{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:56:33Z","timestamp":1790679393845,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100009067","name":"K. Albin Johanssons Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007469","name":"Alfred Benzon Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007469","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Targeted therapies have improved outcomes for patients with chronic lymphocytic leukemia (CLL); yet, not all achieve durable responses. Existing prognostic models, developed for chemoimmunotherapy, have limited predictive value for newer targeted combinations. Here, we used data from a randomized phase II clinical trial to identify predictors of progression\u2010free survival (PFS) in response to Bruton tyrosine kinase (BTK)\u2009+\u2009B\u2010cell lymphoma 2 (Bcl\u20102) inhibitor combination therapy. We studied the functional, genetic, and clinical characteristics of patients with relapsed\/refractory (R\/R) CLL treated with ibrutinib\u2009+\u2009venetoclax in the VISION\/HO141 clinical trial (NCT03226301). Ex vivo drug sensitivity testing, (phospho)protein profiling, and immunophenotyping were performed on baseline peripheral blood mononuclear cells from 177 patients. Ex vivo drug sensitivity correlated with clinical responses to single\u2010agent therapies. (Phospho)protein patterns reflected intracellular pathway activity and predicted ex vivo drug sensitivity. Using stringent feature selection and regularized ridge regression to prevent overfitting, we integrated functional, genetic, and clinical data sets and identified six features\u2014sensitivity to VEGFR\u20102\u2010, JAK1\/2\u2009+\u2009Bcl\u20102\u2010, and BTK\u2009+\u2009PI3K\u2010inhibitors; phosphorylation ratios of Bcl\u20102:BTK and p90RSK:PLC\u03b32; and frequency of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells\u2014that together outperformed the International Prognostic Index for CLL (CLL\u2010IPI) and other clinical scores in predicting PFS. These findings demonstrate that a prognostic model based on the functional features of CLL cell signaling and interaction with the microenvironment has the potential to improve upon conventional prognostic scores, warranting further clinical validation also in the frontline setting.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70467","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:09:41Z","timestamp":1789675781000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A functional prognostic model predicts progression\u2010free survival in patients with relapsed chronic lymphocytic leukemia treated with ibrutinib\u2009+\u2009venetoclax"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3830-2277","authenticated-orcid":false,"given":"Johanne U.","family":"Hermansen","sequence":"first","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1070-7136","authenticated-orcid":false,"given":"Weikaixin","family":"Kong","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM) HiLIFE, University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Brodersen","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"Centre for Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine University of Oslo Oslo Norway"},{"name":"Section for Biochemistry and Molecular Biology, Faculty of Mathematics and Natural Sciences University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Urban","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-8946","authenticated-orcid":false,"given":"Idun D.","family":"Rein","sequence":"additional","affiliation":[{"name":"Department of Core Facilities, Institute for Cancer Research Oslo University Hospital Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liye","family":"He","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM) HiLIFE, University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi","family":"Agius","sequence":"additional","affiliation":[{"name":"Department of Hematology Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark"},{"name":"Danish Cancer Institute Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca S.","family":"Teglgaard","sequence":"additional","affiliation":[{"name":"Department of Hematology Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0705-4314","authenticated-orcid":false,"given":"Juho","family":"Rousu","sequence":"additional","affiliation":[{"name":"Department of Computer Science Aalto University Espoo Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-8106","authenticated-orcid":false,"given":"Christian","family":"Brieghel","sequence":"additional","affiliation":[{"name":"Department of Hematology Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Kersting","sequence":"additional","affiliation":[{"name":"Department of Hematology Haga Ziekenhuis Den Haag The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-3547","authenticated-orcid":false,"given":"Mark\u2010David","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Albert Schweitzer Hospital Dordrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoa T. T.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Hematology Akershus University Hospital L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-8801","authenticated-orcid":false,"given":"Mattias","family":"Mattsson","sequence":"additional","affiliation":[{"name":"Department of Hematology Uppsala University Hospital Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5198-2847","authenticated-orcid":false,"given":"Juha","family":"Ranti","sequence":"additional","affiliation":[{"name":"Department of Hematology and Stem Cell Transplantation Unit, Division of Medicine Turku University Hospital Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit\u2010Jan","family":"Veldhuis","sequence":"additional","affiliation":[{"name":"Department of Hematology Antonius Ziekenhuis Sneek The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-3098","authenticated-orcid":false,"given":"Caspar","family":"da Cunha\u2010Bang","sequence":"additional","affiliation":[{"name":"Department of Hematology Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogier","family":"Mous","sequence":"additional","affiliation":[{"name":"Department of Hematology UMC Utrecht Cancer Center Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Dubois","sequence":"additional","affiliation":[{"name":"Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam Amsterdam University Medical Center, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-1891","authenticated-orcid":false,"given":"Arnon P.","family":"Kater","sequence":"additional","affiliation":[{"name":"Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam Amsterdam University Medical Center, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorrit M.","family":"Enserink","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"Centre for Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine University of Oslo Oslo Norway"},{"name":"Section for Biochemistry and Molecular Biology, Faculty of Mathematics and Natural Sciences University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9880-5242","authenticated-orcid":false,"given":"Carsten U.","family":"Niemann","sequence":"additional","affiliation":[{"name":"Department of Hematology Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark"},{"name":"Danish Cancer Institute Copenhagen Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0886-9769","authenticated-orcid":false,"given":"Tero","family":"Aittokallio","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM) HiLIFE, University of Helsinki Helsinki Finland"},{"name":"Department of Cancer Genetics, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"Oslo Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-356X","authenticated-orcid":false,"given":"Sigrid S.","family":"Sk\u00e5nland","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research Oslo University Hospital Oslo Norway"},{"name":"K.G. 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