CAR T-Cell therapy for mantle cell lymphoma (MCL)

Brexucabtagene autoleucel (Tecartus) was authorized by the FDA in July 2020 for the treatment of adult patients with relapsed or refractory mantle cell lymphoma, demonstrating an 87 percent objective response rate and a 62 percent complete response rate in the phase 2 ZUMA-2 trial when administered as a single infusion. Unlike diffuse large B-cell lymphoma, any patient with MCL who has relapsed after one prior therapy can proceed directly to CAR T-cell therapy, with BTK inhibitors available as a bridging option but not a requirement. James Gerson, MD, assistant professor of clinical medicine at Penn Medicine, noted that induction therapy followed by stem cell transplantation continues to play a role in MCL treatment, and that patients who have undergone transplant can still proceed with CAR T-cell therapy and respond quite well if they relapse, making transplant a viable consolidative option for young and fit patients rather than something to be skipped in anticipation of CAR T-cell therapy.

For young, fit MCL patients, induction therapy typically entails high-dose chemotherapy, with regimens such as R-DHAP and the emerging O-DHAP combination showing promise as frontline options prior to consolidative transplant. In the relapsed setting, second-line BTK inhibition with either ibrutinib or acalabrutinib has become the standard of care, with acalabrutinib generally considered more tolerable over time despite a lack of direct comparative efficacy data between the two agents. A triplet strategy similar to ibrutinib, obinutuzumab, and venetoclax being explored in chronic lymphocytic leukemia is also under investigation in both frontline and relapsed or refractory MCL, a development Gerson described as incredibly exciting and potentially capable of supplanting cytarabine-based induction and transplant, though long-term follow-up data will be needed over approximately ten years to confirm outcomes.

The potential for CAR T-cell therapy to move into the frontline setting is particularly relevant for high-risk MCL patients with features such as high MIPI scores, TP53 mutations, blastoid variant MCL, or pleomorphic variant MCL, all of which tend to confer worse outcomes with current standard approaches. Gerson noted that pursuing frontline CAR T-cell therapy trials will depend on whether companies choose to invest in such investigations or whether the effort falls to investigator-initiated trials, which face significant cost challenges given the high expense associated with CAR T-cell therapy. The use of minimal residual disease as a surrogate endpoint may allow researchers to gauge the effectiveness of new regimens sooner than traditional long-term follow-up would permit, offering a meaningful tool for accelerating the development of next-generation MCL treatment strategies.