{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:01:40Z","timestamp":1790650900487,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo di Ateneo per la Ricerca (FAR)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)\/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of \u201cvery high-risk\u201d CLL patients who could benefit from novel, more effective targeted treatments.<\/jats:p>","DOI":"10.3390\/cancers16152732","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T17:16:49Z","timestamp":1722446209000},"page":"2732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs"],"prefix":"10.3390","volume":"16","author":[{"given":"Antonio","family":"Urso","sequence":"first","affiliation":[{"name":"Hematology Unit, St Anna University Hospital, 44124 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Azienda Ospedaliera Annunziata, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-1308","authenticated-orcid":false,"given":"Antonio","family":"Cuneo","sequence":"additional","affiliation":[{"name":"Hematology Unit, St Anna University Hospital, 44124 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-0726","authenticated-orcid":false,"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Hematology Unit, Azienda Ospedaliera Annunziata, 87100 Cosenza, Italy"},{"name":"Department of Pharmacy, Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8370-5190","authenticated-orcid":false,"given":"Gian Matteo","family":"Rigolin","sequence":"additional","affiliation":[{"name":"Hematology Unit, St Anna University Hospital, 44124 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_2","unstructured":"National Cancer Institute (2022, October 08). Surveillance, Epidemiology, and End Results Program Leukemia-Chronic Lymphocytic Leukemia (CLL), Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1182\/blood.V46.2.219.219","article-title":"Clinical staging of chronic lymphocytic leukemia","volume":"46","author":"Rai","year":"1975","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V","article-title":"A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis","volume":"48","author":"Binet","year":"1981","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","article-title":"Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1182\/blood-2008-02-140582","article-title":"Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia","volume":"112","author":"Tam","year":"2008","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1200\/JCO.2011.39.2688","article-title":"Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group","volume":"30","author":"Fischer","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1182\/blood.V89.7.2516","article-title":"11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis","volume":"89","author":"Stilgenbauer","year":"1997","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Gasc\u00f3n-Y-Mar\u00edn, I., Mu\u00f1oz-Novas, C., Rodr\u00edguez-Vicente, A.E., Quijada-\u00c1lamo, M., Hern\u00e1ndez-S\u00e1nchez, M., P\u00e9rez-Carretero, C., Ramos-Ascanio, V., and Hern\u00e1ndez-Rivas, J.\u00c1. (2021). From biomarkers to models in the changing landscape of chronic lymphocytic leukemia: Evolve or become extinct. Cancers, 13.","DOI":"10.3390\/cancers13081782"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1182\/blood.V120.21.2890.2890","article-title":"Deletion 11q abnormality in patients with chronic lymphocytic leukemia (CLL) may not have poor clinical outcomes and bulky disease (clinical and radiological) at presentation\u2014Clinical characteristics of (n = 172) previously untreated patients with CLL and del11q cytogenetic abnormality","volume":"120","author":"Jain","year":"2012","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1182\/blood-2018-09-873083","article-title":"Cytogenetic complexity in chronic lymphocytic leukemia: Definitions, associations, and clinical impact","volume":"133","author":"Baliakas","year":"2019","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1182\/blood.2020010536","article-title":"The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib","volume":"138","author":"Kittai","year":"2021","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1182\/blood-2012-09-458265","article-title":"Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia","volume":"121","author":"Rossi","year":"2013","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hurtado, A.M., Chen-Liang, T.H., Przychodzen, B., Hamedi, C., Mu\u00f1oz-Ballester, J., Dienes, B., Garc\u00eda-Malo, M.D., Ant\u00f3n, A.I., de Arriba, F., and Teruel-Montoya, R. (2015). Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia. Blood Cancer J., 5.","DOI":"10.1038\/bcj.2015.65"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1177\/107327481201900103","article-title":"Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia","volume":"19","author":"Sagatys","year":"2012","journal-title":"Cancer Control"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1200\/JCO.2013.50.8515","article-title":"CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia","volume":"32","author":"Bulian","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00277-013-1967-y","article-title":"The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia","volume":"93","author":"Brachtl","year":"2014","journal-title":"Ann. