Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity.

Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America.

We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up.

Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate.

Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel.

We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005).

Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6).

Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Disclosures

Valtis:EastRx: Consultancy. Roloff:Kite: Honoraria. Aldoss:Sobi: Other: consulting fees; AbbVie: Other: research support; Pfizer: Honoraria, Other: consulting fees; Kite Pharma: Other: consulting fees; Takeda Pharmaceuticals: Other: consulting fees; Jazz Pharmaceuticals: Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees; Amgen: Honoraria, Other: consulting fees. Sutherland:Orca Bio, Inc.: Consultancy. Advani:BEAM: Other: Research support, Research Funding; OBI: Research Funding; Macrogenics: Research Funding; Immunogen: Research Funding; Servier: Research Funding; MD Education: Honoraria; Amgen: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Springer: Honoraria; American Society of Hematology: Honoraria; MJH Life: Honoraria; Kite: Consultancy, Research Funding; Kura: Research Funding; Novartis: Consultancy; Wolters Kluwer: Honoraria; Web MD: Honoraria; Wiley: Honoraria; Pfizer: Other: Manuscript help, Research Funding; PER: Honoraria; Emmes: Honoraria; Glycomimetics: Research Funding. Luskin:Pfizer: Honoraria; KITE: Honoraria; Jazz: Honoraria; AbbVie: Research Funding; Novartis: Honoraria, Research Funding. Chen:Rigel: Consultancy; AbbVie: Consultancy. Grunwald:Medtronic: Current holder of stock options in a privately-held company; Merck: Research Funding; Janssen: Research Funding; Ajax: Research Funding; Sobi: Consultancy; Servier: Consultancy; Sanofi: Consultancy; Premier: Consultancy; Pfizer: Consultancy; OncLive: Consultancy; Jazz Pharmaceuticals: Consultancy; Incyte Corporation: Consultancy, Research Funding; GSK: Consultancy; Genetech: Consultancy; Daiichi Sankyo: Consultancy; Cardinal Health: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Astellas Pharma: Consultancy; Aptitude Health: Consultancy; Amgen: Consultancy. Leonard:France Foundation: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, accommodations, and expenses; Pfizer: Consultancy, Honoraria; Takeda: Consultancy; Kite/Gilead: Consultancy. Yaghmour:USC Keck School of Medicine: Current Employment; Pharmacyclics: Research Funding; Abbvie: Other: Advisory Board; Daiichi: Other: Advisory Board; Astazeneca: Other: Advisory Board; GSK: Speakers Bureau; Rigel: Speakers Bureau; Servier: Speakers Bureau; Jazz: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Kite: Speakers Bureau; SOBI: Speakers Bureau; Incyte: Speakers Bureau; Secura Bio: Speakers Bureau; Astellas: Speakers Bureau; Blueprint: Speakers Bureau; ABBVie: Speakers Bureau; Stemline therapeutic: Speakers Bureau; Alexion: Other: consult. Tsai:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz, Sanofi: Honoraria. Stock:Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Adaptive: Consultancy, Honoraria. Logan:Talaris: Research Funding; Sanofi: Consultancy; Pfizer: Consultancy; Autolus: Research Funding; Takeda: Consultancy; Actinium: Consultancy; Pharmacyclics: Research Funding; Kadmon/Sanofi: Research Funding; Bristol Myers Squibb: Consultancy; Kite: Consultancy; Kite/Gilead: Research Funding; AbbVie: Consultancy; Amgen: Consultancy, Research Funding; Astellas Pharma: Research Funding. Bezerra:Kite: Consultancy, Other: Travel, Accomodations, Expenses Support; Kyverna: Consultancy, Other: Travel, Accomodations, Expenses Support; Novartis: Consultancy. Vasu:Alexion Inc: Speakers Bureau; Sanofi: Research Funding. Battiwalla:Kite/Gilead: Research Funding; Astra Zeneca/Gracell: Research Funding; JNJ/Janssen: Research Funding; Fate Therapeutics: Research