{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:34:22Z","timestamp":1792092862411,"version":"4.4.0"},"reference-count":122,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Hematol Malig Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose of Review<\/jats:title>\n                    <jats:p>Targeted therapies have revolutionized the treatment of chronic lymphocytic leukemia (CLL), however the disease remains incurable. This is largely due to somatic mutations in proteins targeted by these therapies, like Bruton\u2019s tyrosine kinase (BTK) and B cell lymphoma-2 (Bcl-2), or transcriptional rewiring of CLL cells. Here we review recent findings regarding mechanisms of resistance to targeted agents in CLL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Recent Findings<\/jats:title>\n                    <jats:p>BTK inhibitor (BTKi) resistant CLL is potentiated by mutations disrupting covalent and non-covalent BTKi binding or those conferring loss of BTK\u2019s kinase activity. Point mutations in Bcl-2 impact the efficacy of Bcl-2 inhibitor venetoclax, however cells employ a diverse variety of mechanisms to escape venetoclax-induced apoptosis. These mechanisms function through AKT and result in increased dependency on and stabilization of other antiapoptotic Bcl-2 family members as well as disruption of BAK\/BAX pore formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Recent work in CLL has pinpointed mechanisms hijacked by cells to abrogate treatment efficacy. Ongoing research efforts are focused on the advent of next-generation inhibitors and protein degraders to circumvent resistance. Such studies will prove invaluable in providing CLL patients with a diverse repertoire of therapeutic options following relapse.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11899-026-00776-3","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:12:08Z","timestamp":1772064728000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia"],"prefix":"10.1007","volume":"21","author":[{"given":"Samon","family":"Benrashid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Woyach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"776_CR1","unstructured":"Chronic Lymphocytic Leukemia. - Cancer Stat Facts [Internet]. SEER. https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html"},{"key":"776_CR2","doi-asserted-by":"publisher","first-page":"1910","DOI":"10.1056\/NEJM200012283432602","volume":"343","author":"H D\u00f6hner","year":"2000","unstructured":"D\u00f6hner H, Stilgenbauer S, Benner A, Leupolt E, Kr\u00f6ber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910\u20136. https:\/\/doi.org\/10.1056\/NEJM200012283432602.","journal-title":"N Engl J Med"},{"key":"776_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/gm451","volume":"5","author":"DA Landau","year":"2013","unstructured":"Landau DA, Wu CJ. Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. Genome Med. 2013;5:47. https:\/\/doi.org\/10.1186\/gm451.","journal-title":"Genome Med"},{"key":"776_CR4","doi-asserted-by":"publisher","first-page":"3440","DOI":"10.1182\/bloodadvances.2021006434","volume":"6","author":"PM Barr","year":"2022","unstructured":"Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440\u201350. https:\/\/doi.org\/10.1182\/bloodadvances.2021006434.","journal-title":"Blood Adv"},{"key":"776_CR5","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","volume":"388","author":"B Eichhorst","year":"2023","unstructured":"Eichhorst B, Niemann CU, Kater AP, F\u00fcrstenau M, von Tresckow J, Zhang C, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388:1739\u201354. https:\/\/doi.org\/10.1056\/NEJMoa2213093.","journal-title":"N Engl J Med"},{"key":"776_CR6","doi-asserted-by":"publisher","unstructured":"Fischer K, Al-Sawaf O, Bahlo J, Fink A-M, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225\u201336. https:\/\/doi.org\/10.1056\/NEJMoa1815281.","DOI":"10.1056\/NEJMoa1815281"},{"key":"776_CR7","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1038\/s41467-023-37648-w","volume":"14","author":"O Al-Sawaf","year":"2023","unstructured":"Al-Sawaf O, Zhang C, Jin HY, Robrecht S, Choi Y, Balasubramanian S, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus Chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14:2147. https:\/\/doi.org\/10.1038\/s41467-023-37648-w.","journal-title":"Nat Commun"},{"key":"776_CR8","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/cdd.2017.179","volume":"25","author":"H Kalkavan","year":"2018","unstructured":"Kalkavan H, Green DR. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ Nat Publishing Group. 2018;25:46\u201355. https:\/\/doi.org\/10.1038\/cdd.2017.179.","journal-title":"Cell Death Differ Nat Publishing Group"},{"key":"776_CR9","doi-asserted-by":"publisher","first-page":"6287","DOI":"10.1182\/blood-2011-01-328484","volume":"117","author":"SEM Herman","year":"2011","unstructured":"Herman SEM, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287\u201396. https:\/\/doi.org\/10.1182\/blood-2011-01-328484.","journal-title":"Blood"},{"key":"776_CR10","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1182\/blood-2013-07-515361","volume":"123","author":"JA Woyach","year":"2014","unstructured":"Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, et al. Bruton\u2019s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123:1207\u201313. https:\/\/doi.org\/10.1182\/blood-2013-07-515361.","journal-title":"Blood"},{"key":"776_CR11","doi-asserted-by":"publisher","first-page":"2300","DOI":"10.1182\/bloodadvances.2023012221","volume":"8","author":"C Tam","year":"2024","unstructured":"Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8:2300\u20139. https:\/\/doi.org\/10.1182\/bloodadvances.2023012221.","journal-title":"Blood Adv"},{"key":"776_CR12","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/S0140-6736(21)00224-5","volume":"397","author":"AR Mato","year":"2021","unstructured":"Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1\/2 study. Lancet. 2021;397:892\u2013901. https:\/\/doi.org\/10.1016\/S0140-6736(21)00224-5.","journal-title":"Lancet"},{"key":"776_CR13","doi-asserted-by":"publisher","first-page":"3918","DOI":"10.1158\/1078-0432.CCR-19-2856","volume":"26","author":"JC Byrd","year":"2020","unstructured":"Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, et al. Ibrutinib treatment for first-line and relapsed\/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib\/II PCYC-1102 study. Clin Cancer Res. 2020;26:3918\u201327. https:\/\/doi.org\/10.1158\/1078-0432.CCR-19-2856.","journal-title":"Clin Cancer Res"},{"key":"776_CR14","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1158\/2159-8290.CD-19-1130","volume":"10","author":"JA Woyach","year":"2020","unstructured":"Woyach JA, Blachly JS, Rogers KA, Bhat SA, Jianfar M, Lozanski G, et al. Acalabrutinib plus Obinutuzumab in Treatment-Na\u00efve and Relapsed\/Refractory Chronic Lymphocytic Leukemia. Cancer Discov. 