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"International CLL-IPI Working Group (2016). An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): A meta-analysis of individual patient data. Lancet Oncol., 17, 779\u2013790.","DOI":"10.1016\/S1470-2045(16)30029-8"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1182\/blood-2016-07-728261","article-title":"Validation of the CLL-IPI and comparison with the MDACC prognostic index in newly diagnosed patients","volume":"128","author":"Gentile","year":"2016","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1007\/s11864-022-00953-5","article-title":"Chronic Lymphocytic Leukemia: Chemotherapy Free and Other Novel Therapies Including CAR T","volume":"23","author":"Leis","year":"2022","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Langerbeins, P., Giza, A., Robrecht, S., Cramer, P., von Tresckow, J., Al-Sawaf, O., Fink, A.M., F\u00fcrstenau, M., Kutsch, N., and Simon, F. (2024). Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies. Blood, advance online publication.","DOI":"10.1182\/blood.2023022564"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1182\/blood.2021014960","article-title":"Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: Updated results of the E1912 Trial","volume":"140","author":"Shanafelt","year":"2022","journal-title":"Blood"},{"key":"ref_23","first-page":"97","article-title":"The role of minimal residual disease in chronic lymphocytic leukemia","volume":"20","author":"Hallek","year":"2022","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1182\/blood.V94.6.1840","article-title":"Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia","volume":"94","author":"Damle","year":"1999","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.3324\/haematol.2013.098384","article-title":"The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: Proliferation or anergy","volume":"99","author":"Packham","year":"2014","journal-title":"Haematologica"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/ajh.23668","article-title":"Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients","volume":"89","author":"Cuneo","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1056\/NEJMoa1313984","article-title":"Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions","volume":"370","author":"Goede","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1182\/blood-2015-09-667675","article-title":"Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia","volume":"127","author":"Thompson","year":"2016","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1182\/blood-2015-06-651125","article-title":"Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: Updated results of the CLL8 trial","volume":"127","author":"Fischer","year":"2016","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/S1470-2045(16)30051-1","article-title":"First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial","volume":"17","author":"Eichhorst","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1182\/blood-2018-03-839688","article-title":"Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab","volume":"133","author":"Langerak","year":"2019","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1182\/blood-2005-06-2227","article-title":"Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status","volume":"107","author":"Murray","year":"2006","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1182\/bloodadvances.2021006434","article-title":"Up to 8-year follow-up from RESONATE-2: First-line ibrutinib treatment for patients with chronic lymphocytic leukemia","volume":"6","author":"Barr","year":"2022","journal-title":"Blood Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1182\/blood-2021-153146","article-title":"Long-term results of Alliance A041202 show continued advantage of Ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy","volume":"138","author":"Woyach","year":"2021","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1470-2045(23)00144-4","article-title":"Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): Interim analysis of a multicentre, open-label, randomised, phase 3 trial","volume":"24","author":"Hillmen","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.3324\/haematol.2021.279012","article-title":"First-Line Treatment of Chronic Lymphocytic Leukemia with Ibrutinib plus Obinutuzumab versus Chlorambucil plus Obinutuzumab: Final Analysis of the Randomized, Phase 3 ILLUMINATE Trial","volume":"107","author":"Moreno","year":"2022","journal-title":"Haematologica"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0140-6736(20)30262-2","article-title":"Acalabrutinib with or without Obinutuzumab versus Chlorambucil and Obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): A Randomised, Controlled, Phase 3 Trial","volume":"395","author":"Sharman","year":"2020","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/s41375-021-01485-x","article-title":"Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-na\u00efve chronic lymphocytic leukemia","volume":"36","author":"Sharman","year":"2022","journal-title":"Leukemia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S1470-2045(22)00293-5","article-title":"Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): A randomised, controlled, phase 3 