Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL.

Methods: Retrospective data were collected from 25 centers across the U.S. as part of the real-world outcomes collaborative study of CAR-T in B-ALL (ROCCA). Consecutive patients treated with brexu-cel from 2021 to 2023 were categorized by blinatumomab exposure status. Those exposed were separated into “blinatumomab responders” (B-R), defined as patients achieving a CR/CRi in response to any number of cycles of blinatumomab, and “non-responders” (B-NR). Each cohort was compared for outcomes of interest. The primary outcome was CR/CRi rate at day 28 following brexu-cel administration. Secondary outcomes were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated from day of brexu-cel infusion and were not censored for allogeneic hematopoietic cell transplantation or maintenance therapy. All living patients were censored at data cutoff on June 30, 2023. Survival comparisons were made by log rank test.

Results: Among 152 patients who received brexu-cel, the median follow-up time was 8.4 months. Eighty-eight (57%) of 152 r/r B-ALL brexu-cel recipients had received blinatumomab prior to apheresis. The median number of pre-apheresis blinatumomab cycles was 2 (range 1-12). The baseline characteristics of B-R, B-NR, and blinatumomab-naïve (B-NV) patients were similar, including pre-apheresis disease burden and receipt of maintenance therapy following brexu-cel infusion (Table 1). Seventy percent (N= 62) of the blinatumomab-exposed patients were B-R, while 30% (N=26) were B-NR. Rates of CR/CRi at day 28 following brexu-cel infusion were similar between B-R, B-NR, and B-NV patients (79% vs 84% vs 78%, respectively). Most of these remissions were negative for measurable residual disease (MRD), with similar MRD negativity rates in the three groups (table 2). 1-year DOR and PFS were significantly higher in the B-NV group compared to B-R or B-NR (77% vs 49% vs 50%, p<.0001; 60% vs 37% vs 30%, p<.0001). B-NV and B-R had better 1-year survival compared to B-NR (71% vs 65% vs 32%, p<.0001). There were more CD19-negative relapses following brexu-cel in B-NR (29%) and B-R (18%) compared to B-NV patients (8%), although this was not statistically significant.

Conclusions: Brexu-cel induced deep responses in a majority of adults with r/r B-ALL, irrespective of prior exposure or response to blinatumomab. Similar to data published by the pediatric CAR-T cell groups, our data draw speculation that adult patients who did not respond to blinatumomab experience shorter overall survival following brexu-cel compared to those who responded to or did not receive blinatumomab. This should be confirmed in a larger, prospective clinical trial. Because this analysis could not account for patients who achieved durable remission after blinatumomab, these differences may not reflect superiority of sequencing brexu-cel before blinatumomab. The higher number of CD19-negative relapses in the blinatumomab-exposed cohort add to the interest in pursuing strategies to address antigen escape following CAR-T cell therapy directed against a previously targeted antigen.

Muffly:adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; bms: Research Funding; amgen: Consultancy; orca bio: Research Funding; pfizer: Consultancy; autolus: Consultancy; astellas: Consultancy, Research Funding; jasper: Research Funding; kite: Consultancy, Honoraria, Research Funding. Aldoss:Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy; Sobi: Consultancy; KiTE: Consultancy; Jazz: Consultancy. Lin:Biomarin: Current equity holder in publicly-traded company; Rigel Pharmaceuticals: Consultancy. Schwartz:Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy. Dholaria:Allovir: Research Funding; Lumanity: Consultancy; Angiocrine: Research Funding; Arivan: Consultancy; ADC therapeutics: Consultancy, Honoraria; Gilead: Research Funding; Atara: Research Funding; NCI: Research Funding; Adicet: Research Funding; Wugen: Research Funding; Takeda: Research Funding; Poseida: Research Funding; Molecular Templates: Research Funding; MEI: Research Funding; Pfizer: Research Funding; BEAM therapeutics: Consultancy; gamida cel: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Orca Bio: Research Funding; Poseida: Research Funding; Ellipsis pharma: Consultancy; Boxer Capital: Consultancy; Pluri Biotech: Consultancy; AstraZeneca: Research Funding. Battiwalla:Fate Therapeutics: Research Funding; Novartis: Research Funding. Shaughnessy:BMS: Speakers Bureau; Sanofi: Speakers Bureau. Logan:Amgen, Autolus Therapeutics, Kadmon, Kite, Pharmacyclics, Talaris: Research Funding; AbbVie, Amgen, Actinium, BMS, Pfizer, Sanofi, Takeda: Consultancy. Advani:Seattle Genetics: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Research Funding; Servier: Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria; Kura: Honoraria; OBI: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Kite: Honoraria, Other: consulting, Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nkarta: Honoraria; Incyte: Research Funding; Amgen: Honoraria, Other: advisory board, Research Funding. Hoeg:Orca Bio: Research Funding. Tsai:Bristol Myers Squibb: Speakers Bureau; Jazz Pharmaceutical: Speakers Bureau. Lee:BMS: Honoraria; Kadmon: Honoraria; Fresenius Kabi: Consultancy; Sanofi: Consultancy, Honoraria; Kite Pharma: Honoraria, Speakers Bureau; Incyte Corp: Consultancy, Research Funding. Kota:Novartis: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Incyte: Research Funding. Koura:BMS: Consultancy, Research Funding. Leonard:Pfizer: Consultancy; Kite/Gilead: Consultancy; Takeda: Consultancy; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses. Stock:Amgen: Honoraria; Kite: Consultancy; Kura: Research Funding; Servier: Other: Data Safety Monitoring Board/Advisory Board; Newave: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy. Pullarkat:Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Cassaday:Kite/Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Incyte: 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.. Shah:Moffitt Cancer Center: Current Employment; Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Faramand:Kite: Research Funding; Gilead: Research Funding. Oliai:Pfizer: Research Funding; Jazz Pharmaceuticals: Research Funding; Arog: Research Funding; Novartis: Research Funding; Seagen: Research Funding; Orca Bio: Research Funding.

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