2020;10:394\u2013405. https:\/\/doi.org\/10.1158\/2159-8290.CD-19-1130.","journal-title":"Cancer Discov"},{"key":"776_CR15","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1056\/NEJMoa2211582","volume":"388","author":"JR Brown","year":"2023","unstructured":"Brown JR, Eichhorst B, Hillmen P, Jurczak W, Ka\u017amierczak M, Lamanna N, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388:319\u201332. https:\/\/doi.org\/10.1056\/NEJMoa2211582.","journal-title":"N Engl J Med"},{"key":"776_CR16","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1080\/10428194.2024.2445688","volume":"66","author":"BK Gordon","year":"2025","unstructured":"Gordon BK, Woyach JA. The challenge of targeting key drivers of CLL and sequencing therapy in an era of experimental therapeutics. Leuk Lymphoma. 2025;66:838\u201346. https:\/\/doi.org\/10.1080\/10428194.2024.2445688.","journal-title":"Leuk Lymphoma"},{"key":"776_CR17","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.clml.2023.07.011","volume":"23","author":"S Easaw","year":"2023","unstructured":"Easaw S, Ezzati S, Coombs CC. SOHO state of the art updates and next questions: updates on BTK inhibitors for the treatment of chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2023;23:697\u2013704. https:\/\/doi.org\/10.1016\/j.clml.2023.07.011.","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"776_CR18","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/s41571-024-00956-1","volume":"21","author":"MD Stanchina","year":"2024","unstructured":"Stanchina MD, Montoya S, Danilov AV, Castillo JJ, Alencar AJ, Chavez JC, et al. Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia. Nat Rev Clin Oncol. 2024;21:867\u201387. https:\/\/doi.org\/10.1038\/s41571-024-00956-1.","journal-title":"Nat Rev Clin Oncol"},{"key":"776_CR19","doi-asserted-by":"publisher","first-page":"3441","DOI":"10.1200\/JCO.21.01210","volume":"39","author":"JC Byrd","year":"2021","unstructured":"Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39:3441\u201352. https:\/\/doi.org\/10.1200\/JCO.21.01210.","journal-title":"J Clin Oncol"},{"key":"776_CR20","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1182\/blood.2020006844","volume":"136","author":"CS Tam","year":"2020","unstructured":"Tam CS, Opat S, D\u2019Sa S, Jurczak W, Lee H-P, Cull G, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstr\u00f6m macroglobulinemia: the ASPEN study. Blood. 2020;136:2038\u201350. https:\/\/doi.org\/10.1182\/blood.2020006844.","journal-title":"Blood"},{"key":"776_CR21","doi-asserted-by":"publisher","first-page":"7521","DOI":"10.1200\/JCO.2022.40.16_suppl.7521","volume":"40","author":"CSL Tam","year":"2022","unstructured":"Tam CSL, Garcia-Sanz R, Opat S, D\u2019Sa S, Jurczak W, Lee H-P, et al. ASPEN: Long-term follow-up results of a phase 3 randomized trial of zanubrutinib (ZANU) versus ibrutinib (IBR) in patients with Waldenstr\u00f6m macroglobulinemia (WM). J Clin Oncol Wolters Kluwer. 2022;40:7521\u20137521. https:\/\/doi.org\/10.1200\/JCO.2022.40.16_suppl.7521.","journal-title":"J Clin Oncol Wolters Kluwer"},{"key":"776_CR22","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1056\/NEJMoa1400029","volume":"370","author":"JA Woyach","year":"2014","unstructured":"Woyach JA, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton\u2019s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286\u201394. https:\/\/doi.org\/10.1056\/NEJMoa1400029.","journal-title":"N Engl J Med"},{"key":"776_CR23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-209590","volume":"144","author":"AP Skarbnik","year":"2024","unstructured":"Skarbnik AP, Danilov AV, Hoffmann M, Awan FT, Scarpa F, Davies C, et al. Mutations in the Bruton Tyrosine Kinase (BTK) Gene in Patients with Chronic Lymphocytic Leukemia (CLL) Receiving BTK Inhibitors (BTKis). Blood. 2024;144:4623. https:\/\/doi.org\/10.1182\/blood-2024-209590.","journal-title":"Blood"},{"key":"776_CR24","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1056\/NEJMoa2114110","volume":"386","author":"E Wang","year":"2022","unstructured":"Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, et al. Mechanisms of resistance to noncovalent Bruton\u2019s tyrosine kinase inhibitors. N Engl J Med. 2022;386:735\u201343. https:\/\/doi.org\/10.1056\/NEJMoa2114110.","journal-title":"N Engl J Med"},{"key":"776_CR25","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1002\/ajh.27544","volume":"100","author":"S Molica","year":"2025","unstructured":"Molica S, Allsup D, Giannarelli D. Prevalence of BTK and PLCG2 Mutations in CLL Patients With Disease Progression on BTK Inhibitor Therapy: A Meta-Analysis. Am J Hematol. 2025;100:334\u20137. https:\/\/doi.org\/10.1002\/ajh.27544.","journal-title":"Am J Hematol"},{"key":"776_CR26","doi-asserted-by":"publisher","unstructured":"Blombery P, Chatzikonstantinou T, Gerousi M, Rosenquist R, Gaidano G, Pospisilova S, et al. Resistance to targeted therapies in chronic lymphocytic leukemia: current status and perspectives for clinical and diagnostic practice. Leuk Nat Publishing Group. 2025;1\u201312. https:\/\/doi.org\/10.1038\/s41375-025-02662-y.","DOI":"10.1038\/s41375-025-02662-y"},{"key":"776_CR27","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1182\/blood.2023023659","volume":"144","author":"JA Woyach","year":"2024","unstructured":"Woyach JA, Jones D, Jurczak W, Robak T, Ill\u00e9s \u00c1, Kater AP, et al. Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood. 2024;144:1061\u20138. https:\/\/doi.org\/10.1182\/blood.2023023659.","journal-title":"Blood"},{"key":"776_CR28","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1158\/2159-8290.CD-23-0670","volume":"14","author":"JA Woyach","year":"2024","unstructured":"Woyach JA, Stephens DM, Flinn IW, Bhat SA, Savage RE, Chai F, et al. First-in-human study of the reversible BTK inhibitor nemtabrutinib in patients with relapsed\/refractory chronic lymphocytic leukemia and B-cell non\u2013Hodgkin lymphoma. Cancer Discov. 