{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T14:37:31Z","timestamp":1770907051490,"version":"3.50.1"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"DOI":"10.1007\/s12672-025-02947-9","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T10:52:23Z","timestamp":1749898343000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Beyond BCL2 (B cell lymphoma) and BTK (Bruton tyrosine kinase) inhibitors: novel agents and resistance mechanisms for chronic lymphocytic leukemia"],"prefix":"10.1007","volume":"16","author":[{"given":"Priya","family":"Hays","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"2947_CR1","doi-asserted-by":"crossref","unstructured":"Perutelli F, Jones R, Griggio V, Vitale C, Coscia M. Immunotherapeutic strategies in chronic lymphocytic leukemia: advances and challenges. Front Onc. 2022;12.","DOI":"10.3389\/fonc.2022.837531"},{"key":"2947_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41408-024-01001-1","volume":"14","author":"R Bennett","year":"2024","unstructured":"Bennett R, Seymour JF. Update on the management of relapsed\/refractory chronic lymphocytic leukemia. Blood Can J. 2024;14:33.","journal-title":"Blood Can J"},{"key":"2947_CR3","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.clml.2022.07.013","volume":"11","author":"R Bennett","year":"2022","unstructured":"Bennett R, Thompson E, Tam C. SOHO state of the Art updates and next questions. Mechanisms of resistance to BCL2 inhibitor therapy in chronic lymphocytic leukemia and potential future therapeutic directions. Chronic Lymph Myeloma Leuk. 2022;11:795\u2013804.","journal-title":"Chronic Lymph Myeloma Leuk"},{"issue":"12","key":"2947_CR4","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/S1470-2045(23)00452-7","volume":"24","author":"CU Niemann","year":"2023","unstructured":"Niemann CU, Munir T, Moreno C, Owen C, Follows GA, et al. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukemia (GLOW): 4-year follow-up from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2023;24(12):1423\u201333.","journal-title":"Lancet Oncol"},{"issue":"18","key":"2947_CR5","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1182\/blood.2023019706","volume":"143","author":"J Liu","year":"2024","unstructured":"Liu J, Li S, Wang Q, Feng Y, Xing H, et al. Sonrotoclax overcomes BCL2 G101V mutation-induced Venetolax resistance in preclinical models of hematologic malignancy. Blood. 2024;143(18):1825\u201336.","journal-title":"Blood"},{"key":"2947_CR6","doi-asserted-by":"crossref","unstructured":"Lucas F, Larkin K, Gregory T, Orwick S, Doong T-J et al. Novel BCL2 mutations in venetoclax-resistant CLL patients with BTK\/PLCG mutations. Blood. 2020;135(24).","DOI":"10.1182\/blood.2019003722"},{"key":"2947_CR7","doi-asserted-by":"crossref","unstructured":"Kanagal-Shamanna R, Jain P, Patel KP, Routbort M, Bueso-Ramos C et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer. 2019;125(4).","DOI":"10.1002\/cncr.31831"},{"key":"2947_CR8","doi-asserted-by":"crossref","unstructured":"Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D\u2019Rozario J et al. Venetoclax-Rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12).","DOI":"10.1056\/NEJMoa1713976"},{"key":"2947_CR9","doi-asserted-by":"crossref","unstructured":"Al-Sawaf O, Robrecht S, Zhang C, Oliverieri S, Chang M et al. Venetoclax-obinutuzumab for previously treated chronic lymphocytic leukemia: 6-year resutsl fo the randomized phase 3 CLL14 study. Blood. 2024;144(18).","DOI":"10.1182\/blood.2024024631"},{"key":"2947_CR10","doi-asserted-by":"crossref","unstructured":"Skanland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021.","DOI":"10.1182\/bloodadvances.2020003423"},{"key":"2947_CR11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.clml.2022.09.007","volume":"23","author":"AR Mato","year":"2022","unstructured":"Mato AR, Hess LM, Chen Y, Abada PB, Konig H, et al. Outcomes for patients with chronic lymphocytic leukemia (CLL) previously treated with both a covalent BTK and BCL 2 inhibitor in the united states: A real world database study. Chronic Lymph Myeloma Leuk. 2022;23:57\u201367.","journal-title":"Chronic Lymph Myeloma Leuk"},{"key":"2947_CR12","unstructured":"Mato A, Woyach J, Brown JR, Chia P, Patel K et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. NEJM. 2023;389."},{"key":"2947_CR13","doi-asserted-by":"crossref","unstructured":"Sharman JP, Munir T, Grosicki S, Roeker L, Burke JM et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia\/small lymphocytic lymphoma. Blood. 