{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T11:11:10Z","timestamp":1775646670451,"version":"3.50.1"},"reference-count":21,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    B\u2010cell receptor inhibitors (BCRi) and B\u2010cell lymphoma\u20102 inhibitor (BCL2i) improved outcomes of patients with chronic lymphocytic leukemia (CLL), but relapsing after two inhibitors still represent an unmet clinical need. This multicenter real\u2010world study analyzes outcomes of a cohort treated in Italy between May 2017 and September 2023 following prior exposure to both BCRi and BCL2i. The median follow\u2010up after venetoclax initiation was 47\u00a0months (IQR 28\u201356). Of 153 double\u2010exposed patients, 104 (68%) discontinued venetoclax and 53 of them (51%) received a subsequent treatment. Venetoclax was discontinued due to progressive disease (PD) in 51\/104 cases (49.0%), with nine deaths occurring rapidly after PD without the administration of any further treatment. Fifty\u2010three patients received treatment after venetoclax: 29\/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non\u2010covalent BTKi), 19\/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5\/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Overall response rate was 50%; median event free survival (EFS) in the groups of inhibitors, CT and HSCT was 11, 2, and 10\u00a0months, respectively (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a00.0001); median overall survival (OS) was 12, 5, and 10\u00a0months, respectively (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.020). Disease progression during venetoclax treatment was associated with shorter subsequent EFS compared to discontinuation for other reasons, even if the finding did not reach statistical significance (median EFS 4 vs. 10\u00a0months;\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.11). No decrease in EFS was associated with del17p and\/or TP53 mutations, the use of venetoclax monotherapy or a previous treatment with one versus multiple BCRi. Despite its limitations, this real\u2010world study provides additional insights into double\u2010exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.\n                  <\/jats:p>","DOI":"10.1002\/hon.70184","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:12:21Z","timestamp":1773011541000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Outcomes in Double\u2010Exposed Chronic Lymphocytic Leukemia Patients in Italy"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-7469","authenticated-orcid":false,"given":"Francesco","family":"Autore","sequence":"first","affiliation":[{"name":"Department of Laboratory and Haematological Sciences Haematology Area Fondazione Policlinico Universitario A. Gemelli IRCCS  Roma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Visentin","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Candida","family":"Vitale","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Turin Italy"},{"name":"University Division of Hematology A.O.U. Citt\u00e0 della Salute e della Scienza di Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Giannarelli","sequence":"additional","affiliation":[{"name":"Facility of Epidemiology and Biostatistics GSTeP Fondazione Policlinico Universitario A. Gemelli IRCCS  Roma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Fresa","sequence":"additional","affiliation":[{"name":"Hematology\u2010Oncology and Stem Cell Transplantation Unit Istituto Nazionale Tumori\u2010IRCCS\u2010Fondazione \u201cG. Pascale\u201d  Napoli Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Morelli","sequence":"additional","affiliation":[{"name":"Universit\u00e0 di Firenze e A.O.U. Careggi  Firenze Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Mattiello","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore  Milano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gioacchino","family":"Catania","sequence":"additional","affiliation":[{"name":"AOU SS Antonio e Biagio e C. Arrigo  Alessandria Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7393-1138","authenticated-orcid":false,"given":"Riccardo","family":"Moia","sequence":"additional","affiliation":[{"name":"Universit\u00e0 del Piemonte Orientale A.O.U. Maggiore della Carit\u00e0  Novara Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Quaresmini","sequence":"additional","affiliation":[{"name":"Ospedale Papa Giovanni XXIII  Bergamo Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annamaria","family":"Giordano","sequence":"additional","affiliation":[{"name":"A.O.U. Consorziale Policlinico di Bari  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Scortechini","sequence":"additional","affiliation":[{"name":"Azienda ospedaliero Universitaria delle Marche  Ancona Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-0673","authenticated-orcid":false,"given":"Lucia","family":"Farina","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Nazionale dei Tumori  Milano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5630-9862","authenticated-orcid":false,"given":"Paolo","family":"Sportoletti","sequence":"additional","affiliation":[{"name":"Centro di Ricerca Emato\u2010Oncologica (CREO) Dipartimento di Medicina e Chirurgia Universit\u00e0 di Perugia  Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"AO di Cosenza Presidio Ospedaliero Annunziata  Cosenza Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Angeletti","sequence":"additional","affiliation":[{"name":"Ospedale S. Maria di Terni  Terni Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Idanna","family":"Innocenti","sequence":"additional","affiliation":[{"name":"Department of Laboratory and Haematological Sciences Haematology Area Fondazione Policlinico Universitario A. Gemelli IRCCS  Roma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5015-381X","authenticated-orcid":false,"given":"Alessandro","family":"Sanna","sequence":"additional","affiliation":[{"name":"Universit\u00e0 di Firenze e A.O.U. 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