Meta-Analysis Shows Efficacy, Safety of CAR T-Cell Therapy in R/R Mantle Cell Lymphoma

A systematic review and meta-analysis of 16 prospective clinical trials and real-world studies showed that CAR T-cell therapy demonstrated efficacy and manageable adverse effects (AEs) in patients with relapsed/refractory mantle cell lymphoma (MCL), according to data published in Frontiers in Immunology.¹

Upon pooling data from 984 evaluable patients included in the 16 studies, the estimated overall response rate (ORR) and complete remission (CR) rate were 89% (95% CI, 87%-91%; I², 13%) and 74% (95% CI, 69%-79%; I², 60%), respectively. The 6- and 12-month progression-free survival (PFS) rates were 68% (95% CI, 59%-76%; I², 74%) and 51% (95% CI, 42%-60%; I², 70%), respectively. The respective 6- and 12-month overall survival (OS) rates were 80% (95% CI, 72%-87%; I², 75%) and 69% (95% CI, 54%-82%; I², 86%).

Regarding safety findings of the pooled analysis, any-grade cytokine release syndrome (CRS) occurred in 86% (95% CI, 81%-91%; I², 71%) of patients; grade 3 or higher CRS was seen in 8% (95% CI, 5%-11%; I², 60%) of patients. Immune effector cell–associated neurotoxicity syndrome (ICANS) of any grade was reported in 52% (95% CI, 43%-61%; I², 77%) of patients, and the rate of grade 3 or higher ICANS was 22% (95% CI, 14%-30%; I², 79%).

“CAR-T therapy is highly effective as a salvage treatment for relapsed/refractory MCL, even in patients with high-risk features. However, due to the lack of longer follow-up, the long-term efficacy remains to be determined,” Dr Haixiang Wan of the Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, the 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University in China, and colleagues wrote. “The variability in patient responses underscores the importance of personalized treatment approaches.”

Within the MCL treatment paradigm, the FDA approved brexucabtagene autoleucel (brexu-cel; Tecartus) for the treatment of patients with relapsed/refractory MCL in July 2020.² In May 2024, the regulatory agency also approved lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of patients with relapsed/refractory MCL after at least 2 prior lines of therapy, including a BTK inhibitor.³ These approvals were supported by data from the phase 2 ZUMA-2 trial (NCT02601313) and the phase 1 TRANSCEND NHL 001 trial (NCT02631044), respectively.

Although these therapies are approved for the treatment of select patients with relapsed/refractory MCL, study authors noted that CAR T-cell agents are associated with risks of neurotoxicity, CRS, and other AEs.

To further assess these risks and identify more consistent trends, researchers conducted a search across various databases including PubMed, Embase, Cochrane Systematic Reviews, and ClinicalTrials.gov to further evaluate literature on treatment with these therapies; data were collected up to July 4, 2024.

“The inclusion criteria were studies with patients with MCL undergoing [CAR T-cell] therapy, without any restrictions on date or study design. Exclusion criteria included studies without complete data, basic research, case series with fewer than 10 patients, and studies on dual targets, which were discussed separately,” authors explained.

Information regarding key demographic information, treatment history, and clinical outcomes of CAR T-cell therapy was compiled, including the number of enrolled patients, median age, sex ratio, prior treatments, specific CAR T-cell therapy targets, use of combination therapies, and BTK inhibitor application. Furthermore, high-risk markers such as TP53 mutations and Ki-67 proliferation index were noted, as well as central nervous system (CNS) involvement and past transplantation procedures.

The primary end points were safety and efficacy.

Upon initial screening, investigators reviewed 1317 potentially relevant studies and determined studies were eligible for the meta-analysis based on full-text reviews; these studies encompassed 984 patients. Among these studies, 10 were published in peer-reviewed journals, and 6 were presented at conferences.