2024;Abstract 642.","DOI":"10.1200\/JCO-25-00166"},{"key":"2947_CR14","doi-asserted-by":"crossref","unstructured":"Tadmor T, Eyre TA, Benjamini O, Chaudrhy, Shen J, Leng S et al. May. BELLWAVE-011: Phase 3 randomized trial of nemtabrutinib versus ibrutinib or acalabrutinib in untreated chronic lymphocytic leukemia\/small lymphocytic lymphoma. J Clin Oncol. Meeting Abstract. 2024.","DOI":"10.1016\/S2152-2650(24)00583-4"},{"issue":"16","key":"2947_CR15","doi-asserted-by":"publisher","first-page":"3977","DOI":"10.1182\/bloodadvances.2020001956","volume":"4","author":"LE Roeker","year":"2020","unstructured":"Roeker LE, Dreger P, Brown JR, Lahoud OB, Eyre TA, Brander DM, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977\u201389. https:\/\/doi.org\/10.1182\/bloodadvances.2020001956.","journal-title":"Blood Adv"},{"issue":"1","key":"2947_CR16","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1182\/blood-2017-07-740993","volume":"131","author":"ZY Xu-Monette","year":"2018","unstructured":"Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 Blockade in B-Cell lymphomas. Blood. 2018;131(1):68\u201383.","journal-title":"Blood"},{"key":"2947_CR17","doi-asserted-by":"crossref","unstructured":"1, Sandhu S, Mulligan SP. Ofatumumab and its role as immunotherapy in chronic lymphocytic leukemia. Hematologica. 2015;100(4).","DOI":"10.3324\/haematol.2015.124107"},{"key":"2947_CR18","doi-asserted-by":"crossref","unstructured":"Salles GA, Morschhauser F, Solal-Celigny P, Thieblemont C, Lamy T et al. Obinutuzumab (GA101) in patients with relapsed\/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23).","DOI":"10.1200\/JCO.2012.46.9718"},{"key":"2947_CR19","doi-asserted-by":"crossref","unstructured":"Owen CJ, Stewart DJ. Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective. Ther Adv Hematol. 2015;4.","DOI":"10.1177\/2040620715586528"},{"key":"2947_CR20","doi-asserted-by":"crossref","unstructured":"Roeker LE, Leslie LA, Soumerai JD, Falco V, Panton G. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): a minimal residual disease (MRD)-driven, time-limited approach. Blood. 2021;138(Supplement 1).","DOI":"10.1182\/blood-2021-146999"},{"key":"2947_CR21","doi-asserted-by":"crossref","unstructured":"Staber PB, Jurczak W, Greil R, Vucinic V, Middeke JM. Tafasitamab combined with idelalisib or venetoclax in patients with CLL previously treated with a BTK inhibitor. Leuk Lymphoma. 2021;62(14).","DOI":"10.1080\/10428194.2021.1964020"},{"key":"2947_CR22","doi-asserted-by":"crossref","unstructured":"Robak T, Hellman A, Kloczko J, Loscertales J, Lech-Maranda E et al. Randomized phase 2 study of Otlertuzumab and Bendamustine versus Bendamustine in patients with relapsed chronic lymphocytic leukaemia. B J Haem. 2016.","DOI":"10.1111\/bjh.14464"},{"key":"2947_CR23","doi-asserted-by":"crossref","unstructured":"Choi MY, Widhopf GF, Ghia Em, Kidwell RL, Kamrui Hasan M et al. Phase I trial: Cirmtuzumab inhibits ROR1 signaling and stemness signatures in patients with chronic lymphocytic leukemia. 2018;22(6).","DOI":"10.1016\/j.stem.2018.05.018"},{"key":"2947_CR24","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.3390\/curroncol29050293","volume":"29","author":"Z Todorovic","year":"2022","unstructured":"Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N. CAR T cell therapy for chronic lymphocytic leukemia: successes and shortcomings. Curr Oncol. 2022;29:3647\u201357.","journal-title":"Curr Oncol"},{"key":"2947_CR25","doi-asserted-by":"crossref","unstructured":"Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorrittie K et al. Lisocabtagene Maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1\u20132 study. Lancet. 2023;402.","DOI":"10.1016\/S0140-6736(23)01052-8"},{"key":"2947_CR26","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.3390\/ph7121049","volume":"7","author":"H Fujiwara","year":"2014","unstructured":"Fujiwara H. Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigenspecific receptors. Pharmaceuticals. 