trial","volume":"23","author":"Tam","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/bjh.16434","article-title":"Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations","volume":"189","author":"Raponi","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/S0140-6736(21)00224-5","article-title":"Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): A phase 1\/2 study","volume":"397","author":"Mato","year":"2021","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2300696","article-title":"Pirtobrutinib after a covalent BTK inhibitor in Chronic Lymphocytic Leukemia","volume":"389","author":"Mato","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1111\/bjh.17984","article-title":"Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: A\u2009pooled analysis from four clinical trials","volume":"196","author":"Allan","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1056\/NEJMc2005943","article-title":"Ibrutinib for Chronic Lymphocytic Leukemia with TP53 Alterations","volume":"383","author":"Ahn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/ajh.25638","article-title":"Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma","volume":"94","author":"Munir","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1200\/JCO.21.01210","article-title":"Acalabrutinib versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial","volume":"39","author":"Byrd","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa2211582","article-title":"Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"388","author":"Brown","year":"2023","journal-title":"N. Eng. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41408-023-00865-z","article-title":"Outcomes in Patients with Chronic Lymphocytic Leukemia and TP53 Aberration Who Received First Line Ibrutinib: A Nationwide Registry Study from the Italian Medicines Agency","volume":"13","author":"Rigolin","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1182\/blood-2011-11-395269","article-title":"Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with \u201cnormal\u201d FISH: Correlations with clinicobiologic parameters","volume":"119","author":"Rigolin","year":"2012","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3612","DOI":"10.1002\/cncr.29566","article-title":"Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens","volume":"121","author":"Thompson","year":"2015","journal-title":"Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1182\/blood.2021011883","article-title":"Complex Karyotype in Unfit Patients with CLL Treated with Ibrutinib and Rituximab: The GIMEMA LLC1114 Phase 2 Study","volume":"138","author":"Rigolin","year":"2021","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1182\/blood.2020009617","article-title":"Acalabrutinib in treatment-naive chronic lymphocytic leukemia","volume":"137","author":"Byrd","year":"2021","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1200\/JCO.20.00979","article-title":"Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: Development and validation of a four-factor prognostic model","volume":"39","author":"Ahn","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E168","DOI":"10.1002\/ajh.26127","article-title":"Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study","volume":"96","author":"Morabito","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41375-020-0833-x","article-title":"Survival risk score for real-life relapsed\/refractory chronic lymphocytic leukemia patients receiving ibrutinib. A campus CLL study","volume":"35","author":"Gentile","year":"2021","journal-title":"Leukemia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41408-020-00358-3","article-title":"Validation of a survival-risk score (SRS) in relapsed\/refractory CLL patients treated with idelalisib-rituximab","volume":"10","author":"Gentile","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e366","DOI":"10.1016\/S2352-3026(19)30085-7","article-title":"Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: A retrospective, pooled cohort study with external validations","volume":"6","author":"Soumerai","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"E176","DOI":"10.1002\/ajh.26502","article-title":"Prediction of outcomes in chronic lymphocytic leukemia patients treated with ibrutinib: Validation of current prognostic models and development of a simplified three-factor model","volume":"97","author":"Molica","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood.2018882555","article-title":"Efficacy of Venetoclax in Relapsed Chronic Lymphocytic Leukemia Is Influenced by Disease and Response Variables","volume":"134","author":"Roberts","year":"2019","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1470-2045(24)00070-6","article-title":"Activity of Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukaemia: Analysis of the VENICE-1 Multicentre, Open-Label, Single-Arm, Phase 3b Trial","volume":"25","author":"Kater","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1182\/blood.2021015014","article-title":"Enduring Undetectable MRD and Updated Outcomes in Relapsed\/Refractory CLL after Fixed-Duration Venetoclax-Rituximab","volume":"140","author":"Seymour","year":"2022","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/S1470-2045(20)30443-5","article-title":"Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): Follow-up results from a multicentre, open-label, randomised, phase 3 trial","volume":"21","author":"Zhang","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/s41467-023-37648-w","article-title":"Transcriptomic