CD19 CAR-T therapy has revolutionized the management of high-risk and relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but remains limited by significant toxicities leading to morbidity/mortality and high resource utilization. Single-arm studies have suggested differences in efficacy and toxicity across FDA-approved CD19 CAR-T products. A matching-adjusted indirect treatment comparison showed comparable efficacy and more favorable safety with lisocabtagene maraleucel (liso-cel) compared to axicabtagene ciloleucel (axi-cel), but was limited to clinical trial patients (pts) and suffered from an absence of patient-level data (Maloney, J Hematol Oncol, 2021). In the absence of randomized clinical trial data, adjusted comparative analyses using pt-level data are critically needed to guide product choice. Therefore, we retrospectively evaluated the impact of CAR-T product type on the outcomes of 129 LBCL pts receiving liso-cel or axi-cel per standard of care.

All LBCL pts treated at our center with liso-cel or axi-cel outside of a clinical trial between 1/2018 and 5/2023 were included. Best response was determined within 3 months of CAR-T infusion by PET-CT imaging per Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) were graded using ASTCT criteria.

Of 129 total pts, 37% (n=48) and 63% (n=81) received liso-cel and axi-cel, respectively. Seven pts received out-of-specification liso-cel on an expanded access protocol. Pts who received liso-cel were older (median 67 vs 62 years, p=.003). Other baseline characteristics, including male sex (liso-cel vs axi-cel: 63% vs 69%, p=.4), HCT-CI score (1.0 vs 1.0, p=.6), pre-lymphodepletion (LD) LDH (178 vs 214 U/L, p=.14) and ALC (0.65 vs 0.60 x 10³/µL, p=.3), largest lesion diameter (3.1 vs 3.0 cm, p=.4), and extranodal disease (56% vs 56%, p>.9) were similar. The vein-to-vein time (time from leukapheresis to CAR-T infusion) was longer for liso-cel: median, 35 vs 27 days (p<.001). After liso-cel, the total inpt duration was shorter (median, 5 vs 14 days, p<.001) and fewer pts had ≥2 admissions (8.3% vs 22%, p=0.043). In pts with measurable disease prior to LD (n=113), we observed comparable efficacy with liso-cel vs axi-cel: ORR, 82% vs 77% (p=.5); CR, 56% vs 51% (p=.8). After a median follow-up of 17.7 months, we observed comparable 1-year outcomes with liso-cel vs axi-cel: duration of response (DOR), 56% vs 61% (p=.7); progression-free survival (PFS), 47% vs 47% (p=.99; Figure); and overall survival (OS), 69% vs 60% (p=.39).

In pts evaluable for toxicity assessment (n=129), liso-cel was associated with lower rates of CRS and ICANS compared to axi-cel: any grade CRS, 62% vs 88% (p=.001); ICANS any grade, 32% vs 56% (p=.010); days with fever, median 2 vs 5 days (p<.001). Grade 3-4 CRS, 2.1% vs 9.9% (p=.2) or grade 3-4 ICANS, 23% vs 19% (p=0.5) were similar. We measured lower peak serum inflammatory markers after liso-cel: CRP, 58 vs 114 mg/L (p<.001); ferritin, 622 vs 1,315 ng/mL (p=0.007); IL-6, 55 vs 204 pg/mL (p=.010); and D-dimer, 1.4 vs 2.4 mg/L (p=.017). The incidence of infectious complications after liso-cel vs axi-cel was as follows: bacteremia: 6% vs 9% (p=.7); CMV viremia: 13% vs 6.2% (p=.3). Post-infusion median nadir cytopenias were less severe after liso-cel: ANC, 0.32 vs 0.04 x 10³/µL (p<.001); Plt, 69 vs 35 x 10³/µL (p=.003); and Hgb, 8.9 vs 8.2 g/dL (p<.001). Fewer pts developed severe neutropenia after liso-cel: 72% vs 93% (p=0.002).

In multivariable analysis including pre-LD LDH and ALC, largest lesion diameter, age and HCT-CI score, we could not confirm an independent impact of the product type on CR, PFS, or OS ( Table). However, axi-cel remained independently associated with a higher odds of any grade CRS (adjusted OR [aOR] 4.56, 95% CI 1.65-13.5, p=.004) and any grade ICANS (aOR 3.44, 95% CI 1.42-8.85, p=.008).

Our analysis of CD19 CAR-T therapy for R/R LBCL in the non-trial setting showed similar rates of durable responses following liso-cel and axi-cel. Pts who received liso-cel were older, with otherwise comparable baseline characteristics. Although liso-cel was associated with less toxicity, its vein-to-vein time was longer. In multivariable analyses, pre-LD LDH and largest lesion diameter were the only factors independently associated with response outcomes. We conclude that liso-cel is a robust alternative to other CD19 CAR-T products in older and frailer LBCL pts.

Hirayama:Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. Kimble:Juno/BMS: Research Funding. Iovino:Mustang Bio: Current equity holder in publicly-traded company. Poh:Incyte: Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy; Acrotech: Consultancy. Gopal:Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding. Shadman:Bristol Myers Squibb: Consultancy, Research Funding; Regeneron: Consultancy; ADC therapeutics: Consultancy; MorphoSys/Incyte: Consultancy, Research Funding; Vincerx: Research Funding; Mustang Bio: Consultancy, Research Funding; Fate Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Eli Lilly: Consultancy; Genmab: Consultancy, Research Funding. Till:BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Kiem:Rocket Pharmaceuticals: Consultancy; Ensoma: Consultancy; Homology Medicines: Consultancy; V.O.R. Biopharma: Consultancy; Magenta Therapeutics: Consultancy; CSL Behring: Consultancy. Milano:ExCellThera Inc.: Research Funding. Chapuis:Juno Therapeutics: Research Funding. Cassaday:Incyte: Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Autolus: Membership on an entity's Board of Directors or advisory committees; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.. Maloney:Legend Biotech: Consultancy, Honoraria, Research Funding; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; Amgen: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board , Research Funding; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Bioline Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board ; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board; Lyell Immunopharma: Other: Member, CAR T Steering Committee. Gauthier:Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Angiocrine Bioscience: Research Funding; Century Therapeutics: Other: Independent data review committee; Janssen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Celgene (a Bristol Myers Squibb company): Research Funding; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding.

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2023
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