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Zilovertamab is a humanized monoclonal antibody targeting ROR1. We conducted a multicenter phase 1b\/2 study of zilovertamab plus ibrutinib (Z\u2009+\u2009I) in relapsed\/refractory CLL. Phase 1b\/2a (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200934) established a recommended zilovertamab dose based on safety, pharmacokinetics, and ROR1 occupancy. In phase 2b, patients were randomized to zilovertamab plus ibrutinib (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200918) or ibrutinib alone (I;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200910); the primary endpoint was complete response (CR) per iwCLL, with progression\u2011free survival (PFS) and safety as secondary endpoints. Z\u2009+\u2009I was well tolerated, with no dose\u2011limiting toxicities and safety profile consistent with BTK inhibition. CR rates, overall response, and PFS were similar between randomized arms. In a post hoc subset of 10 patients with del(17p), Z + I was associated with prolonged disease control relative to historical BTK inhibitor experience; this hypothesis-generating observation requires prospective confirmation. Zilovertamab achieved ROR1 occupancy and attenuated NF\u2011\u03baB, ERK1\/2, and mTORC1 signaling in CLL cells, supporting further exploration of ROR1\u2011targeted strategies in biologically high\u2011risk CLL. The study was registered at ClinicalTrials.gov (NCT03088878).\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03131-w","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:01:50Z","timestamp":1790928110000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of ROR1 signaling with zilovertamab plus ibrutinib in chronic lymphocytic leukemia: safety, mechanistic insights, and an exploratory signal in del(17p) disease"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9107-2186","authenticated-orcid":false,"given":"Michael Y.","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6060-6106","authenticated-orcid":false,"given":"Emanuela M.","family":"Ghia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline C.","family":"Barrientos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0522-1406","authenticated-orcid":false,"given":"Joseph","family":"Tuscano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-0489","authenticated-orcid":false,"given":"Jean L.","family":"Koff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Yazji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori A.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Isufi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Lamanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Goldenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suki","family":"Subbiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona H. 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Dr. Breitmeyer was an employee and Board Director, and owned stock in Oncternal Therapeutics, Inc. JMR, SY, SO, were employees of Oncternal Therapeutics. Honoraria and research funding: MYC has received honoraria from Janssen and research funding from AbbVie. JT has research funding from Genetech, AbbVie, Pharmacyclics, Genmab, Regeneron, ADC therapeutics, and Pfizer. JK has received honoraria for consultancy with AbbVie and BeiGene; and research funding from Viracta Therapeutics. LL has received honoraria from SeaGen, ADC therapeutics, Celgene, Janssen, Pharmacyclics, BeiGene, AbbVie, AstraZeneca, TG Therapeutics, Epizyme, Karyopharm, Merck, Eli Lilly, Genmab, and Gilead\/Kite.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}