Profiles and 5-Year Results from the Randomized CLL14 Study of Venetoclax plus Obinutuzumab versus Chlorambucil plus Obinutuzumab in Chronic Lymphocytic Leukemia","volume":"14","author":"Zhang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.1200\/JCO.21.01181","article-title":"Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up from the Randomized CLL14 Study","volume":"39","author":"Zhang","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and Obinutuzumab in patients with CLL and coexisting conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1200\/JCO.20.00948","article-title":"Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study","volume":"38","author":"Kater","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1182\/blood.2019003451","article-title":"High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype and chronic lymphocytic leukemia","volume":"135","author":"Lilienweiss","year":"2020","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41408-021-00429-z","article-title":"Ibrutinib and Venetoclax Target Distinct Subpopulations of CLL Cells: Implication for Resid-ual Disease Eradication","volume":"11","author":"Lu","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1158\/1078-0432.CCR-22-2779","article-title":"Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia","volume":"29","author":"Allan","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1200\/JCO.21.00807","article-title":"Ibrutinib plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results from the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study","volume":"39","author":"Wierda","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/S1470-2045(23)00452-7","article-title":"Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial","volume":"24","author":"Niemann","year":"2003","journal-title":"Lancet Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Munir, T., Cairns, D.A., Bloor, A., Allsup, D., Cwynarski, K., Pettitt, A., Paneesha, S., Fox, C.P., Eyre, T.A., and Forconi, F. (2023). Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N. Engl. J. Med., advance online publication.","DOI":"10.1056\/NEJMoa2310063"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","article-title":"First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia","volume":"388","author":"Eichhorst","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1182\/blood.2023019634","article-title":"High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations","volume":"142","author":"Thus","year":"2023","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/bjh.15174","article-title":"In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics","volume":"181","author":"Rigolin","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1182\/hematology.2023000506","article-title":"Dual-targeted regimens for the frontline treatment of CLL","volume":"2023","author":"Ujjani","year":"2023","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1182\/hematology.2023000441","article-title":"MRD-directed therapy in CLL: Ready for prime time?","volume":"2023","author":"Rhodes","year":"2023","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_78","unstructured":"(2024, July 21). Appendix 4 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man\u2014Condition Specific Guidance\u2014Scientific Guideline|European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/appendix-4-guideline-evaluation-anticancer-medicinal-products-man-condition-specific-guidance-scientific-guideline."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Woyach, J.A., Jones, D., Jurczak, W., Robak, T., Illes, A., Kater, A.P., Ghia, P., Byrd, J.C., Seymour, J.F., and Long, S. (2024). Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib. Blood, in press.","DOI":"10.1182\/blood.2023023659"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1182\/bloodadvances.2022008447","article-title":"Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance","volume":"7","author":"Naeem","year":"2023","journal-title":"Blood Adv."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e434","DOI":"10.3324\/haematol.2019.222588","article-title":"Venetoclax Resistance and Acquired BCL2 Mutations in Chronic Lymphocytic Leukemia","volume":"104","author":"Tausch","year":"2019","journal-title":"Haematologica"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1182\/blood.2022016600","article-title":"Genetic Events Associated with Venetoclax Resistance in CLL Identified by Whole-Exome Sequencing of Patient Samples","volume":"142","author":"Khalsa","year":"2023","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1158\/1078-0432.CCR-22-3934","article-title":"Absence of BTK, BCL2, and PLCG2 Mutations in Chronic Lymphocytic Leukemia Relapsing after First-Line Treatment with Fixed-Duration Ibrutinib plus Venetoclax","volume":"30","author":"Jain","year":"2024","journal-title":"Clin. Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/15\/2732\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:27:32Z","timestamp":1760110052000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/15\/2732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":83,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cancers16152732"],"URL":"https:\/\/doi.org\/10.3390\/cancers16152732","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,31]]}}}