Introduction:
Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Bridging therapy, defined as anti-leukemia therapy given between apheresis and lymphodepleting chemotherapy, was permitted on the pivotal ZUMA-3 trial. The optimal bridging therapy is unknown in this setting. Here we report patient and disease characteristics in those receiving bridging therapies prior to brexu-cel and the impact of bridging on clinical outcomes in a large multicenter cohort.
Methods and Results:
ROCCA includes 25 US institutions contributing retrospective data from 152 B-ALL patients treated with standard of care brexu-cel between 2021-2023. Ninety-nine patients (65%) received bridging therapy, while 53 patients (35%) received no bridging therapy. Bridging therapy consisted of cytotoxic chemotherapy ( n=65, 66%), immunotherapy ( n=26, 26%; 23 inotuzumab, 3 blinatumomab), tyrosine kinase inhibitors (TKI) ( n=20, 20%; 16 ponatinib), steroids only ( n=10, 10%), and intrathecal chemotherapy ( n=22, 22%).
The median age of the cohort was 46 (IQR 32-61). Patients were heavily pre-treated with a median of 4 prior lines of therapy. The median days from apheresis to infusion was 33 (IQR 26-42). 119 patients had known pre-apheresis blast counts; the bridging group had higher pre-apheresis blast burden, with 21 of 76 patients (28%) having ≥ 50% blasts compared to only 5 of 43 patients (12%) in the no bridging group ( p=0.02). In addition, more patients who received bridging had pre-apheresis extramedullary disease (32% vs. 15%, p=0.02). All other baseline characteristics were similar between the two groups (Table 1).
Fifty-four (54%) patients had response assessment after bridging therapy and prior to brexu-cel infusion. In patients who received inotuzumab for pre-apheresis active disease, defined as ≥ 5% blasts, 6 of 13 (46%) who had post-bridging assessment achieved a complete response (CR; 5 measurable residual disease (MRD)+, 1 MRD-), with a mean proportional reduction in blast burden of 46% from baseline. In contrast, after chemotherapy bridging, only 2 of 16 patients (13%) with pre-apheresis active disease had a CR. Patients receiving chemotherapy bridging had a mean proportional increase in blast burden of 4.4%. In recipients of TKI bridging, 2 of 4 patients (50%) with pre-apheresis active disease had a CR.
Compared to no bridging, patients in the bridging group had similar rates of grade 3 or 4 CRS (9% bridging vs. 8% no bridging, p=0.73) and grade 3 or 4 ICANS (34% vs. 26%, p=0.32). In univariate analysis, there was no statistically significant difference in day 28 response with 63 patients (72%) achieving MRD- complete response in the bridging group as compared to 36 patients (78%) in the no bridging group ( p=0.60). Non-relapse mortality was similar between the two groups (17% bridging vs. 9% no bridging, p=0.20). Overall survival (OS) and progression-free survival (PFS) were superior in the no bridging group: 1-year OS 74.7% vs 56.8% (log-rank p=0.04), and 1-year PFS 57.3% vs 41.7% (log-rank p=0.04). In a multivariate analysis stratified by bridging and pre-apheresis disease burden, patients with pre-apheresis blasts ≥ 5% and bridging had worse survival than ≥ 5% blasts and no bridging: 1-year OS 45.3% vs. 87.5% and 1-year PFS 27.7% vs. 64.3% (Figure 1). However, patients with < 5% blasts had similar survival regardless of bridging.
Conclusions:
In our real-world analysis, adults with R/R B-ALL receiving bridging therapy had a higher disease burden at baseline. Despite greater baseline disease, there were no significant differences in toxicity and day 28 response in those receiving bridging therapy vs. not. While survival was inferior in patients with pre-apheresis active disease who received bridging, this may be confounded by the degree of tumor burden. In patients with < 5% blasts pre-apheresis, bridging did not impact survival. Furthermore, inotuzumab bridging demonstrated the most significant disease debulking. However, the comparisons in this study are limited by the variability in practice for post-bridging disease reassessment and the small proportion of patients with active disease who did not receive bridging. A more uniform approach to peri-CAR disease assessment would enable more robust study of optimal bridging strategies.
Disclosures
Lin:Rigel Pharmaceuticals: Consultancy; Biomarin: Current equity holder in publicly-traded company. Tsai:Bristol Myers Squibb: Speakers Bureau; Jazz Pharmaceutical: Speakers Bureau. Aldoss:Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Takeda: Consultancy; Jazz: Consultancy; Sobi: Consultancy; KiTE: Consultancy. Dholaria:ADC therapeutics: Consultancy, Honoraria; Gilead: Research Funding; Wugen: Research Funding; Pfizer: Research Funding; BEAM therapeutics: Consultancy; MEI: Research Funding; Atara: Research Funding; NCI: Research Funding; Orca Bio: Research Funding; Poseida: Research Funding; Allovir: Research Funding; Molecular Templates: Research Funding; Boxer Capital: Consultancy; Pluri Biotech: Consultancy; Lumanity: Consultancy; AstraZeneca: Research Funding; Ellipsis pharma: Consultancy; Adicet: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; Arivan: Consultancy; gamida cel: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Poseida: Research Funding. Logan:AbbVie, Amgen, Actinium, BMS, Pfizer, Sanofi, Takeda: Consultancy; Amgen, Autolus Therapeutics, Kadmon, Kite, Pharmacyclics, Talaris: Research Funding. Solh:Bristol-Myers Squibb: Speakers Bureau. Schwartz:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy. Battiwalla:Novartis: Research Funding; Fate Therapeutics: Research Funding. Shaughnessy:BMS, Sanofi: Speakers Bureau; Autolus Therapeutics, BMS: Honoraria. Mountjoy:Colorado Blood Cancer Institute: Current Employment. Advani:Servier: Research Funding; Kite: Honoraria, Other: consulting, Research Funding; Immunogen: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; OBI: Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria; 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; Kura: Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Macrogenics: Research Funding; Amgen: Honoraria, Other: advisory board, Research Funding. Hoeg:Orca Bio: Research Funding. Lee:Fresenius Kabi: Consultancy; Kite Pharma: Honoraria, Speakers Bureau; BMS: Honoraria; Sanofi: Consultancy, Honoraria; Kadmon: Honoraria; Incyte Corp: Consultancy, Research Funding. Kota:Kite: Honoraria; Novartis: Honoraria; Incyte: Research Funding; Pfizer: Honoraria. Koura:BMS: Consultancy, Research Funding. Leonard:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy; Kite/Gilead: Consultancy; Takeda: Consultancy. Oliai:Novartis: Research Funding; Arog: Research Funding; Orca Bio: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Seagen: Research Funding. Bachanova:Citius: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; 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:Kite: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy; Amgen: Honoraria; Kura: Research Funding; Servier: Other: Data Safety Monitoring Board/Advisory Board; Newave: Honoraria. Pullarkat:Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Cassaday:Merck: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Jazz: Consultancy, Honoraria; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.. Muffly:amgen: Consultancy; pfizer: Consultancy; bms: Research Funding; adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; kite: Consultancy, Honoraria, Research Funding; autolus: Consultancy; astellas: Consultancy, Research Funding; orca bio: Research Funding; jasper: Research Funding. Shah:Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; Moffitt Cancer Center: Current Employment; 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:Gilead: Research Funding; Kite: Research Funding.
