Introduction

In October 2021, brexucabtagene autoleucel (brexu-cel) received U.S. FDA approval as the first CAR T-cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) based on the 55-patient ZUMA-3 Phase II study. We subsequently established ROCCA and now report on the largest cohort of patients treated with commercial brexu-cel for r/r B-ALL to date.

Methods

Adults (18+) with r/r B-ALL infused with commercial brexu-cel across 25 U.S. institutions were included. ASTCT consensus criteria were used to score CRS and ICANS. Methodologies for assessing MRD (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institution practice. Duration of remission (DOR) was calculated from time of complete response (CR); progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023.

Results

Among 152 infused, the median age was 46 (range, 18-81), 57% were male, and 34% were Hispanic. Most (67%) had Ph- ALL, were heavily pre-treated (median 4 prior lines), and entered apheresis with high disease burden (57%). At time of apheresis, 23% of patients only had MRD+ disease and 15% were in complete molecular remission. While 82% developed CRS, the majority was grade 1-2, with 9% of the overall cohort experiencing grade 3-4 CRS. In contrast, 55% developed ICANS, with 32% of the entire cohort experiencing grade 3-4 ICANS. Eight patients (5%) died of toxicity/infection prior to D+28 response assessment.

Among 133 patients with response assessment, 120 (90%) achieved morphologic CR, of whom 82% were MRD-, 15% were MRD+, and 3% MRD unknown. The median follow-up for survivors was 8.4 months; 45 patients have relapsed and 42 patients died. Median DOR was not reached. Median PFS and OS were 8.6 months and 15.6 months, respectively. Estimated PFS and OS of the entire cohort at 6-months were 61% (95% CI, 52-68) and 81% (95% CI, 73-87) and at 12-months were 47% (95% CI, 37-56) and 63% (95% CI, 53-72), respectively. We found no association between pre-CAR disease burden and post-CAR PFS/OS. However, patients with MRD- response to CAR had superior PFS relative to patients with MRD+ CR (median 14 months vs. 5 months, P=0.002). Forty-four patients received post-CAR consolidation/maintenance therapy while in CR: 25 allogeneic HCT, 15 TKI, 2 POMP, and 3 other/unknown. To examine the effect of consolidation/maintenance following brexu-cel, we performed a landmark analysis of PFS limited to patients alive and in CR at 2-months post-CAR infusion (N=113) and suggests superior PFS in patients receiving either HCT or other forms maintenance, relative to those receiving no further therapy following brexu-cel ( P=0.055). We then investigated post-CAR MRD-response in combination with receipt of post-CAR consolidation/maintenance and found that even among patients achieving MRD-negative response, post-CAR consolidation/maintenance led to superior PFS (Figure 1).

Conclusions

Among 152 adults treated with commercial brexu-cel for r/r B-ALL across 25 U.S. institutions, we found very high response rates (CR/CRi: 90%; 82% MRD-) consistent with the Zuma-3 data. While rates of severe CRS are low, grade 3-4 ICANS was observed in 32% of patients and warrants further investigation We demonstrate the prognostic impact of achieving an MRD-negative CR and an emerging role for consolidation/maintenance therapies to enhance the durability of response following brexu-cel in adults r/r B-ALL.

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

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2023
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