2024;14:66\u201375. https:\/\/doi.org\/10.1158\/2159-8290.CD-23-0670.","journal-title":"Cancer Discov"},{"key":"776_CR29","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1182\/blood.2022018674","volume":"142","author":"EB Gomez","year":"2023","unstructured":"Gomez EB, Ebata K, Randeria HS, Rosendahl MS, Cedervall EP, Morales TH, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142:62\u201372. https:\/\/doi.org\/10.1182\/blood.2022018674.","journal-title":"Blood"},{"key":"776_CR30","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-185852","volume":"142","author":"JA Woyach","year":"2023","unstructured":"Woyach JA, Brown JR, Ghia P, Roeker LE, Patel K, Eyre TA, et al. Pirtobrutinib in post-cBTKi CLL\/SLL: ~30 months follow-up and subgroup analysis with\/without prior BCL2i from the phase 1\/2 BRUIN study. Blood. 2023;142:325. https:\/\/doi.org\/10.1182\/blood-2023-185852.","journal-title":"Blood"},{"key":"776_CR31","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1158\/2159-8290.CD-17-1409","volume":"8","author":"SD Reiff","year":"2018","unstructured":"Reiff SD, Mantel R, Smith LL, Greene J, Muhowski EM, Fabian CA, et al. <article-title update=\"added\">The BTK inhibitor ARQ 531 targets ibrutinib-resistant CLL and Richter transformation. Cancer Discov. 2018;8:1300\u201315. https:\/\/doi.org\/10.1158\/2159-8290.CD-17-1409.","journal-title":"Cancer Discov"},{"key":"776_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2018.07.081","volume":"18","author":"B Brandhuber","year":"2018","unstructured":"Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18:S216. https:\/\/doi.org\/10.1016\/j.clml.2018.07.081.","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"776_CR33","doi-asserted-by":"publisher","first-page":"923","DOI":"10.2147\/JEP.S265284","volume":"13","author":"FP Tambaro","year":"2021","unstructured":"Tambaro FP, Novellis DD, Wierda WG. The role of BTK inhibition in the treatment of chronic lymphocytic leukemia: a clinical view. J Exp Pharmacol Dove Press. 2021;13:923\u201335. https:\/\/doi.org\/10.2147\/JEP.S265284.","journal-title":"J Exp Pharmacol Dove Press"},{"key":"776_CR34","doi-asserted-by":"publisher","first-page":"2897","DOI":"10.1021\/acschembio.6b00480","volume":"11","author":"AR Johnson","year":"2016","unstructured":"Johnson AR, Kohli PB, Katewa A, Gogol E, Belmont LD, Choy R, et al. Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem Biol Am Chem Soc. 2016;11:2897\u2013907. https:\/\/doi.org\/10.1021\/acschembio.6b00480.","journal-title":"ACS Chem Biol Am Chem Soc"},{"key":"776_CR35","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1038\/s41375-021-01123-6","volume":"35","author":"HY Estupi\u00f1\u00e1n","year":"2021","unstructured":"Estupi\u00f1\u00e1n HY, Wang Q, Bergl\u00f6f A, Schaafsma GCP, Shi Y, Zhou L, et al. BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leuk Nat Publishing Group. 2021;35:1317\u201329. https:\/\/doi.org\/10.1038\/s41375-021-01123-6.","journal-title":"Leuk Nat Publishing Group"},{"key":"776_CR36","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1182\/bloodadvances.2022008447","volume":"7","author":"A Naeem","year":"2022","unstructured":"Naeem A, Utro F, Wang Q, Cha J, Vihinen M, Martindale S, et al. Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance. Blood Adv. 2022;7:1929\u201343. https:\/\/doi.org\/10.1182\/bloodadvances.2022008447.","journal-title":"Blood Adv"},{"key":"776_CR37","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-25-00166","author":"JP Sharman","year":"2025","unstructured":"Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib\/rituximab or bendamustine\/rituximab in covalent Bruton tyrosine kinase inhibitor\u2013pretreated chronic lymphocytic leukemia\/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025. https:\/\/doi.org\/10.1200\/JCO-25-00166.","journal-title":"J Clin Oncol"},{"key":"776_CR38","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1182\/blood-2021-147599","volume":"138","author":"AR Mato","year":"2021","unstructured":"Mato AR, Pagel JM, Coombs CC, Shah NN, Lamanna N, Munir T, Pirtobrutinib AN, Generation, et al. Highly Selective, Non-Covalent BTK inhibitor in previously treated CLL\/SLL: updated results from the phase 1\/2 BRUIN study. Blood. 2021;138:391. https:\/\/doi.org\/10.1182\/blood-2021-147599.","journal-title":"Blood"},{"key":"776_CR39","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1001\/jamaoncol.2014.218","volume":"1","author":"KJ Maddocks","year":"2015","unstructured":"Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80\u20137. https:\/\/doi.org\/10.1001\/jamaoncol.2014.218.","journal-title":"JAMA Oncol"},{"key":"776_CR40","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1182\/blood-2019-125488","volume":"134","author":"SM Handunnetti","year":"2019","unstructured":"Handunnetti SM, Tang S, Nguyen CP. BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib. Blood. 2019;134:170. https:\/\/doi.org\/10.1182\/blood-2019-125488.","journal-title":"Blood"},{"key":"776_CR41","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1182\/blood-2019-127674","volume":"134","author":"J Woyach","year":"2019","unstructured":"Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 2019;134:504. https:\/\/doi.org\/10.1182\/blood-2019-127674.","journal-title":"Blood"},{"key":"776_CR42","doi-asserted-by":"publisher","first-page":"5589","DOI":"10.1182\/bloodadvances.2022008325","volume":"6","author":"P Blombery","year":"2022","unstructured":"Blombery P, Thompson ER, Lew TE, Tiong IS, Bennett R, Cheah CY, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for Pirtobrutinib cross-resistance. Blood Adv. 2022;6:5589\u201392. https:\/\/doi.org\/10.1182\/bloodadvances.2022008325.","journal-title":"Blood Adv"},{"key":"776_CR43","doi-asserted-by":"publisher","first-page":"eabg5216","DOI":"10.1126\/scisignal.abg5216","volume":"15","author":"K Dhami","year":"2022","unstructured":"Dhami K, Chakraborty A, Gururaja TL, Cheung LW-K, Sun C, DeAnda F, et al. Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK. Sci Signal Am Association Advancement Sci. 2022;15:eabg5216. https:\/\/doi.org\/10.1126\/scisignal.abg5216.","journal-title":"Sci Signal Am Association Advancement Sci"},{"key":"776_CR44","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi5798","volume":"383","author":"S Montoya","year":"2024","unstructured":"Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1\/3 degrader NX-2127. Science. 