{"doi":"10.1002/ajh.27639","title":"<scp>BTK</scp> Inhibitors Versus Venetoclax as First‐ or Second‐Line Therapy in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Real‐World Evidence Study","abstract":"Targeted therapies (e.g., Bruton tyrosine kinase inhibitors [BTKi; ibrutinib, acalabrutinib, zanubrutinib] or B-cell lymphoma-2 inhibitors [BCL-2i; venetoclax]) with or without anti-CD20 monoclonal antibodies (CD20 mAb), have demonstrated consistent survival benefits versus chemoimmunotherapy (CIT) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the front-line (1L) and relapsed/refractory (R/R) settings (summarized in Eichhorst et al. [1]). However, there are currently no prospective data comparing BTKi-based and venetoclax-based therapies directly, and information to guide optimal sequencing strategies for targeted agents is limited [2-4]. An improved understanding of the comparative effectiveness of BTKi and BCL-2i in both 1L and R/R settings, in novel agent–naive and exposed patients, is needed to guide treatment sequencing decisions. To better understand the performance of targeted agents, we conducted a retrospective, observational cohort analysis to evaluate clinical outcomes of comparable patients with CLL/SLL who received either BTKi monotherapy or BCL-2i+CD20 mAb in 1L or second-line (2L) settings. This study used Flatiron Health electronic health record-derived de-identified data from August 1, 2014 to February 28, 2022. Adult patients (≥ 18 years) with CLL/SLL were included if they received BTKi monotherapy (acalabrutinib or ibrutinib) or BCL-2i (venetoclax) in combination with a CD20 mAb in the 1L or 2L setting and had 2 or more clinical encounters during the study period. The study compared time-to-next-treatment-or-death (TTNTD; defined as time from initiation of the current treatment to the starting time of a new line of therapy or death) for patients treated with BTKi monotherapy versus BCL-2i+obinutuzumab (1L), or BTKi monotherapy versus BCL-2i+CD20 mAb (ofatumumab, rituximab, or obinutuzumab) (2L). Kaplan–Meier analysis was used to obtain unadjusted TTNTD curves for each of the cohorts. TTNTD was descriptively compared between cohorts using a Cox proportional-hazards model to estimate adjusted hazard ratios (HR). Propensity score matching (PSM) was used to improve the comparability between cohorts and reduce the effects of confounding. Each patient treated with BCL-2i+obinutuzumab (1L) or BCL-2i+CD20 mAb (2L) was matched with two patients treated with BTKi monotherapy in each setting. PSM balanced key demographic and disease characteristics: age, gender, race, Rai stage, time from diagnosis to index date, del(17p), del(11q), and immunoglobulin heavy chain variable region (IGHV) mutational status, Eastern Cooperative Oncology Group performance status, total number of therapy lines received during the study period, and prior novel agent exposure. Inverse probability of treatment weighting (IPTW) was used as an alternative to PSM to control for potential confounding and reduce noncomparability between cohorts (Supporting Information Methods). A total of 14 602 CLL/SLL patients were included, among whom 6065 unique patients had 6743 treatment episodes that included BTKi monotherapy or BCL2i+CD20 mAb; some patients received both treatments. A total of 3643 patients in the 1L setting and 1772 patients in the 2L setting met the inclusion criteria (Figure S1). In the 1L setting, 93.2% (n = 3397) received BTKi monotherapy and 6.8% (n = 246) received BCL-2i+obinutuzumab. In the 2L setting, 84.4% (n = 1496) received BTKi monotherapy and 15.6% (n = 276) received BCL-2i+CD20 mAb. After applying PSM, the two cohorts were well balanced on all selected matched baseline and disease characteristics in 1L (n = 738) (Table S1) and 2L (n = 828) settings (Table S2). In the 1L setting, the median age across cohorts was 67 years (interquartile range [IQR] 59.0–74.0), and 26.8% were female. In the 2L setting, the median age across cohorts was 70 years (IQR 63.0–77.0), 32.9% were female, and 32.6% had prior treatment with novel agents. In the 2L BTKi-treated cohort, 172 (31.2%) had received a prio","journal":"American Journal of Hematology","year":2025,"id":540384,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"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":603455,"name":"Yi Han","orcid":"0000-0002-0943-613X","position":1,"is_corresponding":false},{"id":1428500,"name":"Anna Teschemaker","orcid":null,"position":2,"is_corresponding":false},{"id":233532,"name":"Anthony R. Mato","orcid":"0000-0001-8724-1875","position":3,"is_corresponding":false},{"id":277067,"name":"Meghan C. Thompson","orcid":"0000-0003-1462-4802","position":4,"is_corresponding":false},{"id":233533,"name":"Lindsey E. Roeker","orcid":"0000-0002-3806-059X","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"39960132","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":[]}