Funding. Ulrickson:Miltenyi Biomedicine: Honoraria; ADC Therapeutics.: Consultancy; Bristol Myers Squibb: Consultancy; Stemline: Consultancy; Autolus: Consultancy. Reshef:Abbvie: Research Funding; TScan: Consultancy, Research Funding; TCR2: Research Funding; Sana Biotechnology: Consultancy; Immatics: Research Funding; Autolus: Consultancy; Synthekine: Research Funding; J&J: Research Funding; Genentech: Research Funding; Precision Biosciences: Research Funding; Sanofi: Research Funding; Atara Biotherapeutics: Research Funding; Bayer: Consultancy; Gilead Sciences: Consultancy, Research Funding; Quell Biotherapeutics: Consultancy; CareDx: Research Funding; Cabaletta: Research Funding; BMS: Research Funding; Takeda: Research Funding; Orca Bio: Consultancy; Incyte: Consultancy, Research Funding; Allogene: Consultancy. Cassaday:Pfizer: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Honoraria, Research Funding; Jazz: Consultancy; Incyte: Research Funding; Autolus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Seagen: Ended employment in the past 24 months; Servier: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding. Hill:Kite/Gilead: Speakers Bureau; March Biosciences: Consultancy. Lee:ScientiaCME: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Aptitude Health: Consultancy; SEI: Consultancy; Incyte: Consultancy, Honoraria, Research Funding. Kota:Novartis: Honoraria; Pfizer: Honoraria; Kite Pharma: Honoraria. Sasine:Kite Pharma: Consultancy; Genmab: Consultancy; Autolus: Consultancy. Merchant:Innate Pharma: Research Funding; Abbvie: Consultancy, Speakers Bureau; Oncovalent: Consultancy, Research Funding; Amgen: Consultancy; Genmab: Consultancy, Speakers Bureau; IMMpact Bio: Research Funding; BMS: Speakers Bureau. Pullarkat:Jazz: Speakers Bureau; Sobi: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria; Rigel: Consultancy, Honoraria. Hilal:BeiGene: Consultancy, Research Funding. Faramand:Autolus: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria; Orca Bio: Research Funding; Novartis: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Solh:GlaxoSmithKline: Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Sanofi: Consultancy. Majhail:Caribou Biosciences: Research Funding; Anthem: Consultancy. Hoeg:Orca Bio: Research Funding. Oliai:Orca Bio: Research Funding; Pfizer: Research Funding; Arog: Research Funding; Ascentage: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Research Funding; Roche: Research Funding; University of California, LA: Current Employment. Koura:BMS: Other: ad board. Bachanova:Gamida Cell: Research Funding; Incyte: Research Funding; Citius: Research Funding; CRISPR: Consultancy; Astra Zeneca: Consultancy; Allogene: Consultancy; Miltenyi: Other: DSMB. Oluwole:Gilead Sciences: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Nektar: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; Caribou Biosciences: Consultancy; Bioheng: Consultancy; Allogene: Research Funding; Daichi Sankyo: Research Funding; TGR: Consultancy; Cargo: Consultancy; ADC: Consultancy, Speakers Bureau; Epizyme: Consultancy. Shaughnessy:Autolus, Sanofi: Consultancy; BMS: Speakers Bureau; Sanofi: Speakers Bureau. Shah:Jazz Pharmaceuticals: Consultancy; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy; Pepromene Bio: Other: DSMB; Kite Pharma: Consultancy; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Adaptive Biotechnologies: Consultancy. Muffly:Bristol Myers Squibb: Consultancy; Jasper: Research Funding; Vor: Consultancy, Research Funding; Autolus: Consultancy; Pfizer: Consultancy; Wugen: Research Funding; Adaptive: Research Funding; Cargo Therapeutics: Consultancy; Astellas: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Park:Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Curocell: Current equity holder in publicly-traded company; Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy; Takeda: Consultancy.

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