 2 prior lines of therapy (range, 1-5). Nineteen patients had received rituximab, 17 had received anthracyclines, 11 had undergone prior autologous transplant, and 10 had prior BTK inhibitor therapy. All 10 patients who had received BTK inhibitor therapy had received ibrutinib. Five were still taking the drug at enrollment, and 5 had previously stopped ibrutinib due to disease progression.
Patients not already taking ibrutinib at enrollment started the drug (at 560 mg daily) at least 7 days prior to leukapheresis. They continued the treatment through optional bridging therapy, through lymphodepletion (with fludarabine and cyclophosphamide), and for at least 6 months after CAR T-cell infusion. Five patients required bridging therapy.
The ORR was 85%, and 80% of patients achieved a complete response (CR). Most responders stopped ibrutinib around 6 months after infusion, but 2 patients continued ibrutinib beyond that point due to minimal residual disease (MRD) positivity.
“The combination was highly effective,” said study presenter Adrian Minson, MBBS, of the University of Melbourne in Australia. “The vast majority of responding patients were able to cease therapy at 6 months and continue in remission despite no active treatment.”
The primary endpoint was CR at 4 months after tisagenlecleucel infusion. At that point, the CR rate was 80% overall, 90% in BTK inhibitor-naïve patients, 70% in BTK inhibitor-exposed patients, 88% in patients with TP53 mutations, 80% in patients with wild-type TP53, and 88% in patients with SWI/SNF aberrations.
By flow cytometry, 70% of complete responders were MRD negative. By high-throughput immunoglobulin sequencing, 40% were MRD negative.
At a median follow-up of 13 months, the median PFS was not reached. The 6-month PFS rate was 85%, and the 12-month PFS rate was 75%. The overall survival rate was 100%.
Grade 3-4 adverse events occurred in 75% of patients, and treatment-related grade 3-4 adverse events occurred in 70%.
Cytokine release syndrome (CRS) was reported in 75% of patients, with 11 patients having grade 1-2 CRS and 4 patients having grade 3 CRS. There were no cases of grade 4 CRS.
One patient had grade 2 immune effector cell-associated neurotoxicity syndrome, but this completely resolved. One patient had atrial fibrillation associated with sepsis prior to CAR T-cell infusion.
“This is the first study to report the combination of a BTK inhibitor and CD19 CAR-T cells in mantle cell lymphoma,” Dr Minson noted. “The study met its primary endpoint and provides strong support for further exploration of the combination of BTK inhibition and T-cell redirecting immunotherapies to better characterize the synergy between these agents and define the optimal role of the combination in treatment sequencing.”
Disclosures: This study was partly supported by Novartis. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Minson A, Hamad N, Cheah CYY, 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 ASH 2022. December 10-13, 2022. Abstract 75.