2024;383:eadi5798. https:\/\/doi.org\/10.1126\/science.adi5798.","journal-title":"Science"},{"key":"776_CR45","doi-asserted-by":"publisher","first-page":"3378","DOI":"10.1182\/bloodadvances.2022009366","volume":"7","author":"RA Jackson","year":"2023","unstructured":"Jackson RA, Britton RG, Jayne S, Lehmann S, Cowley CM, Trethewey CS, et al. BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib. Blood Adv. 2023;7:3378\u201381. https:\/\/doi.org\/10.1182\/bloodadvances.2022009366.","journal-title":"Blood Adv"},{"key":"776_CR46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-180143","volume":"142","author":"JR Brown","year":"2023","unstructured":"Brown JR, Desikan SP, Nguyen B, Won H, Tantawy SI, McNeely S, et al. Genomic evolution and resistance during Pirtobrutinib therapy in covalent BTK-inhibitor (cBTKi) pre-treated chronic lymphocytic leukemia patients: updated analysis from the BRUIN study. Blood. 2023;142:326. https:\/\/doi.org\/10.1182\/blood-2023-180143.","journal-title":"Blood"},{"key":"776_CR47","doi-asserted-by":"publisher","first-page":"5698","DOI":"10.1182\/bloodadvances.2022008955","volume":"7","author":"J Qi","year":"2023","unstructured":"Qi J, Endres S, Yosifov DY, Tausch E, Dheenadayalan RP, Gao X, et al. Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors. Blood Adv. 2023;7:5698\u2013702. https:\/\/doi.org\/10.1182\/bloodadvances.2022008955.","journal-title":"Blood Adv"},{"key":"776_CR48","doi-asserted-by":"publisher","first-page":"6769","DOI":"10.1158\/1538-7445.AM2025-6769","volume":"85","author":"H Wang","year":"2025","unstructured":"Wang H, Feng X, Ren J, Bai L, Li L, Cui C, et al. Abstract 6769: zanubrutinib (zanu) overcomes BTK V416L resistance in B cell lymphoma models. Cancer Res. 2025;85:6769. https:\/\/doi.org\/10.1158\/1538-7445.AM2025-6769.","journal-title":"Cancer Res"},{"key":"776_CR49","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1038\/s41375-024-02317-4","volume":"38","author":"RL Wong","year":"2024","unstructured":"Wong RL, Choi MY, Wang H-Y, Kipps TJ. Mutation in Bruton tyrosine kinase (BTK) A428D confers resistance to BTK-degrader therapy in chronic lymphocytic leukemia. Leuk Nat Publishing Group. 2024;38:1818\u201321. https:\/\/doi.org\/10.1038\/s41375-024-02317-4.","journal-title":"Leuk Nat Publishing Group"},{"key":"776_CR50","doi-asserted-by":"publisher","first-page":"3237","DOI":"10.1182\/blood-2016-01-695098","volume":"127","author":"G Yang","year":"2016","unstructured":"Yang G, Buhrlage SJ, Tan L, Liu X, Chen J, Xu L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood. 2016;127:3237\u201352. https:\/\/doi.org\/10.1182\/blood-2016-01-695098.","journal-title":"Blood"},{"key":"776_CR51","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1002\/cncr.31831","volume":"125","author":"R Kanagal-Shamanna","year":"2019","unstructured":"Kanagal-Shamanna R, Jain P, Patel KP, Routbort M, Bueso-Ramos C, Alhalouli T, et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor\u2013resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer. 2019;125:559\u201374. https:\/\/doi.org\/10.1002\/cncr.31831.","journal-title":"Cancer"},{"key":"776_CR52","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1182\/bloodadvances.2022008821","volume":"7","author":"S Bonfiglio","year":"2023","unstructured":"Bonfiglio S, Sutton L-A, Ljungstr\u00f6m V, Capasso A, Pandzic T, Westr\u00f6m S, et al. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood Adv. 2023;7:2794\u2013806. https:\/\/doi.org\/10.1182\/bloodadvances.2022008821.","journal-title":"Blood Adv"},{"key":"776_CR53","doi-asserted-by":"publisher","unstructured":"Hamasy A, Wang Q, Blomberg KEM, Mohammad DK, Yu L, Vihinen M, et al. Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant. Leukemia. 2017;31:177\u201385. https:\/\/doi.org\/10.1038\/leu.2016.153.","DOI":"10.1038\/leu.2016.153"},{"key":"776_CR54","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","volume":"12","author":"D Hanahan","year":"2022","unstructured":"Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31\u201346. https:\/\/doi.org\/10.1158\/2159-8290.CD-21-1059.","journal-title":"Cancer Discov"},{"key":"776_CR55","doi-asserted-by":"publisher","first-page":"8977","DOI":"10.1158\/0008-5472.CAN-09-2604","volume":"69","author":"S Loeder","year":"2009","unstructured":"Loeder S, Zenz T, Schnaiter A, Mertens D, Winkler D, D\u00f6hner H, et al. A novel paradigm to trigger apoptosis in chronic lymphocytic leukemia. Cancer Res. 2009;69:8977\u201386. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-2604.","journal-title":"Cancer Res"},{"key":"776_CR56","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/nrd.2016.253","volume":"16","author":"A Ashkenazi","year":"2017","unstructured":"Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov Nat Publishing Group. 2017;16:273\u201384. https:\/\/doi.org\/10.1038\/nrd.2016.253.","journal-title":"Nat Rev Drug Discov Nat Publishing Group"},{"key":"776_CR57","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1334","author":"J Montero","year":"2022","unstructured":"Montero J, Haq R. Adapted to survive: targeting cancer cells with BH3 mimetics. Cancer Discov. 2022. https:\/\/doi.org\/10.1158\/2159-8290.CD-21-1334.","journal-title":"Cancer Discov"},{"key":"776_CR58","doi-asserted-by":"publisher","first-page":"13944","DOI":"10.1073\/pnas.0506654102","volume":"102","author":"A Cimmino","year":"2005","unstructured":"Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102:13944\u20139. https:\/\/doi.org\/10.1073\/pnas.0506654102.","journal-title":"Proc Natl Acad Sci USA"},{"key":"776_CR59","doi-asserted-by":"publisher","first-page":"15524","DOI":"10.1073\/pnas.242606799","volume":"99","author":"GA Calin","year":"2002","unstructured":"Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524\u20139. https:\/\/doi.org\/10.1073\/pnas.242606799.","journal-title":"Proc Natl Acad Sci USA"},{"key":"776_CR60","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1172\/JCI28281","volume":"117","author":"VDG Moore","year":"2007","unstructured":"Moore VDG, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest Am Soc Clin Invest. 2007;117:112\u201321. https:\/\/doi.org\/10.1172\/JCI28281.","journal-title":"J Clin Invest Am Soc Clin Invest"},{"key":"776_CR61","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1200\/JCO.2011.34.7898","volume":"30","author":"AW Roberts","year":"2012","unstructured":"Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30:488\u201396. https:\/\/doi.org\/10.1200\/JCO.2011.34.7898.","journal-title":"J Clin Oncol"},{"key":"776_CR62","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nm.3048","volume":"19","author":"AJ Souers","year":"2013","unstructured":"Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202\u20138. https:\/\/doi.org\/10.1038\/nm.3048.","journal-title":"Nat Med"},{"key":"776_CR63","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1182\/bloodadvances.2024014474","volume":"9","author":"JD Soumerai","year":"2025","unstructured":"Soumerai JD, Barrientos J, Ahn I, Coombs C, Gladstone D, Hoffman M, et al. Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL or SLL. Blood Adv. 2025;9:1213\u201329. https:\/\/doi.org\/10.1182\/bloodadvances.2024014474.","journal-title":"Blood Adv"},{"key":"776_CR64","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1056\/NEJMoa1713976","volume":"378","author":"JF Seymour","year":"2018","unstructured":"Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D\u2019Rozario J, Assouline S, et al. Venetoclax\u2013rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107\u201320. https:\/\/doi.org\/10.1056\/NEJMoa1713976.","journal-title":"N Engl J Med"},{"key":"776_CR65","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S1470-2045(24)00070-6","volume":"25","author":"AP Kater","year":"2024","unstructured":"Kater AP, Arslan \u00d6, Demirkan F, Herishanu Y, Ferhanoglu B, Diaz MG, et al. 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. Lancet Oncol. 2024;25:463\u201373. https:\/\/doi.org\/10.1016\/S1470-2045(24)00070-6.","journal-title":"Lancet Oncol"},{"key":"776_CR66","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1182\/blood.2024024631","volume":"144","author":"O Al-Sawaf","year":"2024","unstructured":"Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144:1924\u201335. https:\/\/doi.org\/10.1182\/blood.2024024631.","journal-title":"Blood"},{"key":"776_CR67","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2200006","volume":"1","author":"AP Kater","year":"2022","unstructured":"Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin M-D, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1:EVIDoa2200006. https:\/\/doi.org\/10.1056\/EVIDoa2200006.","journal-title":"NEJM Evid"},{"key":"776_CR68","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1056\/NEJMoa2409804","volume":"392","author":"JR Brown","year":"2025","unstructured":"Brown JR, Seymour JF, Jurczak W, Aw A, Wach M, Illes A, et al. Fixed-Duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med Mass Med Soc. 2025;392:748\u201362. https:\/\/doi.org\/10.1056\/NEJMoa2409804.","journal-title":"N Engl J Med Mass Med Soc"},{"key":"776_CR69","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1158\/2159-8290.CD-18-1119","volume":"9","author":"P Blombery","year":"2019","unstructured":"Blombery P, Anderson MA, Gong J-N, Thijssen R, Birkinshaw RW, Thompson ER, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9:342\u201353. https:\/\/doi.org\/10.1158\/2159-8290.CD-18-1119.","journal-title":"Cancer Discov"},{"key":"776_CR70","doi-asserted-by":"publisher","first-page":"e434","DOI":"10.3324\/haematol.2019.222588","volume":"104","author":"E Tausch","year":"2019","unstructured":"Tausch E, Close W, Dolnik A, Bloehdorn J, Chyla B, Bullinger L, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019;104:e434\u20137. https:\/\/doi.org\/10.3324\/haematol.2019.222588.","journal-title":"Haematologica"},{"key":"776_CR71","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","volume":"388","author":"B Eichhorst","year":"2023","unstructured":"Eichhorst B, Niemann CU, Kater AP, F\u00fcrstenau M, Tresckow J, Zhang C, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388:1739\u201354. https:\/\/doi.org\/10.1056\/NEJMoa2213093.","journal-title":"N Engl J Med"},{"key":"776_CR72","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2025-794","volume":"146","author":"A Rawstron","year":"2025","unstructured":"Rawstron A, Cairns D, Webster N, Dalal S, Shingles J, et al. Optimising MRD-guided treatment: umrd4 as a half-way treatment timepoint for ibrutinib-venetoclax substantially delays MRD relapse after end of treatment in both IGHV-mutated and IGHV-unmutated CLL. Blood. 2025;146:794. https:\/\/doi.org\/10.1182\/blood-2025-794.","journal-title":"Blood"},{"key":"776_CR73","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1056\/NEJMoa2310063","volume":"390","author":"T Munir","year":"2024","unstructured":"Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390:326\u201337. https:\/\/doi.org\/10.1056\/NEJMoa2310063.","journal-title":"N Engl J Med"},{"key":"776_CR74","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1056\/NEJMoa2504341","volume":"393","author":"T Munir","year":"2025","unstructured":"Munir T, Girvan S, Cairns DA, Bloor A, Allsup D, Varghese AM, et al. Measurable residual disease\u2013guided therapy for chronic lymphocytic leukemia. N Engl J Med. 2025;393:1177\u201390. https:\/\/doi.org\/10.1056\/NEJMoa2504341.","journal-title":"N Engl J Med"},{"key":"776_CR75","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065802","volume":"24","author":"L Kotmayer","year":"2023","unstructured":"Kotmayer L, L\u00e1szl\u00f3 T, Mikala G, Kiss R, L\u00e9vay L, Hegyi LL, et al. Landscape of BCL2 resistance mutations in a real-world cohort of patients with relapsed\/refractory chronic lymphocytic leukemia treated with venetoclax. Int J Mol Sci. 2023;24:5802. https:\/\/doi.org\/10.3390\/ijms24065802.","journal-title":"Int J Mol Sci"},{"key":"776_CR76","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1182\/blood.2019004205","volume":"135","author":"P Blombery","year":"2020","unstructured":"Blombery P, Thompson ER, Nguyen T, Birkinshaw RW, Gong J, Chen X, et al. Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135:773\u20137. https:\/\/doi.org\/10.1182\/blood.2019004205.","journal-title":"Blood"},{"key":"776_CR77","doi-asserted-by":"publisher","first-page":"E47","DOI":"10.1002\/ajh.26411","volume":"97","author":"R Popovic","year":"2022","unstructured":"Popovic R, Dunbar F, Lu C, Robinson K, Quarless D, Warder SE, et al. Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy. Am J Hematol. 2022;97:E47-51. https:\/\/doi.org\/10.1002\/ajh.26411.","journal-title":"Am J Hematol"},{"key":"776_CR78","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10363-1","volume":"10","author":"RW Birkinshaw","year":"2019","unstructured":"Birkinshaw RW, Gong J, Luo CS, Lio D, White CA, Anderson MA, et al. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019;10:2385. https:\/\/doi.org\/10.1038\/s41467-019-10363-1.","journal-title":"Nat Commun"},{"key":"776_CR79","doi-asserted-by":"publisher","first-page":"2127","DOI":"10.1182\/blood.2022016040","volume":"140","author":"R Thijssen","year":"2022","unstructured":"Thijssen R, Tian L, Anderson MA, Flensburg C, Jarratt A, Garnham AL, et al. Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy. Blood. 2022;140:2127\u201341. https:\/\/doi.org\/10.1182\/blood.2022016040.","journal-title":"Blood"},{"key":"776_CR80","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1182\/blood.2024025525","volume":"145","author":"AP Kater","year":"2025","unstructured":"Kater AP, Harrup R, Kipps TJ, Eichhorst B, Owen CJ, Assouline S, et al. The MURANO study: final analysis and retreatment\/crossover substudy results of VenR for patients with relapsed\/refractory CLL. Blood. 2025;145:2733\u201345. https:\/\/doi.org\/10.1182\/blood.2024025525.","journal-title":"Blood"},{"key":"776_CR81","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1182\/blood.2021014304","volume":"140","author":"D Thomalla","year":"2022","unstructured":"Thomalla D, Beckmann L, Grimm C, Oliverio M, Meder L, Herling CD, et al. Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood. 2022;140:2113\u201326. https:\/\/doi.org\/10.1182\/blood.2021014304.","journal-title":"Blood"},{"key":"776_CR82","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1182\/blood.2022016600","volume":"142","author":"JK Khalsa","year":"2023","unstructured":"Khalsa JK, Cha J, Utro F, Naeem A, Murali I, Kuang Y, et al. Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples. Blood. 2023;142:421\u201333. https:\/\/doi.org\/10.1182\/blood.2022016600.","journal-title":"Blood"},{"key":"776_CR83","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.ccell.2019.08.005","volume":"36","author":"R Gui\u00e8ze","year":"2019","unstructured":"Gui\u00e8ze R, Liu VM, Rosebrock D, Jourdain AA, Hern\u00e1ndez-S\u00e1nchez M, Martinez Zurita A, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019;36:369-384.e13. https:\/\/doi.org\/10.1016\/j.ccell.2019.08.005.","journal-title":"Cancer Cell"},{"key":"776_CR84","doi-asserted-by":"publisher","first-page":"4403","DOI":"10.1182\/blood-2008-08-173310","volume":"113","author":"M Vogler","year":"2009","unstructured":"Vogler M, Butterworth M, Majid A, Walewska RJ, Sun X-M, Dyer MJS, et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009;113:4403\u201313. https:\/\/doi.org\/10.1182\/blood-2008-08-173310.","journal-title":"Blood"},{"key":"776_CR85","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1182\/blood.2020010167","volume":"137","author":"R Thijssen","year":"2021","unstructured":"Thijssen R, Diepstraten ST, Moujalled D, Chew E, Flensburg C, Shi MX, et al. Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias. Blood. 2021;137:2721\u201335. https:\/\/doi.org\/10.1182\/blood.2020010167.","journal-title":"Blood"},{"key":"776_CR86","doi-asserted-by":"publisher","first-page":"e1593","DOI":"10.1038\/cddis.2014.525","volume":"6","author":"GS Choudhary","year":"2015","unstructured":"Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K\/AKT\/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593. https:\/\/doi.org\/10.1038\/cddis.2014.525.","journal-title":"Cell Death Dis"},{"key":"776_CR87","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1182\/blood.2019004326","volume":"136","author":"MV Haselager","year":"2020","unstructured":"Haselager MV, Kielbassa K, Ter Burg J, Bax DJC, Fernandes SM, Borst J, et al. Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL. Blood. 2020;136:2918\u201326. https:\/\/doi.org\/10.1182\/blood.2019004326.","journal-title":"Blood"},{"key":"776_CR88","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1038\/s41418-020-00692-w","volume":"28","author":"M Haselager","year":"2021","unstructured":"Haselager M, Thijssen R, West C, Young L, Van Kampen R, Willmore E, et al. Regulation of Bcl-XL by non-canonical NF-\u03baB in the context of CD40-induced drug resistance in CLL. Cell Death Differ. 2021;28:1658\u201368. https:\/\/doi.org\/10.1038\/s41418-020-00692-w.","journal-title":"Cell Death Differ"},{"key":"776_CR89","doi-asserted-by":"publisher","first-page":"1612916","DOI":"10.3389\/fphar.2025.1612916","volume":"16","author":"S Liang","year":"2025","unstructured":"Liang S, Shao X, Meng X, Cui Y, Sun C, Sun J, et al. HGF\/c-MET axis contributes to CLL cell survival by regulating multiple mechanisms making it a potential therapeutic target for CLL treatment. Front Pharmacol. 2025;16:1612916. https:\/\/doi.org\/10.3389\/fphar.2025.1612916.","journal-title":"Front Pharmacol"},{"key":"776_CR90","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s12943-025-02260-7","volume":"24","author":"SJF Chong","year":"2025","unstructured":"Chong SJF, Lu J, Valentin R, Lehmberg TZ, Eu JQ, Wang J, et al. BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia. Mol Cancer. 2025;24:62. https:\/\/doi.org\/10.1186\/s12943-025-02260-7.","journal-title":"Mol Cancer"},{"key":"776_CR91","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1038\/s41375-025-02694-4","volume":"39","author":"SJF Chong","year":"2025","unstructured":"Chong SJF, Lai JXH, Iskandar K, et al. Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies. Leukemia. 2025;39:2477\u201391. https:\/\/doi.org\/10.1038\/s41375-025-02694-4.","journal-title":"Leukemia"},{"key":"776_CR92","doi-asserted-by":"publisher","unstructured":"Chong SJF, Zhu F, Dashevsky O, Mizuno R, Lai JXH, Hackett L et al. Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies. J Clin Invest 133:e170169. https:\/\/doi.org\/10.1172\/JCI170169","DOI":"10.1172\/JCI170169"},{"key":"776_CR93","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-205775","volume":"144","author":"JA Woyach","year":"2024","unstructured":"Woyach JA, Brander DM, Hu B, Rogers KA, Omer Z, Stephens DM, et al. LP-168 (rocbrutinib), a novel covalent and non-covalent next-generation inhibitor of Bruton\u2019s tyrosine kinase: updates on the phase 1 trial and initial results of the CLL gatekeeper mutation cohort. Blood. 2024;144:4622. https:\/\/doi.org\/10.1182\/blood-2024-205775.","journal-title":"Blood"},{"key":"776_CR94","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-178259","volume":"142","author":"B Gordon","year":"2023","unstructured":"Gordon B, Muhowski E, Ravikrishnan J, Benrashid S, Mitchell A, He A, et al. Targeting covalent and non-covalent Btki-resistant CLL using the dual irreversible\/reversible 4 th generation BTK inhibitor LP-168. Blood. 