CART in MCL: risk and reward? Open Access

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has revolutionized the management of several lymphoma subtypes, including mantle cell lymphoma (MCL). Brexucabtagene autoleucel (brexu-cel) is an autologous CAR T-cell therapy incorporating a lentiviral vector and CD28 costimulatory domain. The pivotal phase 2 ZUMA2 trial demonstrated unprecedented high overall response rates (ORRs, 91%) and excellent complete response rates (CRRs, 68%) in patients with heavily pretreated MCL who had all received a prior covalent Bruton tyrosine kinase inhibitor (cBTKi). Following ZUMA2, the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approvals for this product were slightly different, with a broader FDA approval including any patients with relapsed or refractory MCL regardless of a patient’s prior exposure to a BTKi whereas the EMA approval requires prior BTKi exposure.

In this issue of Blood Advances,¹ Ahmed et al present an extensive real-world experience of brexu-cel from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. This series represents the largest nontrial population of patients infused with brexu-cel and provides extremely valuable insights into the benefits and challenges of delivering brexu-cel. It is important to note that the analysis, interpretation, and medical writing support for the manuscript was supported by KITE Gilead with multiple co-authors from KITE Gilead.

Overall, the data presented continue to demonstrate the impressive efficacy of brexu-cel, with high initial ORRs and CRRs observed. To date, however, no clear and obvious evidence of a cure in relapsed MCL has been demonstrated with brexu-cel, and the relatively short follow-up in the CIBMTR analysis precludes further assessment of this limitation. The responses and survival were broadly consistent with the ZUMA2² data, although it is particularly noteworthy that 70% of the studied population would have been ineligible for the ZUMA2 trial. The most common reasons for this ineligibility are documented in the supplement and include cytopenias (of those ineligible, 26%), prior malignancy (23%), and cardiorespiratory disease (64%). We could interpret these findings in several ways, but it certainly speaks to the highly selective inclusion/exclusion criteria within clinical trials. Therefore, the interpretation of populations from any modest sized, highly selected phase 2 clinical trial, such as ZUMA2, should be necessarily cautious.

This prospective series represented an opportunity to document, collate, and present a detailed intention to treat (ITT) analysis of patients considered for brexu-cel. It is unfortunate that this opportunity was missed. This is particularly relevant when considering the possible utility of brexu-cel in BTKi naïve patients where any indirect comparison with BTKi results should take into account the fact that all patients with relapsed MCL who receive a BTKi effectively represent an ITT population.

Although brexu-cel was indisputably efficacious, the toxicity that was recapitulated within this prospective nontrial series remains a significant clinical challenge. The grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) rates within ZUMA2 remain among the highest reported, and this rate was again noted to the same magnitude within the CIBMTR series (grade ≥3, 30% [95% confidence interval, 26-34]). When considering brexu-cel as a therapeutic option for patients, it is critical that an individual patient’s ability to withstand grade ≥3 cytokine release syndrome and especially grade ≥3 ICANS is carefully considered. This CIBMTR registry data also confirm that “clinically significant infections” were reported in 50% of the patients. The 12-month nonrelapse mortality (NRM) was noted to be 8% within this series, which is numerically similar to the US Lymphoma Consortium results.³ The UK multicenter experience,⁴ which included all consecutive patients approved by the national CAR-T panel from February 2021 and June 2023, observed a 12- and 24-month NRM of 15% and 25%, respectively, with infection a significant driver of this. We have much still to learn about the effects of anti-CD19 CAR T-cell therapy and associated supportive immunosuppressive therapy on infectious risk,⁵ and this must be an ongoing research priority.

Ahmed et al discuss the potential role of brexu-cel in BTK naïve patients, stating as a key point “the benefits of brexu-cel extend to patients who have no prior exposure to BTKi therapy or have received few lines of therapy.” Although the response rates and depth are retained in the less heavily pretreated patients in the series and the rationale for improved T-cell fitness in earlier lines exists, randomized data and ITT data are critically important even when indirectly comparing to established therapies such as cBTKis. It is important to remember that cBTKis are off-the-shelf, widely applicable, and well-tolerated oral targeted medicines with high efficacy delivered as an outpatient medication. Despite many patients deriving durable benefits from this therapeutic class, it is also well recognized that patients with MCL with very high-risk features such as blastoid morphology, raised Ki67, or TP53 mutations respond poorly to BTKi monotherapy.⁶ Therefore, alternate therapies, including brexu-cel, could be reasonably considered in these patients if available.

In an era where cBTKis are rapidly moving to the first-line setting in combination with immunochemotherapy,^7-9 it remains an open question what the optimum second-line treatment and beyond therapeutic sequence might be. Anti-CD19 CAR T-cell therapy and the non-cBTKi pirtobrutinib^10,11 may compete for this space in the near future, with anti–CD20-CD3 bispecific antibodies,¹² BCL2 inhibitors (NCT05471843), and other targeted therapeutics potentially not far behind.

Although the ZUMA-2 trial and this CIBMTR analysis provide substantial evidence for the benefits of T-cell–directed therapy in relapsed MCL post-BTK inhibition, it is likely that CAR T-cell therapy products will evolve considerably in the future.¹³ These immunotherapeutic products will be aimed at reducing immune-effector–related toxicity as well as manufacturing time and failure, producing CAR T cells within the patients’ home institution, targeting different or multiple antigens,¹⁴ using combination strategies,¹⁵ and assessing natural killer or allogeneic CAR T cells. However, the cellular products that will win out in this competitive space remain to be seen.

Conflict-of-interest disclosure: T.A.E. reports honoraria and advisory work fees from Roche, Gilead, Kite, Janssen, AbbVie, AstraZeneca, Loxo Oncology, BeiGene, Incyte, Autolus, Galapagos, Bristol Myers Squibb, Nurix, Medscape, PeerView, Clinical Care Options, and The Limbic; research funding from AstraZeneca, BeiGene, and Gilead; and travel allowances from Roche, AstraZeneca, and AbbVie.