{"doi":"10.1002/hon.70093_140","title":"140 | PHASE 2 TRIAL OF LISOCABTAGENE MARALEUCEL (LISO‐CEL) IN COMBINATION WITH ACALABRUTINIB IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMAS (LBCL)","abstract":"Background: Liso-cel is an autologous anti-CD19 CAR-T cell which produces durable remissions in relapsed/refractory LBCL where it is FDA approved in both the 2nd line and 3rd line+ settings. Bruton tyrosine kinase inhibitors (BTKi) are a promising strategy to improve CAR-T cell outcomes. The second generation BTKi acalabrutinib combined with liso-cel demonstrated improved CAR-T cell function in mouse models. Methods: We conducted a phase II clinical trial of acalabrutinib plus liso-cel at two academic medical centers. Eligible patients had LBCL with an FDA-approved indication for liso-cel with an ECOG performance status of 0–2 and adequate organ function. Patients received a two week lead-in of acalabrutinib 100 mg orally BID prior to leukapheresis and then could continue acalabrutinib as bridging therapy or switch to an alternative bridging therapy at the discretion of their treating investigator. All patients stopped acalabrutinib at least 24 hours prior to fludarabine/cyclophosphamide lymphodepletion followed by standard liso-cel dosing. Acalabrutinib was resumed on day +14 and continued for up to 1 year. The primary endpoint was best CRR, and the study was designed with a CRR of at least 73% considered promising. Results: 28 patients were enrolled; 1 was subsequently found to be ineligible and did not receive protocol therapy (N = 27). Among 27 patients, median age was 69 years (range: 28–85, 44% > 70) and 52% were female. The most common histology was DLBCL (92.6%), followed by PMBCL (3.7%) and follicular large cell lymphoma (3.7%). 59% of patients had non-GCB cell of origin. The majority (70%) had advanced stage disease, and 7% had active secondary central nervous system involvement. 52% had high-risk IPI score (3+) and 44% had elevated baseline LDH. 78% had 1 prior line of therapy and 26% had primary refractory disease. Acalabrutinib was used as sole bridging therapy in 56%, and 44% received alternate bridging. The ORR to acalabrutinib monotherapy lead-in was 33% (22% CRR). All patients were able to receive liso-cel. The primary endpoint was met, with a best ORR and CRR to liso-cel plus acalabrutinib of 93% and 81%, respectively. Patients with relapsed disease to the most recent therapy were more likely to achieve a CR (95% vs. 43%, p = 0.009). With a median follow up of 9.9 months, the 6 month PFS and DOR rates were both 74% (Figure 1). With liso-cel, 59% experienced CRS (0% grade 3+), and 26% experienced ICANS (11% grade 3, no grade 4). Prolonged (> 30 days) neutropenia and thrombocytopenia occurred in 7% and 4% of patients, respectively. 15% of patients experienced grade 3 infections. 1 patient (4%) had a grade 1 intracranial hemorrhage, and 2 (7%) had grade 2 atrial fibrillation. There have been no fatal adverse events. Conclusion: Acalabrutinib plus liso-cel demonstrated encouraging efficacy outcomes and was well-tolerated. Future work will examine correlative data to understand the potential mechanisms underlying efficacy. Research funding declaration: Funded by AstraZeneca Keywords: cellular therapies; aggressive B-cell non-Hodgkin lymphoma; combination therapies Potential sources of conflict of interest: P. C. Johnson Consultant or advisory role: ADC Therapeutics, Abbvie, AstraZeneca, BMS, Seagen, Incyte Other remuneration: Research-AstraZeneca, Novartis, Medically Home J. E. Arnason Honoraria: Bristol Myers Squibb and Regeneron J. D. Soumerai Consultant or advisory role: AstraZeneca, Bristol Myers Squibb, Genentech/Roche, and Loxo@Lilly Other remuneration: Research funding from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics M. J. Frigault Consultant or advisory role: Novartis, Kite, BMS, Iovance, Cytoagents, JNJ/Legend J. S. Abramson Consultant or advisory role: AbbVie, ADC Therapeutics, Astra-Zeneca, BeiGene, BMS, Celgene, Foresight Diagnostics, Genentech, Gilead, Interius, Miltenyi Biotec, Novartis, Roche, Seagen Other remuneration: Resear","journal":"Hematological Oncology","year":2025,"id":568661,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":481408,"name":"Jon Arnason","orcid":"0000-0001-9038-7277","position":1,"is_corresponding":false},{"id":250460,"name":"Robert Redd","orcid":"0000-0002-1329-5288","position":2,"is_corresponding":false},{"id":289515,"name":"J. Erika Haydu","orcid":"0000-0003-2463-0560","position":3,"is_corresponding":false},{"id":232465,"name":"Jacob D. Soumerai","orcid":"0000-0002-3062-6819","position":4,"is_corresponding":false},{"id":1447146,"name":"Jeffrey A. Barnes","orcid":"0000-0002-4867-1909","position":5,"is_corresponding":false},{"id":1241841,"name":"Ronald W. Takvorian","orcid":null,"position":6,"is_corresponding":false},{"id":1473806,"name":"G. Koutoujian","orcid":null,"position":7,"is_corresponding":false},{"id":1473807,"name":"K. Valencia","orcid":null,"position":8,"is_corresponding":false},{"id":927,"name":"Mark E. Cooper","orcid":"0000-0001-7785-2488","position":9,"is_corresponding":false},{"id":1473808,"name":"M. Frigault","orcid":null,"position":10,"is_corresponding":false},{"id":258324,"name":"Jeremy S. Abramson","orcid":"0000-0001-8467-9257","position":11,"is_corresponding":false},{"id":1473805,"name":"P. C. Johnson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}