2014;7:1049\u201368.","journal-title":"Pharmaceuticals"},{"key":"2947_CR27","doi-asserted-by":"publisher","first-page":"5536","DOI":"10.3390\/ijms22115536","volume":"22","author":"V Mancikova","year":"2021","unstructured":"Mancikova V, Smida M. Current state of CAR T-Cell therapy in chronic lymphocytic leukemia. Int J Mol Sci. 2021;22:5536.","journal-title":"Int J Mol Sci"},{"key":"2947_CR28","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1056\/NEJMoa1103849","volume":"365","author":"DL Porter","year":"2011","unstructured":"Porter DL, Levine BL, Kalos M, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725\u201333.","journal-title":"N Engl J Med"},{"key":"2947_CR29","doi-asserted-by":"publisher","first-page":"4817","DOI":"10.1182\/blood-2011-04-348540","volume":"118","author":"RJ Brentjens","year":"2011","unstructured":"Brentjens RJ, Rivi\u00e8re I, Park JH, Wang X, Wang Y, Purdon TJ, Hsu M, Devlin SM, Halton E, Lamanna N, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817\u201328.","journal-title":"Blood"},{"key":"2947_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.exphem.2022.02.001","volume":"108","author":"I Can","year":"2022","unstructured":"Can I, Cox MJ, Siegler EL, Sakemura R, Kenderian SS. Challenges of chimeric antigen receptor T-cell therapy in chronic lymphocytic leukemia: lessons learned. Exp Hematol. 2022;108:1\u20137.","journal-title":"Exp Hematol"},{"key":"2947_CR31","doi-asserted-by":"crossref","unstructured":"Wong R, Pepper C, Brennan P, Nagorsen D, Man S, Fegan C. Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica. 2013;98(2).","DOI":"10.3324\/haematol.2012.082248"},{"issue":"5","key":"2947_CR32","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1182\/blood-2018-02-830992","volume":"132","author":"HR Robinson","year":"2018","unstructured":"Robinson HR, Qi J, Cook EM, Nichols C, Dadashian EL, et al. A CD19\/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era. Blood. 2018;132(5):521\u201332.","journal-title":"Blood"},{"issue":"5","key":"2947_CR33","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1158\/2767-9764.CRC-22-0083","volume":"2","author":"AWJ Martens","year":"2022","unstructured":"Martens AWJ, Rietveld JM, Boer R, Peters FS, Ngo A, Lotte WHG, et al. Redirecting T-cell activity with Anti-BCMA\/Anti-CD3 bispecific antibodies in chronic lymphocytic leukemia and other B-cell lymphomas. Cancer Res Commun. 2022;2(5):330\u201341.","journal-title":"Cancer Res Commun"},{"key":"2947_CR34","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/978-3-030-96376-7_11","volume":"183","author":"P Hays","year":"2022","unstructured":"Hays P. Clinical development and therapeutic applications of bispecific antibodies for hematologic malignancies. Cancer Treat Res. 2022;183:287\u2013315.","journal-title":"Cancer Treat Res"},{"key":"2947_CR35","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1158\/1078-0432.CCR-20-4576","volume":"27","author":"I Weerdt","year":"2021","unstructured":"Weerdt I, Lameris R, Rubin JM, Boer R, Kloosterman J, et al. A bispecific Single-Domain antibody boosts autologous V(delta9V(gamma)-T cell responses toward a CD1d in chronic lymphocytic leukemia. Clin Canc Res. 2021;27:1744\u201355.","journal-title":"Clin Canc Res"},{"key":"2947_CR36","doi-asserted-by":"crossref","unstructured":"Cyr MG, Mhibik M, Qi J, Peng H, Chang J et al. Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have a potential therapeutic utility in chronic lymphocytic leukemia. J Imm Can. 2022;10.","DOI":"10.1136\/jitc-2022-004850"},{"key":"2947_CR37","doi-asserted-by":"crossref","unstructured":"Lee J, Wang L. Prognostic and predictive biomarkers in chronic lymphocytic leukemia. J Mol Diagn. 2020;22(9).","DOI":"10.1016\/j.jmoldx.2020.06.004"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-02947-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-025-02947-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-02947-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T10:52:28Z","timestamp":1749898348000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-025-02947-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,14]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2947"],"URL":"https:\/\/doi.org\/10.1007\/s12672-025-02947-9","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,14]]},"assertion":[{"value":"10 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"P.H. owns stock in Abbvie. Abbvie manufactures venetoclax and ibrutinib, drugs extensively referenced in this review. The presentation of data and discussion of these therapies were not influenced by this competing interest. The paper highlights drug resistance and presents alternatives to venetoclax and ibrutinib as evidence of impartiality towards these therapeutics.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1100"}}