Thirteen of these studies utilized brexu-cel; treatment with the tisagenlecleucel (tisa-cel; Kymriah), liso-cel, and mixed CAR T-cell therapies including all 3 comprised the remaining 3 studies, respectively. The median age of evaluable patients was 66.5 years (range, 38-89). The majority were male (73%), and most patients had relapsed following multiple lines of prior therapy (range, 1-12), including BTK inhibitors. Notably, 8 studies also included patients with secondary CNS infiltration.

Additional Subgroup Analysis Data

“The subgroup analysis of prognostic high-risk factors for MCL indicated varying CR rates among different patient categories,” authors continued.

For example, patients with Ki-67 index below 30% experienced an ORR of 87% and CR rate of 65%; conversely, an ORR of 88% and CR rate of 74% were observed in patients with a Ki-67 index of 30% or more. Furthermore, patients without TP53 mutations had ORR of 95% and a CR rate of 81% vs 89% and 70%, respectively, in patients harboring these mutations.

“The absence and presence of CNS involvement was associated with ORR of 88% and 89%, and CR rate of 72% and 82%, respectively,” study authors reported. “[Patients with] non-blastoid/pleomorphic [disease] and [those with] blastoid/pleomorphic [disease] had an ORR of 91% and 85%, and a CR rate of 75% and 75%, respectively. Patients who had not received prior BTK inhibitor treatment exhibited an ORR of 93% and CR rate of 83%, whereas those with a history of such treatment exhibited an ORR of 83% and CR rate of 70%.”

Patients who did not have a history of hematopoietic stem cell transplantation (HSCT) experienced a CR rate of 70% vs a CR rate of 83% in those who underwent prior HSCT. Additionally, patients who received 3 or fewer prior treatments achieved a CR rate of 75% vs a CR rate of 71% in those who had more than 3 prior lines of therapy.

Investigators also conducted a subgroup analysis comparing brexu-cel with other CAR T-cell therapies to account for varying products. Investigators determined that brexu-cel had similar ORRs and CR rates compared with other CAR T-cell therapies; the ORR was 88% (95% CI, 86%-90%) for brexu-cel vs 87% (95% CI, 62%-96%) with other CAR T-cell products; the CR rates associated with brexu-cel vs other CAR T-cell therapy options were 73% (95% CI, 67%-78%) and 76% (95% CI, 68%-83%), respectively.

Despite similar efficacy with brexu-cel vs other CAR T-cell therapies, brexu-cel was linked to a higher incidence of CRS and ICANS, particularly grade 3 ICANS; however, brexu-cel showed better short-term efficacy with higher 6-month PFS and OS rates.

Investigators also compared prospective clinical trial data with retrospective and case series data to identify any discrepancies between real-world and clinical trial results by evaluating 456 patients across retrospective studies and 528 patients from prospective studies.

Investigators reported that data from retrospective studies showed an ORR of 91% (95% CI, 88%-93%) and a CR rate of 77% (95% CI, 69%-83%) compared with an ORR of 86% (95% CI: 82%-88%) and a CR rate of 70% (95% CI, 65%-75%) in prospective studies. However, prospective studies demonstrated a 12-month PFS rate of 57% (95% CI, 44%-69%) vs 46% (95% CI, 36%-56%) in retrospective studies; the 12-month OS rate was 80% (95% CI: 54%-94%) for prospective studies vs 61% (95% CI, 47%-73%) in retrospective studies.

The incidence of CRS was similar between prospective and retrospective studies; however, grade 3 CRS was more common in prospective studies. Rates of ICANS were comparable between both.

“Future research should focus on long-term efficacy assessments to optimize treatment strategies and improve overall patient outcomes,” study authors concluded.

References

1. Wan H, Weng S, Sheng S, Kuang Z, Wang Q, Hu L. Chimeric antigen receptor T-cell therapy in relapsed or refractory mantle cell lymphoma: a systematic review and meta-analysis. Front Immunol. 2024;15:1435127. doi:10.3389/fimmu.2024.1435127
2. FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL. FDA. July 24, 2020. Accessed October 11, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl
3. FDA approves lisocabtagene maraleucel for relapsed or refractory mantle cell lymphoma. FDA. May 30, 2024. Accessed October 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-mantle-cell-lymphoma