2023;142:416. https:\/\/doi.org\/10.1182\/blood-2023-178259.","journal-title":"Blood"},{"key":"776_CR95","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s43556-022-00112-0","volume":"3","author":"Z Liu","year":"2022","unstructured":"Liu Z, Hu M, Yang Y, Du C, Zhou H, Liu C, et al. An overview of protacs: a promising drug discovery paradigm. Mol Biomed. 2022;3:46. https:\/\/doi.org\/10.1186\/s43556-022-00112-0.","journal-title":"Mol Biomed"},{"key":"776_CR96","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17030557","volume":"17","author":"RT Salvaris","year":"2025","unstructured":"Salvaris RT, Brennan J, Lewis KL. BTK is the target that keeps on giving: a review of BTK-degrader drug development, clinical data, and future directions in CLL. Cancers. 2025;17:557. https:\/\/doi.org\/10.3390\/cancers17030557.","journal-title":"Cancers"},{"key":"776_CR97","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-199116","volume":"144","author":"MC Thompson","year":"2024","unstructured":"Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia\/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144:885. https:\/\/doi.org\/10.1182\/blood-2024-199116.","journal-title":"Blood"},{"key":"776_CR98","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1182\/blood-2024-194839","volume":"144","author":"NN Shah","year":"2024","unstructured":"Shah NN, Omer Z, Collins GP, et al. Efficacy and safety of the bruton\u2019s tyrosine kinase (BTK) degrader NX-5948 in patients with Relapsed\/Refractory (R\/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a\/b study. Blood. 2024;144:884. https:\/\/doi.org\/10.1182\/blood-2024-194839.","journal-title":"Blood"},{"key":"776_CR99","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1038\/s41375-024-02317-4","volume":"38","author":"RL Wong","year":"2024","unstructured":"Wong RL, Choi MY, Wang HY, et al. Mutation in Bruton tyrosine kinase (BTK) A428D confers resistance to BTK-degrader therapy in chronic lymphocytic leukemia. Leukemia. 2024;38:1818\u201321. https:\/\/doi.org\/10.1038\/s41375-024-02317-4.","journal-title":"Leukemia"},{"key":"776_CR100","doi-asserted-by":"publisher","first-page":"2324","DOI":"10.1182\/blood-2022-171203","volume":"140","author":"JS Blachly","year":"2022","unstructured":"Blachly JS, Stephens DM, Ye JC, et al. Initial results from a phase 1\/2 dose escalation and expansion study evaluating MS-553, a novel and selective PKC\u03b2 Inhibitor, in patients with CLL\/SLL. Blood. 2022;140:2324\u20135.","journal-title":"Blood"},{"key":"776_CR101","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-182024","volume":"142","author":"B Gordon","year":"2023","unstructured":"Gordon B, Muhowski E, Ravikrishnan J, Thangavadivel S, Benrashid S, He A, et al. The PKC-\u03b2 inhibitor MS-553 displays preclinical efficacy in BTK inhibitor resistant chronic lymphocytic leukemia. Blood. 2023;142:2260. https:\/\/doi.org\/10.1182\/blood-2023-182024.","journal-title":"Blood"},{"key":"776_CR102","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1182\/blood-2023-189378","volume":"142","author":"J Singh","year":"2023","unstructured":"Singh J, Sanchez IIJR, Liu C, Slawin B, Jain N, Wierda WG, et al. MS-553 therapy inhibits BCR signaling and increases survival dependence on BCL-2 in BTK-Inhibitor resistant CLL. Blood. 2023;142:2283. https:\/\/doi.org\/10.1182\/blood-2023-189378.","journal-title":"Blood"},{"key":"776_CR103","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1038\/s41591-019-0668-z","volume":"25","author":"S Khan","year":"2019","unstructured":"Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938\u201347. https:\/\/doi.org\/10.1038\/s41591-019-0668-z.","journal-title":"Nat Med"},{"key":"776_CR104","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46922-4","volume":"15","author":"D Nayak","year":"2024","unstructured":"Nayak D, Lv D, Yuan Y, Zhang P, Hu W, Nayak A, et al. Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL. Nat Commun. 2024;15:2743. https:\/\/doi.org\/10.1038\/s41467-024-46922-4.","journal-title":"Nat Commun"},{"key":"776_CR105","doi-asserted-by":"publisher","first-page":"7836","DOI":"10.1021\/acs.jmedchem.4c00027","volume":"67","author":"Y Guo","year":"2024","unstructured":"Guo Y, Xue H, Hu N, Liu Y, Sun H, Yu D, et al. Discovery of the clinical candidate sonrotoclax (BGB-11417), a highly potent and selective inhibitor for both WT and G101V mutant Bcl-2. J Med Chem. 2024;67:7836\u201358. https:\/\/doi.org\/10.1021\/acs.jmedchem.4c00027.","journal-title":"J Med Chem"},{"key":"776_CR106","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, Yang X, et al. Sonrotoclax overcomes BCL2 G101V mutation\u2013induced venetoclax resistance in preclinical models of hematologic malignancy. Blood. 2024;143:1825\u201336. https:\/\/doi.org\/10.1182\/blood.2023019706.","journal-title":"Blood"},{"key":"776_CR107","doi-asserted-by":"publisher","first-page":"5455","DOI":"10.1158\/1078-0432.CCR-21-4037","volume":"28","author":"J Deng","year":"2022","unstructured":"Deng J, Paulus A, Fang DD, Manna A, Wang G, Wang H, et al. Lisaftoclax (APG-2575) is a novel BCL-2 inhibitor with robust antitumor activity in preclinical models of hematologic malignancy. Clin Cancer Res. 2022;28:5455\u201368. https:\/\/doi.org\/10.1158\/1078-0432.CCR-21-4037.","journal-title":"Clin Cancer Res"},{"key":"776_CR108","doi-asserted-by":"publisher","first-page":"TPS7087","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS7087","volume":"42","author":"M Shadman","year":"2024","unstructured":"Shadman M, Kater AP, Woyach JA, Li J, Munir T, Salmi T, et al. CELESTIAL-TNCLL: an ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-na\u00efve (TN) CLL. J Clin Oncol Wolters Kluwer. 2024;42:TPS7087\u20137087. https:\/\/doi.org\/10.1200\/JCO.2024.42.16_suppl.TPS7087.","journal-title":"J Clin Oncol Wolters Kluwer"},{"key":"776_CR109","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-179541","volume":"142","author":"CS Tam","year":"2023","unstructured":"Tam CS, Anderson MA, Lasica M, Verner E, Opat SS, Ma S, et al. Combination treatment with Sonrotoclax (BGB-11417), a second-generation BCL2 inhibitor, and Zanubrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is well tolerated and achieves deep responses in patients with treatment-na\u00efve chronic lymphocytic leukemia\/small lymphocytic lymphoma (TN-CLL\/SLL): data from an ongoing phase 1\/2 study. Blood. 2023;142:327. https:\/\/doi.org\/10.1182\/blood-2023-179541.","journal-title":"Blood"},{"key":"776_CR110","doi-asserted-by":"publisher","unstructured":"Ailawadhi S, Chen Z, Huang B, Paulus A, Collins MC, Fu L (Tommy), editors. Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial. Clin Cancer Res. 2023;29:2385\u201393. https:\/\/doi.org\/10.1158\/1078-0432.CCR-22-3321","DOI":"10.1158\/1078-0432.CCR-22-3321"},{"key":"776_CR111","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1038\/s41418-025-01487-7","volume":"32","author":"J-N Gong","year":"2025","unstructured":"Gong J-N, Djajawi TM, Moujalled DM, Pomilio G, Khong T, Zhang L-P, et al. Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins. Cell Death Differ Nat Publishing Group. 2025;32:1382\u201396. https:\/\/doi.org\/10.1038\/s41418-025-01487-7.","journal-title":"Cell Death Differ Nat Publishing Group"},{"key":"776_CR112","doi-asserted-by":"publisher","first-page":"4738","DOI":"10.1074\/jbc.M411434200","volume":"280","author":"CL Day","year":"2005","unstructured":"Day CL, Chen L, Richardson SJ, Harrison PJ, Huang DCS, Hinds MG. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands*. J Biol Chem. 2005;280:4738\u201344. https:\/\/doi.org\/10.1074\/jbc.M411434200.","journal-title":"J Biol Chem"},{"key":"776_CR113","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nature19830","volume":"538","author":"A Kotschy","year":"2016","unstructured":"Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nat Nat Publishing Group. 2016;538:477\u201382. https:\/\/doi.org\/10.1038\/nature19830.","journal-title":"Nat Nat Publishing Group"},{"key":"776_CR114","doi-asserted-by":"publisher","first-page":"13762","DOI":"10.1021\/acs.jmedchem.0c01234","volume":"63","author":"Z Szlavik","year":"2020","unstructured":"Szlavik Z, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, et al. Discovery of S64315, a potent and selective Mcl-1 inhibitor. J Med Chem. 2020;63:13762\u201395. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c01234.","journal-title":"J Med Chem"},{"key":"776_CR115","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-023-00380-z","volume":"3","author":"J Yuda","year":"2023","unstructured":"Yuda J, Will C, Phillips DC, Abraham L, Alvey C, Avigdor A, et al. Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients. Commun Med. 2023;3:154. https:\/\/doi.org\/10.1038\/s43856-023-00380-z.","journal-title":"Commun Med"},{"key":"776_CR116","doi-asserted-by":"publisher","unstructured":"Hargreaves D, Carbajo RJ, Bodnarchuk MS, Embrey K, Rawlins PB, Packer M et al. Design of rigid protein\u2013protein interaction inhibitors enables targeting of undruggable Mcl-1. Proc Natl Acad Sci. Proceedings of the National Academy of Sciences; 2023;120:e2221967120. https:\/\/doi.org\/10.1073\/pnas.2221967120","DOI":"10.1073\/pnas.2221967120"},{"key":"776_CR117","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1080\/13543776.2023.2219394","volume":"33","author":"J Liu","year":"2023","unstructured":"Liu J, Yin F, Wang Z, Song T, Zhang Z. An updated patent review of Mcl-1 inhibitors (2020\u20132022). Expert Opin Ther Pat. 2023;33:371\u201383. https:\/\/doi.org\/10.1080\/13543776.2023.2219394.","journal-title":"Expert Opin Ther Pat"},{"key":"776_CR118","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1182\/blood-2024-210048","volume":"144","author":"A-L Maragno","year":"2024","unstructured":"Maragno A-L, Seiss K, Newcombe R, Mistry P, Schnell CR, Von Arx F, et al. S227928: A novel Anti-CD74 ADC with MCL-1 inhibitor payload for the treatment of acute myeloid leukemia (AML) and other hematologic malignancies. Blood. 2024;144:1381. https:\/\/doi.org\/10.1182\/blood-2024-210048.","journal-title":"Blood"},{"key":"776_CR119","doi-asserted-by":"publisher","first-page":"5522","DOI":"10.1021\/acs.jmedchem.9b00455","volume":"62","author":"JW Papatzimas","year":"2019","unstructured":"Papatzimas JW, Gorobets E, Maity R, Muniyat MI, MacCallum JL, Neri P, et al. From inhibition to degradation: targeting the antiapoptotic protein Myeloid Cell Leukemia 1 (MCL1). J Med Chem. 2019;62:5522\u201340. https:\/\/doi.org\/10.1021\/acs.jmedchem.9b00455.","journal-title":"J Med Chem"},{"key":"776_CR120","doi-asserted-by":"publisher","first-page":"8152","DOI":"10.1021\/acs.jmedchem.9b00919","volume":"62","author":"Z Wang","year":"2019","unstructured":"Wang Z, He N, Guo Z, Niu C, Song T, Guo Y, et al. Proteolysis targeting chimeras for the selective degradation of Mcl-1\/Bcl-2 derived from nonselective target binding ligands. J Med Chem Am Chem Soc. 2019;62:8152\u201363. https:\/\/doi.org\/10.1021\/acs.jmedchem.9b00919.","journal-title":"J Med Chem Am Chem Soc"},{"key":"776_CR121","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","volume":"21","author":"M B\u00e9k\u00e9s","year":"2022","unstructured":"B\u00e9k\u00e9s M, Langley DR, Crews CM. Protac targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181\u2013200. https:\/\/doi.org\/10.1038\/s41573-021-00371-6.","journal-title":"Nat Rev Drug Discov"},{"key":"776_CR122","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-25-0114","author":"BK Gordon","year":"2025","unstructured":"Gordon BK, Muhowski EM, Singh J, Ravikrishnan J, Peris-Cuesta A, Diaz Rohena D, et al. PKC\u03b2 inhibitor MS-553 displays preclinical efficacy in both treatment-na\u00efve and BTK inhibitor-resistant Chronic Lymphocytic Leukemia. Blood Cancer Discov. 2025. https:\/\/doi.org\/10.1158\/2643-3230.BCD-25-0114.","journal-title":"Blood Cancer Discov"}],"container-title":["Current Hematologic Malignancy Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11899-026-00776-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11899-026-00776-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11899-026-00776-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:53:27Z","timestamp":1781636007000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11899-026-00776-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":122,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["776"],"URL":"https:\/\/doi.org\/10.1007\/s11899-026-00776-3","relation":{},"ISSN":["1558-822X"],"issn-type":[{"value":"1558-822X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]},"assertion":[{"value":"21 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"SB declares that he has no conflict of interest. JAW has consulted for AbbVie, AstraZeneca, BeOne, Genentech, Johnson&Johnson, Loxo\/Lilly, Merck, Newave, and Pharmacyclics.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All reported studies\/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional\/national research committee standards, and international\/national\/institutional guidelines)","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}],"article-number":"6"}}