CTL019 plus ibrutinib is feasible and effective in the treatment of relapsed/refractory MCL

According to the results of the phase 2 TARMAC trial (NCT04234061), CTL019 CAR T cells, investigational tisagelecleucel (Kymriah) and time-limited ibrutinib/ibrutinib (Ibrutinib) combination therapy are effective in patients with relapsed/refractory mantle cell lymphoma (MCL).

The study is one of the first to prospectively test CAR T cells as part of second-line therapy and the first reported study in MCL combining a BTK inhibitor and CAR T cells, building on positive experience from previous chronic lymphocytic leukemia studies. Results from TARMAC showed the study met its primary endpoint; among patients evaluable for efficacy (n=20), the complete response rate was 80% four months after CAR T cell infusion. The overall response rate (ORR) at this time was also 80%. Of the 16 CR patients, 14 were minimal residual disease (MRD) negative by flow cytometry, resulting in an overall MRD-negative rate of 70% for the primary endpoint.

TARMAC was an open-label, single-arm, multicenter study enrolling patients with radiologically or histologically detectable relapsed or refractory MCL who had received at least 1 prior line of therapy; prior BTK inhibitor therapy was allowed. Patients who had previously received allogeneic stem cell transplantation or CAR-T therapy and those with active central nervous system lymphoma were excluded from the trial.

Patients received560 mg of ibrutinib daily, with dose reductions appropriate based on toxicity, and patients who were taking the drug at the start of the study continued to receive treatment. Ibrutinib was administered for at least 1 week prior to leukapheresis and continued during CTL019 production, with additional bridging therapy allowed. All patients received daily lymphodepletion therapy with 25 mg/m2 fludarabine and 250 mg/m2 cyclophosphamide for 3 days, and then received a single dose of autologous CTL 019 (0.6 × 10^8 to 6.0 × 10^8 CAR-positive cells) 2 to 5 days later. The primary endpoint was investigator-assessed CR rate 4 months after infusion of CTL019. Secondary endpoints include ORR at 1, 4, 6, 9 and 12 months, progression-free survival (PFS), duration of response, overall survival (OS), safety and MRD negativity rate.

At baseline, the median age of the entire patient population was66 years old (range 41-74 years). The majority of 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 was 2 (range 1-5) and included rituximab (95%), bendamustine (15%), anthracyclines (85%), cytarabine (80%), autologous transplantation (55%), venetoclax (20%), and/or BTK inhibitors (50%).

Additional findings fromTARMAC showed that at a median follow-up of 13 months (range, 3-21 months), median PFS had not been reached; estimated 12-month PFS and OS rates were 75% and 100%, respectively. The median peak value of CAR T expansion was reported to be 14 days (range, 6-14 days). The time to peak T cells was delayed in patients previously treated with a BTK inhibitor (n = 10) compared with those previously treated with a BTK inhibitor (n = 10), a median of 14 days versus 6 days; there was no difference in peak levels or area under the curve at day 28.

In terms of safety, all patients experienced adverse reactions (AEs) of any grade, with 75% of patients reporting grade 3 or 4 AEs. The most common treatment-related AEs of any grade 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 days), and the median duration was 4 days (range, 1-15 days). Of the 2 patients who developed immune effector cell-related neurotoxic syndrome of any grade, the median duration was 3 days (range, 2-4 days), and both patients were grade 0. Of note, no patients had died at the time of data cutoff.

This study makes a significant contribution to the emerging experience of combining BTK inhibition with T cell redirection therapy, demonstrating feasibility and efficacy in MCL, regardless of prior exposure to BTK inhibitors or the presence of high-risk clinical or molecular characteristics.