CTL019 Plus Ibrutinib is Feasible and Effective in Relapsed/Refractory MCL

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Treatment with CTL019 CAR T cells, the investigational form of tisagenlecleucel (Kymriah), in combination with time-limited ibrutinib (Imbruvica) demonstrated efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL), according to findings from the phase 2 TARMAC trial (NCT04234061) published in Blood.

Results from TARMAC showed that the study met its primary end point; the 4-month complete response (CR) rate following CAR T-cell infusion was 80% in efficacy-evaluable patients (n = 20). The overall response rate (ORR) at this time was also 80%. Among the 16 patients with a CR, 14 were negative for minimal residual disease (MRD) by flow cytometry, which resulted in an overall MRD negativity rate of 70% at the primary end point.

“To the best of our knowledge, our study is one of the first to prospectively test CAR T cells as part of second-line therapy and the first to report the combination of a BTK inhibitor and CAR T cells in MCL, building upon the positive experience in prior chronic lymphocytic leukemia studies,” study authors wrote. “In this setting, we demonstrated high rates of CR, including a significant proportion of patients achieving flow and molecular MRD negativity.”

TARMAC was an open-label, single-arm, multicenter study that enrolled patients withradiologically or histologically detectable relapsed or refractory MCL following at least 1 prior line of therapy; prior BTK inhibitor treatment was permitted. Those who received prior allogeneic stem cell transplantation or CAR-T therapy, as well as patients with active central nervous system lymphoma, were excluded from the trial.

Patients received ibrutinib daily at 560 mg with appropriate dose reduction for toxicity, and those on the agent at study initiation continued treatment. Ibrutinib was administered for at least 1 week prior to leukapheresis and continued throughout CTL019 manufacturing, and additional bridging therapy was permitted. All patients received lymphodepletion with fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² daily for 3 days, followed by a single dose of autologous CTL019 2 to 5 days later ranging from 0.6 x 10⁸ to 6.0 x 10⁸ CAR-positive cells.

The primary end point was investigator-assessed CR rate at 4 months post CTL019 infusion. Secondary end points included ORR, progression-free survival (PFS), duration of response, overall survival (OS), safety, and MRD negativity rates at 1, 4, 6, 9, and 12 months.

At baseline, the median age of the overall patient population was 66 years (range, 41-74). Most patients were male (75%), had stage IV disease (68%), and had an ECOG performance status of 0 (70%). The median number of prior lines of therapy received was 2 (range, 1-5), with treatments including rituximab (Rituxan; 95%), bendamustine (15%), anthracycline (85%), cytarabine (80%), autologous transplant (55%), venetoclax (Venclexta; 20%), and/or a BTK inhibitor (50%).

Additional findings from TARMAC showed that at a median follow-up of 13 months (range, 3-21), the median PFS had not been reached; the estimated 12-month PFS and OS rates were 75% and 100%, respectively. Peak CAR T expansion was reported at a median of 14 days (range, 6-14). Patients who received a prior BTK inhibitor (n = 10) experienced a delayed time to CAR T-cell peak compared with those without prior BTK inhibitor exposure (n = 10), at a median of 14 days vs 6 days, respectively; no difference was reported in peak levels or area under the curve to day 28.

In terms of safety, all patients experienced an any-grade adverse effect (AE) and grade 3 or 4 AEs were reported in 75% of patients. The most common any-grade treatment-related AEs included cytokine release syndrome (CRS; 75%) neutropenia (50%), diarrhea (30%), rash (20%), and thrombocytopenia (15%).

The median time to onset of CRS was 3 days (range, 1-12) and the median duration was 4 days (range, 1-15). Among the 2 patients who experienced any-grade immune effector cell-associated neurotoxicity syndrome, the median duration was 3 days (range, 2-4) and both patients resolved to grade 0. Notably, no patients had died at the data cutoff.

“Our study has limitations, both in its small size and the lack of control arm, which impairs direct interrogation of the relative contribution of ibrutinib in modifying CAR T-cell fitness and toxicity in this context,” the study authors wrote in conclusion. “Nonetheless, this study contributes significantly to the emerging experience of combining BTK inhibition with T-cell redirecting therapies, demonstrating both feasibility and effectiveness in MCL irrespective of prior BTK inhibitor exposure or the presence of high-risk clinical or molecular features. Work is ongoing to translate these lessons into other novel combinations, including a follow-on study of BTK inhibition in combination with a T-cell redirecting bispecific antibody [NCT05833763].”

Reference

Minson A, Hamad N, Cheah CY, et al. CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study. Blood. 2024;143(8):673-684. doi:10.1182/blood.2023021306