Correlation between Peak Absolute Lymphocyte Count Post Brexucabtagene Autoleucel Infusion and Outcomes in Mantle Cell Lymphoma

Background:

In the ZUMA2 study, a higher peak chimeric antigen receptor (CAR) T cell expansion correlated with better outcomes in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving brexucabtagene autoleucel (brexu-cel). However, in clinical practice, peak CAR T cell expansion is not routinely assessed for. Since patients receive lymphodepleting agents prior to CAR T cell infusion, it is hypothesized that peak absolute lymphocyte count (ALC), which can be easily measured, in the first two weeks after CAR T cell infusion represents peak CAR T cell expansion. Our group previously showed that peak ALC was associated with response durability and outcomes in patients with R/R large B-cell lymphoma receiving axicabtagene ciloleucel. In this retrospective study, we assessed the association of peak ALC with clinical outcomes after brexu-cel infusion in patients with R/R MCL.

Methods:

Patients with R/R MCL who received brexu-cel between March 2020-March 2024 at Mayo Clinic were included in this analysis. Peak ALC was defined as maximum ALC value in the first 14 days after CAR T cell infusion. Progression-free survival (PFS) was defined as time from CAR T cell infusion to lymphoma relapse, progression, or death, and overall survival (OS) was defined as time from to CAR T cell infusion to death. The optimal cutoff point for peak ALC that correlated with PFS was determined by the log-rank method using the Cutoff Finder application, a computational method which fits Cox proportional hazard models to the dichotomized variable and survival. The optimal cutoff was the point with the most significant PFS split by log-rank test.

Results:

A total of 43 patients were identified. The median age at time of CAR T cell infusion was 68 years (IQR 58, 73). 34 (79%) were male, 28 (74%) had Ki-67 >30%, 14 (33%) had blastoid or pleomorphic histology, and 19 (44%) had TP53 mutation or deletion. Median number of prior lines of therapy was 3 (IQR 2, 4) and 13 (30%) received prior autologous stem cell transplant. 32 (74%) received bridging therapy prior to CAR T cell infusion. All patients received fludarabine plus cyclophosphamide for lymphodepletion. The best overall response rate was 88%, with a complete response rate of 84%. After a median follow-up of 25.6 months (95% CI 14.4-31.4), the median PFS and OS were 16.6 (95% CI 8.6-NE) and 35.1 (95% CI 24.5-NE) months, respectively. The incidence of cytokine release syndrome (CRS) was 95% (4.7% grade ≥3). The median time to initial CRS and maximum grade CRS onset was 4.5 days (IQR 1, 6.25) and 5.5 days (IQR 2.75, 7), respectively. The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 65% (18% grade ≥ 3). The median time to initial and maximum grade ICANS onset was 9 days (IQR 6, 11) and 10.5 days (IQR 7, 12), respectively.

The median ALC at time of CAR T cell infusion was 0.03 x10⁹/L (IQR 0.02, 0.05). Among 37 patients with identifiable ALC peaks, the median ALC peak was 0.84 (IQR 0.41, 2.45) and the median time to peak ALC was 12 days (IQR 9, 12). 6 patients had no identifiable peak ALC due to no frequent CBC differentials post CAR T cell infusion. A peak ALC of ≥0.45 × 10⁹/L correlated significantly with PFS, with median PFS not reached for the group with peak ALC of ≥0.45 × 10⁹/L (n=27) compared to 9.3 months for the group with peak ALC of <0.45 × 10⁹/L (n=10) and a 1-year PFS rate of 68% vs 33% (p=0.02). OS was also significantly higher in patients with a peak ALC of ≥0.45 × 10⁹/L (median OS not reached vs 11 months, 1-year OS rate of 84% vs 44%, p=0.01). The incidence of ICANS was significantly higher (74% vs 30%, p=0.02) in patients with a peak ALC of ≥0.45 × 10⁹/L. Numerically, the group with peak ALC of ≥0.45 × 10⁹/L had a later onset of initial and maximum grade ICANS, but the difference was not statistically significant. Peak ALC was not associated with ICANS severity. There was a trend towards higher incidence of CRS (100% vs 80%, p=0.07) and earlier CRS onset (3 vs 5 days, p=0.07) in the high peak ALC group. There was no difference in CRS severity.

Conclusion:

Peak ALC after CAR T cell infusion was significantly associated with better PFS and OS and higher incidence of ICANS in patients with R/R MCL receiving brexu-cel. Peak ALC may serve as a surrogate measure for peak CAR T cell expansion in routine practice, but confirmatory studies are needed. Larger studies are warranted to confirm the association of peak ALC with PFS, OS and toxicities in patients with R/R MCL receiving brexu-cel.

Munoz:Verastem: Consultancy, Research Funding; Aurobindo: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Research Funding; Fosunkite: Consultancy; Alexion: Consultancy; Kyowa: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Research Funding; MEI: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Eli Lilly: Consultancy; Bayer: Consultancy, Research Funding; Merck: Research Funding; Portola: Research Funding; Curio: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Genmab: Consultancy; Genzyme: Consultancy; ADC Therapeutics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Targeted Oncology: Honoraria; Alexion: Consultancy; BeiGene: Consultancy; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis,: Consultancy; Gilead/Kite: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding; Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding. Paludo:AbbVie: Membership on an entity's Board of Directors or advisory committees; Biofourmis: Research Funding; AstraZeneca: Research Funding; Karyopharm: Research Funding. Alhaj Moustafa:AbbVie: Consultancy. Villasboas Bisneto:Regeneron: Research Funding; Genentech: Research Funding; Epizyme: Research Funding; Enterome: Research Funding; CRISPR: Research Funding; Aptose: Research Funding. Rosenthal:RMEI, Curio Science, Targeted Oncology, OncLiveU: Other: Educational Workshop Speaker Role. Iqbal:Sanofi US: Consultancy. Kharfan-Dabaja:Kite Pharma: Honoraria; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Bennani:Pfizer: Membership on an entity's Board of Directors or advisory committees; Acrotech Biopharma LLC: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ansell:SeaGen: Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; Pfizer: Research Funding. Lin:Janssen: Consultancy, Research Funding; Legend: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; NexImmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Regeneron: Consultancy. Wang:InnoCare, AbbVie: Consultancy; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board; Kite: Honoraria.