{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:25:51Z","timestamp":1791649551863,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>Dose modifications (DMs) are common in hematology and oncology, yet their causal effect on clinical outcomes remains uncertain. Conventional survival analyses may yield biased results since DM is a time\u2010varying exposure and is often confounded by patient frailty and disease severity. To address these challenges, we applied a causal inference framework to real\u2010world data from 130 patients with chronic lymphocytic leukemia treated with ibrutinib to estimate the effect of DM on clinical outcomes. A Bayesian prognostic risk (PR) model was developed to characterize patients' baseline risk, incorporating patient\u2010level clinical trial data from RESONATE\u20102 as prior information. Baseline (b\u2010sIPW) and time\u2010updated stabilized inverse probability weights (tu\u2010sIPW) were developed to improve covariate balance between patients with and without DM and to account for timing\u2010varying confounding. Baseline Cox models were compared with longitudinal Cox models in which DM was specified as a time\u2010varying exposure. In baseline Cox analyses, DM appeared to be associated with shorter progression\u2010free survival (PFS). However, in longitudinal Cox models accounting for time\u2010varying exposure and confounding using stabilized inverse probability weighting, the estimated DM effect was attenuated and no longer statistically significant. These findings suggest that the apparent detrimental effect of DM on PFS is potentially explained by baseline and time\u2010varying confounding, and improper handling of time\u2010varying exposure, highlighting the importance of causal inference methods when evaluating DM causal effects in oncology therapies.<\/jats:p>","DOI":"10.1002\/cpt.70436","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:15:09Z","timestamp":1786076109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Causal Inference Approaches to Estimating the Effect of Ibrutinib Dose Modifications on Progression\u2010Free Survival in Chronic Lymphocytic Leukemia"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4192-8247","authenticated-orcid":false,"given":"Viet","family":"Dang","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-6676","authenticated-orcid":false,"given":"Benyam","family":"Muluneh","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8134-3376","authenticated-orcid":false,"given":"Kevin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy UNC Medical Center  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-9073","authenticated-orcid":false,"given":"Yanguang","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/cpt.3298","article-title":"Dose optimization in oncology drug development: an international consortium for innovation and quality in pharmaceutical development white paper","volume":"116","author":"Samineni D.","year":"2024","journal-title":"Clin. 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